CN1861051A

CN1861051A - Slow-releasing injection contg. platinum compounds and its potentiator type anticarcinogen

Info

Publication number: CN1861051A
Application number: CNA2006102005880A
Authority: CN
Inventors: 孔庆忠; 张红军; 邹会风
Original assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Current assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Priority date: 2006-06-21
Filing date: 2006-06-21
Publication date: 2006-11-15

Abstract

A slow-release anticancer injection contains the slow-release microspheres and solvent. Said slow-release microsphere contains the active anticancer component chosen from 6 Pt compounds including bicycloplatinum, etc and 3 synergists including taxane, alkylating agent or plant alkaloid, and the slow-release auxiliary.

Description

A kind of slow-releasing anticarcinogen injection that contains platinum-like compounds and synergist thereof

(1) technical field

The present invention relates to a kind of slow-releasing anticarcinogen injection and preparation method thereof, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains platinum-like compounds and platinum-like compounds synergist, be mainly slow releasing injection and sustained-release implant.

(2) background technology

As class chemotherapeutics commonly used, platinum-like compounds has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its tangible general toxicity has greatly limited the application of this medicine.Moreover, 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 et al., 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 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

Platinum-like compounds and platinum-like compounds synergist be as new cancer therapy drug, has been widely used in the multiple entity tumor of treatment both at home and abroad, as the cerebral tumor etc.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.

Be effectively to improve tumor by local drug level, reduce the drug level of medicine in blood circulation, people have studied the slow-released system that contains cancer therapy drug, comprise that sustained-release micro-spheres (capsule) (sees: (China Patent No. ZL00809160.9; Application number 91109723.6), Ciftci K etc. " with the polylactic acid microsphere treatment entity tumor that contains fluorouracil and the research of drug release " " drug development technology " (Pharm Dev Technol.) 2 (2): 151-60,1997), sustained-release implant (sees: China Patent No. ZL96115937.5; ZL97107076.8) etc.Yet, solid sustained-release implant (China Patent No. ZL96115937.5; ZL97107076.8) and existing as be used for the treatment of the cerebral tumor (ZL00809160.9) sustained-release micro-spheres or United States Patent (USP) (US5,651,986) and all have problem such as be not easy more than operation, weak curative effect, the complication.In addition, the sensitivity that many entity tumors are drawn together platinum-like compounds to anticancer medicated bag is relatively poor, and is easy to generate drug resistance in therapeutic process.The present invention finds that medicine of mentioning among the present invention and platinum-like compounds share and can make its antitumaous effect strengthen (the following medicine that the platinum-like compounds antitumaous effect will be increased mutually is referred to as the platinum-like compounds synergist) mutually.In addition, with the assembly packaging of platinum-like compounds or platinum-like compounds and its synergist in specific slow-release auxiliary material and be equipped with special solvent and make drug level that anti-cancer medicine sustained-release injection not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, reduce 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 decapacitation of platinum-like compounds synergist suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.

The drug main that platinum-like compounds is made is wanted conventional route administrations such as oral administration or intravenous injection, and administering mode of the present invention is the local sustained release administration, obviously reduces the toxic action of its whole body in the therapeutic effect that significantly strengthens medicine.Existing several thousand new platinum family chemical compounds are entered the screening back find to have only 28 chemical compounds to enter clinical research, have 4 chemical compounds to get the Green Light and come into the market, also have 2～3 chemical compounds will obtain to produce certification.Therefore, in having the platinum-like compounds of active anticancer, be not all slow release effects that all can in slow-release auxiliary material of the present invention, reach effective release.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected platinum-like compounds among the present invention slowly can be discharged in the regular hour in human body or animal body must could obtain through a large amount of creationary experiments, specific slow-release auxiliary material and can need be passed through a large amount of creative works by the selection of the combination of slow releasing pharmaceutical and could determine.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.

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

The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains platinum-like compounds and platinum-like compounds synergist is provided.

Platinum-like compounds 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 platinum-like compounds and platinum-like compounds synergist, and the platinum-like compounds synergist 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, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

Platinum-like compounds is selected from easypro platinum (sunpla), bicycloplatin (bicycloplatin), according to platinum (eptalatin), picoplatin, citricplatin (citricplatin), ZD 0473 (picoplatin).

