CN101301266A - Anticancer gel sustained-release injection containing alkyl agent - Google Patents
Anticancer gel sustained-release injection containing alkyl agent Download PDFInfo
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- CN101301266A CN101301266A CNA2008103022030A CN200810302203A CN101301266A CN 101301266 A CN101301266 A CN 101301266A CN A2008103022030 A CNA2008103022030 A CN A2008103022030A CN 200810302203 A CN200810302203 A CN 200810302203A CN 101301266 A CN101301266 A CN 101301266A
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Abstract
Anticancer sustained release gel injection consists of alkylating agent microsphere (or microsphere and alkylating agent micropowder) in anticancer useful quantity, amphiphilic block copolymer, dissolvant and medicine release regulator in a certain quantity, wherein the mixture of the amphiphilic block copolymer and the dissolvant not containing an organic solvent has temperature-sensitive gelling characteristics; moreover, the mixture is in the state of fluxible liquid in an environment with the temperature lower than body temperature, and can be automatically converted into non-flowing water-insoluble gel capable of biodegradation and absorption inside the body of a warm blood; and the water-insoluble gel can slowly release the contained alkylating agent in part of a tumor and maintains effective medicine concentration for a plurality of weeks to a plurality of months. When injected into a tumor or around a tumor or placed inside a tumor cavity after an operation, the anticancer sustained release gel injection can remarkably reduce the general reaction of medicine, and can be used in the therapy of tumors at different stages. The alkylating agent is selected from melphalan, norcantharidin, ritrosulfan, etoglucid, pipobroman, piposulfan, pumitepa, uredepa and azatepa, etc. The anticancer sustained release gel injection can be used independently or together with radioactive particle in the therapy of various tumors.
Description
(1) technical field
The present invention relates to a kind of gel rubber sustained-release injection that contains alkylating agent, belong to technical field of pharmaceuticals.Particularly, this invention relates to a kind of alkylating agent 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, in the part or all of sustained-release micro-spheres of alkylating agent in the anticancer gel sustained-release injection, thus can with the alkylating agent forgiven tumor by local slowly discharge from several weeks to the several months.
(2) background technology
Though the treatment method for cancer is more, most patients' survival state not be improved significantly.In various treatments, chemotherapy remains one of selection commonly used.Though conventional chemotherapy is used for a long time, it is to therapeutic effect of entity tumor and uncertain, and its root problem is that traditional chemotherapy can not realize active drug concentration and keeps enough action time at tumor locus.Because the effect of chemotherapy not only depends on the sensitivity of medicine, medicine is even more important at the action time and the drug level of tumor locus, and conventional chemotherapy not only can not be realized above target, and but the diffusion and the transfer that also can stimulate tumor are gone back in the not only chemical sproof generation of inducing tumor cell of the unsuitable chemotherapy of low dosage.
Chemotherapeutics topical application, particularly local sustained release have become the research direction and the focus of current entity tumor chemotherapy, see Chinese patent (ZL200410035923.7; 200410035926; 200410035924.1; 200410035927.5; 200410075840; 200410075839.8; ZL200410075837.9; 200410036098.2; 200510042430; 200510042428.3; 200510042434.9; 2005100434800; 200510043481.5).Yet present biodegradable sustained-release preparation multi-purpose solid polymer such as polyglycolic acid, polylactic acid or its copolymer etc. are as slow-released carrier.Because the hydrophobic performance of this type of macromolecule carrier, these polymer need organic solvent in the slow releasing pharmaceutical preparation process, as dichloromethane, and chloroform, acetic acid or dimethyl formamide etc.For removing deleterious organic solvent, must be extensively dry.Therefore, in most of the cases, final slow releasing preparation mostly is solid shape (for example, microsphere, lamellar or bar-shaped), needs complicated implantation process, and easily causes tissue injury even tumor cell to plant or send out.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 the multiple method of postoperative.
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 alkylating agent is provided, particularly, is a kind of sustained-release gel injection that contains alkylating agent.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; In the part or all of sustained-release micro-spheres of alkylating agent in the anticancer gel sustained-release injection, thereby the alkylating agent of being forgiven slowly can not only be discharged from several weeks to the several months at tumor by local, and can effectively suppress to enter the tumor cell of rest period.
The formed amphipathic copolymer of hydrophobicity polyester and hydrophilic polyglycol has unique temperature sensitivity, is aqueous solution at normal temperatures, can be changed into semisolid or solid gel under the body temperature condition, 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 alkylating agent mixes with slow-release function, this hydrogel is a transparent liquid under room temperature or 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 alkylating agent can slowly discharge alkylating agent 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 alkylating agent.
Find that through lot of experiments sustained-release gel injection of the present invention is grouped into by following one-tenth:
A: alkylating agent 0.01%-40%
B: amphipathic copolymer 5%-40%
C: solvent 60%-90%
D: regulator 0-15%
More than be weight percentage
Wherein, the alkylating agent alkylating agent is selected from, but be not limited to, cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA and salt thereof, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.Serve as preferred wherein with cyclophosphamide, melphalan, ifosfamide, 4H-peroxide cyclophosphamide, norcantharidin.
The percentage by weight of alkylating agent in the slow releasing agent injection be from 0.001%-40%, is preferred with 0.01%-30%, with 1%-20% for the most preferred.
The preparation of sustained-release gel injection has several different methods, and anticancer sustained-release gel 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 alkylating agent (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 alkylating agent, 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 alkylating agent 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 28%, and 15% to 26% for most preferably.
