CN101229150A - Thermostatic sustained release injection containing taxane and preparing method thereof - Google Patents
Thermostatic sustained release injection containing taxane and preparing method thereof Download PDFInfo
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- CN101229150A CN101229150A CNA2007102026307A CN200710202630A CN101229150A CN 101229150 A CN101229150 A CN 101229150A CN A2007102026307 A CNA2007102026307 A CN A2007102026307A CN 200710202630 A CN200710202630 A CN 200710202630A CN 101229150 A CN101229150 A CN 101229150A
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Abstract
A temperature controlled and sow-released injection consists of taxane with anti-cancer effective quantity, amphiphilic block copolymer, menstruum and a certain quantity of medicine release regulating agent; wherein, the amphiphilic block copolymer consists of polyethylene glycol and polyester and the mixture with the menstruum belonging to organic solvent has temperature-sensitive gelation property; the mixture is flow liquid in the environment with the temperature under somatic temperature and can automatically converted into water insoluble gelatin which can not flow, be biodegraded and absorbed in the body of a warm blood animal, can slowly release the taxane in part of a tumor and can maintain the effective medicine concentration for a plurality of weeks and even mouths. The viscocity of the temperature controlled and sow-released injection is 10 to 3000 cp(5 to 30 DEG C), the temperature of the gelation is 35 to 37 DEG C. the anti-cancer slowly-release gelation injection carries on intra-tumor injection or is put into tumor cavity to cure tumors at different stages. The invention has the advantages of small side effect and obvious curing effect. The taxane is chosen from taxol, docetaxel, 2- hydroxide radical paclitaxel, 10-dehanoyl paclitaxel or 7-epi-taxol, etc.
Description
(1) technical field
The present invention relates to a kind of temperature control sustained-release injection that contains taxane, belong to technical field of pharmaceuticals.Particularly, this invention relates to a kind of taxane 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 taxane 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 taxane is provided, particularly, is a kind of sustained-release gel injection that contains taxane.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 taxane 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 taxane can slowly discharge taxane 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 taxane.
Find that through lot of experiments sustained-release gel injection of the present invention is grouped into by following one-tenth:
A: taxane 0.01-40%
B: amphipathic copolymer 5%-40%
C: solvent 60%-90%
D: regulator 0-15%
More than be weight percentage
Wherein, the preparation of sustained-release gel injection has several different methods, and temperature control sustained-release injection of the present invention can prepare with following method and step:
(1) prepares amphipathic aqueous copolymers solution (B+C) with solvent earlier, add a certain amount of taxane (A) 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; This kind method is fit to be easy to the medicine of hydrolysis degeneration.Can finish at workshop with mixing of taxane, 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 taxane 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.
(2) prepare amphipathic aqueous copolymers solution and taxane 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 taxane, uses after intensification is redissolved before using;
(3) the preparation taxane 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; 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.
(4) prepare taxane aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind taxane 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 taxane, add solvent then and make temperature control sustained-release injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Gel process can be finished at workshop, also amphipathic copolymer and taxane 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
Production technology and clinical practice requirement are depended in the packing of taxane and sustained-release gel and application.Taxane 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 taxane is dispersed in the sustained-release gel.Pack alone or in combination with hybrid packed difference and be, mix with sustained-release gel before taxane is injected in vivo when packing alone or in combination, hybrid packed then is taxane to be dispersed in the sustained-release gel in process of production, direct injection after at room temperature heating up with preceding need.
Or
(6) a certain amount of amphipathic copolymer is mixed with a certain amount of taxane, 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.
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).
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.
The percentage by weight of above-mentioned taxane in slow releasing agent is good from 0.001%-40% with 0.1%-30%, is best with 1%-20%.
Be suitable for amphipathic copolymer of the present invention and form by polyester and Polyethylene Glycol, wherein,
Polyester and Polyethylene Glycol block configuration polyester-polyethylene glycol-ester or polyethylene glycol-ester-Polyethylene Glycol are first-selection with polyester-polyethylene glycol-ester; Polyester and polyethyleneglycol block copolymer 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.
Polyester 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 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 ℃-37 ℃, serves as preferred with 31 ℃-36.5 ℃, with 32 ℃-36 ℃ 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.
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.The percentage by weight of solvent in slow releasing injection is 60%-90%, is preferred with 70%-90%, with 75%-85% for most preferably.
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.
