CN1857723A

CN1857723A - Slow released anticancer medicine preparation with both amrubicin and its synergist

Info

Publication number: CN1857723A
Application number: CNA2006102002793A
Authority: CN
Inventors: 孙娟
Original assignee: Jinan Kangquan Medicine Science and Technology Co Ltd
Current assignee: Jinan Kangquan Medicine Science and Technology Co Ltd
Priority date: 2006-03-28
Filing date: 2006-03-28
Publication date: 2006-11-08

Abstract

The slow released anticancer medicine injection containing both amrubicin and its synergist consists of slow released microsphere and solvent. The slow released microsphere includes effective anticancer component and slow releasing supplementary material, and the solvent is special solvent containing suspending agent carboxymethyl cellulose, etc. and with viscosity of 100-3000 cp at 25 deg.c. The effective anticancer component is amrubicin, idarubicin, etc and/or antimetabolite composition selected from carmofur, tegafur, zalcitabine, etc. The slow releasing supplementary material is selected from EVAc, sebacic acid copolymer, lactic acid polymer, etc. The slow released microsphere may be also prepared into slow released implanting agent set around or inside the tumor to strengthen the chemotherapy or radiotherapy effect.

Description

A kind of with the anticancer medicine slow-release preparation containing that carries amrubicin and synergist thereof

(1) technical field

The present invention relates to a kind of anticancer medicine slow-release preparation containing, belong to technical field of pharmaceuticals with year amrubicin and synergist thereof.Particularly, the invention provides a kind of compound anti-cancer medicinal slow release agent that contains amrubicin and/or its synergist, be mainly slow releasing injection and sustained-release implant.

(2) background technology

As a kind of new cancer therapy drug, amrubicin ((+)-(7S, 9S)-9-acetyl group-9-amino-7-[(2-deoxidation-β-D-is red-pyranopentose) and the oxygen base]-7; 8,9,10-tetrahydrochysene-6; 11-dihydroxy-5,12-aphthacene diketone) solid carcinoma is shown the obvious treatment effect.Yet in rabbit long term toxicity test model, the cardiac toxicity that anthracycline compounds such as amrubicin and doxorubicin are shown (Invest.New Drug, 15,219-225 (1997)) has but greatly limited its clinical practice.In addition, many anthracycline compounds are brought into play its antitumor action by its metabolite.Be reduced easily in vivo as amrubicin, generate hydroxylation metabolism product (amrubicin alcohol) at 13, the latter obviously strengthens than the tumor-inhibiting action of amrubicin.Doxorubicin and daunomycin etc. also generate the reductive metabolism product, but opposite, active reduce (CancerChemother.Pharmacol., 30,51-57 (1992)).Therefore, the conventional route administration is difficult in position, entity tumor place and obtains active drug concentration.

Blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fibrin and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q etal., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Pharmaceutical topical application may solve the problem (Chinese patent) of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.

In addition, the DNA repair function in many tumor cells obviously increases after chemotherapy.The latter often causes the enhancing of tumor cell to the toleration of cancer therapy drug, consequently treatment failure.

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

Therefore, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.

(3) summary of the invention

The present invention is directed to the deficiencies in the prior art, a kind of slow releasing injection that contains amrubicin and/or its synergist is provided.

Amrubicin is mainly used in entity tumors such as the treatment cerebral tumor, ovarian cancer, pulmonary carcinoma abroad as a kind of new cancer therapy drug.Yet tangible general toxicity has greatly limited the application of this medicine in application process.

The present invention finds that medicine that has and amrubicin share its antitumaous effect is strengthened mutually, and its synergistic mechanism remains further to be studied.Below the amrubicin antitumaous effect will be increased mutually medicine be referred to as the amrubicin synergist; In addition, amrubicin and/or its synergist are made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, are reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The above unexpected main contents of the present invention of finding to constitute.

Anti-cancer medicine sustained-release 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 microparticle, the one-tenth following by percentage by weight is grouped into:

Biological effective components 0.5-60%

Slow-release auxiliary material 41-99.9%

Suspending agent 0.0-30%

(B) solvent is divided into common solvent and special solvent.