(2) prepare amphipathic aqueous copolymers solution and alkylating agent 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 alkylating agent, uses after intensification is redissolved before using;
(3) the preparation alkylating agent 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 27% for most preferably.
(4) prepare alkylating agent aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind alkylating agent 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 alkylating agent, add solvent then and make anticancer sustained-release gel injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Gel process can be finished at workshop, also amphipathic copolymer and alkylating agent 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 alkylating agent and sustained-release gel and application.Alkylating agent 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 alkylating agent is dispersed in the sustained-release gel.Pack alone or in combination with hybrid packed difference and be, mix with sustained-release gel before alkylating agent is injected in vivo when packing alone or in combination, hybrid packed then is alkylating agent 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 alkylating agent, 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.
Alkylating agent exists with the form of sustained-release micro-spheres or microsphere and micropowder in the slow releasing agent injection, the alkylating agent that is effective anticancer partly or entirely is wrapped in the sustained-release micro-spheres, the part drug release that is wrapped in the microsphere is slow, help controlling the tumor cell that enters rest period, the medicine that exists with the micropowder form in sustained-release gel helps discharging very fast relatively, help controlling the cell faster that rises in value, the two is united and helps steadily slowly release of medicine, acts on each phase tumor cell.
The preparation of method for preparing microsphere has several different methods, as, but be not limited to multi-emulsion method, O/W method, O/O method, phase separation method, spray drying method, cold nebulization extraction method etc.
1, multi-emulsion method (W/O/W method): accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Under high-speed stirred or ultrasonic concussion, inject the two fun gi polysaccharides aqueous solution, homodisperse, form the colostric fluid of W/O, aqueous phase outside this solution is injected under high-speed stirred or under the ultrasonic concussion, emulsion factor minute (1～30min), form the W/O/W emulsion, in gentle agitation a few hours (1～10hr), wave the method organic solvent, solidified microsphere.Centrifugal or the filtration collection with microsphere suspension liquid, and back for several times after 37 ℃ of vacuum dryings or lyophilization with the second distillation water washing, in 4 ℃ of refrigerators, preserve after the powder packing.
Wherein, surfactant can be, and singly is not limited to span 20; Organic solvent is selected from, as, but be not limited to a kind of or mixed liquor of dichloromethane, ethyl acetate, acetonitrile etc.; Outer water can be the saturated solution of medicine, also can add surfactants such as salts such as emulsifying agent, 1～10% sodium chloride, 0.001～2% tween such as 0.1～10%PVA and improve balling-up character.Also can add stabilizing agents such as cosolvent, gelatin solution and improve entrapment efficiency.
2, O/W method
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution
Water (can be the saturated solution of medicine outside above-mentioned suspension or solution was injected under high-speed stirred or under the ultrasonic concussion, also can add surfactants such as salts such as emulsifying agent, sodium chloride, tween such as PVA and improve balling-up character) in, emulsion factor minute (1～30min), form the O/W emulsion, in gentle agitation a few hours (1～10hr), wave the method organic solvent, solidified microsphere.Centrifugal or the filtration collection with microsphere suspension liquid, and back for several times after 37 ℃ of vacuum dryings or lyophilization with the second distillation water washing, in 4 ℃ of refrigerators, preserve after the powder packing.
3, the O/O method one:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution
Be injected into above-mentioned suspension or solution in the saturated dimethicone of dichloromethane under high-speed stirred or under the ultrasonic concussion, under the high-speed stirred or ultrasonic concussion number minute (after 1～30min), put in the petroleum ether of q.s, high-speed stirred number minute (1～30min), centrifugal or the filtration collection with microsphere suspension liquid behind the solidified microsphere, washing in 37 ℃ vacuum dryings or lyophilization after, powder packing after 4 ℃ refrigerators in is preserved after removing outer oil phase for several times.
4, the O/O method two:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
Above-mentioned suspension or solution are injected under high-speed stirred or under the ultrasonic concussion in the inertia oil phases such as liquid paraffin, room temperature or heated and stirred or ultrasonic concussion a few hours (1～30hr), wave the method organic solvent, behind the solidified microsphere, centrifugal or the filtration collection with microsphere suspension liquid, washing in 37 ℃ vacuum dryings or lyophilization, powder packing after 4 ℃ refrigerators in is preserved after removing outer oil phase for several times.
5, phase separation method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution
Organic solvents such as petroleum ether with q.s (1～10 times) under high-speed stirred or under the ultrasonic concussion slowly join in above-mentioned suspension or the solution, continue stirring or ultrasonic concussion tens of minutes (30～120min), wave the method organic solvent, behind the solidified microsphere, centrifugal or the filtration collection with microsphere suspension liquid, washing in 37 ℃ vacuum dryings or lyophilization, powder packing after 4 ℃ refrigerators in is preserved after removing outer oil phase for several times.
6, spray drying method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
Above-mentioned suspension or solution under agitation or under the ultrasonic concussion are carried out spray drying with pumping in the spray dryer.Spray condition: 50 ℃-70 ℃ of inlet temperatures, about 40 ℃ of outlet temperature.In 4 ℃ of refrigerators, preserve after collecting the packing of dried microsphere powder.