Above-mentioned platinum-like compounds 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 platinum-like compounds or platinum-like compounds synergist, slow-releasing anticarcinogen injection is mainly used in the platinum-like compounds of other approach application of increase or the action effect of platinum-like compounds 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 platinum-like compounds or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:

(1) contain the slow releasing injection local injection of platinum-like compounds, and the platinum-like compounds synergist is used through other approach;

(2) local injection contains the slow releasing injection of platinum-like compounds synergist, and other approach are used platinum-like compounds;

(3) local injection contains the slow releasing injection and the slow releasing injection that contains the platinum-like compounds synergist of platinum-like compounds; Or

(4) local injection contains the slow releasing injection of platinum-like compounds 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.

Anticancer effective component platinum-like compounds and/or the percentage by weight of platinum-like compounds synergist in medicament slow-release microsphere are 0.5%-60%, are good with 2%-40%, are best with 5%-30%.The weight ratio of platinum-like compounds and platinum-like compounds synergist is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.

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

(a) the easypro platinum of 2-40%, bicycloplatin, paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%;

(b) the easypro platinum of 2-40%, bicycloplatin, according to platinum, picoplatin, the alestramustine of citricplatin or ZD 0473 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) combination of the easypro platinum of 2-40%, bicycloplatin, vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.

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, 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) EVAc of 55-90%;

(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, 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)-directly of suspending agent for " 0 " 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 is preferably as follows, and all is weight percentage:

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;

(5) EVAc of 55-90%;

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

Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.

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

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 platinum-like compounds (platinum relaxes) 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 easypro platinum of 5mg/kg.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of platinum after different modes is used relaxes, 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 platinum-like compounds (according to platinum) compares

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is 5mg/kg according to platinum.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.The result shows, according to the tumor-inhibiting action significant difference of platinum 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, platinum-like compounds and platinum-like compounds 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	68±10
2(6)	Paclitaxel	44±5.2	＜0.05	1(6)	Contrast	68±10
2(6)	Paclitaxel	44±5.2	＜0.05	3(6)	Platinum relaxes	40±2.0	＜0.01
4(6)	According to platinum	36±2.0	＜0.01	3(6)	Platinum relaxes	40±2.0	＜0.01
4(6)	According to platinum	36±2.0	＜0.01	5(6)	Picoplatin	36±3.0	＜0.01
6(6)	Citricplatin	32±0.0	＜0.01	5(6)	Picoplatin	36±3.0	＜0.01
6(6)	Citricplatin	32±0.0	＜0.01	7(6)	Paclitaxel+platinum relaxes	14±2.0	＜0.001
8(6)	Paclitaxel+according to platinum	20±2.4	＜0.001	7(6)	Paclitaxel+platinum relaxes	14±2.0	＜0.001
8(6)	Paclitaxel+according to platinum	20±2.4	＜0.001	9(6)	Paclitaxel+picoplatin	16±2.2	＜0.001
10(6)	Paclitaxel+citricplatin	12±1.60	＜0.001	9(6)	Paclitaxel+picoplatin	16±2.2	＜0.001

Above result shows, platinum-like compounds (relax platinum, according to platinum, picoplatin, citricplatin) and its synergist (paclitaxel) are grown to kinds of tumor cells when this concentration is used separately all the obvious suppression effect, 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, platinum-like compounds and platinum-like compounds 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.Platinum-like compounds and platinum-like compounds 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	Docetaxel	Platinum relaxes	According to platinum	Bicycloplatin	Docetaxel+platinum relaxes	Docetaxel+according to platinum	Docetaxel+bicycloplatin
Oncocyte	Docetaxel	Platinum relaxes	According to platinum	Bicycloplatin	Docetaxel+platinum relaxes	Docetaxel+according to platinum	Docetaxel+bicycloplatin	CNS	52％	48％	34％	26％	72％	76％	86％
C6	60％	52％	30％	24％	64％	76％	90％	CNS	52％	48％	34％	26％	72％	76％	86％
C6	60％	52％	30％	24％	64％	76％	90％	SA	48％	60％	26％	22％	68％	82％	90％
BC	52％	48％	24％	24％	64％	86％	80％	SA	48％	60％	26％	22％	68％	82％	90％
BC	52％	48％	24％	24％	64％	86％	80％	BA	54％	52％	22％	22％	68％	72％	78％
LH	62％	50％	22％	18％	50％	82％	82％	BA	54％	52％	22％	22％	68％	72％	78％
LH	62％	50％	22％	18％	50％	82％	82％	PAT	60％	58％	20％	18％	72％	84％	88％

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used platinum-like compounds synergist (docetaxel) and platinum-like compounds (relax platinum, according to platinum, bicycloplatin), can show significant potentiation when use in conjunction.Same effect also sees the other types tumor, as esophageal carcinoma, ovarian cancer, cancer of pancreas, intestinal cancer etc.