Wherein, anticancer effective component is the compound anti-cancer medicine of amrubicin and/or its synergist, and the amrubicin synergist is selected from antimetabolitas; Slow-release auxiliary material is selected from one of copolymer (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

Amrubicin also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.

Amrubicin shared ratio in compositions is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 5%-30% is best.

Amrubicin also can be replaced than star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, valrubicin or pirarubicin by pirarubicin, Ai Rou, serve as preferred wherein, because these medicines also can be by the potentiation of amrubicin synergist with aclarubicin, darubicin, doxorubicin, epirubicin, valrubicin or pirarubicin.

Antimetabolitas can stop the synthetic of DNA in different links respectively, suppresses cell division propagation, and cell cycle and DNA are synthetic to play a role by influencing.Antimetabolitas is selected from one of following or combination: comprise, pemetrexed (Alimta), pemetrexed disodium, Rumi Qu Sai, doxifluridine (Doxifloridine, fortulon), the 5-doxifluridine, floxuridine (fluridine), flutamide, propylthiouracil, fluorouracil (Fluoracil, Fluracil), the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine (Mercaptopurine, happy disease is peaceful, 6-Mp), mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine (thioguanine, 6-TG), sulfur crow purine, tisupurin, Hydrazinium sulfate, dianhydrogalactitol, Aziridinyl Benzoquinone, but sweet smell Luoning, isoeuxanthone, chalone, chlorine is bent phosphoric acid, clastoban, cycloleucine, look into the Chinese holly woods, methyl yellow is looked into the Chinese holly woods sourly, Bai Ruikuaer, oxipurinol, Australia Ma Lite, bromine crust acid (sodium), Brytoslatin-I, bromine urea glycosides, fluorine urea hexylamine, folic acid, 10-ethyl denitrification aminopterin deaza-aminopterin), fluoromethotrexate, the dioxy methotrexate, 5, the 10-lonetrexol, N5-Methyltetrahydrohmofotic Acid, buthiopurin, his amide of Dinke, Guang azepine crow glycosides, carmofur (Carmofur), ftorafur (Tegafur, tegafur, FT-207), Tegafur-uracil mixt., 6-prenylindole, 6-thioinosine, UFT (Tegafur-Uracil, UFT), coralyne, N-foymylsarcolysin, ammonia (base) pterin (aminopterin), aminopterin sodium (Aminopterin Sodium), 8-azaguanine (8-azaguanine), 6-dimethylamino-8-azaadenosine, (nitro) imuran (azathioprine), uracil, 5-mercaptomethyluracil, azaserine (azaserine), Raltitrexed (Raltitrexed), nolatrexed dihydrochloride, sophoridine, formyl tetrahydrofolic acid, 5-methyltetrahydrohomofolate, Zoledronate, thunder accounts for for song, the temozolomide, bicalutamide, asparaginase (L-Asparaginase, left-handed asparagine), calcium levofolinate, calcium folinate (Calcium Levofolinate, calcium leucovorin), Quinespar, triazinate, trimetrexate, tramadol, the 5-chlorobarbituric acid, 5-diazonium uracil, piracetam, hycamtin, topotecan hydrochloride, ZD-9331, BHAC, SM108, cytosine arabinoside (cytosine arabinoside, Cytarabine (Ara-C)), ancitabine (cyclotidine, Cyclocytidine), hydroxyurea (Hydroxycarbamide, hydroxyurea), the hydroxyl guanidine, the 5-fluorouracil