CN101283974A - Anticancer sustained-release gel injection and preparation method thereof - Google Patents
Anticancer sustained-release gel injection and preparation method thereof Download PDFInfo
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Abstract
A sustained-release gel injection comprises angiogenesis inhibitor and/or carmustine or nimustine, amphiphilic block copolymer and solvent, wherein the angiogenesis inhibitor is selected from SU5416, SU6668, alemtuzumab, axitinib, ibritumomab, bevacizumab, sutent, dasatinib, tarceva, vandetanib, gefitinib, lapatinib, lapatinib, sunitinib, sorafenib, endostatain, engiostatin, tositumomab, tipifarnib, sirolimus, cetuximab, ematinib, lenalidomide and thalidomide. The mixture of amphiphilic block copolymer and solvent has temperature sensitive gelatinization characteristic, is fluid liquid at room temperature, and automatically becomes non-flowing biodegradable water insoluble gel in warm-blooded animals. The preparation can locally slowly release at tumor foci and maintain effective drug concentration for several weeks to several months; and has effects on killing tumor cells, effectively inhibiting tumor angiogenesis, reducing systemic toxicity of drug, and enhancing the treatment effect of chemotherapy and radiotherapy (particularly radioactive particles).
Description
A kind of anticancer sustained-release gel injection and preparation method thereof
(1) technical field
The present invention relates to a kind of anticancer sustained-release gel injection and preparation method thereof, belong to technical field of pharmaceuticals.Particularly, this invention relate to a kind of can be with the stable partial sustained-release gel preparation of entity tumor that is released to of neovascularization inhibitor and/or stines medicine, be mainly sustained-release gel injection, this sustained-release gel preparation at room temperature is an aqueous solution, can be changed into semisolid or solid gel in the warm-blooded animal body.
(2) background technology
Cancer has become first killer of harm humans health.Though the treatment method for cancer is more, most patients' survival state not be improved significantly.In various treatments, chemotherapy remains one of selection commonly used.Though conventional chemotherapy is used for a long time, it is to therapeutic effect of entity tumor and uncertain, and its root problem is that traditional chemotherapy is difficult to realize active drug concentration and keep enough action time at tumor locus.Because the effect of chemotherapy depends on action time and the drug level of medicine at tumor locus, and conventional chemotherapy not only can not be realized above target, and but the diffusion and the transfer that also can stimulate tumor are gone back in the not only chemical sproof generation of induced tumor cell of the unsuitable chemotherapy of low dosage.
Chemotherapeutics topical application, particularly local sustained release can solve medicine to a certain extent in the action time of tumor locus and the problem of drug level, have become the research direction and the focus of current entity tumor chemotherapy.See Chinese patent (200510042234.3,03148624.X, 200510042236.2,96116041.1,97107078.4,200510042260.6,200510042261.0,200510042262.5,200510042263.X, 200410035923.7; 200410035926; 200410035924.1; 200410035927.5; 200410075840; 200410075839.8; ZL200410075837.9; 200410036098.2; 200510042430; 200510042428.3; 200510042434.9; 2005100434800; 200510043481.5; U.S. Pat 5651986, RE37410, ZL).Yet present biodegradable sustained-release preparation multi-purpose solid polymer such as polyglycolic acid, polylactic acid or its copolymer etc. are as slow-released carrier.Because the hydrophobic performance of this type of macromolecule carrier, these polymer need organic solvent in the slow releasing pharmaceutical preparation process, as dichloromethane, and chloroform, acetic acid or dimethyl formamide etc.For removing deleterious organic solvent, must be extensively dry.Therefore, in most of the cases, final slow releasing preparation mostly is solid shape (for example, microsphere, lamellar or bar-shaped), needs complicated implantation process, and easily causes tissue injury even tumor cell to plant or send out.In addition, organic solvent or high thermal process often cause many anticancer active ingredient degraded degeneration, and the solid implant can not effectively cover the irregular tumor chamber behind the tumor resection, therefore can not effectively remove postoperative residual tumor cell.
In addition, in the growth course of entity tumor, vessel growth plays great support effect for the growth diffusion of tumor cell and the conveying and the picked-up of nutrient substance.
Based on above consideration, research and develop new easy operating, determined curative effect, environmental protection and widely applicable anticancer slow release preparation just become 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 neovascularization inhibitor and/or stines medicine is provided, particularly, is a kind of slow releasing injection that contains neovascularization inhibitor and/or stines medicine.Can be with neovascularization inhibitor and/or the stable partial slow releasing injection of entity tumor that is released to of stines medicine, can not only prolong drug higher drug level can be kept release time, and the sensitivity of medicine can be increased, and environmental protection, gentleness, it is convenient to use, and therapeutic effect is obvious.Thereby effectively remove postoperative residual tumor cell in the irregular tumor chamber that the slow releasing injection of good fluidity can not only effectively cover behind the tumor resection, and postoperative hemostasis and the diffusion of prevention oncocyte are also had preventive effect preferably.
The present invention finds that the formed amphipathic copolymer of hydrophobicity polyester and hydrophilic polyglycol has unique temperature sensitivity, is aqueous solution at normal temperatures, can be changed into semisolid or solid gel at 33 ℃-40 ℃.When with can form water for injection gel after a certain amount of neovascularization inhibitor and/or stines medicine mix with slow-release function, this hydrogel is a transparent liquid under 5 ℃ of-25 ℃ of conditions, can be changed into immobilising semisolid or solid water gel about 36 ℃-37 ℃.
The present invention also finds, the hydrogel that contains neovascularization inhibitor and/or stines medicine can slowly discharge neovascularization inhibitor and/or stines medicine wherein, the cycle of its release can be a few days to the several months, depends primarily on hydrophobicity polyester and the weight ratio of hydrophilic polyglycol in the molecular weight of used polyester and Polyethylene Glycol and block configuration thereof, the amphipathic copolymer, the content of neovascularization inhibitor.
Find through lot of experiments, being suitable for polyester of the present invention can be, but be not limited to, the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), any one or multiple copolymer in the end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH).Serve as preferred wherein with PLA and PLGA, with PLGA for most preferably; The mean molecule quantity of above-mentioned polyester can be 100-36, and 000, wherein with 500-20,000 is preferred, 1000-10,000 for most preferably.
The mean molecule quantity of Polyethylene Glycol can be 200-26, and 000, wherein with 500-18,000 is preferred, 800-5,000 for most preferably.
The block configuration of polyester and Polyethylene Glycol can be, but be not limited to, polylactic acid-polyglycol-polylactic acid (PLA-PEG-PLA), copolymer of poly lactic acid-polyethylene glycol-lactic acid copolymer (PLGA-PEG-PLGA), polyethylene glycol-lactic acid-Polyethylene Glycol (PEG-PLA-PEG), polyethylene glycol-lactic acid copolymer-Polyethylene Glycol (PEG-PLGA-PEG), serve as preferred wherein with PLGA-PEG-PLGA and PEG-PLGA-PEG, with PLGA-PEG-PLGA for most preferably.
