CN101273967A - Anticancer sustained-release injection containing neovascularization inhibitor - Google Patents
Anticancer sustained-release injection containing neovascularization inhibitor Download PDFInfo
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Abstract
The invention relates to an anti-cancer sustained-release injection containing an angiogenesis inhibitor, which comprises the angiogenesis inhibitor, an amphiphilic block copolymer, a solvent and a certain amount of drug release regulator; wherein, the mixture of the amphiphilic block copolymer and a solvent without organic solvent has the temperature-sensitive gelatinization feature, which is flowable liquid in the environment that is lower than the body temperature and can be automatically converted to the water-insoluble gel that can not flow and be biodegradable for absorption in an endotherm, and the water-insoluble gel can allow the contained angiogenesis inhibitor to have the local sustained release in a tumor and maintain the effective drug concentration for a plurality of weeks to a plurality of months. The sustained-release gel injection can be injected in the tumor or the tumor periphery or be arranged in the postoperative tumor cavity, thus significantly reducing the systemic reaction of the drug and being used for the treatment of the tumors in different stages. The angiogenesis inhibitor is selected from tipifarnib, sirolimus, gefitinib, erlotinib, lapatinib, pelitinib, endostatin, simatinib, dasatinib, avastin, sorafenib, sunitinib, ostwald and so on.
Description
(1) technical field
The present invention relates to a kind of slow-releasing anticarcinogen injection that contains neovascularization inhibitor, belong to technical field of pharmaceuticals.Particularly, this invention relates to a kind of neovascularization inhibitor can being stablized and is released to the partial sustained-release gel preparation of entity tumor, 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, thereby the neovascularization inhibitor of being forgiven slowly can be discharged at tumor by local, from a few days to several weeks.
(2) background technology
Chemotherapeutics topical application, particularly local sustained release have become the research direction and the focus of current entity tumor chemotherapy.Yet present biodegradable sustained-release preparation multi-purpose solid polymer such as polyglycolic acid, polylactic acid or its copolymer etc. are as slow-released carrier.Because the hydrophobic performance of this type of macromolecule carrier, these polymer need organic solvent in the slow releasing pharmaceutical preparation process, as dichloromethane, and chloroform, acetic acid or dimethyl formamide etc.For removing deleterious organic solvent, must be extensively dry.Therefore, in most of the cases, final slow releasing preparation mostly is solid shape (for example, microsphere, lamellar or bar-shaped), needs complicated implantation process, and easily causes tissue injury even tumor cell to plant or send out.In addition, organic solvent or high thermal process often cause many anticancer active ingredient degraded degeneration, and the solid implant can not effectively cover the irregular tumor chamber behind the tumor resection, therefore can not effectively remove postoperative residual tumor cell, can not effectively control postoperative recurrence.
Therefore, new easy operating, environmental protection, the effective 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.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.Semisolid or solid gel can not only prolong drug also can be kept higher drug level release time, 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.
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, 300-30, and 000, but with 500-20,000 is preferred, with 1000-10,000 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 96: 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 ℃-37 ℃, serves as preferred with 31 ℃-36.5 ℃, 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.
Production technology and clinical practice requirement are depended in the packing of neovascularization inhibitor and sustained-release gel and application.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.
The preparation of sustained-release gel injection has several different methods, for simplicity, its main component and step can be expressed as follows: " P " represents amphipathic copolymer (Polymer), " W " represents solvent (Water), " D " represents medicine (Drug), do " G " represent hydrogel (Gel) ， Pinch? represent slow-releasing anticarcinogen injection (Injection).
Method one:
Earlier a certain amount of amphipathic copolymer is made the syringeability hydrogel, be mixed into anticancer sustained-release gel injection with a certain amount of neovascularization inhibitor then.Be summarised as, P becomes G with W, adds D again and becomes I pattern, i.e. patent medicine pattern behind XianCheng's glue.This kind method is fit to be easy to the medicine of hydrolysis degeneration.Can finish at workshop with mixing of neovascularization inhibitor, also its independent packing transportation can be stored, before clinical practice, finish.Finish at workshop and to help medical personnel operation.Made anticancer sustained-release gel injection is at-10 ℃ or the following 1-2 that stores.If before clinical practice, carry out mixing of neovascularization inhibitor and syringeability hydrogel, be preferably in injection and finished and be stored in the best freezing state of low temperature in preceding 1 to 3 day, heat up before using redissolve after use.
The content of amphipathic copolymer in the injectivity hydrogel can be 5% to 40%, but serves as preferred with 10% to 30%, and 15% to 28% for most preferably.
Method two:
Earlier a certain amount of neovascularization inhibitor is made medicaments injection, be mixed into anticancer sustained-release gel injection with a certain amount of amphipathic copolymer then.Be summarised as, D becomes liquid with W, adds P again and becomes I pattern, i.e. patent medicine pattern behind XianCheng's liquid.This kind method is applicable to poorly water-soluble but the medicine of good stability.Can finish at workshop with mixing of amphipathic copolymer, also its independent packing transportation can be stored, before clinical practice, finish.If before clinical practice, mix, be preferably in to inject and finished and be stored in the best freezing state of low temperature in preceding 1 to 3 day, use after intensification is redissolved before using.
The content of amphipathic copolymer in the injectivity hydrogel can be 5% to 40%, but serves as preferred with 10% to 30%, and 15% to 28% for most preferably.
