CN101011345A - Slow release injection containing platinum compound and alkylating agent - Google Patents
Slow release injection containing platinum compound and alkylating agent Download PDFInfo
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- CN101011345A CN101011345A CNA2007102001901A CN200710200190A CN101011345A CN 101011345 A CN101011345 A CN 101011345A CN A2007102001901 A CNA2007102001901 A CN A2007102001901A CN 200710200190 A CN200710200190 A CN 200710200190A CN 101011345 A CN101011345 A CN 101011345A
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Abstract
Disclosed is a slow release injection containing platinum-group compounds and/or alkylating agents, which comprises slow release microspheres and dissolvent, the slow release microspheres include platinum-group compounds selected from Tegafur, Capecittabine, Pemetrexed, Carboplatin or Gemcitabine, and/or alkylating agent anticancer 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 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 PLA, Polifeprosan, poly(dodecanedioic acid-tetradecanedioic acid) or poly(fumaric acid-sebacylic acid). The alkylating agent is selected from Carmustine, Nimustine, Fotemustine, Lomustine or bendamustine. 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 slow releasing injection that contains platinum-like compounds and/or alkylating agent and preparation method thereof, belong to technical field of pharmaceuticals.
(2) background technology
As class chemotherapeutics commonly used, platinum-like compounds has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its significant toxic reaction has greatly limited the extensive use of such medicine.
Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, referring to " placing carmustine adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).In addition, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fibrin and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).So, improve the restriction that dosage is subjected to general reaction again merely.Pharmaceutical topical application may solve the problem of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.
In addition, the DNA repair function in many tumor cells obviously increases after chemotherapy.The latter often causes the enhancing of tumor cell to the toleration of cancer therapy drug, consequently treatment failure.In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth " (referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; et al., Int J Cancer.2004; 111 (4): 484-93)).
Therefore, study both handled easilies, can keep high drug level at tumor by local can increase tumor cell again the preparation of the sensitivity of medicine and method are just become when previous important topic.
(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/or alkylating agent is provided, particularly, is a kind of slow releasing injection or sustained-release implant that contains platinum-like compounds and/or alkylating agent.
Platinum-like compounds has been widely used in the multiple entity tumor of treatment both at home and abroad as the new cancer therapy drug of a class.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.
Be effectively to improve tumor by local drug level, reduce the drug level of medicine in blood circulation, people have studied the drug sustained release system that contains platinum-like compounds, comprise that magnetic microsphere (sees: China Patent No. CN200410044113.8; CN200410009233.4), sustained-release micro-spheres (capsule) (see: China Patent No. CN200410023746.0) and nanoparticle (see: China Patent No. CN200410099292.5; CN200510002387.5) etc.Yet, solid sustained-release implant (China Patent No. ZL96115937.5; ZL97107076.8; CN200410084621.9), miniature implantation device (China Patent No. CN200510011250.6), sustained-release micro-spheres (the China Patent No. ZL00809160.9 of band radioactive source; U.S. Pat 5,651,986) all there are the problems such as operation, weak curative effect, complication be many that are not easy.In addition, the sensitivity that many entity tumors are drawn together platinum-like compounds to anticancer medicated bag is relatively poor, and is easy to generate drug resistance in therapeutic process.
The present invention finds that alkylating agent and platinum-like compounds share its antitumaous effect is strengthened mutually; In addition, the combination of platinum-like compounds and alkylating agent is made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduces the drug level of medicine in blood circulation, is reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The above unexpected main contents of the present invention of finding to constitute.
The present invention also 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., CancerResearch (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 40 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 40-100 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/or alkylating agent.