The mean molecule quantity of amphipathic copolymer can be 200-28, and 000, wherein with 300-16,000 is preferred, 300-8,000 for most preferably.
The weight ratio of polyester and Polyethylene Glycol can be 1-15 in the amphipathic copolymer: 15-1, but serve as preferred with 1-9: 9-1, with 1-6: 8-1 for most preferably.
The gelling temperature of amphipathic copolymer promptly becomes the not temperature of flow-gel, can be 30 ℃-40 ℃, serves as preferred with 35 ℃-38 ℃, with 36 ℃-37.5 ℃ for most preferably.
Neovascularization inhibitor is selected from one of following or combination: SU5416 among the present invention, SU6668, TNP-470, alemtuzumab (Campath, Alemtuzumab), A Xi is for Buddhist nun (Axitinib), Ai Buli holds in the palm (Zevalin, Ibritumomab), bevacizumab (A Wasiting, Avastin, Bevacimab), Bosutinib (Bosutinib, SKI-606), Dasatinib (sprycel, dasatinib), strategic point sieve is for Buddhist nun (Te Luokai, Erlotinib, Tarceva, erlotinib), ZD6474 (Vandetanib), gefitinib (Iressa, Gefitinib), the card knob is for Buddhist nun (canertinib), Lapatinib (Lapatinib), come appropriate for Buddhist nun (Lestaurtinib), rapamycin (Rapamycine), Rituximab (Mabthera, Rituxan, Rituximab), Marimastat (Marimastat), Mai Luota monoclonal antibody (Mylotarg, Gemtuzumab ozogamicin), the Marseille is for Buddhist nun (Masitinib), votaranib (Vatalanib), Mo Li is for Buddhist nun (Mubritinib), smooth degree is for Buddhist nun (Tandutinib), nilotinib (nilotinib), Ni La is for Buddhist nun (Neratinib), handkerchief Buddhist nun monoclonal antibody (Vectibix, Panitumumab), WAY-EKB 569 (Pelitinib), for drawing for the Buddhist nun (Telatinib), Herceptin (Herceptin, Trastuzumab), match comes former times cloth (celecoxib, Celebrex), rofecoxib (Refecoxib), Sutent (sunitinib, sutent), Sorafenib (sorafenib), Ta Situo monoclonal antibody (Tositumomab), En Duositating (Endostain), En Jisitating (Engiostatin), Te Situo monoclonal antibody (Bexxar, Tositumomab), Zarnestra (Tipifarnib), sirolimus (Sirolimus), Cetuximab (Erbitux, Cetuximab), imatinib mesylate (Ematinib mesylate), lenalidomide (Lenalidomide), Thalidomide (Thalidomide).
Above vasoinhibitor 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 content of neovascularization inhibitor in sustained-release gel is 0.01%-40%, is good with 1%-30%, is best with 2%-20%, more than all be weight percentage.
Above-mentioned stines medicine 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); a kind of or its combination in the spiromustine (Spiromustine).
Above stines medicine 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 lomustine of above-mentioned stines medicine, nimustine, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, methyl lomustine.
The percentage by weight of above-mentioned stines medicine in slow releasing agent is good from 0.1%-40% with 1%-30%, is best with 3%-20%.
The percentage by weight of vasoinhibitor and stines medicine can be from 1: 1-99 is to 1-10: 1.
Amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1200-1600, accounts for 15% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-6: 1.
Production technology and clinical practice requirement are depended in the packing of neovascularization inhibitor and/or stines medicine and sustained-release gel and application.Neovascularization inhibitor and/or stines medicine and sustained-release gel can separately or be organized (mixing) and close packing.Assembly packaging is stored in the unified packing box after referring to produce separately also packing, and hybrid packed finger neovascularization inhibitor and/or stines medicine are dispersed in the sustained-release gel.The neovascularization inhibitor and/or the stines medicine of local placement the (or injection) also can be used for chemotherapy and radiocurable potentiation, particularly with the radion use in conjunction of topical application, as, but be not limited to iodine 131, iodine 121, iodine 125 etc.
The preparation of sustained-release gel injection has several different methods, and following method is for illustrating unrestricted the present invention.
Method one:
A certain amount of amphipathic copolymer system is become the syringeability hydrogel with solution mixing system, be mixed into anticancer sustained-release gel injection with a certain amount of neovascularization inhibitor and/or stines medicine then, be i.e. patent medicine pattern behind XianCheng's glue.This kind method is fit to be easy to the medicine of hydrolysis degeneration.Can finish at workshop with mixing of neovascularization inhibitor and/or stines medicine, also its independent packing transportation can be stored, before clinical practice, finish.Finish at workshop and to help medical personnel operation.Made anticancer sustained-release gel injection is at-10 ℃ or the following 1-2 that stores.If before clinical practice, carry out mixing of neovascularization inhibitor and/or stines medicine and syringeability hydrogel, be preferably in injection and finished and be stored in the best freezing state of low temperature in preceding 1 to 3 day, heat up before using redissolve after use.
The content of amphipathic copolymer in the injectivity hydrogel can be 5% to 40%, but serves as preferred with 10% to 30%, and 15% to 28% for most preferably.
Method two:
Earlier a certain amount of neovascularization inhibitor and/or stines medicine are made medicaments injection, be mixed into anticancer sustained-release gel injection with a certain amount of amphipathic copolymer then, i.e. patent medicine pattern behind XianCheng's liquid.This kind method is applicable to poorly water-soluble but the medicine of good stability.Can finish at workshop with mixing of amphipathic copolymer, also its independent packing transportation can be stored, before clinical practice, finish.If before clinical practice, mix, be preferably in to inject and finished and be stored in the best freezing state of low temperature in preceding 1 to 3 day, use after intensification is redissolved before using.
The content of amphipathic copolymer in the injectivity hydrogel can be 5% to 40%, but serves as preferred with 10% to 30%, and 15% to 28% for most preferably.
Method three:
Earlier a certain amount of amphipathic copolymer is mixed with a certain amount of neovascularization inhibitor and/or stines medicine, add solvent then and make slow-releasing anticarcinogen injection.Gel process can be finished at workshop, also amphipathic copolymer and neovascularization inhibitor can separately or can be mixed back packing, transportation, store, and adds solvent before clinical practice.If before clinical practice, add solvent, be preferably in and fully mix before the injection and be stored in the best freezing state of low temperature, heat up before using and redissolve the back and use.