Method three:
Earlier a certain amount of amphipathic copolymer is mixed with a certain amount of neovascularization inhibitor, add solvent then and make slow-releasing anticarcinogen injection.Gel process can be finished at workshop, also amphipathic copolymer and neovascularization inhibitor can separately or can be mixed back packing, transportation, store, and adds solvent before clinical practice.If before clinical practice, add solvent, be preferably in and fully mix before the injection and be stored in the best freezing state of low temperature, heat up before using and redissolve the back and use.
Above method just is illustrative rather than definitive thereof the present invention.The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation.Yet the composition of the kind of medicine and content and amphipathic copolymer and monomeric weight ratio are the gelling temperature of decision slow releasing injection and the key factor of drug release behavior, must just can obtain through a large amount of tests and creative work.The viscosity of sustained-release gel is 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, soil temperature 20, soil temperature 40, soil temperature 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: ZD6474, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin, TNP-470.
Above vasoinhibitor also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
The 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 slow releasing injection depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
The tumor of above-mentioned internal organs can be different histological type, and why the tumor of the lymph node of lymph node divides outstanding golden lymphoma and non_hodgkin lymphoma, and pulmonary carcinoma comprises small cell lung cancer and nonsmall-cell lung cancer etc., and the cerebral tumor comprises glioma etc.Yet common tumor comprises entity tumors such as the retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis of the cerebral tumor, cerebral glioma, renal carcinoma, hepatocarcinoma, carcinoma of gallbladder, cancer of biliary duct, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, hemangioma, osteosarcoma, lymphoma, pulmonary carcinoma, thymic carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, eyes.Except that above-mentioned primary tumo(u)r, its metastatic tumor of locating at brain, central nervous system, spinal cord, spinal column, kidney, adrenal gland, liver, incidence, oral cavity, thyroid, skin, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum etc. also makes indication of the present invention.
Slow releasing injection can be used for the tumor resection postoperative, can effectively control remaining oncocyte, thereby the may command postoperative recurrence; Can be used for the patient that a variety of causes can not excision; Can be used for controlling metastatic lesion, as lymph node etc.; Be used for end-stage patients; The control late complication; With the associating of its cancer therapy drug or method, as local injection associating, and the associating of radiotherapy or immunization therapy of cancer therapy drug and the chemotherapeutics of other administration.
The clinical practice dosage of neovascularization inhibitor depends on patient's concrete condition, comprises age, body weight, sex, tumor type, tumor locus, tumor size and number, treatment experience.Can be from 0.01 to 1000mg/kg body weight, be preferred with 0.1-800mg/kg, 0.1-500mg/kg is for most preferably.But for the sustained-release gel injection made from the crude drug of clinical whole body administration, its medication total amount can be the several times of its intravenous administration maximum tolerated dose even tens of times.
Also can add other medicinal ingredient in the made slow releasing injection of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
(4) specific embodiment
Slow-releasing anticarcinogen injection of the present invention can prepare with following method and step:
(1) prepares amphipathic aqueous copolymers solution with solvent earlier, add a certain amount of neovascularization inhibitor then, become anticancer sustained-release gel injection behind the dissolving mixing.-10 ℃ or following storing for future use.Injection in redissolution, the body before using;
(2) prepare amphipathic aqueous copolymers solution and neovascularization inhibitor respectively, packing stores separately, to make anticancer sustained-release gel injection behind amphipathic aqueous copolymers solution and the abundant mixing of neovascularization inhibitor before the injection, be stored in low temperature or freezing state then, use the redissolution back of heating up before using;
(3) the preparation neovascularization inhibitor is made medicaments injection earlier, is mixed into anticancer sustained-release gel injection with a certain amount of amphipathic copolymer then.-10 ℃ or following storing for future use.Injection in the body after redissolving before using;
(4) prepare neovascularization inhibitor aqueous solution and amphipathic copolymer respectively, packing stores separately, before injection, will make anticancer sustained-release gel injection behind neovascularization inhibitor aqueous solution and the abundant mixing of amphipathic copolymer, be stored in low temperature or freezing state then, use the redissolution back of heating up before using;
(5) a certain amount of amphipathic copolymer is mixed with a certain amount of neovascularization inhibitor, add solvent then and make slow-releasing anticarcinogen injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Or
(6) a certain amount of amphipathic copolymer is mixed with a certain amount of neovascularization inhibitor, separately or mix back packing, transportation, store, before clinical practice, add solvent and fully mix and be stored in low temperature, heat up before using and redissolve the back and use to freezing state.
The regulator that can add 0-15% in the above method.
Said method just is used for explanation but not limitation the present invention.Wherein method " (1) " is preferred.
Embodiment 1.
With 4,2,1 and 0.5g amphipathic nature block polymer (PLGA-PEG-PLGA) put into first, second, third, four containers of fourth respectively, then respectively to first, second, third and four containers of fourth in add 6,8,9 and 9.5 milliliters of waters of injection, make 40%, 20%, 10% and 5% hydrogel.
The molecular weight of Polyethylene Glycol is 800-1200 in the amphipathic nature block polymer, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6: 1.
Embodiment 2.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 1, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 28 ℃ (40%) and 35 ℃ (20%), and does not measure under 10 ℃-38 ℃ of the gelling temperatures of 10% and 5% hydrogel.
Embodiment 3.
With 4,2,1 and 0.5g amphipathic nature block polymer (PLGA-PEG-PLGA) put into first, second, third, four containers of fourth respectively, then respectively to first, second, third and four containers of fourth in add 6,8,9 and 9.5 milliliters of waters of injection, make 40%, 20%, 10% and 5% hydrogel.
