(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains methotrexate and/or amethopterin synergist is provided.
The present invention finds that medicine of mentioning among the present invention and methotrexate share and can make its antitumaous effect strengthen (the following medicine that the methotrexate antitumaous effect will be increased mutually is referred to as amethopterin synergist) mutually.In addition, with the assembly packaging of methotrexate or methotrexate 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 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 micro-spheres comprises:
Anticancer effective component 0.5-50%
Slow-release auxiliary material 50-99%
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 methotrexate and amethopterin synergist, and amethopterin synergist is selected from platinum-like compounds, topoenzyme inhibitor and/or tetrazine kind compound; Suspending agent helps the suspension of slow releasing pharmaceutical and then makes things convenient for drug administration by injection, is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
Methotrexate shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-55%, is best with 2%-40%.All be weight percentage.
Platinum-like compounds is selected from one of following or combination: cisplatin (cisplatin, DDP), carboplatin (Carboplatin, carboplatin), ring platinum (Cycloplatin), platinum in heptan (sunplatinum), DNA-2114 (dacarbazine; Dacarbazine; NSC-45388; Dacarbazine), cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin (Enloplatin), sulfatodiamino cyclohexane platinum (ring ethylenediamine platinic sulfate, Sulfatodiaminocy clohexane platinum, SHP), Spiroplatin (spiral shell sulphur platinum amine), dexormaplatin (Dexormaplatin), iproplatin (Iproplatin), lobaplatin (Lobaplatin, happy platinum), rice platinum (Miboplatin), pick up platinum (picoplatin), nedaplatin (Nedaplatin), ormaplatin (Ormaplatin), oxaliplatin (Oxaliplatin, Oxaloplatin), sebriplatin (Sebriplatin, briplatin), spiroplatin (Spiroplatin) or zeniplatin (Zeniplatin).
Above platinum-like compounds with cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin serve as preferred.
The percentage by weight of above-mentioned platinum-like compounds in compositions can be 0.1%-50%, is good with 1%-30%, and 5%-20% is best.
Topoenzyme inhibitor is selected from one of following or combination: Camptothecin (camptothecin, CPT), the derivant of Camptothecin, lurtotecan (Lurtotecan), topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin, topotecan), irinotecan (irinotecan, IRT), 9-nitro Camptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxyl-Camptothecin (7-ethyl-10-hydroxy-camptothecin, SN-38), 7-ethyl-10-[4-(1-piperidino)-1-piperidino] and the carbonyl Camptothecin (7-ethyl-10-[4-(1-pyperidino)-1-piperidino] carbonyloxycamptothecin, CPT-11), 10-hydroxyl-Camptothecin (10-Hydroxycamptothecin, HCPT), Homocamptothecins (Homocamptothecins), MD-CPT (10,11-methylenedioxy, MD-CPT), (RS)-MD-CPT (10,11-MD-20 (RS)-CPT), (S)-MD-CPT glycinate (10,11-MD-20 (S)-cpT-glycinate ester (Gly) .HCl), 9-amino-(S)-MD-CPT glycinate (9-amino-10,11-MD-20 (S)-CPT-Gly), N-[2-(dimethylamino) ethyl] and pyridine-4-carboxylic acid amides (N-[2-(dimethylamino) ethyl] acridine-4-carboxamide, DACA) and the derivant of 5 or 7 replacements, podophyllotoxin (podophyllotoxin), etoposide (Etoposide, epipodophyllotoxins, etoposide, etoposide, VP-16), teniposide (Teniposide, teniposide, VM-26), Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone (Genistein), the 14-doxorubicin, amrubicin (Amrubicin), Ai Rou is than star (4 '-(acridinylamino) methansulfon-m-anisidide (amsacrine, m-AMSA)), the nor-oxygen daunorubicin of 4-(4-demeth oxydaunorubicin), detorubicin, 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), esorubicin (Esorubicin), carubicin, idarubicin (idarubicin, IDA), rodorubicin, leurubicin (Leurubicin), medorubicin, Nemorubicin (Nemorubicin), doxorubicin, valrubicin (N-trifluoro toxin-14-valerate, N-trifluoroacetyladriamycin-14-valerate, AD 32, valrubicin), 2[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid ((2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid, XK469), zorubicin (Zorubicin), N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin (N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin, AD 312), pyrazoles [1,5-a] indole derivatives, as, but be not limited to, GS-2,-3,-4, GS-5; The dioxy piperazine oxazine derivatives, as, but be not limited to, (+)-1, two (3, the 5-dioxo piperazinyl) propane ((+)-1 of 2-, 2-bis (3,5-dioxopiperazinyl-1-yl) propane, ICRF-187) ,-2,3-two (3,5-dioxo piperazine-1-yl) butane (meso-2,3-bis (3,5-dioxopiperazine-1-yl) butane, ICRF-193), two dioxo piperazine (bisdioxopiperazine); Suramin (Suramin), deoxyguanosine (Deoxyguanosine), lithocholic acid (lithocholic acid, LCA) or Hydrazoic acid,sodium salt (sodium azide).