nucleoside, 5-fluorouracil deoxynucleoside (fluorouracil deoxynucleoside), glycerol Citrus chachiensis Hort. alkali, A Lei can loose, HCFU, 5 ' DFUR, TK-177, isoxazole acetic acid, aminoglutethimide (ethylbenzene amine piperidones, aminoglutethimidium, aminoglutethimide), amonafide, 5-chloro-5-deoxyarabinosylcytosine, atamestane, azacytidine (Azacitidine, 5-azacytidine, the atropic cytidine, AzGR), chloramphenalan (betamerphalan, Betamerphalan), decitabing, dexrazoxane (Dexrazoxane), crisnatol, cristatic acid, carat is sharp flat, the sharp guest of carat, zalcitabine, emtricitabine, galocitabine (Galocitabine), gemcitabine (Gemcitabine), ibacitabine (Ibacitabine), enocitabine (Enocitabine), ancitabine (Ancitabine), decitabine (Decitabine), flurocitabine (Flurocitabine), capecitabine (Capecitabine), his shore of imidazoles, the non-Shandong of Crane, the OK a karaoke club amide, carzolamide, carbazylquinone, CB-1-252, curcumin, the curcumin diketone, ketotrexate, trimetrexate, Si Poguning, deoxidation Si Poguning, naphthalene urea phosphamide, Ditercalinium Chloride, F-ara AMP-2, fluorine benzyl thiophene ketone, gamlogic acid, goserelin, nitrogen Chinese holly mountain range, Hellebrigenin, inosine dialdehyde, metoprine, mitobronitol (Dibromomannitol, Mitobronitol), mitolactol (Mitolactol), Ke is for ground, Persian, eriolangin, dopan (Chlorethylaminouracil, Dopan), Mei Luogerui, Methyl GAG, rice holder quinone, mitotane, fazarabine (Fazarabine), fludarabine (fludarabine), cladribine (cladribine), pentoside (pentostatin), phenaline, benzene comes U.S. special, phosphemide, hair Buddhist nun azoles, Polyprenic Acid, Pteroylaspartic Acid, pteroyltriglutamic acid, fast rice tongue pool, riboprine, simtrazene, Schizophyllan, sodium bromebrate, Solvent Yellow 3, bent fourth sulphur ester, TEM, triaziquone, triciribine, TCN-P NSC-280594, triptolide, triptorelin, nine cloth Lip river azoles, UFT, vitamin, Wei Maining, z-azepine adenosine, prick western cytidine, epipropidine (Epipropidine), the A Monuo phase, adozelesin (Adozelesin), acronine (Acronine), alanosine (Alanosine), ametantrone (Ametantrone), Anastrozole, the A Naxi army, anaxirone (Anaxirone), A Si Yin wakes up, acivicin (Acivicin), atevirdine (Atevirdine), idoxifene (idoxifene), AT-236, hold high and rather study carefully Ji, individual Lu Dabuxin, antineoplaston, asaphan, Aspargus Granule, AT-346, Bai Ruikuaer (sodium), (hydrochloric acid) Orang Crush, granisetron, tropisetron, dacarbazine, ondansetron, thymosin, tramadol, imatinib mesylate, diclofenac, Thalidomide, the holder fluorine kills star, toremifene, ambroxol, lappaconitine, anti-general etc. because of, thymosin, flutamide, ethyliminum, amine benzene, neoquini oxydum, the N-methylformamide, the jail can reach azoles, NSC-56045, oxisuran, oxylycorine, paphencyl, it is fixed to moor damp Nip, the penberol, prospidine chloride, protoanemonin, good generation born of the same parents, retelliptine, Sensorad, M3, solapalmitine, solaziquonum, stibenemidine, Temozoromide, the many Shillongs of platform, thiaolivacine, the pyridine of nitre ammonia bifurcation, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one (nolatrexed dihydrochlormide) or SN-11841.

