CN101283975A - Anticancer sustained-release gel injection containing neonatal blood vessel inhibitor - Google Patents
Anticancer sustained-release gel injection containing neonatal blood vessel inhibitor Download PDFInfo
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Abstract
A sustained-release gel injection comprises angiogenesis inhibitor, amphiphilic block copolymer, solvent and release regulator, wherein the mixture of amphiphilic block copolymer and solvent has temperature sensitive gelatinization characteristic, and can automatically become non-flowing degradable water insoluble gel, which can locally and slowly release drug at tumor foci for several weeks to several months, after injection into body. The preparation can be injected into or around tumor for treating solid tumors at different stages and metastatic tumors with remarkably reduced systemic toxicity of drug. The angiogenesis inhibitor is selected from alemtuzumab,ibritumomab, bevacizumab, rituximab, gemtuzumab ozogamicin, panitumumab, trastuzumab, celebrex, refecoxib, tositumomab, endostatain, engiostatin, toxitumomab, and cetuximab. The preparation has effects of controlling residual tumor cell relapse after operation and tumor can not be excised via operation, controlling complications at late stage of tumor, and enhancing treatment effect of chemotherapy and radiotherapy (particularly radioactive particles).
Description
(1) technical field
The present invention relates to a kind of anticancer sustained-release gel injection that contains neovascularization inhibitor, belong to technical field of pharmaceuticals.Particularly, this invention relate to a kind of can with neovascularization inhibitor and or the stable partial sustained-release gel preparation of entity tumor that is released to of sustained-release micro-spheres, be mainly sustained-release gel injection, this sustained-release gel preparation at room temperature is an aqueous solution, in the warm-blooded animal body, can be changed into semisolid or solid gel, wherein, neovascularization inhibitor partly or entirely is wrapped in the sustained-release micro-spheres, and the neovascularization inhibitor that sustained-release micro-spheres is forgiven further extends to the several months at tumor by local slow release time.
(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 can not realize active drug concentration and keeps enough action time at tumor locus.Because the effect of chemotherapy not only depends on the sensitivity of medicine, medicine is even more important at the action time and the drug level of 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 have become the research direction and the focus of current entity tumor chemotherapy, see Chinese patent (ZL200410035923.7; 200410035926; 200410035924.1; 200410035927.5; 200410075840; 200410075839.8; ZL200410075837.9; 200410036098.2; 200510042430; 200510042428.3; 200510042434.9; 2005100434800; 200510043481.5).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.The solid implant can not effectively cover the irregular tumor chamber behind the tumor resection, therefore can not effectively remove postoperative residual tumor cell, can not effectively control postoperative recurrence.In addition, organic solvent or high thermal process often cause many anticancer active ingredient degraded degeneration.
Go out outside this, existing slow releasing agent is prominent to be released obviously, and the release cycle is shorter, and to poky tumor, the cytosis that particularly is in the G0 phase is undesirable.
Therefore, new easy operating, environmental protection, the long-acting and widely applicable slow releasing preparation of research and development just becomes present problem demanding prompt solution.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer medicine slow-release preparation containing that contains neovascularization inhibitor is provided, particularly, is a kind of sustained-release gel injection that contains neovascularization inhibitor.Neovascularization inhibitor wherein with micropowder and or the form of sustained-release micro-spheres be present in the sustained-release gel, 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; Thereby effectively remove postoperative residual tumor cell in the irregular tumor chamber that good fluidity can not only make slow releasing agent effectively cover behind the tumor resection, and postoperative hemostasis and the diffusion of prevention oncocyte are also had preventive effect preferably.The existence of semisolid or solid gel, particularly sustained-release micro-spheres can not only prolong drug release time (several months), also can keep higher drug level, and can increase the sensitivity of medicine; This anticancer medicine slow-release preparation containing not only has good drug release feature, and environmental protection, zest are little, and it is convenient to use, and effect is obvious.
Studies show that the formed amphipathic copolymer of hydrophobicity polyester and hydrophilic polyglycol has unique temperature sensitivity, be aqueous solution at normal temperatures, under the body temperature condition, can be changed into semisolid or solid gel, therefore contained medicinal ingredient slowly can be discharged.Drug release process divides two stages, and the degraded and absorbed of sustained-release gel is before this followed degraded and absorbed by sustained-release micro-spheres.The release that ensures medicine thus is steady more, slow.This is one of major technique feature of the present invention.
The present invention find when the formed amphipathic aqueous copolymers solution of hydrophobicity polyester and hydrophilic polyglycol with can form water for injection gel after a certain amount of neovascularization inhibitor mixes 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 30 ℃-37 ℃.But this gelling temperature is subjected to multiple factor affecting, wherein mainly is monomeric weight ratio in the molecular weight, polyester of weight ratio, the Polyethylene Glycol of hydrophobicity polyester and hydrophilic polyglycol in the molecular weight of hydrogel Chinese medicine kind, medicament contg, amphipathic copolymer, the amphipathic copolymer.
The present invention also finds, the hydrogel that contains neovascularization inhibitor can slowly discharge neovascularization inhibitor 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 molecular weight, polyester and Polyethylene Glycol of used amphipathic copolymer and block configuration thereof, the amphipathic copolymer, the kind and 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).The mean molecule quantity of above-mentioned polyester can be 500-30000, wherein is preferred with 800-20000, and 1000-10000 is for most preferably.
Being suitable in the above-mentioned polyester of the present invention, serves as preferred with PLA and PLGA, with PLGA for most preferably; When select for use polylactic acid/ethanol copolymer (D, in the time of L-PLGA), the weight ratio of lactic acid and hydroxyacetic acid plays important regulating action to control drug release, the weight ratio of the two can be 15-1: 1; Wherein with 9-1: 1 serves as preferred, and with 5-1: 1 for most preferably.In other words, the blend ratio of lactic acid (LA) and glycolic (GA) can be 95/5 to 60/40 (weight), is preferably 75/25 to 40/60 (weight), with 75/25 to 50/50 (weight) for most preferably.The method of blend is arbitrarily.The molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be, but is not limited to, 300-30000, but be preferred with 500-20000, with 1000-10000 for most preferably.
The mean molecule quantity of Polyethylene Glycol can be 200-20000, wherein is preferred with 300-10000, and 500-3000 is 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), Vicryl Rapide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide (PLGA-PEG-PLGA), polyethylene glycol-lactic acid-Polyethylene Glycol (PEG-PLA-PEG), Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide-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 500-28000, wherein is preferred with 600-16000, and 1000-8000 is for most preferably; In the amphipathic copolymer, the weight ratio of polyester and Polyethylene Glycol can be 9-6: 1-4, with 9-7: 1-3 serves as preferred, with 9-7: 1-2 for most preferably, in other words, the percentage by weight of Polyethylene Glycol can be 5%-40% in the amphipathic copolymer, with 7% to 30% serves as preferred, and with 10% to 25% for most preferably, the percentage by weight of polyester can be 60%-95%, with 70% to 93% serves as preferred, with 75% to 90% for most preferably;
The gelling temperature of amphipathic copolymer promptly becomes the not temperature of flow-gel, can be 30 ℃-38 ℃, serves as preferred with 31 ℃-6.5 ℃, with 32 ℃-36 ℃ for most preferably.