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 taxane depends on patient's concrete condition, comprises age, body weight, sex, tumor type, tumor locus, tumor size and number, treatment experience.Can be from 0.001 to 800mg/kg body weight, be preferred with 0.1-600mg/kg, 0.5-500mg/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
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 paclitaxel 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 ℃, 35 ℃, 34 ℃, 33 ℃ and 31.5 ℃.
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 the many rare paclitaxels of 2mg in, make the anticancer sustained-release gel injection that contains rare paclitaxel more than 20%, 10%, 5%, 1% and 0.1%.Record its gelling temperature and be respectively 37 ℃, 36 ℃, 35 ℃, 33 ℃ and 31 ℃.
Embodiment 7.
Measure interior (subcutaneous) release cycle of mice body of variable concentrations paclitaxel and many rare paclitaxels of embodiment 5 and 6, found that be respectively 54 ± 8,47 ± 6,42 ± 6,35 ± 5 and 32 ± 4 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 54 ± 10,44 ± 8,35 ± 6,30 ± 8 and 28 ± 6 days the average time that discharges in the body of rare paclitaxel more than 10%, 5%, 1% and 0.1%.
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, preferred anticancer sustained-release gel injection contain concentration, become to be grouped into percentage by weight as follows:
Rare paclitaxel or paclitaxel more than (1) 0.5%, formulated by the many rare paclitaxels of 5mg or paclitaxel, 300mg amphipathic nature block polymer and 700ul water for injection;
Rare paclitaxel or paclitaxel more than (2) 1%, formulated by the many rare paclitaxels of 10mg or paclitaxel, 280mg amphipathic nature block polymer and 720ul distilled water;
Rare paclitaxel or paclitaxel more than (3) 5%, formulated by the many rare paclitaxels of 50mg or paclitaxel, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 10% paclitaxels or many rare paclitaxels, formulated by 100mg paclitaxel or many rare paclitaxels, 230mg amphipathic nature block polymer and 770ul water for injection;
Rare paclitaxel or paclitaxel more than (5) 20%, formulated by the many rare paclitaxels of 200mg or paclitaxel, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 7% paclitaxels, formulated by 70mg paclitaxel, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 0.5% paclitaxels, formulated by 5mg paclitaxel, 280mg amphipathic nature block polymer, 20mg mannitol and 700ul water for injection;
(8) 1%2 '-hydroxyl paclitaxels, formulated by 10mg2 '-hydroxyl paclitaxel, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 2%2 '-hydroxyl paclitaxels, formulated by 20mg2 '-hydroxyl paclitaxel, 230mg amphipathic nature block polymer, 0.04g mannitol and 730ul normal saline;
(10) 20%2 '-hydroxyl paclitaxels, formulated by 200mg2 '-hydroxyl paclitaxel, 200mg amphipathic nature block polymer, 0.05g mannitol and 750ul water for injection;
(11) 0.8%2 '-hydroxyl paclitaxels, formulated by 8mg2 '-hydroxyl paclitaxel, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 1%10-removes the acetyl paclitaxel, goes acetyl paclitaxel, 200mg amphipathic nature block polymer, 0.02g sorbitol and 780ul normal saline formulated by 10mg10-;
(13) 1.25%10-removes the acetyl paclitaxel, goes acetyl paclitaxel, 230mg amphipathic nature block polymer, 0.07g mannitol and 700ul normal saline formulated by 12.5mg10-;
Rare paclitaxel more than (14) 1.5%, the many rare paclitaxels, formulated of 15mg by 200mg amphipathic nature block polymer, 0.01g mannitol and 790ul water for injection;
(15) 2% paclitaxels or many rare paclitaxels, formulated by 20mg paclitaxel or many rare paclitaxels, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
Rare paclitaxel more than (16) 5%, formulated by the many rare paclitaxels of 50mg, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 10%10-removes the acetyl paclitaxel, goes acetyl paclitaxel, 230mg amphipathic nature block polymer, 90mg mannitol and 680ul normal saline formulated by 100mg10-;
(18) 15%10-removes the acetyl paclitaxel, goes acetyl paclitaxel, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection formulated by 150mg10-;
(19) 20% paclitaxels or many rare paclitaxels, formulated by 200mg paclitaxel or many rare paclitaxels, 220mg amphipathic nature block polymer, 20mg mannitol and 760ul phosphate buffer; Or
(20) 25%2 '-hydroxyl paclitaxels or 7-table-paclitaxel, formulated by 250mg2 '-hydroxyl paclitaxel or 7-table-paclitaxel, 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 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.
