CN101283976A - Anticancer sustained-release gel injection containing taxone medicine - Google Patents
Anticancer sustained-release gel injection containing taxone medicine Download PDFInfo
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Abstract
A sustained-release gel injection comprises sustained-release microspheres containing taxanes drug, amphiphilic block copolymer, solvent and release regulator, wherein the mixture of the amphiphilic block copolymer and the solvent has a 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 a tumor for treating solid tumors at different stages. The preparation has the effects of controlling residual tumor cells relapsed after operation and tumors that can not be excised via operation, controlling complications at late stage of tumors, and enhancing treatment effect of chemotherapy and radiotherapy (particularly radioactive particles). The taxanes are selected from docetaxel, taxol, epitaxol, hydroxyl taxol and deacetyltaxol; the amphiphilic block copolymer is PLGA-PEG-PLGA copolymer, wherein the PEG has molecular weight of 1200-1600, accounting for 20 wt% of the amphiphilic block copolymer; and in the glycolide-lactide copolymer, the mol ratio of glycolide and lactide is 6:1.
Description
(1) technical field
The present invention relates to a kind of anticancer sustained-release gel injection that contains taxone, belong to technical field of pharmaceuticals.Particularly, this invention relate to a kind of can with taxone 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, taxone partly or entirely is wrapped in the sustained-release micro-spheres, and the taxone that sustained-release micro-spheres is forgiven further extends to the several months at tumor by local slow release time.
(2) background technology
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 as yew alkanes medicine.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.
In addition, 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 taxone is provided, particularly, is a kind of sustained-release gel injection that contains taxone.Taxone 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 taxone 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 taxone can slowly discharge taxone 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 taxone.
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 ℃, with 31 ℃? 6.5 ℃ be preferred, 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.
Taxone and or the packing and the application that contain taxone microsphere and sustained-release gel depend on production technology and clinical practice requirement.Taxone 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 taxone is dispersed in the sustained-release gel.Pack alone or in combination with hybrid packed difference and be, mix with sustained-release gel before taxone is injected in vivo when packing alone or in combination, hybrid packed then is taxone 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 taxone, 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 taxone
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.Collect after the packing of dried microsphere powder 4? preserve in the refrigerator.
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, sample-10 ℃ preservation then.
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 taxone and the sustained-release micro-spheres that contains taxone, 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 taxone micropowder in the sustained-release gel again.The weight ratio of taxone is arbitrarily in taxone 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.
Preferred one of following or its combination of available taxone among the present invention: among the present invention available taxane (Taxanes) kind anti-cancer drugs owner to be selected from paclitaxel, Docetaxel (Docetaxel, taxotere, docetaxel), 2 '-hydroxyl paclitaxel (paclitaxel-2 '-hydroxy), 10-removes acetyl paclitaxel (10-deacetyl taxol), 7-table-paclitaxel (7-epi-taxol).With paclitaxel, Docetaxel serves as preferred.
Above taxone also comprises their salt, as, but be not limited to methanesulfonic acid, sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
The percentage by weight of above-mentioned taxone 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.
Sustained-release 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 taxone 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 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 taxone 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 taxone and or sustained-release micro-spheres, packing stores separately, before the injection with amphipathic aqueous copolymers solution and taxone 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 taxone 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 taxone aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind taxone 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) with a certain amount of amphipathic copolymer and a certain amount of taxone 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 taxone 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 prepares with the 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 15,000-38,000, the weight ratio of copolymer and paclitaxel 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 the 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, the weight ratio of copolymer and docetaxel is 7: 3.
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 30 ℃ (40%) and 36.5 ℃ (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 33 ℃ (40%) and 37.5 ℃ (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 paclitaxel micropowder respectively and contain sustained-release micro-spheres, the 100mg paclitaxel micropowder of 200mg paclitaxel and contain sustained-release micro-spheres, the 50mg paclitaxel micropowder of 100mg paclitaxel and contain sustained-release micro-spheres, the 10mg paclitaxel micropowder of 50mg paclitaxel and contain sustained-release micro-spheres, the 1mg paclitaxel micropowder of 10mg paclitaxel and contain the sustained-release micro-spheres of 1mg paclitaxel) then, makes the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% paclitaxel.Record its gelling temperature and be respectively 38.5 ℃, 37 ℃, 36.5 ℃, 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 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 docetaxel sustained-release micro-spheres in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% docetaxel.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 paclitaxel and the docetaxel of embodiment 5 and 6, found that be respectively 156 ± 38,138 ± 36,115 ± 26,88 ± 15 and 66 ± 14 days average time (estimating can measure the time in the blood) that discharges in 20%, 10%, 5%, the 1% and 0.1% paclitaxel body; 20%, was respectively 148 ± 30,127 ± 28,118 ± 26,90 ± 8 and 76 ± 14 days the average time that discharges in the body of 10%, 5%, 1% and 0.1% docetaxel.