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 (Oxaliplatin, 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 can be 0.1%-50%, is good with 1%-30%, and 5%-20% is best
Alkylating agent comprises alestramustine (Alestramustine); atrimustine (Atrimustine); ambamustine (Ambamustine); nimustine (ACNU; Nimustine); bendamustine (Bendamustine); ditiomustine (Ditiomustine); bofumustine (Bofumustine); carmustine (carmustine; BCNU; carmustine); elmustine (Elmustine); ecomustine (Ecomustine); galamustine (Galamustine; GCNU); fotemustine (Fotemustine); estramustine (Estramustine); hemustine heCNU He (hemustine; heCNU); pentamustine (Pentamustine; Neptamustine); mannomustine (Mannomustine; MCNU); lomustine (lomustine; CCNU; lomustine; chlorethyl cyclohexyl nitrosourea); methyl lomustine (methyl-CCNU); semustine (Semustine; CH3-CCNU; Me-CCNU); Ranimustine (Ranimustine); prednimustine (Prednimustine); uracil mustard (Uramustine; UracilMustard); Sarmustine SarCNU (SarCNU); tauromustine (Tauromustine); tallimustine (Tallimustine); spiromustine (Spiromustine); streptozocin (streptozotocin; STZ); the appropriate azoles amine of miaow (mitozolomide, MTZ); a kind of or its combination in ifosfamide and the melphalan (melphalan).
Above alkylating agent also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
The preferred nimustine of above-mentioned alkylating agent, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, lomustine, methyl lomustine, the appropriate azoles amine of miaow, ifosfamide, melphalan.
The percentage by weight of above-mentioned alkylating agent in slow releasing agent is good from 0.1%-60% with 1%-50%, is best with 5%-30%.
The percentage by weight of antitumor drug in medicament slow-release microsphere is 0.5%-70%, is good with 2%-40%, is best with 5%-30%.When use in conjunction, the weight ratio of platinum-like compounds and platinum-like compounds alkylating agent 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 combination of the nimustine of the cisplatin of 1-40%, carboplatin, nedaplatin or oxaliplatin and 1-40%, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, lomustine, methyl lomustine, the appropriate azoles amine of miaow, ifosfamide or melphalan.
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.
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, PLA, the mixture or the copolymer of the mixture of 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-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.
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 are 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 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 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 (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be 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, 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.
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 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 of sustained-release implant and the same slow-releasing anticarcinogen injection of potentiation mode, the cancer therapy drug that place the associating of the chemical-therapy synergistic agent of the associating of the cancer therapy drug of the promptly local chemical-therapy synergistic agent of placing and other administration, the local cancer therapy drug of placing and other administration, part and the associating of the local chemical-therapy synergistic agent of placing.Wherein the cancer therapy drug of topical application and chemical-therapy synergistic agent 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 to make after can granulating respectively as cancer therapy drug and alkylating agent again and can plant dosage form, this process comprises at least granulates and is shaped.
The consumption of the anticancer effective component in the sustained-release implant can be with reference to slow releasing injection.But be preferably as follows:
(a) nimustine of 5-30%, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, lomustine, methyl lomustine, the appropriate azoles amine of miaow, ifosfamide or melphalan; Or
(b) cisplatin of 1-40%, carboplatin, nedaplatin or oxaliplatin; Or
(c) combination of the nimustine of the cisplatin of 1-40%, carboplatin, nedaplatin or oxaliplatin and 1-40%, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, lomustine, methyl lomustine, the appropriate azoles amine of miaow, ifosfamide or melphalan.
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 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 brain tumor cell 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 pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is 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.
The tumor-inhibiting action of test 3, platinum-like compounds and alkylating agent (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pulmonary carcinoma 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.Alkylating agent is 5mg/kg, and platinum-like compounds is 30mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 1) of index with inhibition rate of tumor growth.
Table 1
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Platinum-like compounds | 50 | ＜0.05 |
| 3(6) | Carmustine | 50 | ＜0.01 |
| 4(6) | Nimustine | 52 | ＜0.01 |
| 5(6) | Lomustine | 48 | ＜0.01 |
| 6(6) | Fotemustine | 52 | ＜0.01 |
| 7(6) | Platinum-like compounds+carmustine | 76 | ＜0.001 |
| 8(6) | Platinum-like compounds+nimustine | 74 | ＜0.001 |
| 9(6) | Platinum-like compounds+lomustine | 80 | ＜0.001 |
| 10(6) | Platinum-like compounds+fotemustine | 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) and alkylating agent (carmustine, nimustine, lomustine, fotemustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, platinum-like compounds and alkylating agent (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual colon 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.Alkylating agent is 5mg/kg, and platinum-like compounds is 20mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 2) of index with inhibition rate of tumor growth.