Studies show that the gelling temperature of above-mentioned anticancer sustained-release gel injection is 31 ℃-37 ℃, be 3-7 week release time in the animal body.
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, preferred anticancer sustained-release gel injection also comprises and followingly contains concentration, becomes to be grouped into and percentage by weight:
Rare paclitaxel more than (1) 1%, formulated by the many rare paclitaxels of 10mg, 300mg amphipathic nature block polymer and 700ul water for injection;
Rare paclitaxel more than (2) 5%, formulated by the many rare paclitaxels of 50mg, 280mg amphipathic nature block polymer and 720ul distilled water;
Rare paclitaxel more than (3) 5%, formulated by the many rare paclitaxels of 50mg, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 8% paclitaxels or many rare paclitaxels, formulated by 80mg paclitaxel or many rare paclitaxels, 230mg amphipathic nature block polymer and 770ul water for injection;
Rare paclitaxel more than (5) 10%, formulated by the many rare paclitaxels of 100mg, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 2% paclitaxels, formulated by 20mg paclitaxel, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 5% paclitaxels, formulated by 50mg paclitaxel, 280mg amphipathic nature block polymer, 20mg mannitol and 700ul water for injection;
(8) 2%2-hydroxyl paclitaxel, formulated by 20mg2-hydroxyl paclitaxel, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 3%2 '-hydroxyl paclitaxels, formulated by 30mg2 '-hydroxyl paclitaxel, 230mg amphipathic nature block polymer, 0.04g mannitol and 730ul normal saline;
(10) 2.5%2 '-hydroxyl paclitaxels, formulated by 25mg2 '-hydroxyl paclitaxel, 200mg amphipathic nature block polymer, 0.05g mannitol and 750ul water for injection;
(11) 2%2 '-hydroxyl paclitaxels, formulated by 20mg2 '-hydroxyl paclitaxel, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 5%7-table-paclitaxel, formulated by 50mg7-table-paclitaxel, 200mg amphipathic nature block polymer, 0.02g sorbitol and 780ul normal saline;
(13) 5%7-table-paclitaxel, formulated by 50mg7-table-paclitaxel, 230mg amphipathic nature block polymer, 0.07g mannitol and 700ul normal saline;
(14) 5% paclitaxels, 50mg paclitaxel, formulated by 200mg amphipathic nature block polymer, 0.01g mannitol and 790ul water for injection;
(15) 8% paclitaxels or many rare paclitaxels, formulated by 80mg paclitaxel or many rare paclitaxels, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
Rare paclitaxel more than (16) 0.5% or 2 '-hydroxyl paclitaxel, formulated by the many rare paclitaxels of 50mg or 2 '-hydroxyl paclitaxel, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 2%10-removes acetyl paclitaxel or 2 '-hydroxyl paclitaxel, goes acetyl paclitaxel or 2 '-hydroxyl paclitaxel, 230mg amphipathic nature block polymer, 90mg mannitol and 680ul normal saline formulated by 20mg10-;
(18) 5%10-removes acetyl paclitaxel or 2 '-hydroxyl paclitaxel, goes acetyl paclitaxel or 2 '-hydroxyl paclitaxel, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection formulated by 50mg10-;
(19) 10%10-removes acetyl paclitaxel or 2 '-hydroxyl paclitaxel, by 100mg10-go the acetyl paclitaxel or or 2 '-hydroxyl paclitaxel, 220mg amphipathic nature block polymer, 20mg mannitol and 760ul phosphate buffer formulated; Or
(20) 20%10-removes acetyl paclitaxel or 2 '-hydroxyl paclitaxel, goes acetyl paclitaxel or 2 '-hydroxyl paclitaxel, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline formulated by 200mg10-.
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 1200-1800, 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 2-6: 1.
The therapeutic effect of anticancer sustained-release gel injection can further specify by following test and treatment embodiment:
Embodiment 10
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% 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.30% concentration is safety still.Intratumor injection slow releasing injection operation most convenient, easy.
