CN101011351A - Anti-cancer composition loading both platinum compound and synergist - Google Patents
Anti-cancer composition loading both platinum compound and synergist Download PDFInfo
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Abstract
Disclosed is a slow release injection agent of anticancer composition containing platinum-group compounds and synergistic agent, which comprises slow release microspheres and dissolvent, wherein the slow release microspheres comprise anti-cancer active constituents and slow release auxiliary materials, the dissolvent being conventional dissolvent or specific dissolvent containing suspension adjuvant. The viscosity of the suspension adjuvant is 100-3000cp (at 20-30 deg C), and is selected from sodium carboxymethylcellulose, the platinum-group compounds are selected from cisplatin, Carboplatin, Nedaplatin or Oxaliplatin, the synergistic agent can be selected from tetrazine drugs such as Mitozolomide or Temozolomide, and / or anticancer antibiotics such as Adriamycin, Aclarubicin, Epirubicin, mitomycin or pidorubicin, the slow release auxiliary materials are selected from polyphosphate ester copolymers such as p(LAEG-EOP), p(DAPG-EOP), copolymer or blend of polyphosphate ester with polylactic acid, Polifeprosan, sebacylic acid and PLGA. The anticancer composition can also be prepared into slow release implanting agent for injection or placement in or around tumor with a period of effective concentration maintenance over 60 days, as well as the treatment effect of appreciably lowering general reaction of the drugs, and improving the treatment effect of the non-operative treatment methods such as chemotherapy.
Description
(1) technical field
The present invention relates to a kind of anti-cancer composition that contains platinum-like compounds and synergist, belong to technical field of pharmaceuticals.Particularly, this invention relates to a kind ofly can be released to the partial slow releasing preparation of entity tumor with platinum-like compounds and synergist are stable, is mainly sustained-release implant and slow releasing injection, can prolong drug release time, and can increase the sensitivity of medicine.
(2) background technology
Chemotherapeutics topical application, particularly local sustained release have become the research direction and the focus of current entity tumor chemotherapy.Referring to (Chinese patent application numbers 200510042234.3,03148624.X, 200510042236.2,96116041.1,97107078.4,200510042260.6,200510042261.0,200510042262.5,200510042263.X; U.S. Pat 5651986, RE37410).
Yet existing slow-release auxiliary material above-mentioned and that other pharmaceutical preparation is used causes the prominent of medicine to release or unbalanced release when release more or less.The release medicine that has is slow excessively, is not enough to obtain in the part active drug concentration, thereby effective kill tumor cell; The release that has is too fast, often causes prominent releasing, and causes general toxic reaction as conventional injection easily.
Therefore, research and development can discharge in the specific time different pharmaceutical with stable or constant amount and speed just becomes present problem demanding prompt solution.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer medicine slow-release preparation containing that contains platinum-like compounds and synergist is provided, particularly, is a kind of slow releasing injection or sustained-release implant that contains platinum-like compounds and synergist.Platinum-like compounds and/or the stable partial slow releasing preparation of entity tumor that is released to of synergist can prolong drug can be able to be kept higher drug level, and can increase the sensitivity of medicine release time.
The present invention finds to have the composition of active anticancer, is not the slow release effect that all slow-release auxiliary material all can reach effective release.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that different pharmaceutical 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.Discharged and be not enough to obtain active drug concentration slowly, thereby effective kill tumor cell; Cause prominent releasing if discharge too fast meeting, then cause general toxic reaction easily, as polifeprosan (A.J.Domb etc., Biomaterials (1995), 16 (14): 1069-1072; Wenbin Dang etc., Journal of Controlled Release (1996), 42:83-92; Eric P.Sipos etc., Cancer Chemother Pharmacol (1997), 39:383-389; Lawrence K.Fung etc., Cancer Research (1998), 58:672-684).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 present invention finds, poly-phosphide (polyphosphoesters), poly phosphate (polyphosphate), poly-phosphite ester (polyphosphite), polyphosphonates (polyphosphonate), polyester cyclic phosphate (poly (cycloaliphatic phosphoester)), etherophosphoric acid phosphate ester high molecular polymers such as (EOP) can steadily slowly discharge effective ingredient of the present invention, and deenergized period is more than 50 to 100 days.And do not have prominent releasing, particularly mix or copolymerization with sugared acid anhydride family macromolecule such as polylactic acid.The prominent deficiency of releasing with too fast release of more than finding to have solved existing slow releasing preparation is slowly more than release 50-100 days.More than find to constitute principal character of the present invention.
A kind of form of platinum-like compounds slow releasing agent of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is platinum-like compounds and synergist, and the platinum-like compounds synergist is selected from tetrazine class medicine and/or antitumor antibiotic.
