CN101756888A - Temperature-controlled sustained-release injection containing isoliquiritigenin and preparation method thereof - Google Patents
Temperature-controlled sustained-release injection containing isoliquiritigenin and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a temperature-controlled sustained-release injection containing isoliquiritigenin, which comprises the isoliquiritigenin, amphiphilic block copolymer, solvent and a certain amount of medicine release regulator, wherein the mixture of the amphiphilic block copolymer and the organic solvent-free solvent has a temperature-sensitive gelation characteristic, the mixture is flowable liquid in an environment lower than the body temperature, and can automatically become unflowable, biodegradable and absorbable water-insoluble gel in the body of a warm-blooded animal, and the later can slowly release the contained isoliquiritigenin on part of a solid tumor and maintain the effective medicine concentration for weeks to months; the viscosity of the temperature-controlled sustained-release injection is 10cp to 3000cp (5 DEG C to 30 DEG C), and the gelation temperature is 35 DEG C to 37 DEG C. Cooperating with chemotherapy or surgical therapy, the isoliquiritigenin sustained-release injection is injected in or around the tumor or placed in the cavity of the tumor after surgery, and can evidently induce cancer cells to differentiate, reduce the risk of the metastasis and recrudescence of the tumor, improve patient prognosis and increase survival quality.
Description
Technical field
The present invention relates to a kind of temperature control sustained-release injection that contains isoliquiritigenin, belong to technical field of pharmaceuticals.Particularly, this invention relates to a kind of isoliquiritigenin can being stablized and is released to the partial sustained-release gel preparation of inducing the cancer differentiation of entity tumor, be mainly sustained-release gel injection, this sustained-release gel preparation is solution under the greenhouse, in the warm-blooded animal body, can be changed into semisolid or solid gel, thereby the isoliquiritigenin of being forgiven slowly can be discharged at tumor by local, from a few days to several weeks.
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 anti-tumor 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.
Isoliquiritigenin is a kind of isoflavone compounds in the Radix Glycyrrhizae, it has very strong pharmacologically active, have biological activitys such as the tumor cell proliferation of inhibition, inducing apoptosis of tumour cell, antiviral, free radical resisting, lax blood vessel, inhibition lipid peroxidation, wherein antitumor action is a hot research in recent years.As the existing pertinent literature report of tumor cell induced differentiation agent.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of antitumor drug thing slow releasing agent that contains isoliquiritigenin is provided, particularly, is a kind of sustained-release gel injection that contains isoliquiritigenin.This sustained-release gel injection at room temperature is a 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 induces cancer differentiation medicament slow releasing agent not only to have 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, is 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 copolymer solution of hydrophobicity polyester and hydrophilic polyglycol with can form water for injection gel after a certain amount of isoliquiritigenin 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 temp 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 isoliquiritigenin can slowly discharge isoliquiritigenin 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 isoliquiritigenin.
Find that through lot of experiments sustained-release gel injection of the present invention is grouped into by following one-tenth:
A: isoliquiritigenin 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 copolymer solution and isoliquiritigenin respectively, packing stores separately, injection is preceding induces cancer differentiation sustained-release gel injection with making behind amphipathic copolymer solution and the abundant mixing of isoliquiritigenin, is stored in low temperature or freezing state then, and use the redissolution back of heating up before using;
(2) the preparation isoliquiritigenin is made drug injection earlier, is mixed into a certain amount of amphipathic copolymer then and induces cancer differentiation sustained-release gel injection.-10 ℃ or following storing for future use.Injection in the body after redissolving before using.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.
(3) prepare isoliquiritigenin solution and amphipathic copolymer respectively, packing stores separately, induce cancer differentiation sustained-release gel injection with making behind isoliquiritigenin solution and the abundant mixing of amphipathic copolymer before injection, be stored in low temperature or freezing state then, use the redissolution back of heating up before using;
(4) a certain amount of amphipathic copolymer is mixed with a certain amount of isoliquiritigenin, 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 in the generation workshop, also amphipathic copolymer and isoliquiritigenin 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.