Embodiment 11
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 rare paclitaxel more than 20%, 10%, 0.1% and 0% among the intratumor injection 0.5ml embodiment 5 in its hypochondrium.Measure gross tumor volume every day, the result shows that many rare paclitaxel anticancer sustained-release gel injections 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 12, contain tumor-inhibiting action in the body of taxane 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 8, through intratumor injection.Dosage is 0.1ml, only is equivalent to 1-20mg/.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 | 58±10 | |
| 2(5) | Rare paclitaxel more than 1% | 42±8.2 | ＜0.05 |
| 3(5) | Rare paclitaxel more than 5% | 35±6.0 | ＜0.01 |
| 4(5) | Rare paclitaxel more than 10% | 28±6.2 | ＜0.01 |
| 5(6) | Rare paclitaxel more than 20% | 24±5.8 | ＜0.01 |
| 6(5) | 1% paclitaxel | 38±8.2 | ＜0.01 |
| 7(5) | 5% paclitaxel | 30±6.8 | ＜0.001 |
| 8(5) | 10% paclitaxel | 24±6.2 | ＜0.001 |
| 9(5) | 20% paclitaxel | 18±4.4 | ＜0.001 |
| 10(5) | 2%2 '-hydroxyl paclitaxel | 38±6.0 | ＜0.001 |
| 11(5) | 10%2 '-hydroxyl paclitaxel | 20±4.8 | ＜0.001 |
Above result shows that the taxane slow releasing injection all has the obvious suppression effect to the pancreas tumor growth of tumour cell.Its tumor killing effect is tangible dose dependent.
The tumor-inhibiting action of embodiment 13, taxane 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 8, places in tumor.Taxane dosage only is 0.2ml/, only is equivalent to 0.125mg-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 | 48±10 | |
| 2(5) | Rare paclitaxel more than 0.5% | 38±8.2 | ＜0.05 |
| 3(5) | Rare paclitaxel more than 1% | 32±6.8 | ＜0.01 |
| 4(5) | Rare paclitaxel more than 5% | 26±6.4 | ＜0.01 |
| 5(5) | Rare paclitaxel more than 10% | 20±4.4 | ＜0.001 |
| 6(5) | Rare paclitaxel more than 20% | 16±4.0 | ＜0.001 |
| 7(5) | 0.5% paclitaxel | 36±6.8 | ＜0.01 |
| 8(5) | 1% paclitaxel | 30±4.6 | ＜0.01 |
| 9(5) | 5% paclitaxel | 24±4.6 | ＜0.01 |
| 10(5) | 10% paclitaxel | 20±4.0 | ＜0.001 |
| 11(6) | 20% paclitaxel | 16±2.8 | ＜0.001 |
Above result shows that used taxane slow releasing injection all has the obvious suppression effect to many hepatocarcinoma growth of tumour cell when this concentration, and its tumor killing effect is tangible dose dependent.
The tumor-inhibiting action of embodiment 14, taxane 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 8, places in tumor.Taxane 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) | Rare paclitaxel more than 0.5% | 38 | ＜0.05 |
| 3(5) | Rare paclitaxel more than 1% | 44 | ＜0.01 |
| 4(5) | Rare paclitaxel more than 5% | 58 | ＜0.01 |
| 5(5) | Rare paclitaxel more than 10% | 62 | ＜0.01 |
| 6(5) | Rare paclitaxel more than 20% | 74 | ＜0.01 |
| 7(5) | 0.5% paclitaxel | 32 | ＜0.01 |
| 8(5) | 1% paclitaxel | 40 | ＜0.001 |
| 9(5) | 5% paclitaxel | 52 | ＜0.01 |
| 10(5) | 10% paclitaxel | 60 | ＜0.01 |
| 11(5) | 20% paclitaxel | 84 | ＜0.01 |
The tumor-inhibiting action of embodiment 15 taxane 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 8, places in tumor.Taxane 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) | Rare paclitaxel more than 0.5% | 34 | ＜0.05 |
| 3(5) | Rare paclitaxel more than 1% | 48 | ＜0.01 |
| 4(5) | Rare paclitaxel more than 5% | 62 | ＜0.01 |
| 5(5) | Rare paclitaxel more than 10% | 78 | ＜0.01 |
| 6(5) | Rare paclitaxel more than 20% | 84 | ＜0.01 |
| 7(5) | 0.5% paclitaxel | 46 | ＜0.01 |
| 8(5) | 1% paclitaxel | 54 | ＜0.01 |
| 9(5) | 5% paclitaxel | 60 | ＜0.01 |
| 10(5) | 10% paclitaxel | 70 | ＜0.01 |
| 11(5) | 20% paclitaxel | 82 | ＜0.01 |
The tumor-inhibiting action of embodiment 16, taxane 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 9, places in tumor.Taxane 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) | Rare paclitaxel more than 0.5% | 55 | ＜0.05 |
| 3(5) | Rare paclitaxel more than 1% | 50 | ＜0.05 |