Slow-release auxiliary material range of viscosities IV (dl/g) 0.05～1.8 serves as preferred with 0.1～1.4, with 0.1～1.4 for most preferably.The used slow-release auxiliary material of the present invention is selected from poly-phosphide (polyphosphoesters), poly phosphate (polyphosphate), poly-phosphite ester (polyphosphite), polyphosphonates (polyphosphonate), polyester cyclic phosphate (poly (cycloaliphatic phosphoester)), etherophosphoric acid (EOP), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester, 80/20) (p (BHET-EOP/TC, 80/20)), p (BHET-EOP/TC, 50/50), poly-(L-lactide-co-etherophosphoric acid (p (LAEG-EOP)), poly-(L-lactide-co-phosphoric acid propyl ester) (p (DAPG-EOP)), anti-(formula)-1,4-dimethyl cyclohexane (trans-1,4-cyclohexanedimethanil, CHDM), hexyl dichloro-phosphate ester (hexyl phosphorodichloridate, HOP), 4-dimethylamino pyridine (4-dimethylaminopyridine, DMAP), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride, 80/20) (p (BHDPT-EOP/TC, 80/20)), p (BHDPT-EOP/TC, 50/50), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) (p (CHDM-HOP)), poly-(anti-(formula)-1, a kind of or its combination in the 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)).
Serve as preferred with p (BHET-EOP/TC), p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (BHDPT-EOP/TC), p (CHDM-HOP), p (CHDM-EOP) in the above-mentioned phosphate ester.
The used slow-release auxiliary material of the present invention also is selected from above-mentioned phosphate ester and poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), PPDO (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen protein, the blend of gelatin or albumin glue or 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.
Platinum-like compounds can be, but be not limited to, platinum-like compounds is selected from one of following or its 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 (0xaliplatin, Oxaloplatin), sebriplatin (Sebriplatin, briplatin), spiroplatin (Spiroplatin) or zeniplatin (Zeniplatin).
Above platinum-like compounds serves as preferred with cisplatin, carboplatin, nedaplatin or oxaliplatin.
The percentage by weight of above-mentioned platinum-like compounds in compositions is good from 1%-60% with 2%-50%, is best with 5%-40%.
Antitumor antibiotics class drug main will be selected from bleomycin, daunomycin, aclarubicin, amycin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone, epirubicin, chlorine assistant star.Above antitumor antibiotics medicine also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
Antitumor antibiotic 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.
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 or8-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-ehloroethyl)-N, N-dimethyl-4-oxo-3,4-is dihydroimidazo[5 just, 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.
The percentage by weight of synergist in slow releasing agent is good from 0.01%-60% with 1%-50%, is best with 5%-30%.
The percentage by weight of medicine in sustained-release micro-spheres is 0.5%-70%, is good with 2%-60%, is best with 5%-30%.The weight ratio of platinum-like compounds and synergist is 1-9: 1 to 1: 1-9.With 1-4: 1 to 1: 1-4 serves as preferred, and with 1-4: 1 to 2-1: 1-2 serves as preferred.
Clinical needs are depended in the packing of platinum-like compounds and synergist and application.Platinum-like compounds and synergist can be packed alone or in combination.Assembly packaging is mainly used in local potentiation, and separately packing then is mainly used in to the potentiation of different approaches administration or to the potentiation of other therapies.As, local separately placement (or injection) platinum-like compounds and synergist then can be united with the synergist and the platinum-like compounds of intravenous applications respectively; The platinum-like compounds and/or the synergist of local placement the (or injection) also can be used for radiocurable potentiation.
Therefore, the anticancer effective component percentage by weight in the anticancer slow-release microsphere of the present invention is preferably as follows:
(1) combination of the daunomycin of the cisplatin of 2%-50%, carboplatin, nedaplatin or oxaliplatin and 5%-30%, aclarubicin, amycin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone, epirubicin or chlorine assistant star;
(2) imidazo tetrazine, imidazopyrazine, imidazopyridine, procarbazine, mitozolomide, dacarbazine or the temozolomide's of the cisplatin of 2%-50%, carboplatin, nedaplatin or oxaliplatin and 5%-30% combination.
Anticancer effective component and percentage by weight in the anticancer slow-release microsphere of the present invention further are preferably as follows:
Anticancer effective component in the anticancer slow-release microsphere and percentage by weight are most preferably as follows:
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 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 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 and emulsion process prepare microsphere, dissolution method is 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) 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.
Wherein, the molecular weight peak value of polylactic acid can be, but is not limited to, 5000-200, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of the copolymer of hydroxy carboxylic acid and glycolic (PLGA) can be, but be not limited to 5000-200,000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably, and the blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), is best (weight) with 25/75-75/25.The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned original 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.
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, chitosan, poloxamer 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.
Another form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant.The effective ingredient of anticancer implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.