In the above topology enzyme inhibitor, serve as preferred than star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin with Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou.
Topoenzyme inhibitor shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-40% from 0.01%-50%, is best with 5%-30%.All be weight percentage.
Tetrazine kind compound is selected from one of following or combination: imidazo tetrazine (imidazotetrazine), imidazopyrazine (imidazopyrazine), 1H-imidazo [b] piperazine (1H-imidazo[b] pyrazine), imidazopyridine (imidazopyridine), 1H-imidazo [1,2-a] pyridine (1H-imidazo[1,2-a] pyridinum), procarbazine (procarbazine, PCB), mitozolomide (mitozolomide, MTZ), dacarbazine (dacarbazine, DCB), temozolomide (Temozolomide or 8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4 (3H)-one or NSC 362856)), 4-carboxyl temozolomide [4--carbonyl] temozolomide], 3-N-methyl temozolomide [3-N-methyl] temozolomide), the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide (Pyrrolo[2,1-d] [1,2,3,5] tetrazine-4 (3H)-ones), the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o (Pyrrolo[2,1-d] [1,2,3,5] tetrazinones 10a-o), 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides (MTIC, 5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide (8-nitro-3-methyl-benzo-1,2,3,5-tetrazepin-4 (3H)-one, NIME), 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide (3,5-dimethyl-pyrido-1,2,3,5-tetrazepin-4-one, PYRZ) or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides (3-(2-chloroethyl)-N, N-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, CDODTC).
Be preferred with imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide in the above-mentioned tetrazine kind compound.
Tetrazine kind compound shared ratio in slow releasing agent is decided because of concrete condition, generally speaking, can be good with 1%-40% from 0.01%-55%, is best with 5%-30%.All be weight percentage.
Anticancer effective component is the combination of amethopterin synergist or methotrexate and its synergist.When the cancer therapy drug in the medicament slow-release microsphere only was amethopterin synergist, slow-releasing anticarcinogen injection was mainly used in the action effect that increases the methotrexate that other approach use or is used for potentiation to radiotherapy or other therapies.When being used to increase the action effect of the methotrexate that other approach use, methotrexate can be through tremulous pulse, vein or local injection, placement administration.
The percentage by weight of antitumor drug in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.When use in conjunction, the weight ratio of methotrexate and amethopterin synergist is 1-9: 1 to 1: 1-9, and with 1-2: 1 and 2-1: 1 serves as preferred, 1: 1 for most preferably.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
The methotrexate of 1-40% and the cisplatin of 1-40%, carboplatin, heptan platinum, dexormaplatin, lobaplatin, nedaplatin, ormaplatin, oxaliplatin or zeniplatin combination; Or
The methotrexate of 1-40% and the Camptothecin of 1-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin; Or
The methotrexate of 1-40% and the procarbazine of 1-40%, mitozolomide, dacarbazine or temozolomide.
The slow-release auxiliary material slow-release auxiliary material is selected from one of copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, FAD and decanedioic acid copolymer, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination, one of copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), FAD and the decanedioic acid copolymer of wherein preferred polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, polifeprosan 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, 5000-200, and 000, but with 20,000-80,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-200, and 000, but with 20,000-100,000 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, 5000-200,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferred 25/75-75/25 (weight), most preferably 75: 25.The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.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 representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid one decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer one decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid one 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.
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.
Except that above-mentioned adjuvant, also can select for use other materials to see United States Patent (USP) (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.