But the solvent in the sustained-release gel system for sterilization after the liquid of injection in the body, as, but be not limited to, distilled water, water for injection, physiology is towards liquid, cell culture fluid, the buffer of body fluid, tissue fluid or the preparation of various salt, as, but be not limited to phosphate buffer.The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, but must operate in strict accordance with related standards.
Neovascularization inhibitor and or the packing and the application that contain neovascularization inhibitor microsphere and sustained-release gel depend on production technology and clinical practice requirement.Neovascularization inhibitor 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 is dispersed in the sustained-release gel.Pack alone or in combination with hybrid packed difference and be, mix with sustained-release gel before neovascularization inhibitor is injected in vivo when packing alone or in combination, hybrid packed then is neovascularization inhibitor to be dispersed in the sustained-release gel in process of production, direct injection after at room temperature heating up with preceding need.
Preferred a kind of mode is that sustained-release gel only discharges the sustained-release micro-spheres that contains neovascularization inhibitor, and the used slow-release auxiliary material of sustained-release micro-spheres is preferred with PLGA.Principal agent is the sustained-release micro-spheres that contains neovascularization inhibitor
The preparation of method for preparing microsphere has several different methods, as, but be not limited to multi-emulsion method, O/W method, O/O method, phase separation method, spray drying method, cold nebulization extraction method etc.
1, multi-emulsion method (W/O/W method): accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Under high-speed stirred or ultrasonic concussion, inject the two fun gi polysaccharides aqueous solution, homodisperse, form the colostric fluid of W/O, aqueous phase outside this solution is injected under high-speed stirred or under the ultrasonic concussion, emulsion factor minute (1～30min), form the W/O/W emulsion, in gentle agitation a few hours (1～10hr), the volatilization organic solvent, solidified microsphere.Centrifugal or the filtration collection with microsphere suspension liquid, and back for several times after 37 ℃ of vacuum dryings or lyophilization with the second distillation water washing, in 4 ℃ of refrigerators, preserve after the powder packing.
Wherein, surfactant can be, and singly is not limited to span 20; Organic solvent is selected from, as, singly be not limited to a kind of or mixed liquor of dichloromethane, ethyl acetate, acetonitrile etc.; Outer water can be the saturated solution of medicine, also can add surfactants such as salts such as emulsifying agent, 1～10% sodium chloride, 0.001～2% tween such as 0.1～10%PVA and improve balling-up character.Also can add stabilizing agents such as cosolvent, gelatin solution and improve entrapment efficiency.
2, O/W method
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
Water (can be the saturated solution of medicine outside above-mentioned suspension or solution was injected under high-speed stirred or under the ultrasonic concussion, also can add surfactants such as salts such as emulsifying agent, sodium chloride, tween such as PVA and improve balling-up character) in, emulsion factor minute (1～30min), form the O/W emulsion, in gentle agitation a few hours (1～10hr), the volatilization organic solvent, solidified microsphere.Centrifugal or the filtration collection with microsphere suspension liquid, and back for several times after 37 ℃ of vacuum dryings or lyophilization with the second distillation water washing, in 4 ℃ of refrigerators, preserve after the powder packing.
3, the O/O method one:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
Be injected into above-mentioned suspension or solution in the saturated dimethicone of dichloromethane under high-speed stirred or under the ultrasonic concussion, under the high-speed stirred or ultrasonic concussion number minute (after 1～30min), put in the petroleum ether of q.s, high-speed stirred number minute (1～30min), centrifugal or the filtration collection with microsphere suspension liquid behind the solidified microsphere, washing in 37 ℃ vacuum dryings or lyophilization after, powder packing after 4 ℃ refrigerators in is preserved after removing outer oil phase for several times.
4, the O/O method two:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
Above-mentioned suspension or solution are injected under high-speed stirred or under the ultrasonic concussion in the inertia oil phases such as liquid paraffin, room temperature or heated and stirred or ultrasonic concussion a few hours (1～30hr), the volatilization organic solvent, behind the solidified microsphere, centrifugal or the filtration collection with microsphere suspension liquid, washing in 37 ℃ vacuum dryings or lyophilization, powder packing after 4 ℃ refrigerators in is preserved after removing outer oil phase for several times.
5, phase separation method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
Organic solvents such as petroleum ether with q.s (1～10 times) under high-speed stirred or under the ultrasonic concussion slowly join in above-mentioned suspension or the solution, continue stirring or ultrasonic concussion tens of minutes (30～120min), the volatilization organic solvent, behind the solidified microsphere, centrifugal or the filtration collection with microsphere suspension liquid, washing in 37 ℃ vacuum dryings or lyophilization, powder packing after 4 ℃ refrigerators in is preserved after removing outer oil phase for several times.
6, spray drying method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
Above-mentioned suspension or solution under agitation or under the ultrasonic concussion are carried out spray drying with pumping in the spray dryer.Spray condition: 50 ℃-70 ℃ of inlet temperatures, about 40 ℃ of outlet temperature.In 4 ℃ of refrigerators, preserve after collecting the packing of dried microsphere powder.
7, cold nebulization extraction method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
With above-mentioned suspension or solution under agitation or ultrasonic concussion down with pumping in the spray dryer, method by spraying forms droplet, freezing in liquid nitrogen, obtain microsphere with the organic solvent of a low temperature organic cosolvent (for example ethanol) extracting dissolve polymer.In 4 ℃ of refrigerators, preserve after collecting the packing of dried microsphere powder.
The preparation of sustained-release gel injection has several different methods, as, but be not limited to solwution method, suspendible method, freeze-drying, casting, special solvent method, microsphere or nanosphere method.
1, solwution method: the hydrogel of recipe quantity is placed the solvent of full dose, in ice-water bath,, adds the principal agent of recipe quantity then with the magnetic stirrer dissolving, stirring and dissolving, standardize solution divides in the cillin bottle of packing into, jump a queue, behind the Zha Gai-10 ℃ of preservations.
2, suspendible method: the same solwution method of the course of dissolution of hydrogel, the principal agent that adds recipe quantity then, can suitably add other stabilizing agents such as suspending agent, antioxidant and metal chelating agent, stirring makes it disperse (controlling temperature well in the hope of reaching suitable viscosity) uniformly in hydrogel, standardize solution, stir packing ,-10 ℃ of preservations.