Particularly, the preparation method of slow-releasing anticarcinogen injection is selected from one of following:
(1) prepares amphipathic aqueous copolymers solution with solvent earlier, add a certain amount of neovascularization inhibitor then, become anticancer sustained-release gel injection behind the dissolving mixing.-10 ℃ or following storing for future use.Injection in redissolution, the body before using;
(2) prepare amphipathic aqueous copolymers solution and neovascularization inhibitor respectively, packing stores separately, to make anticancer sustained-release gel injection behind amphipathic aqueous copolymers solution and the abundant mixing of neovascularization inhibitor before the injection, be stored in low temperature or freezing state then, use the redissolution back of heating up before using;
(3) the preparation neovascularization inhibitor is made medicaments injection earlier, is mixed into anticancer sustained-release gel injection with a certain amount of amphipathic copolymer then.-10 ℃ or following storing for future use.Injection in the body after redissolving before using;
(4) prepare neovascularization inhibitor aqueous solution and amphipathic copolymer respectively, packing stores separately, before injection, will make anticancer sustained-release gel injection behind neovascularization inhibitor aqueous solution and the abundant mixing of amphipathic copolymer, be stored in low temperature or freezing state then, use the redissolution back of heating up before using;
(5) a certain amount of amphipathic copolymer is mixed with a certain amount of neovascularization inhibitor, add solvent then and make slow-releasing anticarcinogen injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Or
(6) a certain amount of amphipathic copolymer is mixed with a certain amount of neovascularization inhibitor, separately or mix back packing, transportation, store, before clinical practice, add solvent and fully mix and be stored in low temperature, heat up before using and redissolve the back and use to freezing state.
Above method just is illustrative rather than definitive thereof the present invention.The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation.Yet the composition of the kind of medicine and content and amphipathic copolymer and monomeric weight ratio are the gelling temperature of decision slow releasing injection and the key factor of drug release behavior, must just can obtain through a large amount of tests and creative work.The viscosity of sustained-release gel is 20cp-3000cp (5 ℃-30 ℃ time), preferred 100cp-2000cp (5 ℃-30 ℃ time), most preferably 100cp-1000cp (5 ℃-30 ℃ time).
The present invention finds that also when adding materials such as mannitol, sorbitol in the sustained-release gel, variation to a certain degree can take place for gelling temperature and drug releasing rate, and the material of this type of scalable drug releasing rate or gelling temperature is called regulator.The regulator that can add in the sustained-release gel can be, but be not limited to a kind of or its combination in various sugar or salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, the albumin glue.Regulator can be 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.Its weight ratio in sustained-release gel can be 0.01%-15.0%, because of specifically needing to decide.
Available neovascularization inhibitor and/or stines medicine are a lot of among the present invention, but are preferably as follows:
(1) SU5416 of 0.1%-40%, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, lenalidomide or Thalidomide;
(2) nimustine of 1%-40%, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, lomustine or methyl lomustine;
(3) SU5416 of 0.1%-10%, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, the nimustine of lenalidomide or Thalidomide and 1%-40%, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, the combination of lomustine or methyl lomustine;
(4) SU5416 of 10%-20%, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, the nimustine of lenalidomide or Thalidomide and 10%-20%, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, the combination of lomustine or methyl lomustine; Or
(5) SU5416 of 20%-30%, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, the nimustine of lenalidomide or Thalidomide and 5%-15%, carmustine, bendamustine, galamustine, Ranimustine, fotemustine, estramustine, Sarmustine SarCNU, semustine, the combination of lomustine or methyl lomustine.
The route of administration of slow releasing injection 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 tumor bed, tumor week injection or placement, selective arterial injection, blood vessel embolism, 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, cancer of biliary duct, 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.Except that above-mentioned primary tumo(u)r, its metastatic tumor of locating at brain, central nervous system, spinal cord, spinal column, kidney, adrenal gland, liver, incidence, oral cavity, thyroid, skin, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum etc. also makes indication of the present invention.
Slow releasing injection can be used for the tumor resection postoperative, can effectively control remaining oncocyte, thereby the may command postoperative recurrence; Can be used for the patient that a variety of causes can not excision; Can be used for controlling metastatic lesion, as lymph node etc.; Be used for end-stage patients; The control late complication; With the associating of its cancer therapy drug or method, as local injection associating, and the associating of radiotherapy or immunization therapy of cancer therapy drug and the chemotherapeutics of other administration.
The clinical practice dosage of neovascularization inhibitor depends on patient's concrete condition, comprises age, body weight, sex, tumor type, tumor locus, tumor size and number, treatment experience.Can be from 0.01 to 1000mg/kg body weight, be preferred with 0.1-800mg/kg, 0.1-500mg/kg is for most preferably.But for the sustained-release gel injection made from the crude drug of clinical whole body administration, its medication total amount can be the several times of its intravenous administration maximum tolerated dose even tens of times.
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.
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.
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).
By following test and embodiment technical method of the present invention is further described:
(4) specific embodiment
Slow-releasing anticarcinogen injection of the present invention can prepare with following method and step:
(1) prepares amphipathic aqueous copolymers solution with solvent earlier, add a certain amount of anticancer effective component (neovascularization inhibitor and/or stines medicine) then, become anticancer sustained-release gel injection behind the dissolving mixing.-10 ℃ or following storing for future use.Injection in redissolution, the body before using;
(2) prepare amphipathic aqueous copolymers solution and anticancer effective component respectively, packing stores separately, injection is preceding to be stored in low temperature or freezing state then with making anticancer sustained-release gel injection behind amphipathic aqueous copolymers solution and the abundant mixing of anticancer effective component, uses after intensification is redissolved before using;
(3) the preparation anticancer effective component is made medicaments injection earlier, is mixed into anticancer sustained-release gel injection with a certain amount of amphipathic copolymer then.-10 ℃ or following storing for future use.Injection in the body after redissolving before using;
(4) prepare anticancer effective component aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind anticancer effective component aqueous solution and the abundant mixing of amphipathic copolymer, be stored in low temperature or freezing state then before injection, use the redissolution back of heating up before using;
(5) a certain amount of amphipathic copolymer is mixed with a certain amount of anticancer effective component, add solvent then and make slow-releasing anticarcinogen injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Or
(6) a certain amount of amphipathic copolymer is mixed with a certain amount of anticancer effective component, separately or mix back packing, transportation, store, before clinical practice, add solvent and fully mix and be stored in low temperature, heat up before using and redissolve the back and use to freezing state.
The regulator that can add 0-15% in the above method.
Said method just is used for explanation but not limitation the present invention.Wherein method " (1) " is preferred.
Embodiment 1.
With 4,2,1 and 0.5g amphipathic nature block polymer (PLGA-PEG-PLGA) put into first, second, third, four containers of fourth respectively, then respectively to first, second, third and four containers of fourth in add 6,8,9 and 9.5 milliliters of waters of injection, make 40%, 20%, 10% and 5% hydrogel.
The molecular weight of Polyethylene Glycol is 800-1200 in the amphipathic nature block polymer, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6: 1.
Embodiment 2.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 1, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 28 ℃ (40%) and 35 ℃ (20%), and does not measure under 10 ℃-38 ℃ of the gelling temperatures of 10% and 5% hydrogel.
Embodiment 3.
With 4,2,1 and 0.5g amphipathic nature block polymer (PLGA-PEG-PLGA) put into first, second, third, four containers of fourth respectively, then respectively to first, second, third and four containers of fourth in add 6,8,9 and 9.5 milliliters of waters of injection, make 40%, 20%, 10% and 5% hydrogel.