7, cold nebulization extraction method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
With above-mentioned suspension or solution under agitation or ultrasonic concussion down with pumping in the spray dryer, method by spraying forms droplet, freezing in liquid nitrogen, obtain microsphere with the organic solvent of a low temperature organic cosolvent (for example ethanol) extracting dissolve polymer.In 4 ℃ of refrigerators, preserve after collecting the packing of dried microsphere powder.
The preferred another kind of mode of sustained-release gel injection is that sustained-release gel contains alkylating agent and the sustained-release micro-spheres that contains alkylating agent, and the used slow-release auxiliary material of sustained-release micro-spheres is preferred with PLGA.The preparation method of sustained-release gel is the same, and what novels, anecdotes, etc. were same is to have added the alkylating agent micropowder in the sustained-release gel again.The weight ratio of alkylating agent is arbitrarily in alkylating agent micropowder and the sustained-release micro-spheres, can be 19-1: 1-19 serves as preferred with 9-1: 1-9, and 5-1: 1-5 is for most preferably.
Slow-release auxiliary material also can be, but be not limited to, the copolymer of polylactic acid, lactic acid and glycolic, polifeprosan with and compositions, also can add release regulator in addition, be selected from a kind of or its combination in mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
The molecular weight peak value of polylactic acid is 500-5000,5000-10000,10000-25000,25000-35000 or 30000-50000; The molecular weight peak value of lactic acid and ethanol copolymer is 1000-10000,10000-25000,25000-40000 or 40000-60000; The percentage by weight of poly-lactonaphthol and polyglycolic acid is 90: 10,70-80: 20-30,60-40: 40-60,75: 25,25: 75 or 50: 50; The weight ratio of CPP in the polifeprosan: SA is 50-10: 90-50.
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).
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 also finds, when adding material such as mannitol, sorbitol in the sustained-release gel, gelling temperature and drug releasing rate can method be given birth to variation to a certain degree, and the material of this type of scalable drug releasing rate or gelling temperature is called regulator.The regulator that can add in the sustained-release gel can be, but be not limited to a kind of or its combination in various sugar or salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, the albumin glue.Regulator can be other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.Its weight ratio in sustained-release gel can be 0.01%-15.0%, because of specifically needing to decide.
The route of administration of slow releasing injection depends on multiple factor, for obtaining valid density in former method 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, arterial thrombosis, 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 the former method 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 or cancer or the sarcoma or the carcinosarcoma of transfer.
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 former method tumor, 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 multiple method of may command postoperative; 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; Control late period and method disease are as pernicious ascites pleural fluid etc.; With the associating of its cancer therapy drug or method,, wherein unite for preferably, as share with radion with interior radiotherapy as the associating of the cancer therapy drug of local injection and the chemotherapeutics of other administration, and the associating of radiotherapy or immunization therapy.
The clinical practice dosage of alkylating agent 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 600mg/kg body weight, be preferred with 0.1-300mg/kg, 0.5-200mg/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 more than the several times of its intravenous administration maximum tolerated dose.
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 4: 1.
The preparation of microsphere prepares with multi-emulsion method or O/W method, adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000, and the weight ratio of copolymer and melphalan is 9: 1.
Embodiment 2.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 1, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 29 ℃ (40%) and 36 ℃ (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.
The preparation of microsphere prepares with multi-emulsion method or O/W method, adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 25,000-35,000, the weight ratio of copolymer and norcantharidin is 7: 3.
Embodiment 4.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 3, the result show 40% and 20% hydrogel gelling temperature be respectively 31 ℃ (40%) and 37 ℃ (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 melphalan in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% melphalan.Record its gelling temperature and be respectively 38,36,34.5,32 and 31 ℃.
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 norcantharidin in, make the anticancer sustained-release gel injection that contains 20%, 10%, 5%, 1% and 0.1% norcantharidin.Record its gelling temperature and be respectively 38,37,35,33 and 31 ℃.
Embodiment 7.
Measure interior (subcutaneous) release cycle of mice body of the variable concentrations melphalan and the defosfamide of embodiment 5 and 6, found that be respectively 84,70,65,60 and 40 days average time (estimating can measure the time in the blood) that discharges in 20%, 10%, 5%, the 1% and 0.1% melphalan body; 20%, was respectively 98,76,64,50 and 46 days the average time that discharges in the body of 10%, 5%, 1% and 0.1% defosfamide.
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:
(1) 0.05% melphalan or norcantharidin, formulated by 1mg melphalan or norcantharidin, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1% cyclophosphamide or Chlorambucils, formulated by 10mg cyclophosphamide or Chlorambucil, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2% ifosfamides or 4H-peroxide cyclophosphamide, formulated by 20mg ifosfamide or 4H-peroxide cyclophosphamide, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 4% melphalan or defosfamides are by 40mg melphalan or defosfamide, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 5% perfosfamide or Mafosfamides are by 50mg perfosfamide or Mafosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 7% hexamethylmelamine or cantharidin are by 70mg hexamethylmelamine or cantharidin, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 0.5% mannomustine or treosulfans are by 5mg mannomustine or treosulfan, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 0.1% ritrosulfan or improsulfan are by 1mg ritrosulfan or an improsulfan, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 0.3% etoglucid or pipobromans are by 3mg etoglucid or pipobroman, 230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline;
(10) 0.5% norcantharidin or piposulfans are by 5mg norcantharidin or piposulfan, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection;
(11) 0.8% triethylenemelaine or epoxypiperazines are by 8mg triethylenemelaine or epoxypiperazine, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 1% benzene assistant TEPA or Phopurine are by 10mg benzene assistant TEPA or Phopurine, 200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline;
(13) 1.25% melphalans are by 12.5mg melphalan, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(14) 1.5% defosfamides, by 200mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection;
(15) 2% melphalan or defosfamides are by 20mg melphalan or defosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(16) 5% melphalan or norcantharidin are by 50mg melphalan or norcantharidin, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 10% perfosfamide or meturedepas are by 100mg perfosfamide or meturedepa, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline;
(18) 15% urethimine or etoglucid are by 150mg urethimine or etoglucid, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 20% melphalans or Ah bundle's TEPA are by 200mg melphalan or Ah bundle's TEPA, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(20) 25% norcantharidin or piposulfans are by 250mg norcantharidin or piposulfan, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Medicine in the above-mentioned anticancer sustained-release gel injection is a micropowder, and its gelling temperature is 32 ℃-36.5 ℃, and be 4-8 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Polyethylene Glycol-Vicryl Rapide-Polyethylene Glycol, and wherein the molecular weight of Polyethylene Glycol is 1000-1400, 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.