The molecular weight of Polyethylene Glycol is 1200-1600 in the amphipathic nature block polymer, accounts for 15% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4: 1.
Embodiment 4.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 3, the result 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.
Above result of the test shows, when gel solution concentration is lower than 5%-10%, and the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection
Embodiment 5.
(molecular weight of Polyethylene Glycol is 1500 among the amphipathic nature block polymer PLGA-PEG-PLGA, accounts for 15% of amphipathic nature block polymer weight with the 2.5g amphipathic nature block polymer; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 5: 1) put into container, add 7.5 milliliters of normal saline then, make 25% copolymer aquagel.Then average mark install to 5 fill respectively 400,200,100,20 and the container of 2mg gefitinib in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% gefitinib.Record its gelling temperature and be respectively 37.5 ℃, 36 ℃, 35 ℃, 34 ℃ and 33 ℃.
Embodiment 6.
(molecular weight of Polyethylene Glycol is 1500 among the amphipathic nature block polymer PLGA-PEG-PLGA, accounts for 15% of amphipathic nature block polymer weight with the 2.5g amphipathic nature block polymer; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 5: 1) put into container, add 7.5 milliliters of normal saline then, make 25% copolymer aquagel.Then average mark install to 5 fill respectively 400,200,100,20 and the container of 2mg Erlotinib in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% Erlotinib.Record its gelling temperature and be respectively 37 ℃, 36.5 ℃, 34 ℃, 33.5 ℃ and 32 ℃.
Embodiment 7.
Measure interior (subcutaneous) release cycle of mice body of the variable concentrations gefitinib and the Erlotinib of embodiment 5 and 6, found that be respectively 60 ± 8,55 ± 6,50 ± 6,45 ± 5 and 40 ± 4 days average time (estimating can measure the time in the blood) that discharges in 20%, 10%, 5%, the 1% and 0.1% gefitinib body; 20%, was respectively 62 ± 10,50 ± 8,48 ± 6,42 ± 8 and 38 ± 4 days the average time that discharges in the body of 10%, 5%, 1% and 0.1% Erlotinib.
Embodiment 8.
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, it is one of following that preferred anticancer sustained-release gel injection also comprises:
(1) the block copolymer aqueous solution of 10%-30% contains 0.005%-30% ZD6474 or Zarnestra;
(2) the block copolymer aqueous solution of 10%-30% contains 0.05%-30% sirolimus or rapamycin;
(3) the block copolymer aqueous solution of 12%-28% contains 0.05%-30% lenalidomide or Ai Sha for health;
(4) the block copolymer aqueous solution of 12%-26% contains 0.01%-25% gefitinib or Erlotinib;
(5) the block copolymer aqueous solution of 11%-30% contains 0.01%-25% Lapatinib or votaranib;
(6) the block copolymer aqueous solution of 12%-30% contains 0.01%-25% WAY-EKB 569 or thalidomide;
(7) the block copolymer aqueous solution of 10%-32% contains 0.01%-25% grace degree or imatinib;
(8) the block copolymer aqueous solution of 13%-28% contains 0.1%-25% Sugen 5416 or BMS 354825;
(9) the block copolymer aqueous solution of 14%-29% contains 0.1%-20% Avastin or Cl 1033;
(10) the block copolymer aqueous solution of 12%-28% contains 0.2%-22% Sorafenib or Sutent;
(11) the block copolymer aqueous solution of 15%-30% contains 0.25%-25% TLK286 or ABX-EGF;
(12) the block copolymer aqueous solution of 10%-32% contains 0.5%-25% Marimastat or SU5416;
(13) the block copolymer aqueous solution of 11%-28% contains 0.75%-25%SU6668 or Amebacilin;
(14) the block copolymer aqueous solution of 9%-32% contains 1%-28%TNP-470;
(15) the block copolymer aqueous solution of 10%-28% contains 1%-15% gefitinib or Erlotinib;
(16) the block copolymer aqueous solution of 10%-25% contains 1%-18% ZD6474 or Zarnestra;
(17) the block copolymer aqueous solution of 10%-20% contains 5%-15% Lapatinib or WAY-EKB 569;
(18) the block copolymer aqueous solution of 10%-28% contains 1%-10% BMS 354825 or Avastin;
(19) the block copolymer aqueous solution of 10%-28% contains 1%-15% gefitinib or Erlotinib; Or
(20) the block copolymer aqueous solution of 15%-25% contains 1%-10% Sorafenib or Sutent.
The gelling temperature of above-mentioned anticancer sustained-release gel injection is 32 ℃-37.5 ℃, and be 2-8 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1000, accounts for 15% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6: 1.