3, freeze-drying: the course of dissolution of hydrogel is the same, adds an amount of freeze drying excipient stirring and dissolving then, adds the principal agent stirring and dissolving or the suspension of recipe quantity again, standardize solution divides in the cillin bottle of packing into, puts lyophilization in the freeze dryer, jump a queue Zha Gai after the drying.4 ℃ of preservations of sample.
4, casting: the water that the hydrogel of recipe quantity is placed full dose, in ice-water bath, dissolve with magnetic stirrer, independent or the interpolation excipient stirring and dissolving of principal agent that adds recipe quantity then, standardize solution, divide in the poly-tetrafluoro vessel of packing into, put normal temperature drying in the vacuum drying oven, then sample-10? preserve.
5, special solvent method: hydrogel is dissolved the back direct packaging in proportion, preserve or lyophilization (adding excipient) preservation for-10 ℃, facing time spent rising temperature for dissolving or redissolution, as the special solvent of aseptic subpackaged drug powder or microsphere, to reach the slow release result of anticipation.
6, microsphere or nanosphere method: hydrogel as slow-release auxiliary material, is pressed the preparation technology of microsphere or nanosphere, be prepared into the microsphere or the nanosphere of hydrogel embedding medicinal, lyophilization or vacuum drying, powder branch are packed in the cillin bottle, the Zha Gai that jumps a queue ,-10 ℃ of preservations.
The preferred another kind of mode of sustained-release gel injection is that sustained-release gel contains neovascularization inhibitor and the sustained-release micro-spheres that contains neovascularization inhibitor, and the used slow-release auxiliary material of sustained-release micro-spheres is preferred with PLGA.The preparation method of sustained-release gel is the same, and what novels, anecdotes, etc. were same is to have added the neovascularization inhibitor micropowder in the sustained-release gel again.The weight ratio of neovascularization inhibitor is arbitrarily in neovascularization inhibitor micropowder and the sustained-release micro-spheres.
Slow-release auxiliary material also can be, but be not limited to, the copolymer of polylactic acid, lactic acid and glycolic, polifeprosan with and compositions, also can add release regulator in addition, be selected from a kind of or its combination in mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
The molecular weight peak value of polylactic acid is 500-5000,5000-10000,10000-25000,25000-35000 or 30000-50000; The molecular weight peak value of lactic acid and ethanol copolymer is 1000-10000,10000-25000,25000-40000 or 40000-60000; The percentage by weight of poly-lactonaphthol and polyglycolic acid is 90: 10,70-80: 20-30,60-40: 40-60,75: 25,25: 75 or 50: 50; The weight ratio of CPP in the polifeprosan: SA is 50-10: 90-50.
Selecting for use because of concrete condition of said method decided, and wherein can not satisfy medicine and microsphere preferably freeze drying method, casting, microsphere or the nanosphere method of preparation specification requirement at dissolubility own; The preferred 1000-8000 of the mean molecule quantity of amphipathic copolymer; The preferred 10%-25% of the percentage by weight of Polyethylene Glycol in the amphipathic copolymer; The preferred 15%-28% of the content of amphipathic copolymer in the injectivity hydrogel, as 15%, 17%, 20%, 23%, 25% (w/w); Stirring generally needs 12 hours (600 rev/mins), can suitably add other stabilizing agents such as cosolvent, antioxidant and metal chelating agent; Excipient can be mannitol, dextran, gelatin, sorbitol, sodium hydrogen phosphate, sodium dihydrogen phosphate, lactose, bovine serum albumin, sodium chloride, calcium lactobionate. and PVPk12 etc., can be about 2.5%.
Find that through test of many times not only mouldability is better for the sample of adding mannitol, and redissolution is also very fast, if in the subtractive process of hydrogel, add the dissolution time that the mannitol of preparation requirement can significantly reduce hydrogel in the formulation preparation process.This discovery constitutes another technical characterictic of the present invention.
Above method just is illustrative rather than definitive thereof the present invention.The preparation method of sustained-release gel 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 sustained-release gel 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 10cp-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 is a lot of among the present invention, but preferred one of following or its combination: alemtuzumab (Campath, Alemtuzumab), A Xi is for Buddhist nun (Axitinib), Ai Buli holds in the palm (Zevalin, Ibritumomab), bevacizumab (A Wasiting, Avastin, Bevacimab), Rituximab (Mabthera, Rituxan, Rituximab), Mai Luota monoclonal antibody (Mylotarg, Gemtuzumab ozogamicin), handkerchief Buddhist nun monoclonal antibody (Vectibix, Panitumumab), Herceptin (Herceptin, Trastuzumab), match comes former times cloth (celecoxib, Celebrex), rofecoxib (Refecoxib), Ta Situo monoclonal antibody (Tositumomab), En Duositating (Endostain), En Jisitating (Engiostatin), the blood vessel endothelium chalone, Te Situo monoclonal antibody (Bexxar, Tositumomab), Cetuximab (Erbitux, Cetuximab).
The preferred alemtuzumab of above vasoinhibitor, Ai Buli holder, bevacizumab, Rituximab, Mai Luota monoclonal antibody, handkerchief Buddhist nun monoclonal antibody, Herceptin, match come former times cloth, rofecoxib, Ta Situo monoclonal antibody, En Duositating, En Jisitating, blood vessel endothelium chalone, Te Situo monoclonal antibody, Cetuximab.
The percentage by weight of above-mentioned neovascularization inhibitor in sustained-release gel is 0.005%-40%, is preferred with 0.1%-20%, with 0.2%-10% for most preferably, more than all be weight percentage.
The route of administration of sustained-release gel 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 all injections of tumor 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 sustained-release gel 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.
The annular eclipse gel 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 cancer therapy drug and the chemotherapeutics of other administration associating, implant the associating of interior radiotherapy or immunization therapy with radiotherapy, particle.
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 500mg/kg body weight, be preferred with 0.1-200mg/kg, 0.1-50mg/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 sustained-release gel injection of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
(4) specific embodiment
Anticancer sustained-release gel injection of the present invention can prepare with following method and step:
(1) earlier prepare amphipathic aqueous copolymers solution with solvent, add then a certain amount of neovascularization inhibitor and or sustained-release micro-spheres, 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 respectively amphipathic aqueous copolymers solution and neovascularization inhibitor and or sustained-release micro-spheres, packing stores separately, before the injection with amphipathic aqueous copolymers solution and neovascularization inhibitor and or the abundant mixing of sustained-release micro-spheres after make anticancer sustained-release gel injection, be stored in low temperature or freezing state then, use the redissolution back of heating up before using;
(3) earlier the preparation neovascularization inhibitor and or sustained-release micro-spheres make medicaments injection, be 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) with a certain amount of amphipathic copolymer and a certain amount of neovascularization inhibitor and or sustained-release micro-spheres mix, add solvent then and make anticancer sustained-release gel injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Or
(6) with a certain amount of amphipathic copolymer and a certain amount of neovascularization inhibitor and or sustained-release micro-spheres mix, pack separately or after mixing, transport, 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.