The content of suspending agent is decided because of the medicine that solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule), the preparation method of injection and the kind and the composition thereof of suspending agent, as, sodium carboxymethyl cellulose can be 0.5-5%, but with 1-3% is preferred, mannitol and or sorbitol be 5-30%, but is preferred with 10-20%, and polysorbas20, polysorbate40 or Tween 80 are 0.05-2%, but are preferred with 0.10-0.5%.In most cases, sustained-release microparticle is made up of effective ingredient and slow-release auxiliary material, and solvent is special solvent.When solvent was common solvent, medicine that is suspended or sustained-release micro-spheres (or microcapsule) then were made up of effective ingredient, slow-release auxiliary material and/or suspending agent.In other words, when the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent, and when the suspending agent in the sustained-release microparticle (A) was not " 0 ", solvent (B) can be common solvent or special solvent.The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).
Common solvent can be, but is not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt, and pharmacopeia has respective specified; The special solvent of indication of the present invention is the common solvent that contains suspending agent, suspending agent can be, but be not limited to one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 or its combination.The content of suspending agent is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:
(a) 0.5-5% sodium carboxymethyl cellulose; Or
(b) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
(c) 5-20% mannitol; Or
(d) 5-20% mannitol and 0.1-0.5% Tween 80; Or.
(e) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.
The above-mentioned volume weight percentage ratio that is contains the weight of suspending agent in the common solvent of unit volume, as g/ml, kg/l, down with.
The preparation of injection comprises that the preparation of preparation, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend, and make injection at last in solvent.
Wherein, sustained-release micro-spheres or drug microparticles can prepare with some kinds of methods: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are in conjunction with freezing (drying) comminuting method, liposome bag medicine method and emulsion process etc.Serve as preferred wherein with dissolution method (being the solvent volatility process), freezing (drying) comminuting method, seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection.The particle diameter of suspended drug or sustained-release micro-spheres (or microcapsule) decide because of specifically needing, and can be, but be not limited to, 1-300um, but be that preferably 30-150um most preferably with 20-200um.Medicine or sustained-release micro-spheres can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller.Slow-release auxiliary material is above-mentioned bio-capacitivity, biodegradable or non-biodegradation polymer.
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 with sodium carboxymethyl cellulose (1.5%)+mannitol with or sorbitol (15%) and/or Tween 80 (0.1%) be dissolved in the normal saline mutually deserved 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 application of injection comprises the application of the injection of making after the application of application, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend in solvent.
Microsphere is used to prepare slow releasing injection, as suspension type slow releasing injection, gel injection, block copolymer micelle injection.In various injections, serve as preferred with the suspension type slow releasing injection.The suspension type slow releasing injection is to contain the medicament slow-release microsphere of effective composition or the preparation that drug microparticles is suspended in gained in the solvent, and 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; 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 is (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000) hydrophobic block as the micelle copolymer.The particle size range of block copolymer micelle can be at 1-300um, but is preferred with 20-200um, and 30-150um most preferably; 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.
The application of solvent refers to that mainly the application of special solvent is effective suspension, stablizes and/or protects various medicines or sustained-release micro-spheres (or microcapsule), thereby prepares corresponding injection.The application of special solvent can make prepared injection have better injectivity, good stability and higher viscosity.
The application of injection be with full-bodied special solvent with pastille microgranule, particularly sustained-release microparticle, make corresponding slow releasing injection, thus make corresponding medicine can with the injection mode import in the patient or mammalian body of required medicine.The medicine that is injected can be, but is not limited to, said medicine micropowder or medicament slow release microgranule.
The route of administration of injection depends on multiple factor.For the non-proliferative pathological changes, can be in vein, lymphatic vessel, subcutaneous, muscle, intracavity (in as abdominal cavity, thoracic cavity, articular cavity and in the canalis spinalis), tissue, tumor in, reach in the bone marrow in all, the selective arterial injection of tumor, lymph node and inject.For proliferative lesion, as the entity tumor, though can be through above-mentioned administration, with in selective arterial, intracavity, the tumor, the injection of tumor week serves as preferred.