Table 2
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Platinum-like compounds | 54 | ＜0.05 |
| 3(6) | Carmustine | 50 | ＜0.05 |
| 4(6) | Nimustine | 48 | ＜0.05 |
| 5(6) | Fotemustine | 56 | ＜0.05 |
| 6(6) | Bendamustine | 52 | ＜0.01 |
| 7(6) | Platinum-like compounds+carmustine | 80 | ＜0.01 |
| 8(6) | Platinum-like compounds+nimustine | 86 | ＜0.01 |
| 9(6) | Platinum-like compounds+fotemustine | 80 | ＜0.01 |
| 10(6) | Platinum-like compounds+bendamustine | 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 (carboplatin) and alkylating agent (carmustine, nimustine, fotemustine, bendamustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, platinum-like compounds and alkylating agent (slow releasing injection)
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.Alkylating agent is 5mg/kg, and platinum-like compounds is 30mg/kg.The treatment back was measured the gross tumor volume size on the 30th 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) | Platinum-like compounds | 48 | ＜0.05 |
| 3(6) | Carmustine | 50 | ＜0.01 |
| 4(6) | Nimustine | 52 | ＜0.01 |
| 5(6) | Bendamustine | 48 | ＜0.01 |
| 6(6) | Fotemustine | 52 | ＜0.01 |
| 7(6) | Platinum-like compounds+carmustine | 78 | ＜0.001 |
| 8(6) | Platinum-like compounds+nimustine | 84 | ＜0.001 |
| 9(6) | Platinum-like compounds+bendamustine | 82 | ＜0.001 |
| 10(6) | Platinum-like compounds+fotemustine | 80 | ＜0.001 |
Above result shows, used platinum-like compounds (nedaplatin) and alkylating agent (carmustine, nimustine, bendamustine, fotemustine) all have the obvious suppression effect to the hepatocarcinoma growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6, platinum-like compounds and alkylating agent (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual tumor colli 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.Alkylating agent is 5mg/kg, and platinum-like compounds is 30mg/kg.The treatment back was measured the gross tumor volume size on the 30th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.The results are shown in Table 4.
Table 4
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Platinum-like compounds | 52 | ＜0.05 |
| 3(6) | Carmustine | 50 | ＜0.05 |
| 4(6) | Nimustine | 48 | ＜0.05 |
| 5(6) | Fotemustine | 56 | ＜0.05 |
| 6(6) | Bendamustine | 52 | ＜0.01 |
| 7(6) | Platinum-like compounds+carmustine | 88 | ＜0.01 |
| 8(6) | Platinum-like compounds+nimustine | 84 | ＜0.01 |
| 9(6) | Platinum-like compounds+fotemustine | 88 | ＜0.01 |
| 10(6) | Platinum-like compounds+bendamustine | 90 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells such as esophageal carcinoma, gastric cancer when this concentration is used separately for used platinum-like compounds (oxaliplatin) and alkylating agent (carmustine, nimustine, fotemustine, bendamustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, platinum-like compounds and alkylating agent (sustained-release implant)
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.Alkylating agent is 10mg/kg, and platinum-like compounds is 10mg/kg.The treatment back was measured the gross tumor volume size on the 30th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.The results are shown in Table 5.
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) | Carmustine | 58 | ＜0.01 |
| 4(6) | Nimustine | 56 | ＜0.01 |
| 5(6) | Bendamustine | 46 | ＜0.01 |
| 6(6) | Fotemustine | 50 | ＜0.01 |
| 7(6) | Platinum-like compounds+carmustine | 82 | ＜0.001 |
| 8(6) | Platinum-like compounds+nimustine | 80 | ＜0.001 |
| 9(6) | Platinum-like compounds+bendamustine | 88 | ＜0.001 |
| 10(6) | Platinum-like compounds+fotemustine | 86 | ＜0.001 |
Above result shows, used platinum-like compounds (oxaliplatin) and alkylating agent (carmustine, nimustine, bendamustine, fotemustine) all have the obvious suppression effect to the hepatocarcinoma growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, platinum-like compounds and alkylating agent (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual brain 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.Alkylating agent is 15mg/kg, and platinum-like compounds is 10mg/kg.The treatment back was measured the gross tumor volume size on the 30th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.The results are shown in Table 6.