Can add in the above method 0-15% regulator and or attribute machine excipient, as, but be not limited to, do and reveal alcohol.
Said method just is used for explanation but not limitation the present invention.
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.
The preparation of microsphere is with spray drying method or cold nebulization extraction process, adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000, and the weight ratio of copolymer and rofecoxib is 9: 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 31 ℃ (40%) and 35 ℃ (20%), and does not measure under 10 ℃-38 ℃ of the gelling temperatures of 10% and 5% hydrogel.The gelling temperature of four kinds of hydrogels among the embodiment 1 will be measured behind 5% sustained-release micro-spheres (W/W) the adding hydrogel again, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 33 ℃ (40%) and 37.5 ℃ (20%), and does not measure under 10 ℃-39 ℃ 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.
The preparation of microsphere prepares with multi-emulsion method or O/W method, adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 25,000-35,000, copolymer and sieve in distress are 7: 3 for Buddhist nun's weight ratio.
Embodiment 4.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 3, the result show 40% and 20% hydrogel gelling temperature be respectively 29 ℃ (40%) and 36 ℃ (20%), and do not measure under 10 ℃-38 ℃ of the gelling temperatures of 10% and 5% hydrogel.The gelling temperature of four kinds of hydrogels among the embodiment 3 will be measured behind 5% sustained-release micro-spheres (W/W) the adding hydrogel again, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 32 ℃ (40%) and 36.5 ℃ (20%), and does not measure under 10 ℃-39 ℃ 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.When sustained-release micro-spheres existed, gelling temperature raise to some extent.
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.Average mark installs in 5 containers (fill 200mg rofecoxib micropowder respectively and contain sustained-release micro-spheres, the 100mg rofecoxib micropowder of 200mg rofecoxib and contain sustained-release micro-spheres, the 50mg rofecoxib micropowder of 100mg rofecoxib and contain sustained-release micro-spheres, the 10mg rofecoxib micropowder of 50mg rofecoxib and contain sustained-release micro-spheres, the 1mg rofecoxib micropowder of 10mg rofecoxib and contain the sustained-release micro-spheres of 1mg rofecoxib) then, makes the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% rofecoxib.Record its gelling temperature and be respectively 38 ℃, 37 ℃, 36 ℃, 33 ℃ and 32 ℃.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 20000-30000.
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 Ta Situo monoclonal antibody sustained-release micro-spheres in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% Ta Situo monoclonal antibody.Record its gelling temperature and be respectively 38 ℃, 37.5 ℃, 36 ℃, 33.5 ℃ and 32 ℃.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-28000.
Embodiment 7.
Measure interior (subcutaneous) release cycle of mice body of the variable concentrations rofecoxib and the Ta Situo monoclonal antibody of embodiment 5 and 6, found that be respectively 160 ± 38,135 ± 36,105 ± 26,85 ± 15 and 64 ± 14 days average time (estimating can measure the time in the blood) that discharges in 20%, 10%, 5%, the 1% and 0.1% rofecoxib body; 20%, was respectively 142 ± 30,125 ± 28,108 ± 26,92 ± 8 and 78 ± 14 days the average time that discharges in the body of 10%, 5%, 1% and 0.1% Ta Situo monoclonal antibody.
Embodiment 8.
(molecular weight of Polyethylene Glycol is 1600 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 6: 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 2mg match come in the container of former times cloth sustained-release micro-spheres, make and contain the anticancer sustained-release gel injection that 20%, 10%, 5%, 1% and 0.1% match comes former times cloth.Record its gelling temperature and be respectively 37 ℃, 36.5 ℃, 36 ℃, 34.5 ℃ and 31 ℃.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 28000-42000.
Embodiment 9.
(molecular weight of Polyethylene Glycol is 1400 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 4: 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 Herceptin sustained-release micro-spheres in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% Herceptin.Record its gelling temperature and be respectively 37 ℃, 36.5 ℃, 35 ℃, 34 ℃ and 32 ℃.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 18000-32000.
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, it is one of following that preferred anticancer sustained-release gel injection also comprises:
(1) 18% block copolymer aqueous solution contains the 0.01%-20% alemtuzumab;
(2) 19% block copolymer aqueous solution contains the holder of 0.05%-10% Chinese mugwort background of cloth;
(3) 20% block copolymer aqueous solution contains the 0.05%-30% bevacizumab;
(4) 21% block copolymer aqueous solution contains the 0.01%-25% Rituximab;
(5) 22% block copolymer aqueous solution contains 0.01%-25% Mai Luota monoclonal antibody;
(6) 20% block copolymer aqueous solution contains 0.01%-25% handkerchief Buddhist nun monoclonal antibody;
(7) 22% block copolymer aqueous solution contains the 0.01%-25% Herceptin;
(8) 18% block copolymer aqueous solution contains the 0.1%-25% match and comes former times cloth;
(9) 19% block copolymer aqueous solution contains the 0.1%-20% rofecoxib;
(10) 18% block copolymer aqueous solution contains 0.2%-25% Ta Situo monoclonal antibody;
(11) 20% block copolymer aqueous solution contains 0.25%-25% En Duositating;
(12) 22% block copolymer aqueous solution contains 0.5%-25% En Duositating;
(13) 23% block copolymer aqueous solution contains 0.75%-25% blood vessel endothelium chalone;
(14) 22% block copolymer aqueous solution contains 1%-28% Te Situo monoclonal antibody; Or
(15) 18% block copolymer aqueous solution contains the 1%-15% Cetuximab.
Medicine in the above-mentioned anticancer sustained-release gel injection is a micropowder, and its gelling temperature is 31 ℃-37.5 ℃, and be 4-8 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 1200, 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 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, it is one of following that preferred anticancer sustained-release gel injection also comprises:
(1) 18% block copolymer aqueous solution contains the 0.01%-20% alemtuzumab;
(2) 19% block copolymer aqueous solution contains the holder of 0.05%-10% Chinese mugwort background of cloth;
(3) 20% block copolymer aqueous solution contains the 0.05%-30% bevacizumab;
(4) 21% block copolymer aqueous solution contains the 0.01%-25% Rituximab;
(5) 22% block copolymer aqueous solution contains 0.01%-25% Mai Luota monoclonal antibody;
(6) 20% block copolymer aqueous solution contains 0.01%-25% handkerchief Buddhist nun monoclonal antibody;
(7) 22% block copolymer aqueous solution contains the 0.01%-25% Herceptin;
(8) 18% block copolymer aqueous solution contains the 0.1%-25% match and comes former times cloth;
(9) 19% block copolymer aqueous solution contains the 0.1%-20% rofecoxib;
(10) 18% block copolymer aqueous solution contains 0.2%-25% Ta Situo monoclonal antibody;
(11) 20% block copolymer aqueous solution contains 0.25%-25% En Duositating;
(12) 22% block copolymer aqueous solution contains 0.5%-25% En Duositating;
(13) 23% block copolymer aqueous solution contains 0.75%-25% blood vessel endothelium chalone;
(14) 22% block copolymer aqueous solution contains 1%-28% Te Situo monoclonal antibody; Or
(15) 18% block copolymer aqueous solution contains the 1%-15% Cetuximab.