| 4(5) | Rare paclitaxel more than 5% | 56 | ＜0.05 |
| 5(5) | Rare paclitaxel more than 10% | 58 | ＜0.05 |
| 6(5) | Rare paclitaxel more than 20% | 62 | ＜0.01 |
| 7(5) | 0.5% paclitaxel | 52 | ＜0.01 |
| 8(5) | 1% paclitaxel | 74 | ＜0.01 |
| 9(5) | 5% paclitaxel | 82 | ＜0.01 |
| 10(5) | 10% paclitaxel | 76 | ＜0.001 |
| 11(5) | 20% paclitaxel | 82 | ＜0.01 |
The tumor-inhibiting action of embodiment 17, taxane 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 9, places in tumor.Taxane 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) | 0.5%10-removes the acetyl paclitaxel | 46 | ＜0.05 |
| 3(5) | 2%10-removes the acetyl paclitaxel | 50 | ＜0.05 |
| 4(5) | 5%10-removes the acetyl paclitaxel | 60 | ＜0.05 |
| 5(5) | 10%10-removes the acetyl paclitaxel | 66 | ＜0.05 |
| 6(5) | 20%10-removes the acetyl paclitaxel | 78 | ＜0.01 |
| 7(5) | 0.5%2 '-hydroxyl paclitaxel | 52 | ＜0.01 |
| 8(5) | 2%2 '-hydroxyl paclitaxel | 68 | ＜0.01 |
| 9(5) | 5%2 '-hydroxyl paclitaxel | 70 | ＜0.01 |
| 10(5) | 10%2 '-hydroxyl paclitaxel | 74 | ＜0.001 |
| 11(5) | 20%2 '-hydroxyl paclitaxel | 82 | ＜0.01 |
The tumor-inhibiting action of embodiment 18, taxane 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 9, places in tumor.Taxane dosage only is 0.25ml/, only is equivalent to 3mg-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) | 0.5%10-removes the acetyl paclitaxel | 54 | ＜0.05 |
| 3(5) | 2%10-removes the acetyl paclitaxel | 60 | ＜0.05 |
| 4(5) | 5%10-removes the acetyl paclitaxel | 64 | ＜0.05 |
| 5(5) | 10%10-removes the acetyl paclitaxel | 68 | ＜0.01 |
| 6(5) | 20%10-removes the acetyl paclitaxel | 78 | ＜0.001 |
| 7(5) | 0.5%2 '-hydroxyl paclitaxel | 48 | ＜0.01 |
| 8(5) | 2%2 '-hydroxyl paclitaxel | 54 | ＜0.01 |
| 9(5) | 5%2 '-hydroxyl paclitaxel | 60 | ＜0.01 |
| 10(5) | 10%2 '-hydroxyl paclitaxel | 78 | ＜0.01 |
| 11(5) | 20%2 '-hydroxyl paclitaxel | 86 | ＜0.001 |
Embodiment 19.
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 many rare paclitaxels of 0.005%-5% or paclitaxel;
(2) the block copolymer aqueous solution of 10%-30% contains many rare paclitaxels of 0.5%-10% or paclitaxel;
(3) the block copolymer aqueous solution of 12%-28% contains the many rare paclitaxels of 0.05%-30%;
(4) the block copolymer aqueous solution of 12%-26% contains 0.01%-25% paclitaxel or many rare paclitaxels;
(5) the block copolymer aqueous solution of 11%-30% contains the many rare paclitaxels of 0.01%-25%;
(6) the block copolymer aqueous solution of 12%-30% contains the 0.01%-25% paclitaxel;
(7) the block copolymer aqueous solution of 10%-32% contains the 0.01%-25% paclitaxel;
(8) the block copolymer aqueous solution of 13%-28% contains 0.1%-25%2-hydroxyl paclitaxel;
(9) the block copolymer aqueous solution of 14%-29% contains 0.1%-20%2 '-hydroxyl paclitaxel;
(10) the block copolymer aqueous solution of 12%-28% contains 0.2%-22%2 '-hydroxyl paclitaxel;
(11) the block copolymer aqueous solution of 15%-30% contains 0.25%-25%2 '-hydroxyl paclitaxel;
(12) the block copolymer aqueous solution of 10%-32% contains 0.5%-25%10-and removes the acetyl paclitaxel;
(13) the block copolymer aqueous solution of 11%-28% contains 0.75%-25%10-and removes the acetyl paclitaxel;
(14) the block copolymer aqueous solution of 9%-32% contains the 1%-28% paclitaxel;
(15) the block copolymer aqueous solution of 10%-28% contains 1%-15% paclitaxel or many rare paclitaxels;
(16) the block copolymer aqueous solution of 10%-25% contains many rare paclitaxels of 1%-18% or paclitaxel;
(17) the block copolymer aqueous solution of 10%-20% contains 5%-15%10-and removes the acetyl paclitaxel;
(18) the block copolymer aqueous solution of 10%-28% contains 1%-10%10-and removes the acetyl paclitaxel;
(19) the block copolymer aqueous solution of 10%-28% contains 1%-15% paclitaxel or many rare paclitaxels; Or
(20) the block copolymer aqueous solution of 15%-25% contains 1%-10%2 '-hydroxyl paclitaxel.