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 the container of 2mg taxol slow release microballoons in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% paclitaxel.Record its gelling temperature and be respectively 37.5 ℃, 36.5 ℃, 36 ℃, 34.5 ℃ 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 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 taxol slow release microballoons in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% paclitaxel.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 15000-30000.
Embodiment 10.
Use more convenient according to the anticancer sustained-release gel injection that method " (2) " 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 15%-25% contains the 0.01%-30% paclitaxel;
(2) the block copolymer aqueous solution of 16%-28% contains the 0.05%-30% docetaxel;
(3) the block copolymer aqueous solution of 16%-26% contains 0.05%-30% hydroxyl paclitaxel; Or
(4) the block copolymer aqueous solution of 15%-27% contains the 0.01%-25% Epitaxol.
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%-14%, 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 " (2) " 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% paclitaxel;
(2) 19% block copolymer aqueous solution contains the 0.05%-10% docetaxel;
(3) 20% block copolymer aqueous solution contains 0.05%-30% hydroxyl paclitaxel; Or
(4) 21% block copolymer aqueous solution contains the 0.01%-25% Epitaxol.
Medicine in the above-mentioned anticancer sustained-release gel injection is a sustained-release micro-spheres, and its gelling temperature is 33 ℃-38 ℃, and be 8-14 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 " (2) " 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) 1% paclitaxel, formulated by 10mg paclitaxel, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1% docetaxels, formulated by 10mg docetaxel, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2% hydroxyl paclitaxels, formulated by 20mg hydroxyl paclitaxel, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 4% paclitaxels, formulated by 40mg paclitaxel, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 5% paclitaxels, formulated by 50mg paclitaxel, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection;
(6) 10% docetaxels, formulated by 100mg docetaxel, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(7) 15% paclitaxels are by 150mg paclitaxel, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(8) 20% paclitaxel or docetaxels, formulated by 200mg paclitaxel or docetaxel, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(9) 25% paclitaxel or paclitaxels are by 250mg paclitaxel or paclitaxel, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Medicine in the above-mentioned anticancer sustained-release gel injection is drug powder and sustained-release micro-spheres, and its gelling temperature is 32 ℃-38.5 ℃, 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 1200-1600, 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 13.
Use more convenient according to the anticancer sustained-release gel injection that method " (2) " 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% paclitaxel, formulated by 10mg paclitaxel, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 5% docetaxels, formulated by 50mg docetaxel, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 5% hydroxyl paclitaxels, formulated by 50mg hydroxyl paclitaxel, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 8% paclitaxel or docetaxels, formulated by 80mg paclitaxel or docetaxel, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 2.5% paclitaxels, formulated by 25mg paclitaxel, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection;
(6) 8% paclitaxel or docetaxels, formulated by 80mg paclitaxel or docetaxel, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(7) 10% paclitaxels are by 100mg paclitaxel, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(8) 15% paclitaxel or docetaxels, formulated by 150mg paclitaxel or docetaxel, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(9) 20% paclitaxel or paclitaxels are by 200mg paclitaxel or paclitaxel, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
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 12000-28000.
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% paclitaxel among the intratumor injection 0.1ml embodiment 5 in its hypochondrium.Measure gross tumor volume every day, the result shows that the paclitaxel 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 thyroid adenoncus oncocyte 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% docetaxel among the intratumor injection 0.5ml embodiment 6 in its hypochondrium.Measure gross tumor volume every day, the result shows that the docetaxel 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 taxone sustained-release gel injection
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell 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 5mg-25mg/.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th day.
Table 1
Above result shows under the above concentration of taxone sustained-release gel injection the pancreas tumor growth of tumour cell is all had the obvious suppression effect, and be dose-effect relationship.