The tumor-inhibiting action of test 5, platinum-like compounds and platinum-like compounds 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	60±10
2(6)	Bicycloplatin	436±4.0	＜0.05	1(6)	Contrast	60±10
2(6)	Bicycloplatin	436±4.0	＜0.05	3(6)	Nimustine	40±2.0	＜0.01
4(6)	Bicycloplatin+nimustine	18±2.2	＜0.001	3(6)	Nimustine	40±2.0	＜0.01
4(6)	Bicycloplatin+nimustine	18±2.2	＜0.001	5(6)	Carmustine	38±3.2	＜0.01
6(6)	Bicycloplatin+carmustine	16±1.8	＜0.001	5(6)	Carmustine	38±3.2	＜0.01
6(6)	Bicycloplatin+carmustine	16±1.8	＜0.001	7(6)	Fotemustine	30±2.6	＜0.01
8(6)	Bicycloplatin+fotemustine	20±2.6	＜0.001	7(6)	Fotemustine	30±2.6	＜0.01
8(6)	Bicycloplatin+fotemustine	20±2.6	＜0.001	9(6)	Sarmustine SarCNU	32±4.0	＜0.01
10(6)	Bicycloplatin+Sarmustine SarCNU	16±2.2	＜0.001	9(6)	Sarmustine SarCNU	32±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 platinum-like compounds (bicycloplatin) and platinum-like compounds synergist-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, platinum-like compounds and platinum-like compounds 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 (platinum-like compounds or platinum-like compounds synergist) and therapeutic alliance group (platinum-like compounds and platinum-like compounds 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 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)	Citricplatin	40	＜0.05	1(6)	Contrast	-
2(6)	Citricplatin	40	＜0.05	3(6)	Semustine	48	＜0.01
4(6)	Lomustine	42	＜0.01	3(6)	Semustine	48	＜0.01
4(6)	Lomustine	42	＜0.01	5(6)	Estramustine	52	＜0.01
6(6)	Streptozocin	40	＜0.01	5(6)	Estramustine	52	＜0.01
6(6)	Streptozocin	40	＜0.01	7(6)	Citricplatin+semustine	78	＜0.001
8(6)	Citricplatin+lomustine	84	＜0.001	7(6)	Citricplatin+semustine	78	＜0.001
8(6)	Citricplatin+lomustine	84	＜0.001	9(6)	Citricplatin+estramustine	80	＜0.001
10(6)	Citricplatin+streptozocin	86	＜0.001	9(6)	Citricplatin+estramustine	80	＜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 platinum-like compounds (citricplatin) and platinum-like compounds synergist-alkylating agent (semustine, lomustine, estramustine, streptozocin), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 7, platinum-like compounds and platinum-like compounds 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.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)	Picoplatin	38	＜0.05	1(6)	Contrast	-
2(6)	Picoplatin	38	＜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	40	＜0.01
6(6)	Tallimustine	44	＜0.01	5(6)	Fotemustine	40	＜0.01
6(6)	Tallimustine	44	＜0.01	7(6)	Picoplatin+galamustine	86	＜0.001
8(6)	Picoplatin+Ranimustine	86	＜0.001	7(6)	Picoplatin+galamustine	86	＜0.001
8(6)	Picoplatin+Ranimustine	86	＜0.001	9(6)	Picoplatin+fotemustine	80	＜0.001
10(6)	Picoplatin+tallimustine	88	＜0.001	9(6)	Picoplatin+fotemustine	80	＜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 platinum-like compounds (picoplatin) and platinum-like compounds synergist-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, platinum-like compounds and platinum-like compounds 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.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)	ZD 0473	34	＜0.05	1(6)	Contrast	-
2(6)	ZD 0473	34	＜0.05	3(6)	Vincristine	48	＜0.01
4(6)	Vincaleucoblastine	56	＜0.01	3(6)	Vincristine	48	＜0.01
4(6)	Vincaleucoblastine	56	＜0.01	5(6)	Vinorelbine	48	＜0.01
6(6)	Vindesine	48	＜0.01	5(6)	Vinorelbine	48	＜0.01
6(6)	Vindesine	48	＜0.01	7(6)	ZD 0473+vincristine	82	＜0.001
8(6)	ZD 0473+vincaleucoblastine	72	＜0.001	7(6)	ZD 0473+vincristine	82	＜0.001
8(6)	ZD 0473+vincaleucoblastine	72	＜0.001	9(6)	ZD 0473+vinorelbine	86	＜0.001
10(6)	ZD 0473+vindesine	88	＜0.001	9(6)	ZD 0473+vinorelbine	86	＜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 platinum-like compounds (ZD 0473) and platinum-like compounds synergist-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, platinum-like compounds and platinum-like compounds synergist (slow releasing injection)