For obtaining valid density in former or position, metastatic tumour place, also can unite and give through number of ways, in the time of as vein, lymphatic vessel, subcutaneous, muscle, intracavity (as in abdominal cavity, thoracic cavity, the articular cavity and in the canalis spinalis) or selective arterial injection in conjunction with local injection.So administering drug combinations is specially adapted to entity tumor.As in the tumor, tumor week injection time is in conjunction with systemic injection.
The present invention can be used to prepare the medicine of the various tumors for the treatment of people and animal, is mainly slow releasing injection.
The present invention is example with the antitumor drug, by following test and embodiment technical scheme of the present invention is further described:
Route of administration depends on multiple factor, for obtaining 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, the selective arterial injection of tumor, lymph node and injection in the bone marrow.With in selective arterial, intracavity, the tumor, tumor week injection serves as preferred.
The present invention can be used to prepare the medicine of the various tumors for the treatment of people and animal, be mainly slow releasing injection, 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.
Sustained-release micro-spheres among the present invention can be used to prepare the sustained-release implant of the various tumors for the treatment of people and animal.
Also can add other medicinal ingredient in the made slow releasing injection of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technology of the present invention is further described:
The local drug concentration of methotrexate 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 methotrexate.Measure methotrexate content (%) in the different time tumor.The result shows, the local drug concentration significant difference of methotrexate 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.Not only can greatly improve tumor by local drug level, reduce the drug level of medicine in blood circulation, reduce the toxicity of medicine normal structure, this discovery of complication that can also greatly make things convenient for the medicine injection, reduces operation technique 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 treated behind tumor growth to 0.5 cm diameter it to be divided into following 9 groups (seeing Table 2) in its hypochondrium.Every group of dosage is 5mg/kg methotrexate and 2mg/kgO6-BG.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.
Table 2
Test group (n) | Administering mode | Gross tumor volume (cm
3)
| The P value |
1(6) | - | 70 | |
2(6) | The agent of tail vein injection normal injection | 64 | 0.06 |
3(6) | The agent of lumbar injection normal injection | 63 | 0.06 |
4(6) | The agent of tumor week injection normal injection | 55 | 0.03 |
5(6) | Tumor week injection slow releasing injection | 27 | <0.01 |
6(6) | Tumor week is placed sustained-release implant | 19 | <0.01 |
7(6) | The agent of intratumor injection normal injection | 51 | 0.04 |
8(6) | The intratumor injection slow releasing injection | 17 | <0.001 |
9(6) | Place sustained-release implant in the tumor | 15 | <0.001 |
Above result shows, methotrexate and the cisplatin tumor-inhibiting action significant difference after different modes is used, and topical can obviously improve its tumor-inhibiting action, 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, easily.Good effect not only, toxic and side effects is also little.
The tumor-inhibiting action of test 3, methotrexate and amethopterin 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 3) of index with inhibition rate of tumor growth.
Table 3
Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
1(6) | Contrast | - | |
2(6) | Methotrexate | 58 | <0.05 |
3(6) | Cisplatin | 50 | <0.01 |
4(6) | Carboplatin | 52 | <0.01 |
5(6) | Ormaplatin | 48 | <0.01 |
6(6) | Dexormaplatin | 52 | <0.01 |
7(6) | Methotrexate+cisplatin | 82 | <0.001 |
8(6) | Methotrexate+carboplatin | 86 | <0.001 |
9(6) | Methotrexate+ormaplatin | 92 | <0.001 |
10(6) | Methotrexate+dexormaplatin | 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 methotrexate and amethopterin synergist-platinum-like compounds (cisplatin, carboplatin, ormaplatin, dexormaplatin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, methotrexate and amethopterin 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 4) of index with inhibition rate of tumor growth.
Table 4
Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
1(6) | Contrast | - | |
2(6) | Methotrexate | 58 | <0.05 |
3(6) | Heptan platinum | 50 | <0.05 |
4(6) | Lobaplatin | 48 | <0.05 |
5(6) | Nedaplatin | 56 | <0.05 |
6(6) | Oxaliplatin | 52 | <0.01 |
7(6) | Methotrexate+heptan platinum | 84 | <0.01 |
8(6) | Methotrexate+lobaplatin | 80 | <0.01 |
9(6) | Methotrexate+nedaplatin | 92 | <0.01 |
10(6) | Methotrexate+oxaliplatin | 94 | <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 methotrexate and amethopterin synergist-platinum-like compounds (heptan platinum, lobaplatin, nedaplatin, oxaliplatin)
Test 5, contain tumor-inhibiting action in the body of methotrexate and amethopterin 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 3).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 5) on the 10th day.