The 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 route of administration of slow releasing agent depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
The tumor of above-mentioned internal organs can be different histological type, and why the tumor of the lymph node of lymph node divides outstanding golden lymphoma and non_hodgkin lymphoma, and pulmonary carcinoma comprises small cell lung cancer and nonsmall-cell lung cancer etc., and the cerebral tumor comprises glioma etc.Yet common tumor comprises entity tumors such as the retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis of the cerebral tumor, cerebral glioma, renal carcinoma, hepatocarcinoma, carcinoma of gallbladder, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, hemangioma, osteosarcoma, lymphoma, pulmonary carcinoma, thymic carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, eyes.
The application quantity of sustained-release implant and potentiation mode can be with reference to slow-releasing anticarcinogen injections, the cancer therapy drug that place the associating of the synergist of the associating of the cancer therapy drug of the promptly local synergist of placing and other administration, the local cancer therapy drug of placing and other administration, part and the associating of the local synergist of placing.Wherein the cancer therapy drug of topical application and synergist can be separately or Joint Production, packing, sale, use.Packing refers to medicine carrying process and pastille slow-release agent the exterior and interior packing for transport and/or store of medicine for adjuvant.The medicine carrying process includes, but not limited to weighing, dissolving, mixing, drying, shaping, coating, spraying, granulation etc.Mix on demand after can granulating respectively as cancer therapy drug and synergist again and make various dosage forms, this process comprises at least granulates and is shaped.
(1) combination of the daunomycin of the cisplatin of 2%-50%, carboplatin, nedaplatin or oxaliplatin and 5%-30%, aclarubicin, amycin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone, epirubicin or chlorine assistant star;
(2) imidazo tetrazine, imidazopyrazine, imidazopyridine, procarbazine, mitozolomide, dacarbazine or the temozolomide's of the cisplatin of 2%-50%, carboplatin, nedaplatin or oxaliplatin and 5%-30% combination.
The clinical practice dosage of effective ingredient depends on patient's concrete condition, can be from 0.01 to 1000mg/kg body weight, and 0.1 to 800mg/kg is preferred, 1 to 500mg/kg for there being most choosing.
Also can add other medicinal ingredient in slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technical method of the present invention is further described:
The local drug concentration that test 1, different modes are used behind the cisplatin 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 5mg/kg.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of cisplatin after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.
The interior tumor-inhibiting action of body that test 2, different modes are used behind the carboplatin compares
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 20th day.The result shows, the tumor-inhibiting action significant difference of carboplatin after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Test 3, contain tumor-inhibiting action in the body of platinum-like compounds and 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.The dosage of metabolism class medicine and synergist is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 52±12 | |
| 2(6) | Platinum-like compounds | 42±10.4 | ＜0.05 |
| 3(6) | Procarbazine | 50±8.0 | ＜0.01 |
| 4(6) | Mitozolomide | 48±7.2 | ＜0.01 |
| 5(6) | Dacarbazine | 50±7.2 | ＜0.01 |
| 6(6) | The temozolomide | 40±6.0 | ＜0.01 |
| 7(6) | Platinum-like compounds+procarbazine | 20±5.2 | ＜0.001 |
| 8(6) | Platinum-like compounds+mitozolomide | 32±5.8 | ＜0.001 |
| 9(6) | Platinum-like compounds+dacarbazine | 26±6.4 | ＜0.001 |
| 10(6) | Platinum-like compounds+temozolomide | 20±4.0 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for platinum-like compounds (cisplatin) and used synergist (procarbazine, mitozolomide, dacarbazine, temozolomide), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, platinum-like compounds and synergist (slow releasing injection)
Used tumor cell comprises CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT) etc.Platinum-like compounds and platinum-like compounds synergist are added in 24 hours the various tumor cells of In vitro culture by 10 μ g/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 | Cisplatin | Valrubicin | Ametycin | Epirubicin | Cisplatin+valrubicin | Cisplatin+ametycin | Cisplatin+epirubicin |
| CNS | 56％ | 52％ | 64％ | 60％ | 84％ | 84％ | 86％ |
| C6 | 52％ | 64％ | 64％ | 60％ | 90％ | 88％ | 82％ |
| SA | 46％ | 62％ | 56％ | 62％ | 86％ | 82％ | 82％ |
| BC | 44％ | 64％ | 54％ | 64％ | 86％ | 86％ | 80％ |
| BA | 48％ | 60％ | 62％ | 66％ | 88％ | 84％ | 90％ |
| LH | 54％ | 58％ | 62％ | 52％ | 90％ | 88％ | 86％ |