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 1000-1500, accounts for the 15-25% 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.
Embodiment 20
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 many rare paclitaxels of 0.5%-20% or paclitaxel;
(2) the block copolymer aqueous solution of 20%-26% contains many rare paclitaxels of 0.5%-10% or paclitaxel;
(3) the block copolymer aqueous solution of 20%-28% contains the many rare paclitaxels of 5%-10%;
(4) the block copolymer aqueous solution of 20%-26% contains 0.1%-20% paclitaxel or many rare paclitaxels;
(5) the block copolymer aqueous solution of 18%-30% contains the many rare paclitaxels of 1%-10%;
(6) the block copolymer aqueous solution of 18%-30% contains the 5%-20% paclitaxel;
(7) the block copolymer aqueous solution of 18%-28% contains the 0.1%-5% paclitaxel;
(8) the block copolymer aqueous solution of 18%-26% contains 0.5%-20%2-hydroxyl paclitaxel;
(9) the block copolymer aqueous solution of 18%-28% contains 5%-10%2 '-hydroxyl paclitaxel;
(10) the block copolymer aqueous solution of 18%-26% contains 0.5%-2%2 '-hydroxyl paclitaxel;
(11) the block copolymer aqueous solution of 16%-26% contains 2%-20%2 '-hydroxyl paclitaxel;
(12) the block copolymer aqueous solution of 16%-30% contains 0.5%-25%10-and removes the acetyl paclitaxel;
(13) the block copolymer aqueous solution of 16%-28% contains 5%-10%10-and removes the acetyl paclitaxel;
(14) the block copolymer aqueous solution of 16%-25% contains the many rare paclitaxels of 10%-20%;
(15) the block copolymer aqueous solution of 18%-28% contains 5%-15% paclitaxel or many rare paclitaxels;
(16) the block copolymer aqueous solution of 18%-25% contains many rare paclitaxels of 2%-18% or paclitaxel;
(17) the block copolymer aqueous solution of 18%-26% contains 5%-25%10-and removes the acetyl paclitaxel;
(18) the block copolymer aqueous solution of 18%-28% contains 5%-10%10-and removes the acetyl paclitaxel;
(19) the block copolymer aqueous solution of 18%-28% contains 5%-10% paclitaxel or many rare paclitaxels; Or
(20) the block copolymer aqueous solution of 18%-25% contains 0.5%-5%2 '-hydroxyl paclitaxel.
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 1000-1500, 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 4-8: 1.
In a word, growth all has the obvious suppression effect to used taxane slow releasing injection to kinds of tumor cells.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. temperature control sustained-release injection that contains taxane is characterized in that temperature control sustained-release injection is grouped into by following one-tenth:
A: taxane 0.01-40%
B: amphipathic copolymer 5%-40%
C: solvent 60%-90%
D: regulator 0-15%
More than be weight percentage,
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 taxane and keeps the thoughtful several months of active drug concentration numbers at tumor by local; The viscosity of temperature control sustained-release injection is 10cp-3000cp (5 ℃-30 ℃ time);
Amphipathic copolymer is selected from the block copolymer of 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;
Taxane is selected from paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 10-and removes acetyl paclitaxel or 7-table-paclitaxel;
But solvent is selected from distilled water, water for injection, physiology towards liquid, cell culture fluid, body fluid, tissue fluid, buffer, 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 temperature control sustained-release injection according to claim 1 is characterized in that the percentage by weight of taxane in temperature control sustained-release injection is 0.001%-40%.