Table 6
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Platinum-like compounds | 58 | ＜0.05 |
| 3(6) | Carmustine | 50 | ＜0.05 |
| 4(6) | Nimustine | 48 | ＜0.05 |
| 5(6) | Fotemustine | 56 | ＜0.05 |
| 6(6) | Bendamustine | 52 | ＜0.01 |
| 7(6) | Platinum-like compounds+carmustine | 78 | ＜0.01 |
| 8(6) | Platinum-like compounds+nimustine | 80 | ＜0.01 |
| 9(6) | Platinum-like compounds+fotemustine | 88 | ＜0.01 |
| 10(6) | Platinum-like compounds+bendamustine | 82 | ＜0.001 |
Above result shows, used platinum-like compounds (cisplatin) and alkylating agent (carmustine, nimustine, fotemustine, bendamustine) all have the obvious suppression effect to cerebral tumor growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction
Studies show that further alkylating agent such as carmustine, fotemustine, nimustine, lomustine, bendamustine or zeniplatin and cisplatin, carboplatin or oxaliplatin share has an obvious synergistic effect (P＜0.05) equally to cancer of pancreas, straight colon cancer, esophageal carcinoma, gastric cancer etc. are multiple.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used platinum-like compounds and/or various alkylating agent were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of any one platinum-like compounds and/or any one alkylating agent.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 80,80 and 80mg p (BHET-EOP/TC) (BHET-EOP: TC is 80: 20) copolymer put into first, second and the third three containers respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, add 20mg cisplatin, 20mg carmustine, 10mg cisplatin and 10mg carmustine respectively, shake up the back again and contain 20% cisplatin, 20% carmustine, and the injectable microsphere of 10% cisplatin and 10% carmustine 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 60-65 days, is more than 60 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 used adjuvant is 50: 50 p (BHET-EOP/TC), contains anticancer effective component and percentage by weight thereof and is:
(1) carmustine of 2-30% or nimustine;
(2) cisplatin of 5-40%, nedaplatin or carboplatin; Or
(3) combination of the carmustine of the cisplatin of 5-40%, nedaplatin or carboplatin and 1-20% or nimustine.
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 cisplatin, 30mg nimustine, 25mg cisplatin and 5mg nimustine respectively, shake up the back contains 30% cisplatin, 30% nimustine, 25% cisplatin and 5% nimustine 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 65-70 days, is about 65 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 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) carmustine of 5-30%, nimustine or bendamustine; Or
(2) cisplatin of 5-60%, carboplatin or oxaliplatin; Or;
(3) combination of the carmustine of the cisplatin of 5-50%, carboplatin or oxaliplatin and 5-30%, nimustine or bendamustine.
Embodiment 5.
With 60mg 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 30 milligrams of carboplatins and 10 milligrams of nimustines, shake up the back contains 30% carboplatin and 10% nimustine 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 60-65 days, is about 65 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 the molecular weight peak value of different is used adjuvant is 25000-45000, contains anticancer effective component and is:
(1) carboplatin of 5-30% or cisplatin; Or
(2) nimustine of 1-40% or fotemustine; Or
(3) combination of the nimustine of the carboplatin of 5-30% or cisplatin and 1-40% or fotemustine.
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 25mg nedaplatin and 5mg carmustine, shake up the back contains 25% nedaplatin and 5% carmustine 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 60-70 days, is about 65 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 the molecular weight peak value of different is p (BHDPT-EOP/TC) is 40000-65000, and BHDPT-EOP: TC is 50: 50, and contained anticancer effective component is:
(1) carmustine of 10-20%;
(2) cisplatin of 10-30%; Or
(3) combination of the cisplatin of the carmustine of 10-20% and 10-30%.
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 nimustine, 5mg oxaliplatin and 25mg nimustine respectively, shake up the back again and contain 30% oxaliplatin, 30% nimustine, 5% oxaliplatin and 25% nimustine 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, is about 65 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 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) oxaliplatin of 5-50%;
(2) nimustine of 10-30%;
(3) combination of the nimustine of the oxaliplatin of 5-40% and 5-30%.
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 10mg bendamustine and 20mg cisplatin, shake up the back contains 10% bendamustine and 20% cisplatin 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 60-75 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) bendamustine of 10-20%; Or
(2) carboplatin of 10-40%; Or
(3) combination of the carboplatin of the bendamustine of 10-20% and 10-30%.