The molecular weight of Polyethylene Glycol is 1200-1600 in the amphipathic nature block polymer, accounts for 15% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4: 1.
Embodiment 4.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 3, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 29 ℃ (40%) and 36 ℃ (20%), and does not measure under 10 ℃-38 ℃ of the gelling temperatures of 10% and 5% hydrogel.
Above result of the test shows, when gel solution concentration is lower than 5%-10%, and the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Embodiment 5.
(molecular weight of Polyethylene Glycol is 1500 among the amphipathic nature block polymer PLGA-PEG-PLGA, accounts for 15% of amphipathic nature block polymer weight with the 2.5g amphipathic nature block polymer; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 5: 1) put into container, add 7.5 milliliters of normal saline then, make 25% copolymer aquagel.Then average mark install to 5 fill respectively 400,200,100,20 and the container of 2mg gefitinib in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% gefitinib.Record its gelling temperature and be respectively 37.5 ℃, 36 ℃, 35 ℃, 34 ℃ and 33 ℃.
Embodiment 6.
(molecular weight of Polyethylene Glycol is 1500 among the amphipathic nature block polymer PLGA-PEG-PLGA, accounts for 15% of amphipathic nature block polymer weight with the 2.5g amphipathic nature block polymer; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 5: 1) put into container, add 7.5 milliliters of normal saline then, make 25% copolymer aquagel.Then average mark install to 5 fill respectively 400,200,100,20 and the container of 2mg Erlotinib in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% Erlotinib.Record its gelling temperature and be respectively 37 ℃, 36.5 ℃, 34 ℃, 33.5 ℃ and 32 ℃.
Embodiment 7.
Measure interior (subcutaneous) release cycle of mice body of the variable concentrations gefitinib and the Erlotinib of embodiment 5 and 6, found that be respectively 60 ± 8,55 ± 6,50 ± 6,45 ± 5 and 40 ± 4 days average time (estimating can measure the time in the blood) that discharges in 20%, 10%, 5%, the 1% and 0.1% gefitinib body; 20%, was respectively 62 ± 10,50 ± 8,48 ± 6,42 ± 8 and 38 ± 4 days the average time that discharges in the body of 10%, 5%, 1% and 0.1% Erlotinib.
Embodiment 8.
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, it is one of following that preferred anticancer sustained-release gel injection also comprises:
(1) the block copolymer aqueous solution of 10%-30% contains 0.005%-30% ZD6474 or nimustine;
(2) the block copolymer aqueous solution of 10%-30% contains 0.05%-30% sirolimus or carmustine;
(3) the block copolymer aqueous solution of 12%-28% contains 0.05%-30% lenalidomide or fotemustine;
(4) the block copolymer aqueous solution of 12%-26% contains 0.01%-25% gefitinib or fotemustine;
(5) the block copolymer aqueous solution of 11%-30% contains 0.01%-25% Lapatinib or votaranib;
(6) the block copolymer aqueous solution of 12%-30% contains 0.01%-25% WAY-EKB 569 or Sha Liduan;
(7) the block copolymer aqueous solution of 10%-32% contains 0.01%-25% fotemustine or imatinib;
(8) the block copolymer aqueous solution of 13%-28% contains 0.1%-25% galamustine or BMS 354825;
(9) the block copolymer aqueous solution of 14%-29% contains 0.1%-20% nimustine or Cl 1033;
(10) the block copolymer aqueous solution of 12%-28% contains 0.2%-22% Sorafenib or carmustine;
(11) the block copolymer aqueous solution of 15%-30% contains 0.25%-25% galamustine or ABX-EGF;
(12) the block copolymer aqueous solution of 10%-32% contains 0.5%-25% Marimastat or SU5416;
(13) the block copolymer aqueous solution of 11%-28% contains 0.75%-25%SU6668 or Sarmustine SarCNU;
(14) the block copolymer aqueous solution of 9%-32% contains 1%-28%TNP-470 or Ranimustine;
(15) the block copolymer aqueous solution of 10%-28% contains 1%-15% carmustine or Erlotinib;
(16) the block copolymer aqueous solution of 10%-25% contains 1%-18% nimustine or Zarnestra;
(17) the block copolymer aqueous solution of 10%-20% contains 5%-15% Lapatinib or estramustine;
(18) the block copolymer aqueous solution of 10%-28% contains 1%-10% BMS 354825 or estramustine;
(19) the block copolymer aqueous solution of 10%-28% contains 1%-15% gefitinib or carmustine; Or
(20) the block copolymer aqueous solution of 15%-25% contains 1%-10% carmustine or Sutent.
The gelling temperature of above-mentioned anticancer sustained-release gel injection is 32 ℃-37.5 ℃, and be 2-8 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1000, accounts for 15% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6: 1.
Embodiment 9
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, it is one of following that preferred anticancer sustained-release gel injection also comprises:
(1) the block copolymer aqueous solution of 20%-25% contains 0.5%-20% carmustine or Zarnestra;
(2) the block copolymer aqueous solution of 20%-26% contains 0.5%-10% sirolimus or nimustine;
(3) the block copolymer aqueous solution of 20%-28% contains 0.5%-20% lenalidomide or carmustine;
(4) the block copolymer aqueous solution of 20%-26% contains 0.1%-20% carmustine or Erlotinib;
(5) the block copolymer aqueous solution of 18%-30% contains 0.1%-20% Lapatinib or votaranib;
(6) the block copolymer aqueous solution of 18%-30% contains 0.1%-20% WAY-EKB 569 or nimustine;
(7) the block copolymer aqueous solution of 18%-28% contains 0.1%-20% carmustine or imatinib;
(8) the block copolymer aqueous solution of 18%-26% contains 0.5%-20% Ranimustine or Sarmustine SarCNU;
(9) the block copolymer aqueous solution of 18%-28% contains 0.5%-20% bendamustine or Cl 1033;
(10) the block copolymer aqueous solution of 18%-26% contains 0.6%-20% lomustine or Sutent;
(11) the block copolymer aqueous solution of 16%-26% contains 2%-20% Ranimustine or galamustine;
(12) the block copolymer aqueous solution of 16%-30% contains 5%-25% bendamustine or SU5416;
(13) the block copolymer aqueous solution of 16%-28% contains 5%-20%SU6668 or fotemustine;
(14) the block copolymer aqueous solution of 16%-25% contains the 10%-20% methyl lomustine;
(15) the block copolymer aqueous solution of 18%-28% contains 5%-15% gefitinib or Erlotinib;
(16) the block copolymer aqueous solution of 18%-25% contains 2%-18% ZD6474 or nimustine;
(17) the block copolymer aqueous solution of 18%-26% contains 5%-15% Lapatinib or WAY-EKB 569;
(18) the block copolymer aqueous solution of 18%-28% contains 5%-10% BMS 354825 or fotemustine;
(19) the block copolymer aqueous solution of 18%-28% contains 5%-15% gefitinib or nimustine; Or
(20) the block copolymer aqueous solution of 18%-25% contains 5%-10% Sorafenib or semustine.