Above-mentioned antimetabolitas with his shore of pemetrexed, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, thunder for song account for, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one serve as preferred.

The percentage by weight of above-mentioned antimetabolitas in compositions is good from 0.01%-99.99% with 1%-50%, is best with 5%-30%.

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

(1) contain the slow releasing injection local injection of amrubicin, the amrubicin synergist is used through other approach;

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

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

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

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

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

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

(a) amrubicin of 1-40%, aclarubicin, darubicin, doxorubicin, epirubicin, valrubicin or pirarubicin;

(b) Ismipur of 1-50%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, flutamide, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside; Or

(c) 1-40% amrubicin, aclarubicin, darubicin, doxorubicin, epirubicin, the Ismipur of valrubicin or pirarubicin and 1-50%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, flutamide, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.

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

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

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

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

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

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

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

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

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

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

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

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

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

The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).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, 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) 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 pill, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.

The main anticancer active ingredient of sustained-release implant and the percentage composition in implant are preferably as follows:

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.

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

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

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 of amrubicin relatively after test 1, the different modes administration

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 1 cm diameter its grouping.Every group of dosage is the 5mg/kg amrubicin.Measure amrubicin content (%) in the different time tumor.The result shows, the local drug concentration significant difference of amrubicin 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 in the tumor, secondly is the intratumor injection slow releasing injection.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.

Tumor-inhibiting action relatively in the body after test 2, the different modes administration

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

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

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

Table 1

Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value
Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value	1 (6)	Contrast	62±8
2 (6)	Pemetrexed	48±5.0	＜0.05	1 (6)	Contrast	62±8
2 (6)	Pemetrexed	48±5.0	＜0.05	3 (6)	Amrubicin	40±2.0	＜0.01
4 (6)	Epirubicin	34±2.0	＜0.01	3 (6)	Amrubicin	40±2.0	＜0.01
4 (6)	Epirubicin	34±2.0	＜0.01	5 (6)	Darubicin	36±3.2	＜0.01
6 (6)	Valrubicin	30±3.0	＜0.01	5 (6)	Darubicin	36±3.2	＜0.01
6 (6)	Valrubicin	30±3.0	＜0.01	7 (6)	Pemetrexed+amrubicin	16±2.0	＜0.001
8 (6)	Pemetrexed+epirubicin	20±3.4	＜0.001	7 (6)	Pemetrexed+amrubicin	16±2.0	＜0.001
8 (6)	Pemetrexed+epirubicin	20±3.4	＜0.001	9 (6)	Pemetrexed+darubicin	20±3.2	＜0.001
10 (6)	Pemetrexed+valrubicin	16±2.0	＜0.001	9 (6)	Pemetrexed+darubicin	20±3.2	＜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 amrubicin, epirubicin, darubicin or valrubicin and amrubicin synergist-pemetrexed, can show significant potentiation when use in conjunction.

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

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

Table 2

Oncocyte	Carmofur	Aclarubicin	Doxorubicin	Pirarubicin	Carmofur+aclarubicin	Carmofur+doxorubicin	Carmofur+mitoxantrone
Oncocyte	Carmofur	Aclarubicin	Doxorubicin	Pirarubicin	Carmofur+aclarubicin	Carmofur+doxorubicin	Carmofur+mitoxantrone	CNS	58％	54％	66％	68％	90％	82％	88％
C6	60％	60％	60％	64％	90％	86％	92％	CNS	58％	54％	66％	68％	90％	82％	88％
C6	60％	60％	60％	64％	90％	86％	92％	SA	52％	62％	58％	62％	86％	94％	90％
BC	54％	64％	54％	64％	90％	84％	84％	SA	52％	62％	58％	62％	86％	94％	90％
BC	54％	64％	54％	64％	90％	84％	84％	BA	52％	62％	62％	60％	92％	92％	88％
LH	56％	58％	62％	58％	90％	90％	82％	BA	52％	62％	62％	60％	92％	92％	88％
LH	56％	58％	62％	58％	90％	90％	82％	PAT	60％	56％	60％	58％	94％	86％	88％

Above result shows that growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used aclarubicin, doxorubicin or pirarubicin and amrubicin synergist-carmofur, can show significant potentiation when use in conjunction.Same potentiation also sees amrubicin, aclarubicin, darubicin, doxorubicin, epirubicin, valrubicin or pirarubicin and Ismipur, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, hydroxyurea, the 5-fluorouracil nucleoside, thunder accounts for for song, dexrazoxane, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.