Embodiment 9
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, it is one of following that preferred anticancer sustained-release gel injection also comprises:
(1) the block copolymer aqueous solution of 20%-25% contains 0.5%-20% ZD6474 or Zarnestra;
(2) the block copolymer aqueous solution of 20%-26% contains 0.5%-10% sirolimus or rapamycin;
(3) the block copolymer aqueous solution of 20%-28% contains 0.5%-20% lenalidomide or Ai Sha for health;
(4) the block copolymer aqueous solution of 20%-26% contains 0.1%-20% gefitinib or Erlotinib;
(5) the block copolymer aqueous solution of 18%-30% contains 0.1%-20% Lapatinib or votaranib;
(6) the block copolymer aqueous solution of 18%-30% contains 0.1%-20% WAY-EKB 569 or thalidomide;
(7) the block copolymer aqueous solution of 18%-28% contains 0.1%-20% grace degree or imatinib;
(8) the block copolymer aqueous solution of 18%-26% contains 0.5%-20% Sugen 5416 or BMS 354825;
(9) the block copolymer aqueous solution of 18%-28% contains 0.5%-20% Avastin or Cl 1033;
(10) the block copolymer aqueous solution of 18%-26% contains 0.6%-20% Sorafenib or Sutent;
(11) the block copolymer aqueous solution of 16%-26% contains 2%-20% TLK286 or ABX-EGF;
(12) the block copolymer aqueous solution of 16%-30% contains 5%-25% Marimastat or SU5416;
(13) the block copolymer aqueous solution of 16%-28% contains 5%-20%SU6668 or Amebacilin;
(14) the block copolymer aqueous solution of 16%-25% contains 10%-20%TNP-470;
(15) the block copolymer aqueous solution of 18%-28% contains 5%-15% gefitinib or Erlotinib;
(16) the block copolymer aqueous solution of 18%-25% contains 2%-18% ZD6474 or Zarnestra;
(17) the block copolymer aqueous solution of 18%-26% contains 5%-15% Lapatinib or WAY-EKB 569;
(18) the block copolymer aqueous solution of 18%-28% contains 5%-10% BMS 354825 or Avastin;
(19) the block copolymer aqueous solution of 18%-28% contains 5%-15% gefitinib or Erlotinib; Or
(20) the block copolymer aqueous solution of 18%-25% contains 5%-10% Sorafenib or Sutent.
The gelling temperature of above-mentioned anticancer sustained-release gel injection is 32 ℃-37.5 ℃, and be 2-8 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is 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 4: 1.
Embodiment 10.
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, preferred anticancer sustained-release gel injection contain concentration, become to be grouped into percentage by weight as follows:
(1) 0.1% ZD6474 or Zarnestra, formulated by 1mg ZD6474 or Zarnestra, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1% sirolimus or rapamycins, formulated by 10mg sirolimus or rapamycin, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2% lenalidomides or Ai Sha are for health, and be formulated for health, 250mg amphipathic nature block polymer and 750ul normal saline by 20mg lenalidomide or Ai Sha;
(4) 4% gefitinib or Erlotinib, formulated by 40mg gefitinib or Erlotinib, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 5% Lapatinib or votaranibs, formulated by 50mg Lapatinib or votaranib, 220mg amphipathic nature block polymer and 780ul phosphate buffer
(6) 7% WAY-EKB 569 or thalidomide, formulated by 70mg WAY-EKB 569 or thalidomide, 260mg amphipathic nature block polymer and 740ul normal saline
(7) 0.5% grace degree or imatinibs, formulated by 5mg grace degree or imatinib, 280mg amphipathic nature block polymer, 20mg mannitol and 700ul water for injection;
(8) 0.1% Sugen 5416 or BMS 354825, formulated by 1mg Sugen 5416 or BMS 354825,260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 0.3% Avastin or Cl 1033s, formulated by 3mg Avastin or Cl 1033,230mg amphipathic nature block polymer, 0.04g mannitol and 730ul normal saline
(10) 0.5% Sorafenib or Sutents, formulated by 5mg Sorafenib or Sutent, 200mg amphipathic nature block polymer, 0.05g mannitol and 750ul water for injection;
(11) 0.8% TLK286 or ABX-EGF, formulated by 8mg TLK286 or ABX-EGF, 260mg amphipathic nature block polymer and 740ul phosphate buffer
(12) 1% Marimastat or SU5416, formulated by 10mg Marimastat or SU5416,200mg amphipathic nature block polymer, 0.02g sorbitol and 780ul normal saline
(13) 1.25%SU6668 or Amebacilin, formulated by 12.5mgSU6668 or Amebacilin, 230mg amphipathic nature block polymer, 0.07g mannitol and 700ul normal saline
(14) 1.5%TNP-470,15mgTNP-470, formulated by 200mg amphipathic nature block polymer, 0.01g mannitol and 790ul water for injection;
(15) 2% gefitinib or Erlotinib, formulated by 20mg gefitinib or Erlotinib, 220mg amphipathic nature block polymer and 780ul phosphate buffer
(16) 5% ZD6474 or Zarnestras, formulated by 50mg ZD6474 or Zarnestra, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 10% Lapatinib or WAY-EKB 569, formulated by 100mg Lapatinib or WAY-EKB 569,230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline
(18) 15% BMS 354825 or Avastins, formulated by 150mg BMS 354825 or Avastin, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 20% gefitinib or Erlotinib, by the 200mg gefitinib or Erlotinib, 220mg amphipathic nature block polymer, 20mg mannitol and 760ul phosphate buffer are formulated or
(20) 25% Sorafenib or Sutents, formulated by 250mg Sorafenib or Sutent, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Above amphipathic nature block polymer is Polyethylene Glycol-Vicryl Rapide-Polyethylene Glycol, and wherein the molecular weight of Polyethylene Glycol is 800-1200, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-6: 1.
Studies show that the gelling temperature of above-mentioned anticancer sustained-release gel injection is 30 ℃-37 ℃, be 2-8 week release time in the animal body.
Embodiment 11.