The gelling temperature of above-mentioned anticancer sustained-release gel injection is 32 ℃-37.5 ℃, and be 2-8 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1500, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4: 1.
Embodiment 10.
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, preferred anticancer sustained-release gel injection contain concentration, become to be grouped into percentage by weight as follows:
(1) 1mg ZD6474 and 10mg nimustine, 300mg amphipathic nature block polymer and 700ul water for injection are formulated;
(2) 10mg sirolimus and nimustine, 280mg amphipathic nature block polymer and 720ul distilled water are formulated;
(3) 20mg lenalidomide or nimustine, 250mg amphipathic nature block polymer and 750ul normal saline are formulated;
(4) 40mg gefitinib or carmustine, 230mg amphipathic nature block polymer and 770ul water for injection are formulated;
(5) 50mg Lapatinib and carmustine, 220mg amphipathic nature block polymer and 780ul phosphate buffer are formulated;
(6) 70mg WAY-EKB 569 or nimustine, 260mg amphipathic nature block polymer and 740ul normal saline are formulated;
(7) 5mg carmustine and imatinib, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection are formulated;
(8) 1mg Ni Mosi or BMS 354825,260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water are formulated;
(9) 3mg Avastin or Cl 1033,230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline are formulated;
(10) 5mg Ni Mosi or Sutent, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection are formulated;
(11) 8mg Sorafenib, 260mg amphipathic nature block polymer and 740ul phosphate buffer are formulated;
(12) 10mg Marimastat and SU5416,200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline are formulated;
(13) 12.5mg SU6668 and lomustine, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline are formulated;
(14) 12.5mg lomustine and Sorafenib, 200mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection are formulated;
(15) 20m nimustine and Erlotinib, 220mg amphipathic nature block polymer and 780ul phosphate buffer are formulated;
(16) 50mg ZD6474 and Zarnestra, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline are formulated;
(17) 100mg Lapatinib and carmustine, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline are formulated;
(18) 150mg BMS 354825 and nimustine, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection are formulated;
(19) 200mg gefitinib or carmustine, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer are formulated; Or
(20) 250mg Sorafenib and fotemustine, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline are formulated.
Above amphipathic nature block polymer is Polyethylene Glycol-Vicryl Rapide-Polyethylene Glycol, and wherein the molecular weight of Polyethylene Glycol is 800-1200, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-6: 1.
Studies show that the gelling temperature of above-mentioned anticancer sustained-release gel injection is 30 ℃-37 ℃, be 2-8 week release time in the animal body.
Embodiment 11.
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, preferred anticancer sustained-release gel injection also comprises and followingly contains concentration, becomes to be grouped into and percentage by weight:
(1) 300mg amphipathic nature block polymer and the formulated sustained-release gel of 700ul water for injection contain 5% carmustine or nimustine and 1% alemtuzumab, A Xi replace Buddhist nun, ZD6474 or gefitinib for Buddhist nun, Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, sieve in distress combination;
(2) 280mg amphipathic nature block polymer and the formulated sustained-release gel of 720ul distilled water contain 10% carmustine or nimustine and 5% card knob and replace Buddhist nun, Lapatinib, come the appropriate Buddhist nun of replacing, rapamycin, Rituximab, Marimastat, Mai Luota monoclonal antibody, Marseille to replace Buddhist nun, votaranib, the upright Buddhist nun of replacing, smooth degree to draw the combination for Buddhist nun, handkerchief Buddhist nun monoclonal antibody or WAY-EKB 569 for Buddhist nun, nilotinib, Buddhist nun;
(3) 250mg amphipathic nature block polymer and the formulated sustained-release gel of 750ul normal saline contain 15% carmustine or nimustine and 10% smooth degree and draw for Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, replace and draw the combination that comes former times cloth, rofecoxib, Sutent, Sorafenib, Ta Situo monoclonal antibody, En Duositating, En Jisitating or Te Situo monoclonal antibody for Buddhist nun, Herceptin, match for Buddhist nun, nilotinib, Buddhist nun;
(4) 230mg amphipathic nature block polymer and the formulated sustained-release gel of 770ul water for injection contain the combination of 20% carmustine or nimustine and 5% Zarnestra, sirolimus, Cetuximab, imatinib mesylate, lenalidomide or Thalidomide;
(5) 300mg amphipathic nature block polymer and the formulated sustained-release gel of 700ul water for injection contain 2% carmustine or nimustine and 2% alemtuzumab, A Xi replace Buddhist nun, ZD6474 or gefitinib for Buddhist nun, Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, sieve in distress combination;
(6) 280mg amphipathic nature block polymer and the formulated sustained-release gel of 720ul distilled water contain 1% carmustine or nimustine and 0.5% card knob and replace Buddhist nun, Lapatinib, come the appropriate Buddhist nun of replacing, rapamycin, Rituximab, Marimastat, Mai Luota monoclonal antibody, Marseille to replace Buddhist nun, votaranib, the upright Buddhist nun of replacing, smooth degree to draw the combination for Buddhist nun, handkerchief Buddhist nun monoclonal antibody or WAY-EKB 569 for Buddhist nun, nilotinib, Buddhist nun;
(7) 250mg amphipathic nature block polymer and the formulated sustained-release gel of 750ul normal saline contain 1% carmustine or nimustine and 0.1% smooth degree and draw for Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, replace and draw the combination that comes former times cloth, rofecoxib, Sutent, Sorafenib, Ta Situo monoclonal antibody, En Duositating, En Jisitating or Te Situo monoclonal antibody for Buddhist nun, Herceptin, match for Buddhist nun, nilotinib, Buddhist nun; Or
(8) 230mg amphipathic nature block polymer and the formulated sustained-release gel of 770ul water for injection contain the combination of 0.5% carmustine or nimustine and 0.05% Zarnestra, sirolimus, Cetuximab, imatinib mesylate, lenalidomide or Thalidomide.
Studies show that the gelling temperature of above-mentioned anticancer sustained-release gel injection is 31 ℃-37.5 ℃, be 3-8 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.Amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, wherein the molecular weight of Polyethylene Glycol is that 1000-1800 is advisable, with 1200-1600 is preferred, account for 14% to 18% of amphipathic nature block polymer weight and be advisable, and be excellent with 15%-16%; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6-9: 1.