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

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

Table 3

Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value
Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value	1 (6)	Contrast	70±10
2 (6)	2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one	58±5.0	＜0.05	1 (6)	Contrast	70±10
2 (6)		58±5.0	＜0.05	3 (6)	Amrubicin	52±4.2	＜0.01
4 (6)	2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one+amrubicin	34±2.4	＜0.001	3 (6)	Amrubicin	52±4.2	＜0.01
4 (6)		34±2.4	＜0.001	5 (6)	Pemetrexed	46±3.0	＜0.01
6 (6)	Pemetrexed+amrubicin	30±3.0	＜0.001	5 (6)	Pemetrexed	46±3.0	＜0.01
6 (6)	Pemetrexed+amrubicin	30±3.0	＜0.001	7 (6)	Enocitabine	50±2.6	＜0.01
8 (6)	Enocitabine+amrubicin	22±2.0	＜0.001	7 (6)	Enocitabine	50±2.6	＜0.01
8 (6)	Enocitabine+amrubicin	22±2.0	＜0.001	9 (6)	Carmofur	56±4.8	＜0.01
10 (6)	Carmofur+amrubicin	18±2.0	＜0.001	9 (6)	Carmofur	56±4.8	＜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 amrubicin and amrubicin synergist-antimetabolitas (2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed, enocitabine, carmofur), can show significant potentiation when use in conjunction.

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

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

Table 4

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1 (6)	Contrast	-
2 (6)	Amrubicin	42	＜0.05	1 (6)	Contrast	-
2 (6)	Amrubicin	42	＜0.05	3 (6)	Ftorafur	46	＜0.01
4 (6)	Decitabine	44	＜0.01	3 (6)	Ftorafur	46	＜0.01
4 (6)	Decitabine	44	＜0.01	5 (6)	Cytosine arabinoside	50	＜0.01
6 (6)	Capecitabine	42	＜0.01	5 (6)	Cytosine arabinoside	50	＜0.01
6 (6)	Capecitabine	42	＜0.01	7 (6)	Amrubicin+ftorafur	82	＜0.001
8 (6)	Amrubicin+decitabine	84	＜0.001	7 (6)	Amrubicin+ftorafur	82	＜0.001
8 (6)	Amrubicin+decitabine	84	＜0.001	9 (6)	Amrubicin+cytosine arabinoside	90	＜0.001
10 (6)	Amrubicin+capecitabine	92	＜0.001	9 (6)	Amrubicin+cytosine arabinoside	90	＜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 amrubicin and amrubicin synergist-antimetabolitas (ftorafur, decitabine, cytosine arabinoside, capecitabine), can show significant potentiation when use in conjunction.

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

With the rat is subjects, with 2 * 10 ⁵Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Amrubicin is through the injection of tumor week, the intravenous injection of amrubicin synergist.Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 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)	Amrubicin	52	＜0.05	1 (6)	Contrast	-
2 (6)	Amrubicin	52	＜0.05	3 (6)	Gemcitabine	50	＜0.01
4 (6)	Fludarabine	40	＜0.01	3 (6)	Gemcitabine	50	＜0.01
4 (6)	Fludarabine	40	＜0.01	5 (6)	Raltitrexed	44	＜0.01
6 (6)	Cladribine	48	＜0.01	5 (6)	Raltitrexed	44	＜0.01
6 (6)	Cladribine	48	＜0.01	7 (6)	Amrubicin+gemcitabine	88	＜0.001
8 (6)	Amrubicin+fludarabine	92	＜0.001	7 (6)	Amrubicin+gemcitabine	88	＜0.001
8 (6)	Amrubicin+fludarabine	92	＜0.001	9 (6)	Amrubicin+Raltitrexed	94	＜0.001
10 (6)	Amrubicin+cladribine	90	＜0.001	9 (6)	Amrubicin+Raltitrexed	94	＜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 amrubicin and amrubicin synergist-antimetabolitas (gemcitabine, fludarabine, Raltitrexed, cladribine), can show significant potentiation when use in conjunction.