The tumor-inhibiting action of embodiment 17, taxone 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 selected from embodiment 10, places in tumor.Taxone 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
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| ?1(5) | Contrast | 42±10 | |
| ?2(5) | 0.1% paclitaxel | 38±8.8 | ?＜0.05 |
| ?3(5) | 1% paclitaxel | 32±7.8 | ?＜0.01 |
| ?4(5) | 7.5% paclitaxel | 24±6.4 | ?＜0.001 |
| ?5(5) | 15% paclitaxel | 20±6.0 | ?＜0.01 |
| ?6(5) | 1% hydroxyl paclitaxel | 34±8.0 | ?＜0.001 |
| ?7(5) | 5% hydroxyl paclitaxel | 26±6.8 | ?＜0.01 |
| ?8(5) | 15% hydroxyl paclitaxel | 18±4.6 | ?＜0.01 |
| ?9(5) | 2% docetaxel | 32±5.6 | ?＜0.05 |
| ?10(5) | 8% docetaxel | 22±4.20 | ?＜0.01 |
| ?11(6) | 15% docetaxel | 16±3.8 | ?＜0.001 |
Above result shows, during the above concentration of used taxone sustained-release gel injection many hepatocarcinoma growth of tumour cell all had the obvious suppression effect, and is dose-effect relationship.
The tumor-inhibiting action of embodiment 18, 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 3).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 3) on the 30th day.
Table 3
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| ?1(5) | Contrast | - | |
| ?2(5) | 5% paclitaxel (micropowder) | 52 | ＜0.05 |
| ?3(5) | 5% paclitaxel (microsphere) | 60 | ＜0.01 |
| ?4(5) | 5% docetaxel (micropowder) | 50 | ＜0.05 |
| ?5(5) | 5% docetaxel (microsphere) | 62 | ＜0.01 |
| ?6(5) | 5% hydroxyl paclitaxel (micropowder) | 62 | ＜0.05 |
| ?7(5) | 5% hydroxyl paclitaxel (microsphere) | 74 | ＜0.01 |
| ?8(5) | 5% Epitaxol (micropowder) | 54 | ＜0.05 |
| ?9(5) | 5% Epitaxol (microsphere) | 62 | ＜0.01 |
| ?10(5) | 8% removes acetyl paclitaxel (micropowder) | 56 | ＜0.05 |
| ?11(5) | 8% removes acetyl paclitaxel (microsphere) | 64 | ＜0.01 |
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 19, 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 4).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 4) on the 30th day.
Table 4
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, pulmonary carcinoma, bladder cancer
In a word, growth all has the obvious suppression effect to used taxone sustained-release gel injection to kinds of tumor cells.Therapeutic effect is directly proportional with metering.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 taxone is characterized in that anticancer sustained-release gel injection is made up of taxone, amphipathic nature block polymer, solvent and a certain amount of drug release regulator of effective anticancer;
Wherein, taxone partly or entirely is wrapped in the sustained-release micro-spheres, and the percentage by weight of taxone in anticancer sustained-release gel injection is 0.005%-40%; 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%.
2. 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:
Taxone 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.
3. according to claim 1 and 2 described anticancer sustained-release gel injections, it is characterized in that taxone is selected from paclitaxel, hydroxyl paclitaxel, Epitaxol, goes one of acetyl paclitaxel or its combination.
4. the anticancer sustained-release gel injection according to claim 1, it is characterized in that 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.
5. according to claim 1 and 2 described anticancer sustained-release gel injections, it is characterized in that used 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.
6. it is one of following that the anticancer sustained-release gel injection according to claim 1, the preparation method that it is characterized in that described anticancer sustained-release gel injection are selected from:
(1) prepares amphipathic aqueous copolymers solution with solvent earlier, add a certain amount of taxone 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 taxone 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 taxone, uses after intensification is redissolved before using;
(3) the preparation taxone 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 taxone aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind taxone 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 taxone, 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 taxone, 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.
7. the anticancer sustained-release gel injection according to claim 1 is characterized in that described anticancer sustained-release gel injection contains one of following ingredients:
(1) the block copolymer aqueous solution of 15%-25% contains the 0.01%-30% paclitaxel;
(2) the block copolymer aqueous solution of 16%-28% contains the 0.05%-30% docetaxel;
(3) the block copolymer aqueous solution of 16%-26% contains 0.05%-30% hydroxyl paclitaxel; Or
(4) the block copolymer aqueous solution of 15%-27% contains the 0.01%-25% Epitaxol.