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:
(1) 1% melphalan or norcantharidin, formulated by 10mg melphalan or norcantharidin, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 5% cyclophosphamide or Chlorambucils, formulated by 50mg cyclophosphamide or Chlorambucil, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 5% ifosfamides or 4H-peroxide cyclophosphamide, formulated by 50mg ifosfamide or 4H-peroxide cyclophosphamide, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 8% melphalan or defosfamides are by 80mg melphalan or defosfamide, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 10% perfosfamide or Mafosfamides are by 100mg perfosfamide or Mafosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 2% hexamethylmelamine or cantharidin are by 20mg hexamethylmelamine or cantharidin, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 5% mannomustine or treosulfans are by 50mg mannomustine or treosulfan, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 2% ritrosulfan or improsulfan are by 20mg ritrosulfan or an improsulfan, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 3% etoglucid or pipobromans are by 30mg etoglucid or pipobroman, 230mg amphipathic nature block polymer, 40mgg mannitol and 730ul normal saline;
(10) 2.5% norcantharidin or piposulfans are by 25mg norcantharidin or piposulfan, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection;
(11) 5% triethylenemelaine or epoxypiperazines are by 20mg triethylenemelaine or epoxypiperazine, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 5% benzene assistant TEPA or Phopurine are by 50mg benzene assistant TEPA or Phopurine, 200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline;
(13) 5% Ah bundle's TEPA or melphalans are by 50mg Ah bundle TEPA or melphalan, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(14) 5% melphalans, 50mg melphalan, by 200mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection;
(15) 8% melphalan or defosfamides are by 80mg melphalan or defosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(16) 10% melphalan or norcantharidin are by 100mg melphalan or norcantharidin, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 2% perfosfamide or hexamethylmelamine are by 20mg perfosfamide or hexamethylmelamine, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline;
(18) 5% improsulfan or etoglucid are by a 50mg improsulfan or etoglucid, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 15% melphalan or defosfamides are by 150mg melphalan or defosfamide, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(20) 20% norcantharidin or piposulfans are by 200mg norcantharidin or piposulfan, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Medicine in the above-mentioned anticancer sustained-release gel injection is a sustained-release micro-spheres, and its gelling temperature is 32 ℃-38.5 ℃, and be 6-14 week release time in the animal body, obviously prolongs than micropowder gel injection drug release time.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1500, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6: 1.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15,000-38,000.
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 also comprises and followingly contains concentration, becomes to be grouped into and percentage by weight:
(1) 1% melphalan or norcantharidin, formulated by 10mg melphalan or norcantharidin, 300mg amphipathic nature block polymer and 700ul water for injection, the ratio of micropowder and microsphere is 9: 1;
(2) 5% cyclophosphamide or Chlorambucils, formulated by 50mg cyclophosphamide or Chlorambucil, 280mg amphipathic nature block polymer and 720ul distilled water, the ratio of micropowder and microsphere is 19: 1;
(3) 5% ifosfamides or 4H-peroxide cyclophosphamide, formulated by 50mg ifosfamide or 4H-peroxide cyclophosphamide, 250mg amphipathic nature block polymer and 750ul normal saline, the ratio of micropowder and microsphere is 14: 1;
(4) 8% melphalan or defosfamides, by 80mg melphalan or defosfamide, 230mg amphipathic nature block polymer and 770ul water for injection, the ratio of micropowder and microsphere is 14: 1;
(5) 10% perfosfamide or Mafosfamides, by 100mg perfosfamide or Mafosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer, the ratio of micropowder and microsphere is 5: 1;
(6) 2% hexamethylmelamine or cantharidin are by 20mg hexamethylmelamine or cantharidin, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 5% mannomustine or treosulfans, by 50mg mannomustine or treosulfan, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection, the ratio of micropowder and microsphere is 2: 1;
(8) 2% ritrosulfan or improsulfan, by 20mg ritrosulfan or an improsulfan, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water, the ratio of micropowder and microsphere is 1: 1;
(9) 3% etoglucid or pipobromans, by 30mg etoglucid or pipobroman, 230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline, the ratio of micropowder and microsphere is 1: 2;
(10) 2.5% norcantharidin or piposulfans, by 25mg norcantharidin or piposulfan, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection, the ratio of micropowder and microsphere is 1: 4;
(11) 5% triethylenemelaine or epoxypiperazines, by 20mg triethylenemelaine or epoxypiperazine, 260mg amphipathic nature block polymer and 740ul phosphate buffer, the ratio of micropowder and microsphere is 1: 5;
(12) 5% benzene assistant TEPA or Phopurine, by 50mg benzene assistant TEPA or Phopurine, 200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline, the ratio of micropowder and microsphere is 1: 9;
(13) 5% Ah bundle's TEPA or melphalans, by 50mg Ah bundle TEPA or melphalan, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline, the ratio of micropowder and microsphere is 1: 12;
(14) 5% melphalans, 50mg melphalan, by 200mg amphipathic nature block polymer, 0.01g mannitol and 790ul water for injection, the ratio of micropowder and microsphere is 1: 14;
(15) 8% melphalan or defosfamides, by 80mg melphalan or defosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer, the ratio of micropowder and microsphere is 1: 16;
(16) 10% melphalan or norcantharidin, by 100mg melphalan or norcantharidin, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline, the ratio of micropowder and microsphere is 1: 19;
(17) 2% perfosfamide or hexamethylmelamine, by 20mg perfosfamide or hexamethylmelamine, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline, the ratio of micropowder and microsphere is 1: 1;
(18) 5% improsulfan or etoglucid, by a 50mg improsulfan or etoglucid, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection, the ratio of micropowder and microsphere is 10: 1;
(19) 15% melphalan or defosfamides, by 150mg melphalan or defosfamide, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer, the ratio of micropowder and microsphere is 1: 9; Or
(20) 20% norcantharidin or piposulfans, by 200mg norcantharidin or piposulfan, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline, the ratio of micropowder and microsphere is 1: 5.