| PAT | 54％ | 50％ | 60％ | 52％ | 90％ | 88％ | 80％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used cisplatin and synergist-antitumor antibiotics (valrubicin, ametycin, epirubicin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, platinum-like compounds and synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual esophageal carcinoma 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 sustained-release implant is placed in tumor.The dosage of metabolism class medicine and synergist is respectively 35mg/kg and 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 30th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1 (6) | Contrast | 60±10 | |
| 2 (6) | Amycin | 50±8.0 | ＜0.05 |
| 3 (6) | Platinum-like compounds | 44±6.8 | ＜0.01 |
| 4 (6) | Amycin+platinum-like compounds | 32±4.4 | ＜0.001 |
| 5 (6) | Epirubicin | 46±3.2 | ＜0.01 |
| 6 (6) | Epirubicin+platinum-like compounds | 24±6.0 | ＜0.001 |
| 7 (6) | Epirubicin | 36±3.8 | ＜0.01 |
| 8 (6) | Epirubicin+platinum-like compounds | 20±4.6 | ＜0.001 |
| 9 (6) | Daunomycin | 40±8.6 | ＜0.01 |
| 10 (6) | Daunomycin+platinum-like compounds | 18±4.0 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used platinum-like compounds (carboplatin) and synergist (amycin, epirubicin, epirubicin, daunomycin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6, platinum-like compounds and 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 synergist) and therapeutic alliance group (platinum-like compounds and synergist).Medicine is through intratumor injection.The dosage of metabolism class medicine and synergist is respectively 20mg/kg and 10mg/kg.The treatment back was measured the gross tumor volume size on the 30th 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) | Platinum-like compounds | 42 | ＜0.05 |
| 3(6) | Amycin | 32 | ＜0.01 |
| 4(6) | Pirarubicin | 48 | ＜0.01 |
| 5(6) | Valrubicin | 46 | ＜0.01 |
| 6(6) | Ametycin | 44 | ＜0.01 |
| 7(6) | Platinum-like compounds+amycin | 80 | ＜0.001 |
| 8(6) | Platinum-like compounds+pirarubicin | 78 | ＜0.001 |
| 9(6) | Platinum-like compounds+valrubicin | 76 | ＜0.001 |
| 10(6) | Platinum-like compounds+ametycin | 84 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used platinum-like compounds (nedaplatin) and synergist (amycin, pirarubicin, valrubicin, ametycin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, platinum-like compounds and synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual gastric cancer 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.The dosage of metabolism class medicine and synergist is respectively 15mg/kg and 15mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 5) of index with inhibition rate of tumor growth.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Platinum-like compounds | 50 | ＜0.05 |
| 3(6) | Aclarubicin | 48 | ＜0.01 |
| 4(6) | Epirubicin | 42 | ＜0.01 |
| 5(6) | Amycin | 48 | ＜0.01 |
| 6(6) | Darubicin | 42 | ＜0.01 |
| 7(6) | Platinum-like compounds+aclarubicin | 76 | ＜0.001 |
| 8(6) | Platinum-like compounds+epirubicin | 70 | ＜0.001 |
| 9(6) | Platinum-like compounds+amycin | 80 | ＜0.001 |
| 10(6) | Platinum-like compounds+darubicin | 84 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used platinum-like compounds (oxaliplatin) and synergist (aclarubicin, amycin, epirubicin, darubicin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, platinum-like compounds and synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual rectal cancer 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.The dosage of metabolism class medicine and synergist is respectively 15mg/kg and 15mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.
Table 6
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Epirubicin | 58 | ＜0.05 |
| 3(6) | Cisplatin | 46 | ＜0.01 |
| 4(6) | Carboplatin | 48 | ＜0.01 |
| 5(6) | Nedaplatin | 44 | ＜0.01 |
| 6(6) | Oxaliplatin | 46 | ＜0.01 |
| 7(6) | Cisplatin+epirubicin | 82 | ＜0.001 |
| 8(6) | Carboplatin+epirubicin | 78 | ＜0.001 |
| 9(6) | Nedaplatin+epirubicin | 80 | ＜0.001 |
| 10(6) | Oxaliplatin+epirubicin | 82 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used platinum-like compounds (cisplatin, carboplatin, nedaplatin, oxaliplatin) and synergist (epirubicin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 9, platinum-like compounds and synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Medicine is through intratumor injection.The dosage of metabolism class medicine and synergist is respectively 10mg/kg and 20mg/kg.The treatment back was measured the gross tumor volume size on the 20th 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) | Synergist | 58 | ＜0.05 |
| 3(6) | Cisplatin | 46 | ＜0.01 |
| 4(6) | Carboplatin | 42 | ＜0.01 |
| 5(6) | Nedaplatin | 44 | ＜0.01 |
| 6(6) | Oxaliplatin | 46 | ＜0.01 |
| 7(6) | Synergist+cisplatin | 80 | ＜0.001 |
| 8(6) | Synergist+carboplatin | 76 | ＜0.001 |
| 9(6) | Synergist+nedaplatin | 74 | ＜0.001 |
| 10(6) | Synergist+oxaliplatin | 84 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used platinum-like compounds (cisplatin, carboplatin, nedaplatin, oxaliplatin) and synergist (amycin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 10, platinum-like compounds and synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Medicine is through intratumor injection.The dosage of metabolism class medicine and synergist is respectively 10mg/kg and 20mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 8) of index with inhibition rate of tumor growth.