Table 5
Test group (n) | Suffered treatment | Gross tumor volume (cm
3)
| The P value |
1(6) | Contrast | 72±10 | |
2(6) | Methotrexate | 48±5.4 | <0.05 |
3(6) | Camptothecin | 48±2.0 | <0.01 |
4(6) | Hydroxy-camptothecin alkali | 46±2.2 | <0.01 |
5(6) | Topotecan | 42±3.2 | <0.01 |
6(6) | Irinotecan | 44±3.0 | <0.01 |
7(6) | Methotrexate+Camptothecin | 22±2.0 | <0.001 |
8(6) | Methotrexate+hydroxy-camptothecin alkali | 30±3.6 | <0.001 |
9(6) | Methotrexate+topotecan | 32±3.6 | <0.001 |
10(6) | Methotrexate+irinotecan | 18±2.2 | <0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for methotrexate and used amethopterin synergist-topoenzyme inhibitor (Camptothecin, hydroxy-camptothecin alkali, topotecan, irinotecan), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6, methotrexate and amethopterin 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.Methotrexate and amethopterin 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 6.
Table 6
Oncocyte | Methotrexate | Lurtotecan | Etoposide | Teniposide | Methotrexate+lurtotecan | Methotrexate+etoposide | Methotrexate+teniposide |
CNS | 62% | 58% | 64% | 68% | 92% | 88% | 98% |
C6 | 64% | 64% | 60% | 64% | 94% | 84% | 96% |
SA | 58% | 62% | 56% | 62% | 88% | 92% | 92% |
BC | 54% | 64% | 54% | 64% | 94% | 84% | 82% |
BA | 58% | 60% | 62% | 60% | 98% | 92% | 92% |
LH | 60% | 58% | 62% | 58% | 90% | 88% | 88% |
PAT | 64% | 54% | 62% | 58% | 92% | 88% | 92% |
Above result shows, used methotrexate and amethopterin synergist-topoenzyme inhibitor (lurtotecan, etoposide, teniposide) phosphate) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.Further experiment shows that methotrexate can also obviously strengthen the tumor killing effect of other topoenzyme inhibitor, as amrubicin, Ai Rou than star, rodorubicin, leurubicin, zorubicin, valrubicin, idarubicin etc.
The tumor-inhibiting action of test 7, methotrexate and amethopterin 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 (methotrexate or amethopterin synergist) and therapeutic alliance group (methotrexate and amethopterin 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 7) of index with inhibition rate of tumor growth.
Table 7
Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
1(6) | Contrast | - | |
2(6) | Methotrexate | 42 | <0.05 |
3(6) | Procarbazine | 40 | <0.01 |
4(6) | Mitozolomide | 36 | <0.01 |
5(6) | Dacarbazine | 34 | <0.01 |
6(6) | The temozolomide | 32 | <0.01 |
7(6) | Methotrexate+procarbazine | 86 | <0.001 |
8(6) | Methotrexate+mitozolomide | 84 | <0.001 |
9(6) | Methotrexate+dacarbazine | 86 | <0.001 |
10(6) | Methotrexate+temozolomide | 92 | <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 methotrexate and amethopterin synergist-tetrazine kind compound (procarbazine, mitozolomide, dacarbazine, temozolomide), can show significant potentiation when use in conjunction.
Test 8, injection viscosity are to the influence of slow releasing agent injectivity
Methotrexate is dissolved in the solvent that contains different viscosity suspending agents, makes the slow releasing injection of different viscositys according to the described method of embodiment 1-16.Represent its syringeability with the success rate (%) of mouse subcutaneous injection 20 times then.See Table 8.The viscosity scope of solvent is 10cp-650 (20 ℃-30 ℃ time).Equivalent sustained-release micro-spheres (about 2-5 milligram) is suspended in 5 milliliters of solvents, and it is subcutaneous with 5 milliliters of syringes with No. 18 syringe needles it to be expelled to mice.The time of per injection is 1-2 minute, and the drug residue in the syringe of injection back is the injection failure greater than 5%.