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; 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.
8. the anticancer sustained-release gel injection according to claim 1 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% paclitaxel;
(2) 19% block copolymer aqueous solution contains the 0.05%-10% docetaxel;
(3) 20% block copolymer aqueous solution contains 0.05%-30% hydroxyl paclitaxel; Or
(4) 21% block copolymer aqueous solution contains the 0.01%-25% Epitaxol.
Medicine in the above-mentioned anticancer sustained-release gel injection is a sustained-release micro-spheres, and its gelling temperature is 33 ℃-38 ℃, and be 8-14 week release time in the animal body; 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.
9. the anticancer sustained-release gel injection according to claim 1 is characterized in that described anticancer sustained-release gel injection contains one of following ingredients:
(1) 1% paclitaxel, formulated by 10mg paclitaxel, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1% docetaxels, formulated by 10mg docetaxel, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2% hydroxyl paclitaxels, formulated by 20mg hydroxyl paclitaxel, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 4% paclitaxels, formulated by 40mg paclitaxel, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 5% paclitaxels, formulated by 50mg paclitaxel, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection;
(6) 10% docetaxels, formulated by 100mg docetaxel, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(7) 15% paclitaxels are by 150mg paclitaxel, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(8) 20% paclitaxel or docetaxels, formulated by 200mg paclitaxel or docetaxel, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(9) 25% paclitaxel or paclitaxels are by 250mg paclitaxel or paclitaxel, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Medicine in the above-mentioned anticancer sustained-release gel injection is drug powder and sustained-release micro-spheres, and its gelling temperature is 32 ℃-38.5 ℃, and be 5-14 week release time in the 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; Amphipathic nature block polymer is a Vicryl Rapide Polyethylene Glycol Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1200-1600, 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.
10. described according to Claim 8 anticancer sustained-release gel injection is characterized in that described sustained-release gel injection is used to prepare former or the cancer of transfer or the anticancer injection of sarcoma or carcinosarcoma that treatment 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.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008103018355A CN101283976A (en) | 2008-05-30 | 2008-05-30 | Anticancer sustained-release gel injection containing taxone medicine |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008103018355A CN101283976A (en) | 2008-05-30 | 2008-05-30 | Anticancer sustained-release gel injection containing taxone medicine |
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| CN101283976A true CN101283976A (en) | 2008-10-15 |
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| CNA2008103018355A Withdrawn CN101283976A (en) | 2008-05-30 | 2008-05-30 | Anticancer sustained-release gel injection containing taxone medicine |
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| CN101697963B (en) * | 2009-10-29 | 2012-04-18 | 福建医科大学附属协和医院 | Method for preparing PLGA slow-release microsphere carrying docetaxel and application thereof in chemotherapy of mesenchyma stroma of tumors under ultrasonic mediation |
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| CN105708789B (en) * | 2016-03-16 | 2018-12-21 | 四川大学 | A kind of medicament-carrying nano-fiber microballoon/hydrogel composites and its preparation method and application |
| CN105708789A (en) * | 2016-03-16 | 2016-06-29 | 四川大学 | Drug-loaded nanofiber microsphere/hydrogel compound and preparation method and application thereof |
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| CN112165949A (en) * | 2018-03-16 | 2021-01-01 | Dfb索里亚有限责任公司 | Topical therapy using taxane nanoparticles for the treatment of Cervical Intraepithelial Neoplasia (CIN) and cervical cancer |
| CN110051624A (en) * | 2019-05-30 | 2019-07-26 | 西南医科大学附属医院 | It is a kind of for treat malignant tumour and splanchnocoel transfer microballoon-gel sustained-release preparation |
| CN112972761A (en) * | 2021-02-09 | 2021-06-18 | 长春圣博玛生物材料有限公司 | Injectable filler and injection |
| CN114767879A (en) * | 2022-06-02 | 2022-07-22 | 平顶山学院 | Docetaxel malignant tumor targeting microsphere and preparation method and application thereof |
| CN115317665A (en) * | 2022-08-12 | 2022-11-11 | 济南格莱威医疗科技有限公司 | Polyester particle composite temperature-sensitive in-situ gel subcutaneous implant |
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