Table 8
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 54±12 | |
| 2(6) | Platinum-like compounds | 44±10.4 | ＜0.05 |
| 3(6) | Procarbazine | 46±10.0 | ＜0.01 |
| 4(6) | Mitozolomide | 48±7.2 | ＜0.01 |
| 5(6) | Dacarbazine | 50±7.2 | ＜0.01 |
| 6(6) | The temozolomide | 40±6.0 | ＜0.01 |
| 7(6) | Platinum-like compounds+procarbazine | 24±5.2 | ＜0.001 |
| 8(6) | Platinum-like compounds+mitozolomide | 30±5.8 | ＜0.001 |
| 9(6) | Platinum-like compounds+dacarbazine | 28±6.4 | ＜0.001 |
| 10(6) | Platinum-like compounds+temozolomide | 22±4.0 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for platinum-like compounds (carboplatin) and used synergist (procarbazine, mitozolomide, dacarbazine, temozolomide), can show significant potentiation when use in conjunction.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used platinum-like compounds and various synergist were used separately, when use in conjunction, can show significant potentiation, growth all had the obvious suppression effect to kinds of tumor cells when various synergists were used separately, also can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of platinum-like compounds and/or any one or several 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.
With 90,90 and 80mg p (BHET-EOP/TC), BHET-EOP: TC is 80: 20) copolymer puts into first, second and the third three containers respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, add 10mg cisplatin, 10mg epirubicin, 10mg cisplatin and 10mg epirubicin respectively, shake up the back again and contain 10% cisplatin, 10% epirubicin, and the injectable microsphere of 10% cisplatin and 10% epirubicin with spray drying method for preparation.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 60-70 days, and the drug release time in the subcutaneous colon cancer of mice is more than 60 days.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that used adjuvant is 50: 50 p (BHET-EOP/TC), contains anticancer effective component and percentage by weight thereof and is:
(1) cisplatin of 5-30%, carboplatin or oxaliplatin;
(2) epirubicin of 5-30%, amycin, pirarubicin, valrubicin or epirubicin; Or
(3) combination of epirubicin, amycin, pirarubicin, valrubicin or the epirubicin of the cisplatin carboplatin of 5-30% or oxaliplatin and 5-30%.
Embodiment 3.
With 70mg molecular weight peak value is that the p (LAEG-EOP) of 10000-25000 puts into first, second and the third three containers respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in three containers, add 30mg oxaliplatin, 30mg amycin, 15mg oxaliplatin and 15mg amycin respectively, shake up the back contains 30% oxaliplatin, 30% amycin, 15% oxaliplatin and 15% amycin with spray drying method for preparation injectable microsphere again.Dried microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 60-65 days, and the drug release time in the subcutaneous pulmonary carcinoma of mice is about 60 days.
Embodiment 4
The method step that is processed into slow releasing injection is identical with embodiment 3, but the molecular weight peak value of different is p (LAEG-EOP) is 25000-45000, and contained anticancer effective component and percentage by weight thereof are:
(1) amycin of 5-30%, epirubicin or epirubicin; Or
(2) oxaliplatin of 5-30%, cisplatin or carboplatin; Or
(3) combination of the amycin of the oxaliplatin of 5-30%, cisplatin or carboplatin and 5-30%, epirubicin or epirubicin.
Embodiment 5.
With 70mg molecular weight peak value is that the p (DAPG-EOP) of 10000-25000 puts into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of mitozolomides and 10 milligrams of cisplatin, shake up the back contains 20% mitozolomide and 10% cisplatin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains 15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 75-85 days, and the drug release time in the subcutaneous cancer of pancreas of mice is about 75 days.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but the molecular weight peak value of different is used adjuvant is 25000-45000, contains anticancer effective component and is:
(1) cisplatin of 5-30%, carboplatin or oxaliplatin; Or
(2) mitozolomide of 5-30%, temozolomide, amycin, epirubicin or epirubicin; Or
(3) combination of the mitozolomide of the cisplatin of 5-30%, carboplatin or oxaliplatin and 5-30%, temozolomide, amycin, epirubicin or epirubicin.
Embodiment 7.