Table 8
Solvent viscosity (cp) | The injection number of success | Injection success rate (%) |
10 | 1 | 5 |
50 | 2 | 10 |
100 | 4 | 20 |
200 | 7 | 35 |
300 | 9 | 45 |
400 | 12 | 60 |
500 | 14 | 70 |
550 | 14 | 70 |
600 | 16 | 80 |
650 | 18 | 90 |
Above result shows that the principal element that influences the injection syringeability is the viscosity of solvent, wherein, 400 to the success rate of the solvent of 650cp viscosity more than 50%.This discovery constitutes another principal character of the present invention.With No. 22 syringe needle repeated trials 8, draw equifinality.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used methotrexate and various amethopterin synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of methotrexate and any one amethopterin 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.
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 methotrexate and 10mg cisplatin, shake up the back contains 20% methotrexate and 10% cisplatin 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 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component is:
(1) methotrexate of 5-30%; Or
(2) cisplatin of the methotrexate of 2-40% and 1-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin combination.
Embodiment 3.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg methotrexate and 10mg Camptothecin, shake up the back contains 10% methotrexate and 10% Camptothecin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 15-25 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are:
(1) methotrexate of 2-40%; Or
(2) Camptothecin of the methotrexate of 2-40% and 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin.
Embodiment 5.
With 70mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg methotrexate and 15mg nedaplatin, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the nedaplatin micropowder that contains 10% methotrexate and 10%, 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 30-35 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 and percentage by weight thereof are: the methotrexate of 2-40% and the cisplatin of 2-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin combination.
Embodiment 7.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of methotrexates and 10 milligrams of temozolomides, shake up the back contains 20% methotrexate and 10% temozolomide 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 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is:
(1) methotrexate of 2-40%; Or
(2) the imidazo tetrazine of the methotrexate of 2-40% and 2-40%, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide's 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 20mg methotrexate and 10mg etoposide, shake up the back contains 20% methotrexate and 10% etoposide with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 10
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is:
(1) methotrexate of 2-40%; Or
(2) Camptothecin of the methotrexate of 2-40% and 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin.
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 Camptothecin and 20mg methotrexate, shake up the back contains 10% Camptothecin and 20% methotrexate 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 methotrexate of 2-40% and the Camptothecin of 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin.
Embodiment 13
With 70mg molecular weight peak value is that 35000 polylactic acid (PLA) is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg methotrexate and 20mg mitozolomide, shake up the back contains 10% methotrexate and 20% mitozolomide 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: 10% methotrexate and 20% imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide's combination.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 5000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 5000-30000,30000-60000,60000-100000 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) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
D) FAD and certain herbaceous plants with big flowers diacid (SA) copolymer;
E) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-15, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Embodiment 17
With 80mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg oxaliplatin and 10mg methotrexate, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the methotrexate micropowder that contains 10% oxaliplatin 10%, 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 18.
The method step that is processed into slow releasing injection is identical with embodiment 1-17, but different is that contained anticancer effective component is:
(a) 15% methotrexate; Or
(b) 15% methotrexate and 10% cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin combination; Or
(c) 15% methotrexate and 15% Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin; Or
(d) 15% methotrexate and 15% procarbazine, mitozolomide, dacarbazine or temozolomide's combination.
Embodiment 19.
The method step that is processed into slow releasing injection is identical with embodiment 1-18, but different is:
Slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid, molecular weight peak value are 10000-30000,30000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid, molecular weight peak value are 10000-30000,30000-60000,60000-100000 or 100000-150000, and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 75: 25;
C) FAD and certain herbaceous plants with big flowers diacid copolymer;
D) in the 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;
The viscosity of suspending agent is 100cp-2000cp (20 ℃-30 ℃ time), is selected from one of following or its combination:
A) 1% sodium carboxymethyl cellulose;
B) 10% mannitol;
C) 5% sorbitol;
D) 0.3% polysorbas20;
E) 1% sodium carboxymethyl cellulose+0.5% soil temperature 80;
F) 12% mannitol+0.5% soil temperature 80;
G) 1.5% sodium carboxymethyl cellulose+10% sorbitol+0.5% soil temperature 80;
H) 1% sodium carboxymethyl cellulose+15% mannitol+0.5% soil temperature 20.
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.