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, preferred anticancer sustained-release gel injection also comprises and followingly contains concentration, becomes to be grouped into and percentage by weight:
(1) 1% ZD6474 or Zarnestra, formulated by 10mg ZD6474 or Zarnestra, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 5% sirolimus or rapamycins, formulated by 50mg sirolimus or rapamycin, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 5% lenalidomides or Ai Sha are for health, and be formulated for health, 250mg amphipathic nature block polymer and 750ul normal saline by 50mg lenalidomide or Ai Sha;
(4) 8% gefitinib or Erlotinib, formulated by 80mg gefitinib or Erlotinib, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 10% Lapatinib or votaranibs, formulated by 100mg Lapatinib or votaranib, 220mg amphipathic nature block polymer and 780ul phosphate buffer
(6) 2% WAY-EKB 569 or thalidomide, formulated by 20mg WAY-EKB 569 or thalidomide, 260mg amphipathic nature block polymer and 740ul normal saline
(7) 5% grace degree or imatinibs, formulated by 50mg grace degree or imatinib, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 2% Sugen 5416 or BMS 354825, formulated by 20mg Sugen 5416 or BMS 354825,260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 3% Avastin or Cl 1033s, formulated by 30mg Avastin or Cl 1033,230mg amphipathic nature block polymer, 0.04g mannitol and 730ul normal saline
(10) 2.5% Sorafenib or Sutents, formulated by 25mg Sorafenib or Sutent, 200mg amphipathic nature block polymer, 0.05g mannitol and 750ul water for injection;
(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, 0.02g sorbitol and 780ul normal saline
(13) 5%SU6668 or Amebacilin, formulated by 50mgSU6668 or Amebacilin, 230mg amphipathic nature block polymer, 0.07g mannitol and 700ul normal saline
(14) 5%TNP-470,50mgTNP-470, formulated by 200mg amphipathic nature block polymer, 0.01g mannitol and 790ul water for injection;
(15) 8% gefitinib or Erlotinib, formulated by 80mg gefitinib or Erlotinib, 220mg amphipathic nature block polymer and 780ul phosphate buffer
(16) 10% ZD6474 or Zarnestras, formulated by 100mg ZD6474 or Zarnestra, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline
(17) 2% Lapatinib or WAY-EKB 569, formulated by 20mg Lapatinib or WAY-EKB 569,230mg amphipathic nature block polymer, 90mg mannitol and 680ul normal saline
(18) 5% BMS 354825 or Avastins, formulated by 50mg BMS 354825 or Avastin, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 15% gefitinib or Erlotinib, by the 150mg gefitinib or Erlotinib, 220mg amphipathic nature block polymer, 20mg mannitol and 760ul phosphate buffer are formulated or
(20) 20% Sorafenib or Sutents, formulated by 200mg Sorafenib or Sutent, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Studies show that the gelling temperature of above-mentioned anticancer sustained-release gel injection is 32 ℃-37.5 ℃, be 2-8 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1200-1600, accounts for 15% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6-9: 1.
The therapeutic effect of anticancer sustained-release gel injection can further specify by following test and treatment embodiment.
Embodiment 12
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% gefitinib among the intratumor injection 0.1ml embodiment 5 in its hypochondrium.Measure gross tumor volume every day, the result shows that the gefitinib 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 slow releasing injection operation most convenient, easy.
Embodiment 13
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% Erlotinib among the intratumor injection 0.5ml embodiment 5 in its hypochondrium.Measure gross tumor volume every day, the result shows that the Erlotinib 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 slow releasing injection.Good effect not only, toxic and side effects is also little.
Embodiment 14, contain tumor-inhibiting action in the body of neovascularization inhibitor slow releasing injection
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 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% ZD6474 | 36±8.2 | ?＜0.05 |
| 3(5) | 5% Zarnestra | 32±6.0 | ?＜0.01 |
| 4(5) | 10% Lapatinib | 36±6.2 | ?＜0.01 |
| 5(6) | 10% WAY-EKB 569 | 38±5.8 | ?＜0.01 |
| 6(5) | 15% BMS 354825 | 36±6.2 | ?＜0.01 |
| 7(5) | 15% Avastin | 30±6.2 | ?＜0.001 |
| 8(5) | 25% Sorafenib | 24±6.8 | ?＜0.001 |
| 9(5) | 25% Sutent | 28±4.4 | ?＜0.001 |
| 10(5) | 20% gefitinib | 20±4.0 | ?＜0.001 |
| 11(5) | 20% Erlotinib | 22±4.8 | ?＜0.001 |
Above result shows that the neovascularization inhibitor slow releasing injection all has the obvious suppression effect to the pancreas tumor growth of tumour cell under this concentration.
The tumor-inhibiting action of embodiment 15, neovascularization inhibitor slow releasing injection
With the rat is subjects, with 2 * 10
5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 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 slow releasing injection is selected from embodiment 10, places 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
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(5) | Contrast | 42±10 | |
| 2(5) | 0.1% ZD6474 | 36±8.2 | ?＜0.05 |
| 3(5) | 0.1% Zarnestra | 38±6.8 | ?＜0.01 |
| 4(5) | 1% sirolimus | 34±6.4 | ?＜0.001 |
| 5(5) | 1% rapamycin | 36±6.0 | ?＜0.01 |
| 6(5) | 2% lenalidomide | 34±6.0 | ?＜0.001 |
| 7(5) | 2% Ai Sha is for health | 36±6.8 | ?＜0.01 |
| 8(5) | 4% gefitinib | 30±4.6 | ?＜0.001 |
| 9(5) | 4% Erlotinib | 32±5.6 | ?＜0.01 |
| 10(5) | 5% Lapatinib | 28±4.0 | ?＜0.001 |
| 11(6) | 5% votaranib | 28±2.80 | ?＜0.01 |
Above result shows that used neovascularization inhibitor slow releasing injection all has the obvious suppression effect to many hepatocarcinoma growth of tumour cell when this concentration.