With 70mg molecular weight peak value is the p (BHDPT-EOP/TC of 10000-25000,80/20) puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg carboplatin and 10mg mitozolomide, shake up the back contains 20% carboplatin and 10% mitozolomide 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 70-75 days, and the drug release time in the subcutaneous esophageal carcinoma of mice is about 70 days.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but the molecular weight peak value of different is p (BHDPT-EOP/TC) is 40000-65000, BHDPT-EOP: TC position 50: 50, and contained anticancer effective component is:
(1) combination of the cisplatin of the mitozolomide of 10-20% or temozolomide and 10-25%, carboplatin or oxaliplatin; Or
(2) mitozolomide of the oxaliplatin of 5-30%, cisplatin or carboplatin and 10-20% or temozolomide's combination; Or
(3) combination of the epirubicin of the oxaliplatin of 5-30%, cisplatin or carboplatin and 5-20%, amycin or epirubicin.
Embodiment 9.
With 30mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) and 40mg molecular weight peak value is that p (DAPG-EOP) copolymer of 30000-45000 is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 30mg oxaliplatin, 30mg epirubicin, 15mg epirubicin and 15mg oxaliplatin respectively, shake up the back again and contain 30% oxaliplatin, 30% epirubicin, 15% epirubicin and 15% oxaliplatin injectable microsphere with spray drying method for preparation.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 60-65 days, and the drug release time in the subcutaneous rectal cancer of mice is about 65 days.
Embodiment 10.
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is in the polifeprosan to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 50: 50, and the molecular weight peak value of p (DAPG-EOP) is 40000-65000, and contained anticancer effective component is:
(1) epirubicin of 20-40% or amycin;
(2) cisplatin of 20-40%, carboplatin or nedaplatin;
The combination of the cisplatin of (3) 20% epirubicin or amycin and 20-40%, carboplatin or nedaplatin.
Embodiment 11
With 40mg molecular weight peak value is that (LAEG-EOP) of 20000-45000p and PLA copolymer that 30mg molecular weight peak value is 10000-25000 are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 5mg epirubicin and 25mg oxaliplatin, shake up the back contains 5% epirubicin and 25% oxaliplatin 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 60-65 days, is about 65 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 used adjuvant contains anticancer effective component to be for the molecular weight peak value is that (LAEG-EOP) and the molecular weight peak value of 40000-65000p is the PLA of 25000-45000:
(1) amycin of 10-20% or epirubicin; Or
(2) cisplatin of 10-20% or carboplatin;
(3) combination of the amycin of the cisplatin of 10-20% or carboplatin and 10-20%, epirubicin or epirubicin.
Embodiment 13
With 40mg molecular weight peak value is the polylactic acid (PLGA of 15000-35000,50: 50) and 30 molecular weight peak values be that (LAEG-EOP) of 20000-45000p puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg mitozolomide and 20mg amycin, shake up the back contains 10% mitozolomide and 20% amycin 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 60-70 days, is about 60 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step of processing sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is:
(1) amycin of 10-20% or epirubicin; Or
(2) mitozolomide of 10-20%; Or
(3) combination of the amycin of the mitozolomide of 10-20% and 10-20% or epirubicin.
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) p (BHET-EOP/TC), p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP);
B) p (BHET-EOP/TC), p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) are the combination of the polyglycolic acid of 10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA) with the molecular weight peak value, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) p (BHET-EOP/TC), p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and of the combination of molecular weight peak value for the polylactic acid (PLA) of 10000-30000,30000-60000,60000-100000 or 100000-150000;
D) combination of p (BHET-EOP/TC), p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and polifeprosan, wherein 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;
E) p (BHET-EOP/TC), p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and 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)], xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, the combination of 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) the 0.10.5% leaf mixes 20.
Embodiment 17
The method step of processing sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is:
(1) combination of the oxaliplatin of the amycin of 5-25%, epirubicin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin or actinomycin D and 10-40%, cisplatin, carboplatin or nedaplatin; Or
(2) combination of the amycin of the cisplatin of 5-30%, carboplatin or oxaliplatin and 10-40% or epirubicin;
(3) procarbazine of the cisplatin of 5-15%, carboplatin or oxaliplatin and 10-20%, mitozolomide, dacarbazine or temozolomide's combination; Or
(4) combination of the amycin of the oxaliplatin of 5-15% and 10-20% or epirubicin; Or
(5) combination of the amycin of 5-20% cisplatin and 10-20% or epirubicin; Or
(6) combination of the carboplatin of the amycin of 5-15% or epirubicin and 10-25% or nedaplatin.
Drug release characteristic (table 9) after embodiment 18 more different slow-release auxiliary material and the combination thereof
The method step of processing sustained-release implant is identical with embodiment 11, the drug release characteristic after more different slow-release auxiliary material and the combination thereof.First day release amount of medicine (external) surpass 20% of total amount and release for prominent.