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

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

Table 6

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1 (6)	Contrast	-
2 (6)	Doxorubicin	58	＜0.05	1 (6)	Contrast	-
2 (6)	Doxorubicin	58	＜0.05	3 (6)	Zalcitabine	52	＜0.05
4 (6)	Emtricitabine	54	＜0.05	3 (6)	Zalcitabine	52	＜0.05
4 (6)	Emtricitabine	54	＜0.05	5 (6)	Galocitabine	60	＜0.05
6 (6)	Ibacitabine	62	＜0.01	5 (6)	Galocitabine	60	＜0.05
6 (6)	Ibacitabine	62	＜0.01	7 (6)	Doxorubicin+zalcitabine	88	＜0.01
8 (6)	Doxorubicin+emtricitabine	86	＜0.01	7 (6)	Doxorubicin+zalcitabine	88	＜0.01
8 (6)	Doxorubicin+emtricitabine	86	＜0.01	9 (6)	Doxorubicin+galocitabine	92	＜0.01
10 (6)	Doxorubicin+ibacitabine	94	＜0.001	9 (6)	Doxorubicin+galocitabine	92	＜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 amrubicin (doxorubicin) and amrubicin synergist (zalcitabine, emtricitabine, galocitabine, ibacitabine), can show significant potentiation when use in conjunction.Potentiation is in 50-90% (P＜0.01).

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

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

Table 7

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1 (6)	Contrast	-
2 (6)	Valrubicin	58	＜0.05	1 (6)	Contrast	-
2 (6)	Valrubicin	58	＜0.05	3 (6)	Ancitabine	48	＜0.01
4 (6)	Flurocitabine	56	＜0.01	3 (6)	Ancitabine	48	＜0.01
4 (6)	Flurocitabine	56	＜0.01	5 (6)	Enocitabine	48	＜0.01
6 (6)	His shore of imidazoles	48	＜0.01	5 (6)	Enocitabine	48	＜0.01
6 (6)	His shore of imidazoles	48	＜0.01	7 (6)	Valrubicin+ancitabine	80	＜0.001
8 (6)	Valrubicin+enocitabine	82	＜0.001	7 (6)	Valrubicin+ancitabine	80	＜0.001
8 (6)	Valrubicin+enocitabine	82	＜0.001	9 (6)	Valrubicin+fluorine west Rui Bin	90	＜0.001
10 (6)	His shore of valrubicin+imidazoles	92	＜0.001	9 (6)	Valrubicin+fluorine west Rui Bin	90	＜0.001

Above result shows, 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 for used valrubicin and amrubicin synergist (ancitabine, flurocitabine, enocitabine, imidazoles he shore).

In a word, growth all had the obvious suppression effect to kinds of tumor cells when above-mentioned amrubicin and/or various amrubicin synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is above-mentioned any one amrubicin and/or any one amrubicin synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection or sustained-release 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.

With 90,90,80 milligrams of polifeprosans (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into 3 containers respectively, all add 100 milliliters of dichloromethane, add medicine (10mg pemetrexed after the dissolving mixing, the 10mg amrubicin, 10mg pemetrexed and 10mg amrubicin), again shake up the back and contain 10% pemetrexed with spray drying method for preparation, 10% amrubicin, the medicine injectable microsphere of 10% pemetrexed and 10% amrubicin, then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of gained slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 2.

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

Embodiment 3.

The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that used slow-release auxiliary material is polylactic acid (PLA), and its molecular weight peak value is 30000-50000; Contained anticancer effective component and percentage by weight thereof are:

Embodiment 4.

The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that used slow-release auxiliary material is the copolymer (PLGA) of polyglycolic acid and hydroxyacetic acid, and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-50; Contained anticancer effective component and percentage by weight thereof are:

Embodiment 5.

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

Embodiment 6.

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

(a) his shore of the pemetrexed of 5-40%, pemetrexed disodium, Rumi Qu Sai, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, thunder for song account for, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one;

(b) aclarubicin of 5-30%, darubicin, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin or pirarubicin; Or

(c) aclarubicin of 5-30%, darubicin, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, the Ismipur of valrubicin or pirarubicin and 5-40%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.

Embodiment 7.

70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 10mg pirarubicin, shake up the back contains 20% 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 10% pirarubicin with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 8.

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

(c) aclarubicin of 5-30%, darubicin, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, the pemetrexed of valrubicin or pirarubicin and 5-40%, pemetrexed disodium, Rumi Qu Sai, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.