The therapeutic effect of anticancer sustained-release gel injection can further specify by following test and treatment embodiment:
Embodiment 12, contain tumor-inhibiting action in the body of neovascularization inhibitor and stines medicine (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumour cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±12 | |
| 2(6) | Neovascularization inhibitor | 46±6.2 | ＜0.05 |
| 3(6) | Carmustine | 48±6.0 | ＜0.01 |
| 4(6) | Nimustine | 46±6.2 | ＜0.01 |
| 5(6) | Fotemustine | 48±5.8 | ＜0.01 |
| 6(6) | Bendamustine | 46±6.2 | ＜0.01 |
| 7(6) | Neovascularization inhibitor+carmustine | 30±6.2 | ＜0.001 |
| 8(6) | Neovascularization inhibitor+nimustine | 24±6.8 | ＜0.001 |
| 9(6) | Neovascularization inhibitor+fotemustine | 18±4.4 | ＜0.001 |
| 10(6) | Neovascularization inhibitor+bendamustine | 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 neovascularization inhibitor (Lapatinib) and used stines medicine (carmustine, nimustine, fotemustine, bendamustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of embodiment 13, neovascularization inhibitor and stines medicine (slow releasing injection)
Used tumor cell comprises the cerebral tumor (CNS-1, C6,9L), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Neovascularization inhibitor (gefitinib) and stines medicine 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 | Gefitinib | Nimustine | Fotemustine | Bendamustine | Gefitinib+nimustine | Gefitinib+fotemustine | Gefitinib+bendamustine |
| CNS | 56％ | 52％ | 64％ | 60％ | 90％ | 84％ | 84％ |
| C6 | 52％ | 64％ | 64％ | 60％ | 90％ | 88％ | 92％ |
| SA | 46％ | 62％ | 56％ | 62％ | 86％ | 90％ | 90％ |
| BC | 44％ | 64％ | 54％ | 64％ | 88％ | 86％ | 80％ |
| BA | 48％ | 60％ | 62％ | 66％ | 82％ | 84％ | 90％ |
| LH | 54％ | 58％ | 62％ | 52％ | 90％ | 88％ | 86％ |
| PAT | 58％ | 50％ | 60％ | 52％ | 90％ | 88％ | 86％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used neovascularization inhibitor (gefitinib) and stines medicine (nimustine, fotemustine, bendamustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of embodiment 14, neovascularization inhibitor and stines medicine (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and slow releasing agent is through intratumor injection.Stines medicine dosage is 5mg/kg, and neovascularization inhibitor dosage is 15mg/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 | 80±10 | |
| 2(6) | Carmustine | 52±5.3 | ＜0.05 |
| 3(6) | Neovascularization inhibitor | 48±2.0 | ＜0.01 |
| 4(6) | Carmustine+neovascularization inhibitor | 32±2.4 | ＜0.001 |
| 5(6) | Nimustine | 46±3.0 | ＜0.01 |
| 6(6) | Nimustine+neovascularization inhibitor | 22±2.0 | ＜0.001 |
| 7(6) | Fotemustine | 36±3.8 | ＜0.01 |
| 8(6) | Fotemustine+neovascularization inhibitor | 20±2.6 | ＜0.001 |
| 9(6) | Bendamustine | 44±4.6 | ＜0.01 |
| 10(6) | Bendamustine+neovascularization inhibitor | 18±2.0 | ＜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 neovascularization inhibitor (rapamycin) and stines medicine (carmustine, nimustine, fotemustine, bendamustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of embodiment 15, neovascularization inhibitor and stines medicine (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 (neovascularization inhibitor or stines medicine) and therapeutic alliance group (neovascularization inhibitor and stines medicine).Medicine is through intratumor injection.Stines medicine dosage is 5mg/kg, and neovascularization inhibitor dosage is 25mg/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) | Neovascularization inhibitor | 40 | ＜0.05 |
| 3(6) | Lomustine | 32 | ＜0.01 |
| 4(6) | Bendamustine | 48 | ＜0.01 |
| 5(6) | Sarmustine SarCNU | 46 | ＜0.01 |
| 6(6) | Ranimustine | 44 | ＜0.01 |
| 7(6) | Neovascularization inhibitor+lomustine | 82 | ＜0.001 |
| 8(6) | Neovascularization inhibitor+bendamustine | 88 | ＜0.001 |
| 9(6) | Neovascularization inhibitor+Sarmustine SarCNU | 82 | ＜0.001 |
| 10(6) | Neovascularization inhibitor+Ranimustine | 78 | ＜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 neovascularization inhibitor (WAY-EKB 569) and stines medicine (bendamustine, lomustine, Sarmustine SarCNU, Ranimustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of embodiment 16, neovascularization inhibitor and stines medicine (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.Stines medicine dosage is 2.5mg/kg, and neovascularization inhibitor dosage is 20mg/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) | Neovascularization inhibitor | 42 | ＜0.05 |
| 3(6) | Lomustine | 46 | ＜0.01 |
| 4(6) | Sarmustine SarCNU | 30 | ＜0.01 |
| 5(6) | Ranimustine | 38 | ＜0.01 |
| 6(6) | Estramustine | 38 | ＜0.01 |
| 7(6) | Neovascularization inhibitor+lomustine | 82 | ＜0.001 |
| 8(6) | Neovascularization inhibitor+Sarmustine SarCNU | 80 | ＜0.001 |
| 9(6) | Neovascularization inhibitor+Ranimustine | 82 | ＜0.001 |
| 10(6) | Neovascularization inhibitor+estramustine | 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 neovascularization inhibitor (BMS 354825) and stines medicine (lomustine, Sarmustine SarCNU, Ranimustine, estramustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of embodiment 17, neovascularization inhibitor and stines medicine
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Slow releasing agent is through intratumor injection.Stines medicine dosage is 25mg/kg, and neovascularization inhibitor dosage is 5mg/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) | Neovascularization inhibitor | 40 | ＜0.05 |
| 3(6) | Bendamustine | 42 | ＜0.05 |
| 4(6) | Lomustine | 40 | ＜0.05 |
| 5(6) | Sarmustine SarCNU | 54 | ＜0.05 |
| 6(6) | Ranimustine | 60 | ＜0.01 |
| 7(6) | Neovascularization inhibitor+bendamustine | 82 | ＜0.01 |
| 8(6) | Neovascularization inhibitor+lomustine | 74 | ＜0.01 |
| 9(6) | Neovascularization inhibitor+Sarmustine SarCNU | 80 | ＜0.01 |
| 10(6) | Neovascularization inhibitor+Ranimustine | 78 | ＜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 neovascularization inhibitor (Zarnestra) and stines medicine (bendamustine, lomustine, Sarmustine SarCNU, Ranimustine), can show significant potentiation when use in conjunction.
Embodiment 18, contain tumor-inhibiting action in the body of neovascularization inhibitor and stines medicine (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 following 10 groups (seeing Table 7).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Carmustine dosage is 2mg/kg, and all the other are 0.1mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 30th day.
Table 7
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 64±12 | |
| 2(6) | Carmustine | 36±5.8 | ＜0.05 |
| 3(6) | Alemtuzumab | 50±8.0 | ＜0.01 |
| 4(6) | The Ai Buli holder | 46±6.2 | ＜0.01 |
| 5(6) | SU5416 | 48±7.8 | ＜0.01 |
| 6(6) | SU6668 | 48±6.2 | ＜0.01 |
| 7(6) | Alemtuzumab+carmustine | 32±5.2 | ＜0.001 |
| 8(6) | Ai Buli holder+carmustine | 22±5.8 | ＜0.001 |
| 9(6) | The SU5416+ carmustine | 18±4.0 | ＜0.001 |
| 10(6) | The SU6668+ carmustine | 26±4.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for carmustine and neovascularization inhibitor (alemtuzumab, Ai Buli holder, SU5416, SU6668), can show significant potentiation when use in conjunction.