3. the temperature control sustained-release injection according to claim 1 is characterized in that the mean molecule quantity of amphipathic nature block polymer is selected from 500-5000,5000-20000,20000-30000.
4. the temperature control sustained-release injection according to claim 1 is characterized in that 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.
5. the temperature control sustained-release injection according to claim 1 is characterized in that the mean molecule quantity of Polyethylene Glycol can be 200-20000.
6. according to claim 1 and 5 described temperature control sustained-release 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, soil temperature 20, soil temperature 40, soil temperature 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 slow releasing injection.
7. it is one of following that the temperature control sustained-release injection according to claim 1, the preparation method that it is characterized in that described temperature control sustained-release injection are selected from:
(1) prepares amphipathic aqueous copolymers solution with solvent earlier, add a certain amount of taxane 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 taxane 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 taxane, uses after intensification is redissolved before using;
(3) the preparation taxane 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 taxane aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind taxane 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 taxane, add solvent then and make temperature control sustained-release 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 taxane, 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 temperature control sustained-release injection according to claim 1 is characterized in that described temperature control sustained-release injection contains one of following ingredients:
(1) the block copolymer aqueous solution of 10%-30% contains many rare paclitaxels of 0.005%-5% or paclitaxel;
(2) the block copolymer aqueous solution of 10%-30% contains many rare paclitaxels of 0.5%-10% or paclitaxel;
(3) the block copolymer aqueous solution of 12%-28% contains the many rare paclitaxels of 0.05%-30%;
(4) the block copolymer aqueous solution of 12%-26% contains 0.01%-25% paclitaxel or many rare paclitaxels;
(5) the block copolymer aqueous solution of 11%-30% contains the many rare paclitaxels of 0.01%-25%;
(6) the block copolymer aqueous solution of 12%-30% contains the 0.01%-25% paclitaxel;
(7) the block copolymer aqueous solution of 10%-32% contains the 0.01%-25% paclitaxel;
(8) the block copolymer aqueous solution of 13%-28% contains 0.1%-25%2-hydroxyl paclitaxel;
(9) the block copolymer aqueous solution of 14%-29% contains 0.1%-20%2 '-hydroxyl paclitaxel;
(10) the block copolymer aqueous solution of 12%-28% contains 0.2%-22%2 '-hydroxyl paclitaxel;
(11) the block copolymer aqueous solution of 15%-30% contains 0.25%-25%2 '-hydroxyl paclitaxel;
(12) the block copolymer aqueous solution of 10%-32% contains 0.5%-25%10-and removes the acetyl paclitaxel;
(13) the block copolymer aqueous solution of 11%-28% contains 0.75%-25%10-and removes the acetyl paclitaxel;
(14) the block copolymer aqueous solution of 9%-32% contains the 1%-28% paclitaxel;
(15) the block copolymer aqueous solution of 10%-28% contains 1%-15% paclitaxel or many rare paclitaxels;
(16) the block copolymer aqueous solution of 10%-25% contains many rare paclitaxels of 1%-18% or paclitaxel;
(17) the block copolymer aqueous solution of 10%-20% contains 5%-15%10-and removes the acetyl paclitaxel;
(18) the block copolymer aqueous solution of 10%-28% contains 1%-10%10-and removes the acetyl paclitaxel;
(19) the block copolymer aqueous solution of 10%-28% contains 1%-15% paclitaxel or many rare paclitaxels; Or
(20) the block copolymer aqueous solution of 15%-25% contains 1%-10%2 '-hydroxyl paclitaxel.