Table 9
| Slow-release auxiliary material | Molecular weight | Medicine and content | Drug release time (my god) | Not prominent releasing arranged |
| (1)PLA | 10000-25000 | Cisplatin (20%) | 20 | Do not have |
| (2)PLGA(50/50) | 20000-40000 | Cisplatin (20%) | 26 | Do not have |
| (3) polifeprosan (20/80) | 20000-40000 | Cisplatin (20%) | 9 | Have |
| (4)p(LAEG-EOP) | 15000-35000 | Cisplatin (20%) | 68 | Do not have |
| (1)∶(4)＝1∶1 | Cisplatin (20%) | 64 | Do not have | |
| (2)∶(4)＝1∶1 | Cisplatin (20%) | 62 | Do not have | |
| (3)∶(4)＝1∶1 | Cisplatin (20%) | 60 | Do not have | |
| (5)PLA | 25000-45000 | Epirubicin (10%) | 25 | Do not have |
| (6)PLGA(75/25) | 10000-20000 | Epirubicin (10%) | 24 | Do not have |
| (7) polifeprosan (50/50) | 10000-20000 | Epirubicin (10%) | 10 | Have |
| (8)p(DAPG-EOP) | 35000-55000 | Epirubicin (40%) | 76 | Do not have |
| (5)∶(8)＝6∶4 | Epirubicin (40%) | 72 | Do not have | |
| (6)∶(8)＝7∶3 | Epirubicin (40%) | 64 | Do not have | |
| (7)∶(8)＝5∶5 | Epirubicin (40%) | 62 | Do not have |
Data show in the table 9, and when PLA, PLGA (50/50) and polifeprosan sugared acid anhydride family macromolecule polymer such as (20/80) were used separately, drug release was very fast, and wherein the drug release time of polifeprosan is 9-10 days and obviously prominent releasing arranged.P (LAEG-EOP) and p poly phosphate high molecular polymer releases such as (DAPG-EOP) slow (more than 60 days) and steadily, can alleviate caused prominent the releasing of the latter when share with sugared acid anhydride family macromolecule polymer such as PLA, PLGA, polifeprosans, but its steadily slowly drug release feature be not subjected to too big influence.
Drug release characteristic (table 10) after embodiment 19 more different slow-release auxiliary material and the combination thereof
The method step of processing sustained-release implant is identical with embodiment 11, the drug release characteristic after more different slow-release auxiliary material and the combination thereof.First day release amount of medicine (external) surpass 20% of total amount and release for prominent.
Table 10
| Slow-release auxiliary material | Molecular weight | Medicine and content | Drug release time (my god) | Not prominent releasing arranged |
| (1)PLA | 10000-25000 | Oxaliplatin (20%) | 22 | Do not have |
| (2)PLGA(50/50) | 20000-40000 | Oxaliplatin (20%) | 26 | Do not have |
| (3) polifeprosan (20/80) | 20000-40000 | Oxaliplatin (20%) | 11 | Have |
| (4)p(LAEG-EOP) | 15000-35000 | Oxaliplatin (20%) | 78 | Do not have |
| (1)∶(4)＝1∶1 | Oxaliplatin (20%) | 68 | Do not have | |
| (2)∶(4)＝1∶1 | Oxaliplatin (20%) | 64 | Do not have | |
| (3)∶(4)＝1∶1 | Oxaliplatin (20%) | 62 | Do not have | |
| (5)PLA | 25000-45000 | Amycin (10%) | 28 | Do not have |
| (6)PLGA(75/25) | 10000-20000 | Amycin (10%) | 26 | Do not have |
| (7) polifeprosan (50/50) | 10000-20000 | Amycin (10%) | 12 | Have |
| (8)p(DAPG-EOP) | 35000-55000 | Amycin (40%) | 68 | Do not have |
| (5)∶(8)＝6∶4 | Amycin (40%) | 64 | Do not have | |
| (6)∶(8)＝7∶3 | Amycin (40%) | 64 | Do not have | |
| (7)∶(8)＝5∶5 | Amycin (40%) | 62 | Do not have |
Data show in the table, and when PLA, PLGA (50/50) and polifeprosan sugared acid anhydride family macromolecule polymer such as (20/80) were used separately, drug release was very fast, and wherein the drug release time of polifeprosan is 10-12 days and obviously prominent releasing arranged.P (LAEG-EOP) and p poly phosphate high molecular polymer releases such as (DAPG-EOP) slow (more than 60 days) and steadily, can alleviate caused prominent the releasing of the latter when share with sugared acid anhydride family macromolecule polymer such as PLA, PLGA, polifeprosans, but its steadily slowly drug release feature be not subjected to too big influence.
Because the poly phosphate high molecular polymer costs an arm and a leg, this discovery can help reducing the cost of slow releasing preparation.This beyond thought discovery constitutes another major technique feature of the present invention.Because the poly phosphate high molecular polymer costs an arm and a leg, this discovery will help reducing the cost of slow releasing preparation, and improve its drug release feature.