The tumor-inhibiting action of embodiment 16, neovascularization inhibitor slow releasing 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 slow releasing injection is selected from embodiment 10, places 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
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(5) | Contrast | - | |
| 2(5) | 7% WAY-EKB 569 | 88 | ?＜0.05 |
| 3(5) | 7% thalidomide | 82 | ?＜0.01 |
| 4(5) | 0.5% grace degree | 68 | ?＜0.01 |
| 5(5) | 0.5% grace degree | 66 | ?＜0.01 |
| 6(5) | 0.1% Sugen 5416 | 64 | ?＜0.01 |
| 7(5) | 0.1% BMS 354825 | 62 | ?＜0.01 |
| 8(5) | 0.3% Avastin | 68 | ?＜0.001 |
| 9(5) | 0.3% Cl 1033 | 72 | ?＜0.01 |
| 10(5) | 0.5% Sorafenib | 78 | ?＜0.01 |
| 11(5) | 0.5% Sutent | 68 | ?＜0.01 |
The tumor-inhibiting action of embodiment 17 neovascularization inhibitor slow releasing injection
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 slow releasing injection is selected from embodiment 11, places 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% ZD6474 | 62 | ＜0.05 |
| 3(5) | 1% Zarnestra | 56 | ＜0.01 |
| 4(5) | 5% sirolimus | 62 | ＜0.01 |
| 5(5) | 5% rapamycin | 68 | ＜0.01 |
| 6(5) | 5% lenalidomide | 58 | ＜0.01 |
| 7(5) | 5% Ai Sha is for health | 52 | ＜0.01 |
| 8(5) | 8% gefitinib | 70 | ＜0.01 |
| 9(5) | 8% Erlotinib | 72 | ＜0.01 |
| 10(5) | 10% Lapatinib | 80 | ＜0.01 |
| 11(5) | 10% votaranib | 80 | ＜0.01 |
The tumor-inhibiting action of embodiment 18, 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 slow releasing injection is selected from embodiment 11, places 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% WAY-EKB 569 | 50 | ?＜0.05 |
| 3(5) | 2% thalidomide | 52 | ?＜0.05 |
| 4(5) | 5% grace degree | 50 | ?＜0.05 |
| 5(5) | 5% imatinib | 54 | ?＜0.05 |
| 6(5) | 2% Sugen 5416 | 62 | ?＜0.01 |
| 7(5) | 2% BMS 354825 | 52 | ?＜0.01 |
| 8(5) | 3% Avastin | 74 | ?＜0.01 |
| 9(5) | 3% Cl 1033 | 80 | ?＜0.01 |
| 10(5) | 2.5% Sorafenib | 78 | ?＜0.001 |
| 11(5) | 2.5% Sutent | 80 | ?＜0.01 |
The tumor-inhibiting action of embodiment 19, 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 slow releasing injection is selected from embodiment 11, places in tumor.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
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(5) | Contrast | - | |
| 2(5) | 5% TLK286 | 58 | ?＜0.05 |
| 3(5) | 5% ABX-EGF | 52 | ?＜0.05 |
| 4(5) | 5% Marimastat | 50 | ?＜0.05 |
| 5(5) | ?5％SU5416 | 54 | ?＜0.05 |
| 6(5) | ?5％SU6668 | 62 | ?＜0.01 |
| 7(5) | 5% Amebacilin | 52 | ?＜0.01 |
| 8(5) | ?5％TNP-470 | 74 | ?＜0.01 |
| 9(5) | 3% Cl 1033 | 50 | ?＜0.01 |
| 10(5) | 8% gefitinib | 78 | ?＜0.001 |
| 11(5) | 8% Erlotinib | 80 | ?＜0.01 |
The tumor-inhibiting action of embodiment 20, neovascularization inhibitor slow releasing agent
With the rat is subjects, with 2 * 10
5Individual oophoroma 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 slow releasing injection is selected from embodiment 11, places in tumor.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) | 10% ZD6474 | 78 | ?＜0.05 |
| 3(5) | 10% Zarnestra | 72 | ?＜0.05 |
| 4(5) | 2% Lapatinib | 52 | ?＜0.05 |
| 5(5) | 2% WAY-EKB 569 | 56 | ?＜0.05 |
| 6(5) | 5% BMS 354825 | 64 | ?＜0.01 |
| 7(5) | 5% Avastin | 58 | ?＜0.01 |
| 8(5) | 15% gefitinib | 84 | ?＜0.01 |
| 9(5) | 15% Erlotinib | 80 | ?＜0.01 |
| 10(5) | 20% Sorafenib | 88 | ?＜0.001 |
| 11(5) | 20% Sutent | 82 | ?＜0.01 |
In a word, growth all has the obvious suppression effect to used neovascularization inhibitor slow releasing 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. slow-releasing anticarcinogen injection that contains neovascularization inhibitor is characterized in that slow-releasing anticarcinogen injection is made up of neovascularization inhibitor, amphipathic nature block polymer, solvent and a certain amount of drug release regulator of effective anticancer; Wherein, the mixture of amphipathic nature block polymer and solvent has temperature sensitive gelling characteristics, in being lower than the environment of body temperature, be flowable liquid, can be transformed into the water-insoluble gel of immobilising and biodegradable absorption in the warm-blooded animal body automatically, the latter can slowly discharge contained neovascularization inhibitor and keeps the thoughtful several months of active drug concentration numbers at tumor by local; The viscosity of slow-releasing anticarcinogen injection is 10cp-3000cp (5 ℃-30 ℃ time).