Measure the tumor-inhibiting action of platinum-like compounds and platinum-like compounds synergist (slow releasing injection) by test 7 described methods; the result shows the easypro platinum that is selected from; bicycloplatin; according to platinum; picoplatin; the platinum-like compounds of citricplatin or ZD 0473 can significantly strengthen 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; the tumor killing effect of alkylating agents such as the appropriate azoles amine of streptozocin or miaow, potentiation is in 38-70% (P＜0.01).

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

Measure the tumor-inhibiting action of platinum-like compounds and platinum-like compounds synergist (slow releasing injection) by test 7 described methods, the result shows the easypro platinum that is selected from, bicycloplatin, can significantly strengthen paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 10-according to the platinum-like compounds of platinum, picoplatin, citricplatin or ZD 0473 goes taxaneses such as acetyl paclitaxel or 7-table-paclitaxel to see the tumor killing effect of this medicine, and potentiation is in 40-80% (P＜0.01).

The tumor-inhibiting action of test 11, platinum-like compounds synergist (slow releasing injection)

Measure the tumor-inhibiting action of platinum-like compounds and platinum-like compounds synergist (slow releasing injection) by test 7 described methods, the result shows the easypro platinum that is selected from, bicycloplatin, according to platinum, picoplatin, the platinum-like compounds of citricplatin or ZD 0473 can significantly strengthen vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, the tumor killing effect of monocrotaline or cephalotaxin, potentiation is in 60-80% (P＜0.01).

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

With the rat is subjects, grouping (3/group) and the easypro platinum sustained-release implant of equivalent 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 easypro platinum 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, the bacteriostatic rate increases with the polylactic acid molecule amount and improves, and is followed successively by 68% (MW:5000), 66% (MW:15000), 54% (MW:25000), 50% (MW:40000) and 48 (MW:60000).

Same result also see with polylactic acid be adjuvant make see this medicinal slow release agent, contain according to platinum-like compounds and its synergists such as platinum, picoplatin, citricplatin.

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, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination; Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.

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

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

(4) specific embodiment

Embodiment 1.

80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the easypro platinum of 10mg paclitaxel and 10mg, shake up the back contains 10% paclitaxel and 10% easypro platinum 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 contained anticancer effective component and percentage by weight thereof are:

Used adjuvant is: 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; The viscosity of slow releasing injection is 10cp-650cp (20 ℃-30 ℃ time).

Embodiment 3.

With 70mg molecular weight peak value is that 65000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg according to platinum and 15mg nimustine, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing made contain 15% micropowder according to platinum 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 contained anticancer effective component and percentage by weight thereof are: the easypro platinum of 2-40%; bicycloplatin; according to platinum; picoplatin; the alestramustine of citricplatin or ZD 0473 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

Embodiment 5.

(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of vincristine and 10 milligrams of picoplatins, shake up the back contains 20% vincristine and 10% picoplatin 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 contained anticancer effective component is: the combination of the easypro platinum of 2-40%, the vincristine according to platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and 2-40%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.

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 paclitaxel and 10mg according to platinum, shake up the back again and contain 20% paclitaxel and 10% injectable microsphere according to platinum with spray drying method for preparation.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 contained anticancer effective component is:

The easypro platinum of the paclitaxel of 2-40% or docetaxel and 2-40%, according to platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and combination.

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 the easypro platinum of 20mg Docetaxel and 10mg, shake up the back again and contain 20% Docetaxel and 10% easypro cisplatin for injection 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: 10% paclitaxel or Docetaxel and 10% easypro platinum, according to platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and combination.

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 carmustine and 20mg according to platinum, shake up the back again and contain 10% carmustine and 20% injectable microsphere according to platinum with spray drying method for preparation.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 easypro platinum of 15% 2-40%; according to platinum; bicycloplatin; picoplatin; citricplatin or ZD 0473 and with 10% 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; the combination of the appropriate azoles amine of spiromustine or miaow.