Embodiment 19, contain tumor-inhibiting action in the body of neovascularization inhibitor and stines medicine
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 following 10 groups (seeing Table 8).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Carmustine dosage is 4mg/kg, and all the other are 0.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 8) on the 30th day.
Table 8
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 64±11 | |
| 2(6) | Carmustine | 40±6 | ＜0.05 |
| 3(6) | Bevacizumab | 52±8.0 | ＜0.05 |
| 4(6) | Bosutinib | 46±6.2 | ＜0.05 |
| 5(6) | Dasatinib | 48±7.2 | ＜0.01 |
| 6(6) | Strategic point sieve is for the Buddhist nun | 42±8.2 | ＜0.01 |
| 7(6) | Bevacizumab+carmustine | 26±5.6 | ＜0.001 |
| 8(6) | Bosutinib+carmustine | 20±5.0 | ＜0.001 |
| 9(6) | Dasatinib+carmustine | 22±4.0 | ＜0.001 |
| 10(6) | Strategic point sieve is for Buddhist nun+carmustine | 16±3.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction for carmustine and neovascularization inhibitor (bevacizumab, Bosutinib, Dasatinib, sieve in distress are for the Buddhist nun).
Embodiment 20, contain tumor-inhibiting action in the body of neovascularization inhibitor and stines medicine
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 following 10 groups (seeing Table 9).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Carmustine dosage is 6mg/kg, and all the other are 1.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 9) on the 30th day.
Table 9
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±14 | |
| 2(6) | Carmustine | 30±6 | ＜0.05 |
| 3(6) | ZD6474 | 44±8.8 | ＜0.05 |
| 4(6) | Gefitinib | 42±8.2 | ＜0.05 |
| 5(6) | The card knob is for the Buddhist nun | 46±7.8 | ＜0.01 |
| 6(6) | Lapatinib | 50±8.8 | ＜0.01 |
| 7(6) | ZD6474+carmustine | 22±5.6 | ＜0.001 |
| 8(6) | Gefitinib+carmustine | 24±5.8 | ＜0.001 |
| 9(6) | The card knob is for Buddhist nun+carmustine | 20±4.0 | ＜0.001 |
| 10(6) | Lapatinib+carmustine | 18±3.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction for carmustine and neovascularization inhibitor (ZD6474, gefitinib, card knob are for Buddhist nun, Lapatinib).
Embodiment 21, contain tumor-inhibiting action in the body of neovascularization inhibitor and stines medicine
With the rat is subjects, with 2 * 10
5Individual renal 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 10).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Carmustine dosage is 8mg/kg, and all the other are 2.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 10) on the 30th day.
Table 10
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 54±14 | |
| 2(6) | Carmustine | 32±8 | ＜0.05 |
| 3(6) | The Mai Luota monoclonal antibody | 44±8.8 | ＜0.05 |
| 4(6) | The Marseille is for the Buddhist nun | 42±8.2 | ＜0.05 |
| 5(6) | Smooth degree is for the Buddhist nun | 46±7.8 | ＜0.01 |
| 6(6) | Handkerchief Buddhist nun monoclonal antibody | 48±8.8 | ＜0.01 |
| 7(6) | Mai Luota monoclonal antibody+carmustine | 26±5.6 | ＜0.001 |
| 8(6) | The Marseille is for Buddhist nun+carmustine | 18±5.8 | ＜0.001 |
| 9(6) | Smooth degree is for Buddhist nun+carmustine | 24±4.0 | ＜0.001 |
| 10(6) | Handkerchief Buddhist nun monoclonal antibody+carmustine | 18±3.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction for carmustine and neovascularization inhibitor (Buddhist nun, handkerchief Buddhist nun monoclonal antibody are replaced for Buddhist nun, smooth degree in Mai Luota monoclonal antibody, Marseille).
Embodiment 22, contain tumor-inhibiting action in the body of neovascularization inhibitor and stines medicine
With the rat is subjects, with 2 * 10
5Individual oophoroma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 11).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Carmustine dosage is 10mg/kg, and all the other are 2mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 11) on the 30th day.
Table 11
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 56±14 | |
| 2(6) | Nimustine | 30±8 | ＜0.05 |
| 3(6) | Sutent | 40±8.8 | ＜0.05 |
| 4(6) | Sorafenib | 44±8.2 | ＜0.05 |
| 5(6) | Zarnestra | 48±7.8 | ＜0.01 |
| 6(6) | Sirolimus | 46±8.8 | ＜0.01 |
| 7(6) | Sutent+nimustine | 22±5.6 | ＜0.001 |
| 8(6) | Sorafenib+nimustine | 16±5.8 | ＜0.001 |
| 9(6) | Zarnestra+nimustine | 22±4.0 | ＜0.001 |
| 10(6) | Sirolimus+nimustine | 20±3.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for carmustine and neovascularization inhibitor (Sutent, Sorafenib, Zarnestra, sirolimus), can show significant potentiation when use in conjunction.
Embodiment 23, contain tumor-inhibiting action in the body of neovascularization inhibitor and stines medicine
With the rat is subjects, with 2 * 10
5Individual oophoroma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 12).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Carmustine dosage is 1mg/kg, and all the other are 0.2mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 12) on the 30th day.
Table 12
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 52±14 | |
| 2(6) | Carmustine | 32±8.4 | ＜0.05 |
| 3(6) | Sutent | 42±8.8 | ＜0.05 |
| 4(6) | Sorafenib | 40±8.2 | ＜0.05 |
| 5(6) | Zarnestra | 38±6.8 | ＜0.01 |
| 6(6) | Sirolimus | 36±8.8 | ＜0.01 |
| 7(6) | Sutent+carmustine | 24±5.6 | ＜0.001 |
| 8(6) | Sorafenib+carmustine | 18±5.8 | ＜0.001 |
| 9(6) | Zarnestra+carmustine | 20±4.0 | ＜0.001 |
| 10(6) | Sirolimus+carmustine | 16±3.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for carmustine and neovascularization inhibitor (Sutent, Sorafenib, Zarnestra, sirolimus), 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 neovascularization inhibitor and various stines medicine 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 stines medicines were used separately, also can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of neovascularization inhibitor and/or any one or several stines medicine.The medicine that contains above effective ingredient can be made into sustained-release gel injection and has overcome the deficiencies in the prior art, has beyond thought effect.
Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
The present invention disclosed and the protection the content see claim.