Medicine in the above-mentioned anticancer sustained-release gel injection is a sustained-release micro-spheres, and its gelling temperature is 33 ℃-38.5 ℃, and be 4-14 week release time in the animal body, obviously prolongs than micropowder gel injection drug release time.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 5: 1.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
Embodiment 12.
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) 5% alemtuzumab or bevacizumab, formulated by 1mg alemtuzumab or bevacizumab, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1% Ta Situo monoclonal antibody or alemtuzumabs, formulated by 10mg Ta Situo monoclonal antibody or alemtuzumab, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2% Chinese mugwort background of cloth holder or bevacizumabs, formulated by 20mg Chinese mugwort background of cloth holder or bevacizumab, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 4% rofecoxibs, formulated by 40mg rofecoxib, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 5% Chinese mugwort background of cloth holder or bevacizumabs, formulated by 50mg Chinese mugwort background of cloth holder or bevacizumab, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 7% Rituximabs, formulated by 70mg Rituximab, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 0.5% Chinese mugwort background of cloth holders, formulated by the holder of 5mg Chinese mugwort background of cloth, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 0.1% Mai Luota monoclonal antibodies, formulated by 1mg Mai Luota monoclonal antibody, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 0.3% handkerchief Buddhist nun monoclonal antibodies, formulated by 3mg handkerchief Buddhist nun monoclonal antibody, 230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline;
(10) 0.5% Herceptins or match come former times cloth, come former times cloth, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection formulated by 5mg Herceptin or match;
(11) 0.8% Rituximabs, formulated by 8mg Rituximab, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 1% En Duositating or SU5416, formulated by 10mg En Duositating or SU5416,200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline;
(13) 1.25% Cetuximab or Amebacilins, formulated by 12.5mg Cetuximab or Amebacilin, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(14) 1.5% Te Situo monoclonal antibodies, 15mg Te Situo monoclonal antibody, formulated by 200mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection;
(15) 2% En Jisitating or Ta Situo monoclonal antibody, formulated by 20mg En Jisitating or Ta Situo monoclonal antibody, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(16) 5% alemtuzumab or bevacizumabs are by 50mg alemtuzumab or bevacizumab, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 10% Chinese mugwort background of cloth holder or Rituximabs, formulated by 100mg Chinese mugwort background of cloth holder or Rituximab, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline;
(18) 15% Mai Luota monoclonal antibodies or handkerchief Buddhist nun monoclonal antibody, formulated by 150mg Mai Luota monoclonal antibody or handkerchief Buddhist nun monoclonal antibody, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 20% rofecoxibs or Ta Situo monoclonal antibody, formulated by 200mg rofecoxib or Ta Situo monoclonal antibody, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(20) 25% Herceptins or match come former times cloth, come former times cloth, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline by 250mg Herceptin or match.
Medicine in the above-mentioned anticancer sustained-release gel injection is drug powder and sustained-release micro-spheres, and its gelling temperature is 31 ℃-37.8 ℃, and be 5-14 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.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1300-1500, 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 13.
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) 1% alemtuzumab or bevacizumab, formulated by 10mg alemtuzumab or bevacizumab, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 5% Ta Situo monoclonal antibody or alemtuzumabs, formulated by 50mg Ta Situo monoclonal antibody or alemtuzumab, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 5% Chinese mugwort background of cloth holder or bevacizumabs, formulated by 50mg Chinese mugwort background of cloth holder or bevacizumab, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 8% rofecoxibs or Ta Situo monoclonal antibody, formulated by 80mg rofecoxib or Ta Situo monoclonal antibody, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 10% Chinese mugwort background of cloth holder or bevacizumabs, formulated by 100mg Chinese mugwort background of cloth holder or bevacizumab, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 2% Rituximabs, formulated by 20mg Rituximab, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 5% imatinibs, formulated by 50mg imatinib, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 2% Sugen 5416s or Mai Luota monoclonal antibody, formulated by 20mg Sugen 5416 or Mai Luota monoclonal antibody, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 3% handkerchief Buddhist nun monoclonal antibody or Cl 1033s, formulated by 30mg handkerchief Buddhist nun's monoclonal antibody or Cl 1033,230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline;
(10) 2.5% Herceptins or match come former times cloth, come former times cloth, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection formulated by 25mg Herceptin or match;
(11) 5% TLK286 or ABX-EGF, formulated by 20mg TLK286 or ABX-EGF, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 5% Marimastat or SU5416, formulated by 50mg Marimastat or SU5416,200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline;
(13) 5%SU6668 or Amebacilin, formulated by 50mgSU6668 or Amebacilin, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(14) 5%TNP-470, formulated by 50mgTNP-470,200mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection;
(15) 8% rofecoxibs or Ta Situo monoclonal antibody, formulated by 80mg rofecoxib or Ta Situo monoclonal antibody, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(16) 10% alemtuzumab or bevacizumabs are by 100mg alemtuzumab or bevacizumab, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 2% Chinese mugwort background of cloth holder or Rituximabs, formulated by 20mg Chinese mugwort background of cloth holder or Rituximab, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline;
(18) 5% Mai Luota monoclonal antibodies or handkerchief Buddhist nun monoclonal antibody, formulated by 50mg Mai Luota monoclonal antibody or handkerchief Buddhist nun monoclonal antibody, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 15% rofecoxibs or Ta Situo monoclonal antibody, formulated by 150mg rofecoxib or Ta Situo monoclonal antibody, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(20) 20% Herceptins or match come former times cloth, come former times cloth, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline by 200mg Herceptin or match.
Studies show that the principal agent of above-mentioned anticancer sustained-release gel injection is a microsphere, its gelling temperature is 33 ℃-37.5 ℃, and be 6-12 week release time in the animal body.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1300-1600, 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 6: 1.Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 50/50 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
The therapeutic effect of anticancer sustained-release gel injection can further specify by following test and treatment embodiment:
Embodiment 14
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is treated to be divided into 4 groups behind tumor growth to 1 cm diameter, respectively the anticancer sustained-release gel injection that contains 20%, 10%, 0.1% and 0.05% rofecoxib among the intratumor injection 0.1ml embodiment 5 in its hypochondrium.Measure gross tumor volume every day, the result shows that the rofecoxib anticancer sustained-release gel injection can significantly suppress tumor growth, and its tumor-inhibiting action is obvious dose dependent.20% concentration is safety still.Intratumor injection sustained-release gel injection operation most convenient, easy.