Medicine in the above-mentioned anticancer sustained-release gel injection is drug powder and sustained-release micro-spheres, and its gelling temperature is 33 ℃-37 ℃, and be 4-16 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1300-1600, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-6: 1.
The therapeutic effect of anticancer sustained-release gel injection can further specify by following test and treatment embodiment:
Embodiment 11
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% melphalan among the intratumor injection 0.1ml embodiment 5 in its hypochondrium.Measure gross tumor volume every day, the result shows that the melphalan 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 12
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is treated to be divided into 4 groups behind tumor growth to 0.5 cm diameter, respectively the anticancer sustained-release gel injection that contains 20%, 10%, 0.1% and 0% norcantharidin among the intratumor injection 0.5ml embodiment 5 in its hypochondrium.Measure gross tumor volume every day, the result shows that the norcantharidin 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 13, contain tumor-inhibiting action in the body of alkylating agent slow releasing injection
With the rat is subjects, with 2 * 10
5Individual oophoroma 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 5mg-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 | 44±10 | |
| 2 (5) | 5% melphalan | 28±8.2 | ＜0.05 |
| 3 (5) | 5% norcantharidin | 30±6.0 | ＜0.01 |
| 4 (5) | 10% perfosfamide | 26±6.2 | ＜0.01 |
| 5 (6) | 10% hexamethylmelamine | 28±5.8 | ＜0.01 |
| 6 (5) | 15% improsulfan | 28±6.2 | ＜0.01 |
| 7 (5) | 15% etoglucid | 20±6.2 | ＜0.001 |
| 8 (5) | 25% skin norcantharidin | 20±6.8 | ＜0.001 |
| 9 (5) | 25% piposulfan | 22±4.4 | ＜0.001 |
| 10 (5) | 20% melphalan | 16±4.0 | ＜0.001 |
| 11 (5) | 20% defosfamide | 20±4.8 | ＜0.001 |
Above result shows that the alkylating agent slow releasing injection all has the obvious suppression effect to the oophoroma tumor growth of tumour cell under this concentration.
The tumor-inhibiting action of embodiment 14, alkylating agent 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 (micropowder), places in tumor.Alkylating agent dosage only is 0.2ml/, only is equivalent to 0.2mg-10mg/.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 (cm3) | The P value |
| 1 (5) | Contrast | 58±10 | |
| 2 (5) | 0.1% melphalan | 34±8.2 | ＜0.05 |
| 3 (5) | 0.1% norcantharidin | 36±6.8 | ＜0.01 |
| 4 (5) | 1% cyclophosphamide | 32±6.4 | ＜0.001 |
| 5 (5) | 1% Chlorambucil | 30±6.0 | ＜0.01 |
| 6 (5) | 2% ifosfamide | 32±6.0 | ＜0.001 |
| 7 (5) | 2%4H peroxide cyclophosphamide | 26±6.8 | ＜0.01 |
| 8 (5) | 4% melphalan | 22±4.6 | ＜0.001 |
| 9 (5) | 4% defosfamide | 30±5.6 | ＜0.01 |
| 10 (5) | 5% perfosfamide | 22±4.0 | ＜0.001 |
| 11 (6) | 5% Mafosfamide | 24±2.8 | ＜0.01 |
Above result shows that used alkylating agent slow releasing injection all has the obvious suppression effect to the hepatocarcinoma growth of tumour cell when this concentration, and is dose dependent.