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that neovascularization inhibitor is selected from ZD6474, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin, one of TNP-470 or its combination.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the percentage by weight of neovascularization inhibitor in slow-releasing anticarcinogen injection is:
0.005％-10％；
10%-20%; Or
20％-40％。
4. the slow-releasing anticarcinogen injection according to claim 1 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-polyglycol-polylactic acid, Vicryl Rapide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, polyethylene glycol-lactic acid-Polyethylene Glycol or Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol;
Wherein, 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. the slow-releasing anticarcinogen injection according to claim 1, but it is characterized in that solvent is the aqueous solution of injecting in the body after the sterilization, is selected from distilled water, water for injection, physiology towards liquid, cell culture fluid, body fluid, tissue fluid, buffer, phosphate buffer.Wherein, the percentage ratio of solvent in the hydrogel of amphipathic nature block polymer and solvent composition is 60%-99%.
6. according to claim 1 and 5 described slow-releasing anticarcinogen injections, it is characterized in that used drug release regulator is selected from a kind of or its combination in glue of sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, egg; The drug release regulator is 0-15% at the percentage by weight of slow releasing injection.
7. it is one of following that the slow-releasing anticarcinogen injection according to claim 1, the preparation method that it is characterized in that described slow-releasing anticarcinogen injection are 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 slow-releasing anticarcinogen injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Or
(6) a certain amount of amphipathic copolymer is mixed with a certain amount of neovascularization inhibitor, separately or mix back packing, transportation, store, before clinical practice, add solvent and fully mix and be stored in low temperature, heat up before using and redissolve the back and use to freezing state.
The regulator that can add 0-15% in the above method.
8. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that described slow-releasing anticarcinogen injection contains one of following ingredients:
(1) 0.1% ZD6474 or Zarnestra, formulated by 1mg ZD6474 or Zarnestra, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1% sirolimus or rapamycins, formulated by 10mg sirolimus or rapamycin, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2% lenalidomides or Ai Sha are for health, and be formulated for health, 250mg amphipathic nature block polymer and 750ul normal saline by 20mg lenalidomide or Ai Sha;
(4) 4% gefitinib or Erlotinib, formulated by 40mg gefitinib or Erlotinib, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 5% Lapatinib or votaranibs, formulated by 50mg Lapatinib or votaranib, 220mg amphipathic nature block polymer and 780ul phosphate buffer
(6) 7% WAY-EKB 569 or thalidomide, formulated by 70mg WAY-EKB 569 or thalidomide, 260mg amphipathic nature block polymer and 740ul normal saline
(7) 0.5% grace degree or imatinibs, formulated by 5mg grace degree or imatinib, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 0.1% Sugen 5416 or BMS 354825, formulated by 1mg Sugen 5416 or BMS 354825,260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 0.3% Avastin or Cl 1033s, formulated by 3mg Avastin or Cl 1033,230mg amphipathic nature block polymer, 0.04g mannitol and 730ul normal saline
(10) 0.5% Sorafenib or Sutents, formulated by 5mg Sorafenib or Sutent, 200mg amphipathic nature block polymer, 0.05g mannitol and 750ul water for injection;
(11) 0.8% TLK286 or ABX-EGF, formulated by 8mg TLK286 or ABX-EGF, 260mg amphipathic nature block polymer and 740ul phosphate buffer
(12) 1% Marimastat or SU5416, formulated by 10mg Marimastat or SU5416,200mg amphipathic nature block polymer, 0.02g sorbitol and 780ul normal saline
(13) 1.25%SU6668 or Amebacilin, formulated by 12.5mgSU6668 or Amebacilin, 230mg amphipathic nature block polymer, 0.07g mannitol and 700ul normal saline
(14) 1.5%TNP-470,15mgTNP-470, formulated by 200mg amphipathic nature block polymer, 0.01g mannitol and 790ul water for injection;
(15) 2% gefitinib or Erlotinib, formulated by 20mg gefitinib or Erlotinib, 220mg amphipathic nature block polymer and 780ul phosphate buffer
(16) 5% ZD6474 or Zarnestras, formulated by 50mg ZD6474 or Zarnestra, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline
(17) 10% Lapatinib or WAY-EKB 569, formulated by 100mg Lapatinib or WAY-EKB 569,230mg amphipathic nature block polymer, 90mg mannitol and 680ul normal saline
(18) 15% BMS 354825 or Avastins, formulated by 150mg BMS 354825 or Avastin, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 20% gefitinib or Erlotinib, by the 200mg gefitinib or Erlotinib, 220mg amphipathic nature block polymer, 20mg mannitol and 760ul phosphate buffer are formulated or
(20) 25% Sorafenib or Sutents, formulated by 250mg Sorafenib or Sutent, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Above amphipathic nature block polymer is Polyethylene Glycol-Vicryl Rapide-Polyethylene Glycol, and wherein the molecular weight of Polyethylene Glycol is 1000-1200, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6-9: 1.