Embodiment 15
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is treated to be divided into 4 groups behind tumor growth to 0.5 cm diameter, respectively the anticancer sustained-release gel injection that contains 20%, 10%, 0.1% and 0% Ta Situo monoclonal antibody among the intratumor injection 0.5ml embodiment 6 in its hypochondrium.Measure gross tumor volume every day, the result shows that Ta Situo monoclonal antibody anticancer sustained-release gel injection can significantly suppress tumor growth, and its tumor-inhibiting action is obvious dose dependent.20% concentration is safety still.Effective, the operation most convenient, easy of intratumor injection sustained-release gel injection.Good effect not only, toxic and side effects is also little.
Embodiment 16, contain tumor-inhibiting action in the body of neovascularization inhibitor sustained-release gel injection
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 20 days is divided into it following 11 groups (seeing Table 1).First group is contrast, and the 2nd to 11 group is the treatment group, and medicine is selected from embodiment 10, through intratumor injection.Dosage is 0.1ml, only is equivalent to 5-25mg/.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(5) | Contrast | 48±10 | |
| ?2(5) | 5% alemtuzumab | 34±8.2 | ?＜0.05 |
| ?3(5) | 5% bevacizumab | 30±6.0 | ?＜0.01 |
| ?4(5) | 10% Chinese mugwort background of cloth holder | 38±6.6 | ?＜0.01 |
| ?5(6) | 10% Rituximab | 36±5.8 | ?＜0.01 |
| ?6(5) | 15% Mai Luota monoclonal antibody | 36±6.2 | ?＜0.01 |
| ?7(5) | 15% handkerchief Buddhist nun monoclonal antibody | 34±6.2 | ?＜0.001 |
| ?8(5) | 25% Herceptin | 28±6.8 | ?＜0.001 |
| ?9(5) | 25% match comes former times cloth | 28±4.4 | ?＜0.001 |
| ?10(5) | 20% rofecoxib | 26±4.8 | ?＜0.001 |
| ?11(5) | 20% Ta Situo monoclonal antibody | 28±5.8 | ?＜0.001 |
Above result shows that the neovascularization inhibitor sustained-release gel injection all has the obvious suppression effect to the tumor of prostate growth of tumour cell under this concentration.
The tumor-inhibiting action of embodiment 17, neovascularization inhibitor sustained-release gel 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 21 days is divided into it following 11 groups (seeing Table 2).First group is contrast, and the 2nd to 11 group is the treatment group, and sustained-release gel injection is placed in tumor.Neovascularization inhibitor dosage only is 0.2ml/, only is equivalent to 0.25mg-12.5mg/.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 30th day.
Table 2
Above result shows that used neovascularization inhibitor sustained-release gel injection all has the obvious suppression effect to many hepatocarcinoma growth of tumour cell when this concentration.
The tumor-inhibiting action of embodiment 18, neovascularization inhibitor sustained-release gel injection
With the rat is subjects, with 2 * 10
5Pulmonary carcinoma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 3).First group is contrast, and the 2nd to 11 group is the treatment group, and sustained-release gel injection is placed in tumor.Neovascularization inhibitor dosage only is 0.5ml/, only is equivalent to 0.5mg-35mg/.The treatment back was measured the gross tumor volume size on the 30th day, compared therapeutic effect, calculated tumor control rate according to following formula:
Tumor control rate (%)=((matched group gross tumor volume-treatment group gross tumor volume)/matched group gross tumor volume) * 100 (%).
Table 3
Above result shows that used neovascularization inhibitor sustained-release gel injection all has tangible dose-dependent inhibitory action to many pulmonary carcinoma growth of tumour cell when this concentration.
The tumor-inhibiting action of embodiment 19 neovascularization inhibitor sustained-release gel injections
With the rat is subjects, with 2 * 10
5Esophageal carcinoma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 4).First group is contrast, and the 2nd to 11 group is the treatment group, and sustained-release gel injection is placed in tumor.Neovascularization inhibitor dosage only is 0.2ml/, only is equivalent to 2mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 4) on the 30th day.
Table 4
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| ?1(5) | Contrast | - | |
| ?2(5) | 1% alemtuzumab | 32 | ?＜0.05 |
| ?3(5) | 5% alemtuzumab | 46 | ?＜0.01 |
| ?4(5) | 7.5% alemtuzumab | 52 | ?＜0.01 |
| ?5(5) | 10% alemtuzumab | 68 | ?＜0.01 |
| ?6(5) | 5% bevacizumab | 48 | ?＜0.05 |
| ?7(5) | 10% bevacizumab | 62 | ?＜0.01 |
| ?8(5) | 20% bevacizumab | 76 | ?＜0.01 |
| ?9(5) | 5% rofecoxib | 42 | ?＜0.05 |
| ?10(5) | 10% rofecoxib | 60 | ?＜0.01 |
| ?11(5) | 20% rofecoxib | 80 | ?＜0.01 |
Above result shows that used neovascularization inhibitor sustained-release gel injection all has tangible dose-dependent inhibitory action to polyphagia road cancerous protuberance tumor cell growth when this concentration.
The tumor-inhibiting action of embodiment 20, neovascularization inhibitor slow releasing agent
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 5).First group is contrast, and the 2nd to 11 group is the treatment group, and sustained-release gel injection is placed in tumor.Neovascularization inhibitor dosage only is 0.2ml/, only is equivalent to 2mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 5) on the 30th day.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| ?1(5) | Contrast | - | |
| ?2(5) | 2% Rituximab | 50 | ?＜0.05 |
| ?3(5) | 2% Chinese mugwort background of cloth holder | 58 | ?＜0.05 |
| ?4(5) | 5% Chinese mugwort background of cloth holder | 56 | ?＜0.05 |
| ?5(5) | 5% imatinib | 54 | ?＜0.05 |
| ?6(5) | 2% Sugen 5416 | 62 | ?＜0.01 |
| ?7(5) | 2% Mai Luota monoclonal antibody | 52 | ?＜0.01 |
| ?8(5) | 3% handkerchief Buddhist nun monoclonal antibody | 74 | ?＜0.01 |
| ?9(5) | 3% Cl 1033 | 80 | ?＜0.01 |
| ?10(5) | 2.5% Herceptin | 78 | ?＜0.001 |
| ?11(5) | 2.5% match comes former times cloth | 80 | ?＜0.01 |
The tumor-inhibiting action of embodiment 21, neovascularization inhibitor slow releasing agent
With the rat is subjects, with 2 * 10
5Individual gastric cancer tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 6).First group is contrast, and the 2nd to 11 group is the treatment group, and sustained-release gel injection is placed in tumor from embodiment 10 (micropowder) and 11 (microspheres).Neovascularization inhibitor dosage only is 0.25ml/, only is equivalent to 12.5mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 6) on the 30th day.