Embodiment 9

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

Embodiment 10

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

The 5-30% pirarubicin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, the Ismipur of darubicin or pirarubicin and 5-30%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.

Embodiment 11

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

Embodiment 12

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

The 5-30% amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, the Ismipur of pirarubicin or valrubicin and 5-30%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.

Embodiment 13

With 70mg molecular weight peak value 85000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg darubicin and 20mg cladribine, shake up the back contains 10% darubicin and 20% cladribine 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

Be processed into the method step and the embodiment 11 of sustained-release implant, 13 is identical, but different is that contained anticancer effective component is: the amrubicin of 5-30%, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, the pemetrexed of pirarubicin or valrubicin and 5-30%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.

Embodiment 15.

70mg bis-fatty acid and decanedioic acid copolymer are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg pemetrexed and 15mg zorubicin, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% pemetrexed and 15% zorubicin, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 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 pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the amrubicin of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside and 5-30%, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, the combination of pirarubicin or valrubicin.

Embodiment 17

The method step that is processed into slow releasing agent is identical with embodiment 1-16, 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 5000-30000,30000-50000,50000-100000 or 100000-150000;

B) the molecular weight peak value is the polyglycolic acid of 5000-30000,30000-50000,50000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;

C) ethylene vinyl acetate copolymer (EVAc);

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;

D) bis-fatty acid and decanedioic acid copolymer;

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

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

E) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera.

Embodiment 18

The method step that is processed into slow releasing injection is identical with embodiment 1-17, 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 sustained-release implant is identical with embodiment 11-13, but different is that contained anticancer effective component is:

(a) amrubicin of 1-40%, Ai Rou are than star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, pirarubicin or valrubicin;

(b) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Or

(c) 1-40% amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, the Ismipur of pirarubicin or valrubicin and 1-50%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.

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. an anticancer medicine slow-release preparation containing that contains amrubicin and synergist thereof is characterized in that this anticancer medicine slow-release preparation containing 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

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

Wherein,

Anticancer effective component is amrubicin and/or antimetabolitas;

The slow-release auxiliary material choosing:

A) polylactic acid;

B) copolymer of polyglycolic acid and hydroxyacetic acid;

C) polifeprosan;

D) ethylene vinyl acetate copolymer; Or

E) bis-fatty acid and decanedioic acid copolymer;

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

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

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

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

2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that amrubicin is replaced than star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, pirarubicin or valrubicin by Ai Rou.

3. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that antimetabolitas is selected from pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, the 5-doxifluridine, floxuridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, sulfur crow purine, tisupurin, Hydrazinium sulfate, dianhydrogalactitol, Aziridinyl Benzoquinone, but sweet smell Luoning, isoeuxanthone, chalone, chlorine is bent phosphoric acid, clastoban, cycloleucine, look into the Chinese holly woods, methyl yellow is looked into the Chinese holly woods sourly, Bai Ruikuaer, oxipurinol, Australia Ma Lite, the acid of bromine crust, Brytoslatin-I, bromine urea glycosides, fluorine urea hexylamine, folic acid, fluoromethotrexate, the dioxy methotrexate, 5, the 10-lonetrexol, N5-Methyltetrahydrohmofotic Acid, buthiopurin, his amide of Dinke, Guang azepine crow glycosides, carmofur, ftorafur, Tegafur-uracil mixt., 6-prenylindole, 6-thioinosine, UFT, coralyne, N-foymylsarcolysin, ammonia (base) pterin, aminopterin sodium, the 8-azaguanine, 6-dimethylamino-8-azaadenosine, imuran, uracil, 5-mercaptomethyluracil, azaserine, Raltitrexed, nolatrexed dihydrochloride, sophoridine, formyl tetrahydrofolic acid, 5-methyltetrahydrohomofolate, Zoledronate, thunder accounts for for song, the temozolomide, bicalutamide, asparaginase, calcium levofolinate, calcium folinate, Quinespar, triazinate, trimetrexate, tramadol, the 5-chlorobarbituric acid, 5-diazonium uracil, piracetam, hycamtin, topotecan hydrochloride, ZD-9331, BHAC, SM108, cytosine arabinoside, ancitabine, hydroxyurea, the hydroxyl guanidine, the 5-fluorouracil nucleoside, the 5-fluorouracil deoxynucleoside claims the fluorouracil deoxynucleoside again, glycerol Citrus chachiensis Hort. alkali, A Lei can loose, isoxazole acetic acid, aminoglutethimide, amonafide, 5-chloro-5-deoxyarabinosylcytosine, atamestane, azacytidine, chloramphenalan, decitabing, dexrazoxane, crisnatol, cristatic acid, carat is sharp flat, the sharp guest of carat, zalcitabine, emtricitabine, galocitabine, gemcitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine, his shore of imidazoles, the non-Shandong of Crane, the OK a karaoke club amide, carzolamide, carbazylquinone, CB-1-252, curcumin, the curcumin diketone, ketotrexate, trimetrexate, Si Poguning, deoxidation Si Poguning, naphthalene urea phosphamide, Ditercalinium Chloride, F-ara AMP-2, fluorine benzyl thiophene ketone, gamlogic acid, goserelin, nitrogen Chinese holly mountain range, Hellebrigenin, inosine dialdehyde, metoprine, mitobronitol, mitolactol, Ke is for ground, Persian, eriolangin, dopan, Mei Luogerui, Methyl GAG, rice holder quinone, mitotane, fazarabine, fludarabine, cladribine, pentoside, phenaline, benzene comes U.S. special, phosphemide, hair Buddhist nun azoles, Polyprenic Acid, Pteroylaspartic Acid, pteroyltriglutamic acid, fast rice tongue pool, riboprine, simtrazene, Schizophyllan, sodium bromebrate, Solvent Yellow 3, bent fourth sulphur ester, TEM, triaziquone, triciribine, TCN-P NSC-280594, triptolide, triptorelin, nine cloth Lip river azoles, UFT, vitamin, Wei Maining, z-azepine adenosine, prick western cytidine, epipropidine, the A Monuo phase, adozelesin, acronine, alanosine, ametantrone, Anastrozole, the A Naxi army, anaxirone, A Si Yin wakes up, acivicin, atevirdine, idoxifene, AT-236, hold high and rather study carefully Ji, individual Lu Dabuxin, antineoplaston, asaphan, Aspargus Granule, AT-346, Bai Ruikuaer, Bisantrene Hydrochloride, granisetron, tropisetron, dacarbazine, ondansetron, thymosin, tramadol, imatinib mesylate, diclofenac, Thalidomide, the holder fluorine kills star, toremifene, ambroxol, lappaconitine, anti-general etc. because of, thymosin, flutamide, ethyliminum, amine benzene, neoquini oxydum, the N-methylformamide, the jail can reach azoles, NSC-56045, oxisuran, oxylycorine, paphencyl, it is fixed to moor damp Nip, the penberol, prospidine chloride, protoanemonin, good generation born of the same parents, retelliptine, Sensorad, M3, solapalmitine, solaziquonum, stibenemidine, Temozoromide, the many Shillongs of platform, thiaolivacine, the pyridine of nitre ammonia bifurcation, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or SN-11841.

4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that anticancer effective component is:

Below all be weight percentage.

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

A) 0.5-3.0% carboxymethyl cellulose or 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% 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.

6. the slow-releasing anticarcinogen injection 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.

7. the anti-cancer sustained-released implantation agent according to claim 6 is characterized in that the anticancer effective component in the anti-cancer sustained-released implantation agent is that amrubicin, Ai Rou are than star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, pirarubicin or valrubicin.

8. the anti-cancer sustained-released implantation agent according to claim 6 is characterized in that the anticancer effective component in the anti-cancer sustained-released implantation agent is a pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.

9. the anti-cancer sustained-released implantation agent according to claim 6 is characterized in that anticancer effective component in the anti-cancer sustained-released implantation agent is for being selected from amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, pirarubicin or valrubicin and be selected from Ismipur, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of the antimetabolite of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.

10. the anti-cancer sustained-released implantation agent according to claim 6 is characterized in that the anticancer effective component in the anti-cancer sustained-released implantation agent is:

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