The tumor-inhibiting action of embodiment 15, alkylating agent 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 (micropowder), places in tumor.Alkylating agent 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% hexamethylmelamine | 76 | ＜0.05 |
| 3 (5) | 7% cantharidin | 82 | ＜0.01 |
| 4 (5) | 0.5% mannomustine | 68 | ＜0.01 |
| 5 (5) | 0.5% mannomustine | 62 | ＜0.01 |
| 6 (5) | 0.1% ritrosulfan | 44 | ＜0.01 |
| 7 (5) | 0.1% improsulfan | 42 | ＜0.01 |
| 8 (5) | 0.3% etoglucid | 60 | ＜0.001 |
| 9 (5) | 0.3% pipobroman | 72 | ＜0.01 |
| 10 (5) | 0.5% skin norcantharidin | 60 | ＜0.01 |
| 11 (5) | 0.5% piposulfan | 64 | ＜0.01 |
The tumor-inhibiting action of embodiment 16, alkylating agent slow releasing agent
With the rat is subjects, with 2 * 10
5Individual cervical cancer 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 9 (microsphere), places in tumor.Alkylating agent 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) | 2% hexamethylmelamine | 55 | ＜0.05 |
| 3 (5) | 2% cantharidin | 50 | ＜0.05 |
| 4 (5) | 5% mannomustine | 56 | ＜0.05 |
| 5 (5) | 5% treosulfan | 58 | ＜0.05 |
| 6 (5) | 2% ritrosulfan | 62 | ＜0.01 |
| 7 (5) | 2% improsulfan | 52 | ＜0.01 |
| 8 (5) | 3% etoglucid | 74 | ＜0.01 |
| 9 (5) | 3% pipobroman | 82 | ＜0.01 |
| 10 (5) | 2.5% norcantharidin | 76 | ＜0.001 |
| 11 (5) | 2.5% piposulfan | 82 | ＜0.01 |
Above result shows that used alkylating agent slow releasing injection all has the obvious suppression effect to the cervical cancer growth of tumour cell when this concentration, and is dose dependent.
The tumor-inhibiting action of embodiment 17, alkylating agent 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 5).First group is contrast, and the 2nd to 11 group is the treatment group, and slow releasing injection is selected from embodiment 9 (microsphere), places in tumor.Alkylating agent 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 5) on the 30th day.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1 (5) | Contrast | ||
| 2 (5) | 5% triethylenemelaine | 66 | ＜0.05 |
| 3 (5) | 5% epoxypiperazine | 54 | ＜0.05 |
| 4 (5) | 5% benzene assistant TEPA | 50 | ＜0.05 |
| 5 (5) | 5% Phopurine | 54 | ＜0.05 |
| 6 (5) | 5% defosfamide | 62 | ＜0.01 |
| 7 (5) | 1% melphalan | 42 | ＜0.01 |
| 8 (5) | 5% melphalan | 70 | ＜0.01 |
| 9 (5) | 3% pipobroman | 50 | ＜0.01 |
| 10 (5) | 8% melphalan | 84 | ＜0.001 |
| 11 (5) | 8% defosfamide | 82 | ＜0.01 |
The tumor-inhibiting action of embodiment 18, alkylating agent slow releasing agent
With the rat is subjects, with 2 * 10
5Individual rectal 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 (microsphere), places in tumor.Alkylating agent 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) | 10% melphalan | 74 | ＜0.05 |
| 3 (5) | 10% norcantharidin | 70 | ＜0.05 |
| 4 (5) | 2% perfosfamide | 54 | ＜0.05 |
| 5 (5) | 2% hexamethylmelamine | 58 | ＜0.05 |
| 6 (5) | 5% improsulfan | 60 | ＜0.01 |
| 7 (5) | 5% etoglucid | 48 | ＜0.01 |
| 8 (5) | 15% melphalan | 84 | ＜0.01 |
| 9 (5) | 15% defosfamide | 70 | ＜0.01 |
| 10 (5) | 20% norcantharidin | 78 | ＜0.001 |
| 11 (5) | 20% piposulfan | 72 | ＜0.01 |
The tumor-inhibiting action of embodiment 19, alkylating agent slow releasing agent
With the rat is subjects, with 2 * 10
5Individual esophageal carcinoma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 7).First group is contrast, and the 2nd to 11 group is the treatment group, and sustained-release gel injection is placed in tumor from embodiment 8 (micropowder) and 9 (microspheres).Alkylating agent dosage only is 0.25ml/, only is equivalent to 12.5mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 7) on the 30th day.
Table 7
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1 (5) | Contrast | ||
| 2 (5) | 5% melphalan (micropowder) | 60 | ＜0.05 |
| 3 (5) | 5% melphalan (microsphere) | 76 | ＜0.01 |
| 4 (5) | 5% norcantharidin (micropowder) | 50 | ＜0.05 |
| 5 (5) | 5% norcantharidin (microsphere) | 68 | ＜0.01 |
| 6 (5) | 5% cantharidin (micropowder) | 62 | ＜0.05 |
| 7 (5) | 5% cantharidin (microsphere) | 72 | ＜0.01 |
| 8 (5) | 5% cyclophosphamide (micropowder) | 56 | ＜0.05 |
| 9 (5) | 5% cyclophosphamide (microsphere) | 64 | ＜0.01 |
| 10 (5) | 8% etoglucid (micropowder) | 56 | ＜0.05 |
| 11(5) | 8% etoglucid (microsphere) | 72 | ＜0.01 |
Above result shows that used alkylating agent sustained-release gel injection all has the obvious suppression effect to many gastric cancer growth of tumour cell when this concentration, and wherein microsphere is than the micropowder better effects if.