Table 6
Above result shows that used neovascularization inhibitor sustained-release gel injection all has the obvious suppression effect to many gastric cancer growth of tumour cell when this concentration, and wherein microsphere is than the micropowder better effects if.
The tumor-inhibiting action of embodiment 22, neovascularization inhibitor slow releasing agent
With the rat is subjects, with 2 * 10
5Individual renal carcinoma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 7).First group is contrast, and the 2nd to 11 group is the treatment group, and release injectable is placed in tumor from embodiment 10 (micropowder) and 11 (microspheres) and 12 (micropowder and microsphere).Neovascularization inhibitor dosage only is 0.25ml/, only is equivalent to 12.5mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 7) on the 30th day.
Table 7
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| ?1(5) | Contrast | - | |
| ?2(5) | 5% alemtuzumab (micropowder) | 38 | ?＜0.05 |
| ?3(5) | 5% alemtuzumab (microsphere) | 42 | ?＜0.05 |
| ?4(5) | 5% alemtuzumab (micropowder and microsphere) | 62 | ?＜0.01 |
| ?5(5) | 2% En Jisitating (micropowder) | 46 | ?＜0.05 |
| ?6(5) | 2% En Jisitating (microsphere) | 54 | ?＜0.01 |
| ?7(5) | 2% En Jisitating (micropowder and microsphere) | 68 | ?＜0.001 |
| ?8(5) | 25% Herceptin (micropowder) | 74 | ?＜0.01 |
| ?9(5) | 25% Herceptin (microsphere) | 80 | ?＜0.01 |
| ?10(5) | 25% Herceptin (micropowder and microsphere) | 88 | ?＜0.001 |
Above result shows that used neovascularization inhibitor sustained-release gel injection all has the obvious suppression effect to the renal carcinoma growth of tumour cell when this concentration, and wherein microsphere is better than the micropowder effect, and micropowder and microsphere are best.
Discover that further used neovascularization inhibitor sustained-release gel injection all has the obvious suppression effect to growth of tumour cell such as carcinoma of the colon and rectum, ovarian cancer, the cerebral tumor, bladder cancer
In a word, growth all has the obvious suppression effect to used neovascularization inhibitor sustained-release gel injection to kinds of tumor cells.Therapeutic effect is directly proportional with metering, and wherein microsphere is better than the micropowder effect, and micropowder and microsphere are best.
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. anticancer sustained-release gel injection that contains neovascularization inhibitor is characterized in that anticancer sustained-release gel injection is made up of neovascularization inhibitor, amphipathic nature block polymer, solvent and a certain amount of drug release regulator of effective anticancer; Wherein,
Amphipathic nature block polymer is made up of Polyethylene Glycol and polyester: wherein, the block configuration of polyester and Polyethylene Glycol 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; The mean molecule quantity of polylactic acid or Vicryl Rapide is selected from 500-5000,5000-20000,20000-30000, and 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; The weight ratio of Polyethylene Glycol and polyester is selected from 1-5: 5-9;
But solvent is selected from distilled water, water for injection, physiology towards liquid, cell culture fluid, body fluid, tissue fluid, buffer or phosphate buffer for the aqueous solution of injection in the body after sterilizing.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 sugar, 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; The drug release regulator is 0-15% at the percentage by weight of sustained-release gel injection;
Anticancer sustained-release gel injection is flowable liquid in being lower than the environment of body temperature, 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 neovascularization inhibitor and keeps the thoughtful several months of active drug concentration numbers at tumor by local; The viscosity of anticancer sustained-release gel injection is 20cp-3000cp (5 ℃-30 ℃ time).
2. the anticancer sustained-release gel injection according to claim 1 is characterized in that neovascularization inhibitor is selected from alemtuzumab, Ai Buli holder, bevacizumab, Rituximab, Mai Luota monoclonal antibody, handkerchief Buddhist nun monoclonal antibody, Herceptin, match and comes one of former times cloth, rofecoxib, Ta Situo monoclonal antibody, En Duositating, En Jisitating, Te Situo monoclonal antibody, Cetuximab or its combination.
3. the anticancer sustained-release gel injection according to claim 1 is characterized in that neovascularization inhibitor partly or entirely is wrapped in the sustained-release micro-spheres, and the percentage by weight of neovascularization inhibitor in anticancer sustained-release gel injection is 0.005%-40%.
4. the anticancer sustained-release gel injection according to claim 1 is characterized in that sustained-release micro-spheres is by becoming to be grouped into once:
Neovascularization inhibitor 1%-40%
Slow-release auxiliary material 60%-99%
Drug release regulator 0-15%
More than be weight percentage, total amount is 100%.
Slow-release auxiliary material is selected from polifeprosan, polylactic acid or Vicryl Rapide,
Wherein,
The weight ratio of CPP in the polifeprosan: SA is 50-10: 90-50;
The molecular weight peak value of polylactic acid is 500-5000,5000-10000,10000-25000,25000-35000 or 30000-50000;
The molecular weight peak value of Vicryl Rapide is 1000-10000,10000-25000,25000-40000 or 40000-60000, and the percentage by weight of Acetic acid, hydroxy-, bimol. cyclic ester lactide is 90: 10,70-80: 20-30,60-40: 40-60,75: 25,25: 75 or 50: 50.
5. according to claim 1 and 4 described anticancer sustained-release gel injections, it is one of following that the preparation method that it is characterized in that described anticancer sustained-release gel injection is selected from:
(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 anticancer sustained-release gel 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.
The regulator that can add 0-15% in the above method.
6. according to claim 1 and 4 described anticancer sustained-release gel injections, it is characterized in that described anticancer sustained-release gel injection contains one of following ingredients:
(1) 18% block copolymer aqueous solution contains the 0.01%-20% alemtuzumab;
(2) 19% block copolymer aqueous solution contains the holder of 0.05%-10% Chinese mugwort background of cloth;
(3) 20% block copolymer aqueous solution contains the 0.05%-30% bevacizumab;
(4) 21% block copolymer aqueous solution contains the 0.01%-25% Rituximab;
(5) 22% block copolymer aqueous solution contains 0.01%-25% Mai Luota monoclonal antibody;
(6) 20% block copolymer aqueous solution contains 0.01%-25% handkerchief Buddhist nun monoclonal antibody;
(7) 22% block copolymer aqueous solution contains the 0.01%-25% Herceptin;
(8) 18% block copolymer aqueous solution contains the 0.1%-25% match and comes former times cloth;
(9) 19% block copolymer aqueous solution contains the 0.1%-20% rofecoxib;
(10) 18% block copolymer aqueous solution contains 0.2%-25% Ta Situo monoclonal antibody;
(11) 20% block copolymer aqueous solution contains 0.25%-25% En Duositating;
(12) 22% block copolymer aqueous solution contains 0.5%-25% En Duositating;
(13) 23% block copolymer aqueous solution contains 0.75%-25% blood vessel endothelium chalone;
(14) 22% block copolymer aqueous solution contains 1%-28% Te Situo monoclonal antibody; Or
(15) 18% block copolymer aqueous solution contains the 1%-15% Cetuximab.