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 carboplatin and 20mg carmustine, shake up the back contains 10% carboplatin and 20% carmustine 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) carmustine of 10-20% or nimustine; Or
(2) cisplatin of 10-20% or carboplatin; Or
(3) combination of the cisplatin of the carmustine of 10-20% or nimustine and 10-20% or carboplatin.
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) 0.1-0.5% polysorbas20.
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) carmustine of 5-30%, nimustine, fotemustine, lomustine or bendamustine; Or
(2) cisplatin of 5-30%, carboplatin, nedaplatin or oxaliplatin; Or
(3) combination of the carmustine of the cisplatin of 5-20% and 5-20%, nimustine, fotemustine, lomustine or bendamustine; Or
(4) combination of the carmustine of the carboplatin of 5-20% and 5-20%, nimustine, fotemustine, lomustine or bendamustine; Or
(5) combination of the carmustine of the nedaplatin of 5-20% or oxaliplatin and 5-20%, nimustine, fotemustine, lomustine or bendamustine.
Drug release characteristic (table 7) 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 7
| Slow-release auxiliary material | Molecular weight | Medicine and content | Drug release time (my god) | Not prominent releasing arranged |
| (1)PLA | 10000-25000 | Carmustine (20%) | 22 | Do not have |
| (2)PLGA(50/50) | 20000-40000 | Carmustine (20%) | 28 | Do not have |
| (3) polifeprosan (20/80) | 20000-40000 | Carmustine (20%) | 10 | Have |
| (4)p(LAEG-EOP) | 15000-35000 | Carmustine (20%) | 66 | Do not have |
| (1)∶(4) ＝1∶1 | Carmustine (20%) | 64 | Do not have | |
| (2)∶(4) ＝1∶1 | Carmustine (20%) | 62 | Do not have | |
| (3)∶(4) ＝1∶1 | Carmustine (20%) | 60 | Do not have | |
| (5)PLA | 25000-45000 | Cisplatin (10%) | 26 | Do not have |
| (6)PLGA(75/25) | 10000-20000 | Cisplatin (10%) | 25 | Do not have |
| (7) polifeprosan (50/50) | 10000-20000 | Cisplatin (10%) | 10 | Have |
| (8)p(DAPG-EOP) | 35000-55000 | Cisplatin (10%) | 70 | Do not have |
| (5)∶(8)＝6∶4 | Cisplatin (10%) | 68 | Do not have | |
| (6)∶(8)＝7∶3 | Cisplatin (10%) | 66 | Do not have | |
| (7)∶(8)＝5∶5 | Cisplatin (10%) | 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 8-10 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.Because the poly phosphate high molecular polymer costs an arm and a leg, this discovery can help reducing the cost of slow releasing preparation.
Drug release characteristic (table 8) 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 8
| Slow-release auxiliary material | Molecular weight | Medicine and content | Drug release time (my god) | Not prominent releasing arranged |
| (1)PLA | 20000-35000 | Nimustine (20%) | 24 | Do not have |
| (2)PLGA(50/50) | 30000-45000 | Nimustine (20%) | 32 | Do not have |
| (3) polifeprosan (20/80) | 20000-40000 | Nimustine (20%) | 12 | Have |
| (4)p(LAEG-EOP) | 25000-45000 | Nimustine (20%) | 70 | Do not have |
| (1)∶(4)＝1∶1 | Nimustine (20%) | 66 | Do not have | |
| (2)∶(4)＝1∶1 | Nimustine (20%) | 64 | Do not have | |
| (3)∶(4)＝1∶1 | Nimustine (20%) | 60 | Do not have | |
| (5)PLA | 25000-45000 | Carboplatin (10%) | 26 | Do not have |
| (6)PLGA(75/25) | 20000-40000 | Carboplatin (10%) | 26 | Do not have |
| (7) polifeprosan (50/50) | 20000-40000 | Carboplatin (10%) | 12 | Have |
| (8)p(DAPG-EOP) | 35000-55000 | Carboplatin (10%) | 68 | Do not have |
| (5)∶(8)＝6∶4 | Carboplatin (10%) | 64 | Do not have | |
| (6)∶(8)＝7∶3 | Carboplatin (10%) | 62 | Do not have | |
| (7)∶(8)＝5∶5 | Carboplatin (10%) | 60 | 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 8-10 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.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 will help reducing the cost of slow releasing preparation, and improve its drug release feature.