The tumor-inhibiting action of embodiment 20, alkylating agent slow releasing agent
With the rat is subjects, with 2 * 10
5Individual breast cancer tumour cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 8).First group is contrast, and the 2nd to 11 group is the treatment group, and release injectable is placed in tumor from embodiment 8 (micropowder) and 9 (microspheres) and 10 (micropowder and microsphere).Alkylating agent 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 8) on the 30th day.
Table 8
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1 (5) | Contrast | ||
| 2 (5) | 5% melphalan (micropowder) | 58 | ＜0.05 |
| 3 (5) | 5% melphalan (microsphere) | 64 | ＜0.05 |
| 4 (5) | 5% melphalan (micropowder and microsphere) | 70 | ＜0.01 |
| 5 (5) | 2% norcantharidin (micropowder) | 56 | ＜0.05 |
| 6 (5) | 2% norcantharidin (microsphere) | 66 | ＜0.01 |
| 7 (5) | 2% norcantharidin (micropowder and microsphere) | 72 | ＜0.001 |
| 8 (5) | 25% etoglucid (micropowder) | 68 | ＜0.01 |
| 9 (5) | 25% etoglucid (microsphere) | 76 | ＜0.01 |
| 10 (5) | 25% etoglucid (micropowder and microsphere) | 80 | ＜0.001 |
Above result shows that used alkylating agent sustained-release gel injection all has the obvious suppression effect to the renal carcinoma growth of tumour cell when this concentration, and wherein microsphere is better than the micropowder effect, and micropowder and microsphere are best.
Discover that further used alkylating agent sustained-release gel injection all has the obvious suppression effect to growth of tumour cell such as carcinoma of the colon and rectum, ovarian cancer, the cerebral tumor, bladder cancer
In a word, growth all has the obvious suppression effect to used alkylating agent sustained-release gel injection to kinds of tumor cells.Therapeutic effect is directly proportional with dosage.Wherein, the simple micropowder of sustained-release gel injection that contains microsphere or microsphere and micropowder is for well.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
In a word, growth all has the obvious suppression effect to used alkylating agent 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. anticancer sustained-release gel injection that contains alkylating agent is characterized in that sustained-release gel injection is grouped into by following one-tenth:
A: alkylating agent 0.001-40%
B: amphipathic copolymer 5%-40%
C: solvent 60%-90%
D: regulator 0-15%
More than be weight percentage,
Wherein, the viscosity of sustained-release gel injection is 10cp-3000cp (5 ℃-30 ℃ time);
Amphipathic copolymer 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-polyethyleneglycol block copolymer, and the mean molecule quantity of amphipathic nature block polymer is selected from 500-5000,5000-20000,20000-30000;
Solvent is selected from distilled water, water for injection, physiology towards liquid, cell culture fluid, body fluid, tissue fluid, buffer, phosphate buffer;
Release regulator is selected from a kind of or its combination in sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, the albumin glue
2. the anticancer sustained-release gel injection according to claim 1 is characterized in that alkylating agent is selected from one of cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine, Ah bundle's TEPA or its combination.
3. the anticancer sustained-release gel 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.
4. the anticancer sustained-release gel injection according to claim 1 is characterized in that the mean molecule quantity of Polyethylene Glycol can be 200-20000.
5. it is one of following that the anticancer sustained-release gel injection according to claim 1, the preparation method that it is characterized in that described anticancer sustained-release gel injection are selected from:
(1) prepares amphipathic aqueous copolymers solution with solvent earlier, add a certain amount of alkylating agent 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 alkylating agent 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 alkylating agent, uses after intensification is redissolved before using;
(3) the preparation alkylating agent 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 alkylating agent aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind alkylating agent 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 alkylating agent, add solvent then and make anticancer sustained-release gel injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Or
(6) a certain amount of amphipathic copolymer is mixed with a certain amount of alkylating agent, separately or mix back packing, transportation, store, before clinical practice, add solvent and fully mix and be stored in low temperature, heat up before using and redissolve the back and use to freezing state.
The regulator that can add 0-15% in the above method.