Above-mentioned anticancer sustained-release gel injection gelling temperature is 31 ℃-37.5 ℃, and be 4-8 week release time in the animal body; It is micropowder that new vessels suppresses, and amphipathic nature block polymer is a Vicryl Rapide Polyethylene Glycol Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1200, 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.
7. according to claim 1 and 4 described anticancer sustained-release gel injections, it is characterized in that described anticancer sustained-release gel injection contains one of following ingredients:
(1) 18% block copolymer aqueous solution contains the 0.01%-20% alemtuzumab;
(2) 19% block copolymer aqueous solution contains the holder of 0.05%-10% Chinese mugwort background of cloth;
(3) 20% block copolymer aqueous solution contains the 0.05%-30% bevacizumab;
(4) 21% block copolymer aqueous solution contains the 0.01%-25% Rituximab;
(5) 22% block copolymer aqueous solution contains 0.01%-25% Mai Luota monoclonal antibody;
(6) 20% block copolymer aqueous solution contains 0.01%-25% handkerchief Buddhist nun monoclonal antibody;
(7) 22% block copolymer aqueous solution contains the 0.01%-25% Herceptin;
(8) 18% block copolymer aqueous solution contains the 0.1%-25% match and comes former times cloth;
(9) 19% block copolymer aqueous solution contains the 0.1%-20% rofecoxib;
(10) 18% block copolymer aqueous solution contains 0.2%-25% Ta Situo monoclonal antibody;
(11) 20% block copolymer aqueous solution contains 0.25%-25% En Duositating;
(12) 22% block copolymer aqueous solution contains 0.5%-25% En Duositating;
(13) 23% block copolymer aqueous solution contains 0.75%-25% blood vessel endothelium chalone;
(14) 22% block copolymer aqueous solution contains 1%-28% Te Situo monoclonal antibody; Or
(15) 18% block copolymer aqueous solution contains the 1%-15% Cetuximab.
Gelling temperature in the above-mentioned anticancer sustained-release gel injection is 33 ℃-38.5 ℃, and be 4-14 week release time in the animal body, and new vessels suppresses to be sustained-release micro-spheres; Amphipathic nature block polymer is a 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 5: 1;
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
8. according to claim 1 and 2 described anticancer sustained-release gel injections, it is characterized in that described anticancer sustained-release gel injection contains one of following ingredients:
(1) 5% alemtuzumab or bevacizumab, formulated by 1mg alemtuzumab or bevacizumab, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1% Ta Situo monoclonal antibody or alemtuzumabs, formulated by 10mg Ta Situo monoclonal antibody or alemtuzumab, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2% Chinese mugwort background of cloth holder or bevacizumabs, formulated by 20mg Chinese mugwort background of cloth holder or bevacizumab, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 4% rofecoxibs, formulated by 40mg rofecoxib, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 5% Chinese mugwort background of cloth holder or bevacizumabs, formulated by 50mg Chinese mugwort background of cloth holder or bevacizumab, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 7% Rituximabs, formulated by 70mg Rituximab, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 0.5% Chinese mugwort background of cloth holders, formulated by the holder of 5mg Chinese mugwort background of cloth, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 0.1% Mai Luota monoclonal antibodies, formulated by 1mg Mai Luota monoclonal antibody, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 0.3% handkerchief Buddhist nun monoclonal antibodies, formulated by 3mg handkerchief Buddhist nun monoclonal antibody, 230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline;
(10) 0.5% Herceptins or match come former times cloth, come former times cloth, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection formulated by 5mg Herceptin or match;
(11) 0.8% Rituximabs, formulated by 8mg Rituximab, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 1% En Duositating or SU5416, formulated by 10mg En Duositating or SU5416,200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline;
(13) 1.25% Cetuximab or Amebacilins, formulated by 12.5mg Cetuximab or Amebacilin, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(14) 1.5% Te Situo monoclonal antibodies, 15mg Te Situo monoclonal antibody, formulated by 200mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection;
(15) 2% En Jisitating or Ta Situo monoclonal antibody, formulated by 20mg En Jisitating or Ta Situo monoclonal antibody, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(16) 5% alemtuzumab or bevacizumabs are by 50mg alemtuzumab or bevacizumab, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 10% Chinese mugwort background of cloth holder or Rituximabs, formulated by 100mg Chinese mugwort background of cloth holder or Rituximab, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline;
(18) 15% Mai Luota monoclonal antibodies or handkerchief Buddhist nun monoclonal antibody, formulated by 150mg Mai Luota monoclonal antibody or handkerchief Buddhist nun monoclonal antibody, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 20% rofecoxibs or Ta Situo monoclonal antibody, formulated by 200mg rofecoxib or Ta Situo monoclonal antibody, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(20) 25% Herceptins or match come former times cloth, come former times cloth, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline by 250mg Herceptin or match.
The gelling temperature of above-mentioned anticancer sustained-release gel injection is 31 ℃-37.8 ℃, and new vessels suppresses the combination for micropowder and sustained-release micro-spheres, and be 5-14 week release time in its animal body;
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
Above amphipathic nature block polymer is a Vicryl Rapide Polyethylene Glycol Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1300-1500, 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.
9. according to claim 1 and 4 described anticancer sustained-release gel injections, it is characterized in that described sustained-release gel injection is used to prepare the pharmaceutical preparation of the retinoblastoma of the treatment 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, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis.
10. according to claim 1 and 4 described anticancer sustained-release gel injections, it is characterized in that described sustained-release gel injection is used for the preparation treatment 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, the retinoblastoma of eyes, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, the pharmaceutical preparation of carcinoma of testis metastatic tumor.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784105A (en) * | 2015-04-17 | 2015-07-22 | 北京大学 | Gel compound of monoclonal antibody drugs |
| CN113398063A (en) * | 2021-06-27 | 2021-09-17 | 烟台大学 | Long-acting injection microsphere gel containing meloxicam and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784105A (en) * | 2015-04-17 | 2015-07-22 | 北京大学 | Gel compound of monoclonal antibody drugs |
| CN113398063A (en) * | 2021-06-27 | 2021-09-17 | 烟台大学 | Long-acting injection microsphere gel containing meloxicam and preparation method thereof |
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