Because the poly phosphate high molecular polymer costs an arm and a leg, this discovery can help reducing the cost of slow releasing preparation.
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. anti-cancer medicine sustained-release injection that contains platinum-like compounds is characterized in that 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/or alkylating agent;
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:
Platinum-like compounds cisplatin, carboplatin, nedaplatin or oxaliplatin;
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 anti-cancer medicine sustained-release injection according to claim 1 is characterized in that alkylating agent is selected from carmustine, nimustine, carmustine, DNA-2114, grace nimustine, sulfatodiamino cyclohexane platinum, Spiroplatin, fotemustine, iproplatin, nimustine, fotemustine, lomustine, bendamustine, spiroplatin or zeniplatin.
3. the anti-cancer medicine sustained-release injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
(1) carmustine of 5-30%, nimustine, fotemustine, lomustine or bendamustine; Or
(2) cisplatin of 5-30%, carboplatin, nedaplatin or oxaliplatin; Or
(3) combination of the carmustine of the cisplatin of 5-20% and 5-20%, nimustine, fotemustine, lomustine or bendamustine; Or
(4) combination of the carmustine of the carboplatin of 5-20% and 5-20%, nimustine, fotemustine, lomustine or bendamustine; Or
(5) combination of the carmustine of the nedaplatin of 5-20% or oxaliplatin and 5-20%, nimustine, fotemustine, lomustine or bendamustine.
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.
4. the slow-releasing anticarcinogen injection according to claim 1 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.
5. 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.
6. be used to prepare sustained-release implant according to the described anticancer slow-release microsphere of claim 1.
7. the anti-cancer sustained-released implantation agent according to claim 6 is characterized in that anticancer effective component is:
(1) carmustine of 5-30%, nimustine, fotemustine, lomustine or bendamustine; Or
(2) cisplatin of 5-30%, carboplatin, nedaplatin or oxaliplatin; Or
(3) combination of the carmustine of the cisplatin of 5-20% and 5-20%, nimustine, fotemustine, lomustine or bendamustine; Or
(4) combination of the carmustine of the carboplatin of 5-20% and 5-20%, nimustine, fotemustine, lomustine or bendamustine; Or
(5) combination of the carmustine of the nedaplatin of 5-20% or oxaliplatin and 5-20%, nimustine, fotemustine, lomustine or bendamustine.
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.
8. the described anti-cancer sustained-released implantation agent according to claim 6, 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.
9. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that effective ingredient in the slow-releasing anticarcinogen injection is used to prepare the pharmaceutical preparation that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal 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 or rectum former or secondary.
10. according to claim 1 and 6 described slow-releasing anticarcinogen injection and slow releasing injection, it is characterized in that anticancer sustained-release agent in tumor or tumor week injection or place administration, in sustained release profile in vivo test more than 60 days.
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| CNA2007102001901A CN101011345A (en) | 2007-02-12 | 2007-02-12 | Slow release injection containing platinum compound and alkylating agent |
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|---|---|---|---|
| CNA2007102001901A CN101011345A (en) | 2007-02-12 | 2007-02-12 | Slow release injection containing platinum compound and alkylating agent |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11690806B2 (en) | 2018-05-24 | 2023-07-04 | Celanese Eva Performance Polymers Llc | Implantable device for sustained release of a macromolecular drug compound |
| US11690807B2 (en) | 2018-05-24 | 2023-07-04 | Celanese Eva Performance Polymers Llc | Implantable device for sustained release of a macromolecular drug compound |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11690806B2 (en) | 2018-05-24 | 2023-07-04 | Celanese Eva Performance Polymers Llc | Implantable device for sustained release of a macromolecular drug compound |
| US11690807B2 (en) | 2018-05-24 | 2023-07-04 | Celanese Eva Performance Polymers Llc | Implantable device for sustained release of a macromolecular drug compound |
| US11951215B2 (en) | 2018-05-24 | 2024-04-09 | Celanese Eva Performance Polymers Llc | Implantable device for sustained release of a macromolecular drug compound |
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