Claims (10)
1. an anticancer sustained-release gel injection is characterized in that anticancer sustained-release gel injection contains the anticancer effective component of effective anticancer, amphipathic nature block polymer, solvent and a certain amount of drug release regulator; Wherein, the mixture of amphipathic nature block polymer and solvent has temperature sensitive gelling characteristics, in being lower than the environment of body temperature, be flowable liquid, can be transformed into the water-insoluble gel of immobilising and biodegradable absorption in the warm-blooded animal body automatically, the latter can slowly discharge contained anticancer effective component and keeps the thoughtful several months of active drug concentration numbers at tumor by local; The viscosity of slow-releasing anticarcinogen injection is 10cp-3000cp (5 ℃-30 ℃ time), wherein,
Anticancer effective component is neovascularization inhibitor and/or stines medicine;
Amphipathic nature block polymer is selected from polylactic acid poly ethylene glycol polylactic acid, Vicryl Rapide Polyethylene Glycol Acetic acid, hydroxy-, bimol. cyclic ester lactide, Polyethylene Glycol polylactic acid poly ethylene glycol or Polyethylene Glycol Acetic acid, hydroxy-, bimol. cyclic ester lactide Polyethylene Glycol;
Solvent is selected from distilled water, water for injection, physiology towards liquid, cell culture fluid, body fluid, tissue fluid, buffer, phosphate buffer.Wherein, the percentage ratio of solvent in the hydrogel of amphipathic nature block polymer and solvent composition is 60%99%;
The drug release regulator is selected from a kind of or its combination in mannitol, sorbitol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, the albumin glue, and the drug release regulator is 015% at the percentage by weight of slow releasing injection.
2. the anticancer sustained-release gel injection according to claim 1 is characterized in that the mean molecule quantity of polylactic acid or Vicryl Rapide is selected from 500-5000,5000-20000,20000-30000; The mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is selected from 10-15 in the Vicryl Rapide: 1,5-10: 1 or 1-5: 1; The mean molecule quantity of Polyethylene Glycol is selected from 200-2000,2000-10000,10000-20000.
3. the anticancer sustained-release gel injection according to claim 1, the weight ratio that it is characterized in that neovascularization inhibitor and stines medicine is 1: 1-99 is to 1-10: 1.
4. the anticancer sustained-release gel injection according to claim 1 is characterized in that the anticancer effective component of anticancer sustained-release gel injection is:
(1) neovascularization inhibitor of 0.1%-40%;
(2) stines medicine of 1%-40%;
(3) combination of the stines medicine of the neovascularization inhibitor of 0.1%-10% and 1%-40%;
(4) combination of the stines medicine of the neovascularization inhibitor of 10%-20% and 10%-20%; Or
(5) combination of the stines medicine of the neovascularization inhibitor of 20%-30% and 5%-15%.
Amphipathic nature block polymer is a Vicryl Rapide Polyethylene Glycol Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1,200-1, and 400, account for 15% of amphipathic nature block polymer weight; The mean molecule quantity of Vicryl Rapide is selected from 5,000-8, and 000, in the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4: 1.
Below all be weight percentage.
5. the anticancer sustained-release gel injection according to claim 1 is characterized in that the anticancer effective component of anticancer sustained-release gel injection is:
(1) neovascularization inhibitor of 0.1%-40%;
(2) stines medicine of 1%-40%;
(3) combination of the neovascularization inhibitor of 0.1%-10% and 1%40% stines medicine;
(4) combination of the neovascularization inhibitor of 10%-20% and 10%20% stines medicine; Or
(5) combination of the neovascularization inhibitor of 20%-30% and 5%15% stines medicine.
Amphipathic nature block polymer is a Vicryl Rapide Polyethylene Glycol Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1400-1600, accounts for 15% of amphipathic nature block polymer weight; The mean molecule quantity of Vicryl Rapide is selected from 8,000-10, and 000, in the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 5-6: 1.
Below all be weight percentage.
6. according to claim 1,3, anticancer sustained-release gel injection described in 4 and 5 is characterized in that neovascularization inhibitor mainly is selected from SU5416, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, a kind of or its combination of lenalidomide and Thalidomide.
7. according to claim 1; 3; anticancer sustained-release gel injection described in 4 and 5 is characterized in that stines medicine is selected from alestramustine; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; tallimustine; one of spiromustine or its combination.
8. the anticancer sustained-release gel injection according to claim 1 is characterized in that the anticancer effective component of described anticancer sustained-release gel injection is:
(1) SU5416 of 0.1%-40%, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, lenalidomide or Thalidomide;
(2) carmustine of 1%-40% or nimustine; Or
(3) SU5416 of 0.1%-30%, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, the carmustine of lenalidomide and Thalidomide and 1%-30% or the combination of nimustine;
Amphipathic nature block polymer is a Vicryl Rapide Polyethylene Glycol Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1400, accounts for 15% of amphipathic nature block polymer weight; The mean molecule quantity of Vicryl Rapide is selected from 5,000, and in the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4: 1.
The mannitol that can add 0-15% in the above method, more than all be weight percentage.
9. the anticancer sustained-release gel injection according to claim 1 is characterized in that the anticancer effective component of described anticancer sustained-release gel injection is:
(1) SU5416 of 0.1%-20%, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, lenalidomide or Thalidomide;
(2) carmustine of 3%-20% or nimustine; Or
(3) SU5416 of 0.1%-20%, SU6668, TNP-470, alemtuzumab, A Xi is for the Buddhist nun, the Ai Buli holder, bevacizumab, Bosutinib, Dasatinib, strategic point sieve is for the Buddhist nun, ZD6474, gefitinib, the card knob is for the Buddhist nun, Lapatinib, come appropriate for the Buddhist nun, rapamycin, Rituximab, Marimastat, the Mai Luota monoclonal antibody, the Marseille is for the Buddhist nun, votaranib, Mo Li is for the Buddhist nun, smooth degree is for the Buddhist nun, nilotinib, Ni La is for the Buddhist nun, handkerchief Buddhist nun monoclonal antibody, WAY-EKB 569, for drawing for the Buddhist nun, Herceptin, match comes former times cloth, rofecoxib, Sutent, Sorafenib, the Ta Situo monoclonal antibody, En Duositating, En Jisitating, the Te Situo monoclonal antibody, Zarnestra, sirolimus, Cetuximab, imatinib mesylate, the carmustine of lenalidomide and Thalidomide and 1%-20% or the combination of nimustine.
Amphipathic nature block polymer is a Vicryl Rapide Polyethylene Glycol Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1500, accounts for 15% of amphipathic nature block polymer weight; The mean molecule quantity of Vicryl Rapide is selected from 8,000, and in the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6: 1.
Below all be weight percentage.
The sorbitol that can add 0-15% in the above method.
10. the anticancer sustained-release gel injection according to claim 1, it is characterized in that anticancer sustained-release gel injection is used for preparation treatment cancer for coming from 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, colon, former or the cancer of transfer or the pharmaceutical preparation of sarcoma or carcinosarcoma of rectum, comprise 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, the retinoblastoma of eyes, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, the He Jiejin lymphoma, non_hodgkin lymphoma, nonsmall-cell lung cancer.
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