9. described according to Claim 8 slow-releasing anticarcinogen injection is characterized in that described slow-releasing anticarcinogen injection contains one of following ingredients:
(1) 1% ZD6474 or Zarnestra, formulated by 10mg ZD6474 or Zarnestra, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 5% sirolimus or rapamycins, formulated by 50mg sirolimus or rapamycin, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 5% lenalidomides or Ai Sha are for health, and be formulated for health, 250mg amphipathic nature block polymer and 750ul normal saline by 50mg lenalidomide or Ai Sha;
(4) 8% gefitinib or Erlotinib, formulated by 80mg gefitinib or Erlotinib, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 10% Lapatinib or votaranibs, formulated by 100mg Lapatinib or votaranib, 220mg amphipathic nature block polymer and 780ul phosphate buffer
(6) 2% WAY-EKB 569 or thalidomide, formulated by 20mg WAY-EKB 569 or thalidomide, 260mg amphipathic nature block polymer and 740ul normal saline
(7) 5% grace degree or imatinibs, formulated by 50mg grace degree or imatinib, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 2% Sugen 5416 or BMS 354825, formulated by 20mg Sugen 5416 or BMS 354825,260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 3% Avastin or Cl 1033s, formulated by 30mg Avastin or Cl 1033,230mg amphipathic nature block polymer, 0.04g mannitol and 730ul normal saline
(10) 2.5% Sorafenib or Sutents, formulated by 25mg Sorafenib or Sutent, 200mg amphipathic nature block polymer, 0.05g mannitol and 750ul water for injection;
(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, 0.02g sorbitol and 780ul normal saline
(13) 5%SU6668 or Amebacilin, formulated by 50mgSU6668 or Amebacilin, 230mg amphipathic nature block polymer, 0.07g mannitol and 700ul normal saline
(14) 5%TNP-470,50mgTNP-470, formulated by 200mg amphipathic nature block polymer, 0.01g mannitol and 790ul water for injection;
(15) 8% gefitinib or Erlotinib, formulated by 80mg gefitinib or Erlotinib, 220mg amphipathic nature block polymer and 780ul phosphate buffer
(16) 10% ZD6474 or Zarnestras, formulated by 100mg ZD6474 or Zarnestra, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline
(17) 2% Lapatinib or WAY-EKB 569, formulated by 20mg Lapatinib or WAY-EKB 569,230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline
(18) 5% BMS 354825 or Avastins, formulated by 50mg BMS 354825 or Avastin, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 15% gefitinib or Erlotinib, by the 150mg gefitinib or Erlotinib, 220mg amphipathic nature block polymer, 20mg mannitol and 760ul phosphate buffer are formulated or
(20) 20% Sorafenib or Sutents, formulated by 200mg Sorafenib or Sutent, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
The gelling temperature of above-mentioned anticancer sustained-release gel injection is 32 ℃-37.5 ℃, and be 2-8 week release time in the animal body; Amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1200-1600, accounts for 15% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-6: 1.
10. described according to Claim 8 described slow-releasing anticarcinogen injection is characterized in that described slow releasing injection is used to prepare former or the cancer of transfer or the anticancer preparation 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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| CNA2007102026275A CN101273967A (en) | 2007-11-22 | 2007-11-22 | Anticancer sustained-release injection containing neovascularization inhibitor |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007102026275A CN101273967A (en) | 2007-11-22 | 2007-11-22 | Anticancer sustained-release injection containing neovascularization inhibitor |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940569B (en) * | 2009-07-07 | 2013-02-13 | 鼎泓国际投资（香港）有限公司 | Medicament composition containing sorafenib, artemisinin and artemisinin derivative and application thereof in preparing medicament for treating cancer |
| CN108680658A (en) * | 2018-03-27 | 2018-10-19 | 苏州桓晨医疗科技有限公司 | A kind of detection method of sirolimus |
| CN113242734A (en) * | 2018-11-26 | 2021-08-10 | 艾葳生物科技有限公司 | Pharmaceutical biosoluble gels for drug delivery |
| CN114306342A (en) * | 2020-09-30 | 2022-04-12 | 江苏先声药业有限公司 | Pharmaceutical composition of imatinib salt for injection and preparation method thereof |
| CN114306342B (en) * | 2020-09-30 | 2024-06-28 | 江苏先声药业有限公司 | Pharmaceutical composition of imatinib salt for injection and preparation method thereof |
-
2007
- 2007-11-22 CN CNA2007102026275A patent/CN101273967A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940569B (en) * | 2009-07-07 | 2013-02-13 | 鼎泓国际投资（香港）有限公司 | Medicament composition containing sorafenib, artemisinin and artemisinin derivative and application thereof in preparing medicament for treating cancer |
| CN108680658A (en) * | 2018-03-27 | 2018-10-19 | 苏州桓晨医疗科技有限公司 | A kind of detection method of sirolimus |
| CN113242734A (en) * | 2018-11-26 | 2021-08-10 | 艾葳生物科技有限公司 | Pharmaceutical biosoluble gels for drug delivery |
| CN114306342A (en) * | 2020-09-30 | 2022-04-12 | 江苏先声药业有限公司 | Pharmaceutical composition of imatinib salt for injection and preparation method thereof |
| CN114306342B (en) * | 2020-09-30 | 2024-06-28 | 江苏先声药业有限公司 | Pharmaceutical composition of imatinib salt for injection and preparation method thereof |
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