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 (10)
1. the anti-cancer composition of loaded with platinum compound and synergist thereof is characterized in that anti-cancer composition is a slow releasing injection, is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is platinum-like compounds and synergist, the platinum-like compounds synergist be selected from tetrazine class medicine and or antitumor antibiotic;
Platinum-like compounds mainly is selected from oxaliplatin, cisplatin, carboplatin, nedaplatin;
Slow-release auxiliary material is selected from mixing or copolymer of phosphate ester high molecular polymer or phosphate ester high molecular polymer and dextranomer family macromolecule polymer:
The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that tetrazine class medicine is selected from imidazo tetrazine, imidazopyrazine, imidazopyridine, procarbazine, mitozolomide, dacarbazine or temozolomide.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that antitumor antibiotic is selected from bleomycin, daunomycin, aclarubicin, amycin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone, epirubicin, chlorine assistant star.
4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
(1) combination of the oxaliplatin of the amycin of 5-25%, epirubicin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin or actinomycin D and 10-40%, cisplatin, carboplatin or nedaplatin; Or
(2) combination of the amycin of the cisplatin of 5-30%, carboplatin or oxaliplatin and 10-40% or epirubicin;
(3) procarbazine of the cisplatin of 5-15%, carboplatin or oxaliplatin and 10-20%, mitozolomide, dacarbazine or temozolomide's combination; Or
(4) combination of the amycin of the oxaliplatin of 5-15% and 10-20% or epirubicin; Or
(5) combination of the amycin of 5-20% cisplatin and 10-20% or epirubicin; Or
(6) combination of the carboplatin of the amycin of 5-15% or epirubicin and 10-25% or nedaplatin.
Below all be weight percentage.
Slow-release auxiliary material is one of following or its combination:
A) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1,4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP));
B) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of the copolymer of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polyglycolic acid and hydroxyacetic acid, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polylactic acid;
D) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polifeprosan, wherein 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; Or
E) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1,4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, the combination of gelatin or white tempera.
5. 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; Or
F) glycerol, simethicone, propylene glycol or carbomer.
6. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is one of following:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
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.
7. be used to prepare sustained-release implant according to the described anticancer slow-release microsphere of claim 1.
8. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that anticancer effective component is:
(1) combination of the oxaliplatin of the amycin of 5-25%, epirubicin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin or actinomycin D and 10-40%, cisplatin, carboplatin or nedaplatin; Or
(2) combination of the amycin of the cisplatin of 5-30%, carboplatin or oxaliplatin and 10-40% or epirubicin;
(3) procarbazine of the cisplatin of 5-15%, carboplatin or oxaliplatin and 10-20%, mitozolomide, dacarbazine or temozolomide's combination; Or
(4) combination of the amycin of the oxaliplatin of 5-15% and 10-20% or epirubicin; Or
(5) combination of the amycin of 5-20% cisplatin and 10-20% or epirubicin; Or
(6) combination of the carboplatin of the amycin of 5-15% or epirubicin and 10-25% or nedaplatin.
Slow-release auxiliary material is selected from mixing or copolymer of phosphate ester high molecular polymer or phosphate ester high molecular polymer and dextranomer family macromolecule polymer.
9. the described anti-cancer sustained-released implantation agent according to claim 7, it is one of following to it is characterized in that slow-release auxiliary material is selected from:
A) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1,4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP));
B) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of the copolymer of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polyglycolic acid and hydroxyacetic acid, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polylactic acid;
D) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polifeprosan, wherein 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; Or
E) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1,4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, the combination of gelatin or white tempera.
10. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that effective ingredient in the slow-releasing anticarcinogen injection 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 pharmaceutical preparation of sarcoma or carcinosarcoma, in tumor or tumor week injection or place administration, in sustained release profile in vivo test more than 60 days.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102597779A (en) * | 2009-10-30 | 2012-07-18 | 学校法人庆应义塾 | Method for determination of sensitivity to anti-cancer ag |
| US9089540B2 (en) | 2008-01-31 | 2015-07-28 | Keio University | Method for determination of sensitivity to anti-cancer agent |
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2007
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9089540B2 (en) | 2008-01-31 | 2015-07-28 | Keio University | Method for determination of sensitivity to anti-cancer agent |
| CN102597779A (en) * | 2009-10-30 | 2012-07-18 | 学校法人庆应义塾 | Method for determination of sensitivity to anti-cancer ag |
| US8765713B2 (en) | 2009-10-30 | 2014-07-01 | Keio University | Method for determination of sensitivity to anti-cancer agent |
| CN102597779B (en) * | 2009-10-30 | 2016-03-23 | 学校法人庆应义塾 | The decision method of sensitivity to anti-cancer agent |
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