Embodiment 13

With 70mg molecular weight peak value 35000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg ZD 0473 and 20mg vinorelbine, shake up the back contains 10% ZD 0473 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: 15% easypro platinum, according to the combination of new alkali of the spring of platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and 15%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.

Embodiment 15.

With 70mg molecular weight peak value is that 35000 polylactic acid (PLA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg relax platinum 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% easypro platinum 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 10% easypro platinum, vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin according to platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and 10%.

Embodiment 17.

With 70mg molecular weight peak value is that 30000 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) are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg, shake up the dry organic solvent of removing of final vacuum again according to platinum and 15mg vincristine.Dried pastille solid composite freezing and pulverizing made contain 15% micropowder according to platinum 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 that contained anticancer effective component and percentage by weight thereof are:

5% easypro platinum, according to the combination of new alkali of the spring of platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and 15%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.

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) 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;

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, 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 easypro platinum of 5-25%; according to platinum; bicycloplatin; picoplatin; the paclitaxel of citricplatin or ZD 0473 5-25%; docetaxel; 2 '-hydroxyl taxol; 10-removes the acetyl taxol; 7-table-taxol; 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; the appropriate azoles amine of miaow; vincristine; vincaleucoblastine; vinorelbine; vindesine; Vinmegallate; vinleurosine; vinleucinol; vinglycinate; vinfosiltine; vinformide; vinflunine; vinepidine; vinzolidine; vintriptol; vinrosidine; the combination of monocrotaline or cephalotaxin.

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:

(a) the easypro platinum of 5-15%, according to the combination of paclitaxel or the docetaxel of platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and 5-35%;

(b) combination of the easypro platinum of 5-15%, nimustine, carmustine, fotemustine, estramustine, hemustine heCNU He, lomustine, methyl lomustine, semustine or Ranimustine according to platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and 5-20%; Or

(c) combination of the easypro platinum of 5-15%, vincristine, vincaleucoblastine, vinorelbine, vindesine, vinleurosine, vinepidine, vinzolidine, vintriptol or vinrosidine according to platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and 15%.

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

One kind contain platinum-like compounds and synergist thereof slow-releasing anticarcinogen injection be 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 be selected from easypro platinum, according to the platinum-like compounds of platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and the combination that is selected from the platinum-like compounds synergist of taxane, alkylating agent and/or plant alkaloid;

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

A) polylactic acid;

B) copolymer of polyglycolic acid and hydroxyacetic acid;

C) polifeprosan;

D) ethylene vinyl acetate copolymer;

E) bis-fatty acid and decanedioic acid copolymer;

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

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

H) 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.

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

The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time).
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that taxane is selected from paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 10-and removes acetyl paclitaxel or 7-table-paclitaxel.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that 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.
4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that plant alkaloid is selected from vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection and percentage by weight are:

(a) the easypro platinum of 2-40%, bicycloplatin, paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%;

(b) the easypro platinum of 2-40%, bicycloplatin, according to platinum, picoplatin, the alestramustine of citricplatin or ZD 0473 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) combination of the easypro platinum of 2-40%, bicycloplatin, vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
6. according to claim 1 and 5 described slow-releasing anticarcinogen injections, it is characterized in that in the slow-release auxiliary material,

A) polylactic acid molecule amount peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;

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

C) in the polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
7. according to claim 1 and 5 described slow-releasing anticarcinogen injections, it is characterized in that used suspending agent is respectively one of following or its combination:

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

B) 5-15% mannitol;

C) 5-15% sorbitol;

D) 0.1-1.5% surfactant;

E) 0.1-0.5% polysorbas20;

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

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

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

I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
8. according to claim 1 and 5 described slow-releasing anticarcinogen injections, 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.
9. described according to Claim 8 anti-cancer sustained-released implantation agent is characterized in that the constituent of sustained-release implant is:

Anticancer effective component is:

(a) the easypro platinum of 2-40%, bicycloplatin, paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%;

(b) the easypro platinum of 2-40%, bicycloplatin, according to platinum, picoplatin, the alestramustine of citricplatin or ZD 0473 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) combination of the easypro platinum of 2-40%, bicycloplatin, vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
10. the anti-cancer sustained-released implantation agent according to claim 9, the slow-release auxiliary material that it is characterized in that being used to preparing sustained-release implant are selected from one of following or its combination:

A) polylactic acid;

B) copolymer of polyglycolic acid and hydroxyacetic acid;

C) polifeprosan;

D) ethylene vinyl acetate copolymer;

E) bis-fatty acid and decanedioic acid copolymer;

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

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

H) 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.