Wherein, the gelling temperature of 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 1000-1500, accounts for the 15-25% 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 temperature control sustained-release injection is characterized in that described temperature control sustained-release injection contains one of following ingredients:
Rare paclitaxel or paclitaxel more than (1) 0.1%, formulated by the many rare paclitaxels of 1mg or paclitaxel, 300mg amphipathic nature block polymer and 700ul water for injection;
Rare paclitaxel or paclitaxel more than (2) 1%, formulated by the many rare paclitaxels of 10mg or paclitaxel, 280mg amphipathic nature block polymer and 720ul distilled water;
Rare paclitaxel more than (3) 2%, formulated by the many rare paclitaxels of 20mg, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 4% paclitaxels or many rare paclitaxels, formulated by 40mg paclitaxel or many rare paclitaxels, 230mg amphipathic nature block polymer and 770ul water for injection;
Rare paclitaxel more than (5) 5%, formulated by the many rare paclitaxels of 50mg, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 7% paclitaxels, formulated by 70mg paclitaxel, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 0.5% paclitaxels, formulated by 5mg paclitaxel, 280mg amphipathic nature block polymer, 20mg mannitol and 700ul water for injection;
(8) 0.1%2-hydroxyl paclitaxel, formulated by 1mg2-hydroxyl paclitaxel, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 0.3%2 '-hydroxyl paclitaxels, formulated by 3mg2 '-hydroxyl paclitaxel, 230mg amphipathic nature block polymer, 0.04g mannitol and 730ul normal saline;
(10) 0.5%2 '-hydroxyl paclitaxels, formulated by 5mg2 '-hydroxyl paclitaxel, 200mg amphipathic nature block polymer, 0.05g mannitol and 750ul water for injection;
(11) 0.8%2 '-hydroxyl paclitaxels, formulated by 8mg2 '-hydroxyl paclitaxel, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 1%10-removes the acetyl paclitaxel, goes acetyl paclitaxel, 200mg amphipathic nature block polymer, 0.02g sorbitol and 780ul normal saline formulated by 10mg10-;
(13) 1.25%10-removes the acetyl paclitaxel, goes acetyl paclitaxel, 230mg amphipathic nature block polymer, 0.07g mannitol and 700ul normal saline formulated by 12.5mg10-;
Rare paclitaxel more than (14) 1.5%, the many rare paclitaxels, formulated of 15mg by 200mg amphipathic nature block polymer, 0.01g mannitol and 790ul water for injection;
(15) 2% paclitaxels or many rare paclitaxels, formulated by 20mg paclitaxel or many rare paclitaxels, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
Rare paclitaxel or paclitaxel more than (16) 5%, formulated by the many rare paclitaxels of 50mg or paclitaxel, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 10%10-removes the acetyl paclitaxel, goes acetyl paclitaxel, 230mg amphipathic nature block polymer, 90mg mannitol and 680ul normal saline formulated by 100mg10-;
(18) 15%10-removes the acetyl paclitaxel, goes acetyl paclitaxel, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection formulated by 150mg10-;
(19) 20% paclitaxels or many rare paclitaxels, formulated by 200mg paclitaxel or many rare paclitaxels, 220mg amphipathic nature block polymer, 20mg mannitol and 760ul phosphate buffer; Or
(20) 25%2 '-hydroxyl paclitaxels, formulated by 250mg2 '-hydroxyl paclitaxel, 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 4-9: 1.
10. described according to Claim 8 described temperature control sustained-release injection, it is characterized in that described anticancer slow-release injection is used for the preparation treatment cerebral tumor, cerebral glioma, renal carcinoma, hepatocarcinoma, carcinoma of gallbladder, cancer of biliary duct, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, hemangioma, osteosarcoma, lymphoma, pulmonary carcinoma, thymic carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, the He Jiejin lymphoma, non_hodgkin lymphoma, the preparation of the cancer of nonsmall-cell lung cancer or its transfer.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007102026307A CN101229150A (en) | 2007-11-22 | 2007-11-22 | Thermostatic sustained release injection containing taxane and preparing method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102120756A (en) * | 2010-12-07 | 2011-07-13 | 南开大学 | Taxol-based small molecule hydrogel-nanosphere transmission system and preparation method thereof |
| CN107952079A (en) * | 2017-11-09 | 2018-04-24 | 复旦大学 | A kind of heat-induced gel of administering drug combinations is slow-release injected and preparation method thereof |
| CN114514043A (en) * | 2019-07-08 | 2022-05-17 | 株式会社再生生物链 | Temperature-sensitive hydrogel composition for preventing tissue adhesion and preparation method thereof |
-
2007
- 2007-11-22 CN CNA2007102026307A patent/CN101229150A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102120756A (en) * | 2010-12-07 | 2011-07-13 | 南开大学 | Taxol-based small molecule hydrogel-nanosphere transmission system and preparation method thereof |
| CN107952079A (en) * | 2017-11-09 | 2018-04-24 | 复旦大学 | A kind of heat-induced gel of administering drug combinations is slow-release injected and preparation method thereof |
| CN107952079B (en) * | 2017-11-09 | 2020-01-10 | 复旦大学 | Combined administration thermal gel sustained-release injection and preparation method thereof |
| CN114514043A (en) * | 2019-07-08 | 2022-05-17 | 株式会社再生生物链 | Temperature-sensitive hydrogel composition for preventing tissue adhesion and preparation method thereof |
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