6. the anticancer sustained-release gel injection according to claim 1 is characterized in that described anticancer sustained-release gel injection contains one of following ingredients:
(1) 1% melphalan or norcantharidin, formulated by 10mg melphalan or norcantharidin, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 5% cyclophosphamide or Chlorambucils, formulated by 50mg cyclophosphamide or Chlorambucil, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 5% ifosfamides or 4H-peroxide cyclophosphamide, formulated by 50mg ifosfamide or 4H-peroxide cyclophosphamide, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 8% melphalan or defosfamides are by 80mg melphalan or defosfamide, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 10% perfosfamide or Mafosfamides are by 100mg perfosfamide or Mafosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 2% hexamethylmelamine or cantharidin are by 20mg hexamethylmelamine or cantharidin, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 5% mannomustine or treosulfans are by 50mg mannomustine or treosulfan, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 2% ritrosulfan or improsulfan are by 20mg ritrosulfan or an improsulfan, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 3% etoglucid or pipobromans are by 30mg etoglucid or pipobroman, 230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline;
(10) 2.5% norcantharidin or piposulfans are by 25mg norcantharidin or piposulfan, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection;
(11) 5% triethylenemelaine or epoxypiperazines are by 20mg triethylenemelaine or epoxypiperazine, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 5% benzene assistant TEPA or Phopurine are by 50mg benzene assistant TEPA or Phopurine, 200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline;
(13) 5% Ah bundle's TEPA or melphalans are by 50mg Ah bundle TEPA or melphalan, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(14) 5% melphalans, 50mg melphalan, by 200mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection
(15) 8% melphalan or defosfamides are by 80mg melphalan or defosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(16) 10% melphalan or norcantharidin are by 100mg melphalan or norcantharidin, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 2% perfosfamide or hexamethylmelamine are by 20mg perfosfamide or hexamethylmelamine, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline;
(18) 5% improsulfan or etoglucid are by a 50mg improsulfan or etoglucid, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 15% melphalan or defosfamides are by 150mg melphalan or defosfamide, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(20) 20% norcantharidin or piposulfans are by 200mg norcantharidin or piposulfan, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Medicine in the above-mentioned anticancer sustained-release gel injection is a sustained-release micro-spheres, and its gelling temperature is 32 ℃-38.5 ℃, and be 6-14 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 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 6: 1; Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
7. the anticancer sustained-release gel injection according to claim 1 is characterized in that described anticancer sustained-release gel injection contains one of following ingredients:
(1) 1% melphalan or norcantharidin, formulated by 10mg melphalan or norcantharidin, 300mg amphipathic nature block polymer and 700ul water for injection, the ratio of micropowder and microsphere is 9: 1;
(2) 5% cyclophosphamide or Chlorambucils, formulated by 50mg cyclophosphamide or Chlorambucil, 280mg amphipathic nature block polymer and 720ul distilled water, the ratio of micropowder and microsphere is 19: 1;
(3) 5% ifosfamides or 4H-peroxide cyclophosphamide, formulated by 50mg ifosfamide or 4H-peroxide cyclophosphamide, 250mg amphipathic nature block polymer and 750ul normal saline, the ratio of micropowder and microsphere is 14: 1;
(4) 8% melphalan or defosfamides, by 80mg melphalan or defosfamide, 230mg amphipathic nature block polymer and 770ul water for injection, the ratio of micropowder and microsphere is 14: 1;
(5) 10% perfosfamide or Mafosfamides, by 100mg perfosfamide or Mafosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer, the ratio of micropowder and microsphere is 5: 1;
(6) 2% hexamethylmelamine or cantharidin are by 20mg hexamethylmelamine or cantharidin, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 5% mannomustine or treosulfans, by 50mg mannomustine or treosulfan, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection, the ratio of micropowder and microsphere is 2: 1;
(8) 2% ritrosulfan or improsulfan, by 20mg ritrosulfan or an improsulfan, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water, the ratio of micropowder and microsphere is 1: 1;
(9) 3% etoglucid or pipobromans, by 30mg etoglucid or pipobroman, 230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline, the ratio of micropowder and microsphere is 1: 2;
(10) 2.5% norcantharidin or piposulfans, by 25mg norcantharidin or piposulfan, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection, the ratio of micropowder and microsphere is 1: 4;
(11) 5% triethylenemelaine or epoxypiperazines, by 20mg triethylenemelaine or epoxypiperazine, 260mg amphipathic nature block polymer and 740ul phosphate buffer, the ratio of micropowder and microsphere is 1: 5;
(12) 5% benzene assistant TEPA or Phopurine, by 50mg benzene assistant TEPA or Phopurine, 200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline, the ratio of micropowder and microsphere is 1: 9;
(13) 5% Ah bundle's TEPA or melphalans, by 50mg Ah bundle TEPA or melphalan, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline, the ratio of micropowder and microsphere is 1: 12;
(14) 5% melphalans, 50mg melphalan, by 200mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection, the ratio of micropowder and microsphere is 1: 14;
(15) 8% melphalan or defosfamides, by 80mg melphalan or defosfamide, 220mg amphipathic nature block polymer and 780ul phosphate buffer, the ratio of micropowder and microsphere is 1: 16;
(16) 10% melphalan or norcantharidin, by 100mg melphalan or norcantharidin, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline, the ratio of micropowder and microsphere is 1: 19;
(17) 2% perfosfamide or hexamethylmelamine, by 20mg perfosfamide or hexamethylmelamine, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline, the ratio of micropowder and microsphere is 1: 1;
(18) 5% improsulfan or etoglucid, by a 50mg improsulfan or etoglucid, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection, the ratio of micropowder and microsphere is 10: 1;
(19) 15% melphalan or defosfamides, by 150mg melphalan or defosfamide, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer, the ratio of micropowder and microsphere is 1: 9; Or
(20) 20% norcantharidin or piposulfans, by 200mg norcantharidin or piposulfan, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline, the ratio of micropowder and microsphere is 1: 5.
Medicine in the above-mentioned anticancer sustained-release gel injection is drug powder and sustained-release micro-spheres, and its gelling temperature is 33 ℃-37 ℃, and be 4-16 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1300-1600, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-6: 1.
8. the anticancer sustained-release gel injection according to claim 1 is characterized in that the injection of described anticancer slow-release is in subcutaneous, intracavity, abdominal cavity, thoracic cavity, canalis spinalis, in the tumor, in tumor week, tremulous pulse, lymph node and inject in the bone marrow
9. the anticancer sustained-release gel injection according to claim 1 is characterized in that described anticancer slow-release injection is used to prepare former method or the cancer of transfer or the pharmaceutical 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.
10. the anticancer sustained-release gel injection v agent according to claim 1 is characterized in that described anticancer slow-release injection is used for preparation treatment He Jiejin lymphoma, non_hodgkin lymphoma, small cell lung cancer, nonsmall-cell lung cancer, 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, the retinoblastoma of eyes, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, the medicine of carcinoma of testis.
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