Generation technology and clinical practice requirement are depended in the packing of isoliquiritigenin and sustained-release gel and application.Isoliquiritigenin 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 in hybrid packed finger isoliquiritigenin homodisperse and the sustained-release gel.Pack alone or in combination with hybrid packed difference and be, mix with sustained-release gel before isoliquiritigenin is injected in vivo when packing alone or in combination, hybrid packed then is isoliquiritigenin to be dispersed in the sustained-release gel in process of production, direct injection after at room temperature heating up with preceding need.Or
(5) a certain amount of amphipathic copolymer is mixed with a certain amount of isoliquiritigenin, 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).
The percentage by weight of isoliquiritigenin 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 be made up of 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, Vicryl Rapide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, polyethylene glycol-lactic acid-Polyethylene Glycol, Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol, serving as preferred with Vicryl Rapide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide and Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol wherein, is optimum with Vicryl Rapide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide.
Polyester can be, but be not limited to any one in the copolymer of polylactic acid, polyglycolic acid and hydroxyacetic acid, poly-dl-lactide, poly-dl-lactide/ethanol copolymer, end carboxyl polylactic acid, the end carboxyl polylactic acid/ethanol copolymer or multiple copolymer.The mean molecule quantity of above-mentioned polyester is 500-30000, wherein is preferred with 800-20000, and 1000-10000 is 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: 11-4, with 9-7: 1-3 serves as preferred, for most preferably, the percentage by weight of Polyethylene Glycol can be 5%-40% in the promptly amphipathic copolymer, serves as preferred with 7%-to 30% with 9-7: 1-2, with 10%-25% for most preferably, the percentage by weight of polyester can be 60%-95%, is preferred with 70%-93%, with 75%-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 is the liquid of injection in the body after sterilizing, as, but be not limited to, distilled water, water for injection, buffer, physiology are towards liquid, cell culture fluid, body fluid, tissue fluid.The kind of solvent is 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.
This aspect 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, salt, sodium carboxymethyl cellulose, (iodine) glycerol, dimethicone, 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, gel, porogen, excipient or blocker etc.Its weight ratio in sustained-release gel can be 0.10%-15%.
The route of administration of slow releasing injection depends on multiple factor, for obtain valid density at former or position, metastatic tumour place, medicine can give through number of ways, as subcutaneous, in the intracavity, 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 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, the blood vessel cancer, the kindred cancer, lymphatic cancer, pulmonary carcinoma, thymic carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, prostate is suffered from hunger, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, the He Jiejin lymphoma, the non-hodgkin's lymphoma, the cancer of nonsmall-cell lung cancer or its transfer.
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 other cancer therapy drug or method coupling, as the associating of the chemotherapeutics of the cancer therapy drug of local injection and other administration, with the associating of radiotherapy or immunization therapy.
Isoliquiritigenin clinical practice dosage depends on patient's concrete condition, comprise age, body weight, sex, tumor type, tumor locus, tumor size and number, treatment experience, can be from the 0.001%-800mg/kg body weight, with the 0.1%-6800mg/kg body weight serves as preferred, and the 0.5%-500mg/kg body weight 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, tranquilizer, antidepressants etc.
The specific embodiment
Embodiment 1.
With 4,2g amphipathic nature block polymer Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide puts into No. one, No. two, two containers respectively, adds 6,8 milliliters of waters for injection then respectively in two containers, is mixed with 40%, 20% 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 lactide is 6: 1.
Embodiment 2.
Measure the gelling temperature of hydrogel among the embodiment 1, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 28 ℃ and 35 ℃.
Embodiment 3.
With 4,2g amphipathic nature block polymer Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide puts into No. one, No. two, two containers respectively, adds 6,8 milliliters of waters for injection then respectively in two containers, is mixed with 40%, 20% 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 lactide is 4: 1.
Embodiment 4.
Measure the gelling temperature of hydrogel among the embodiment 3, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 29 ℃ and 36 ℃.
Above result of the test shows that when gel solution concentration was between 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is excessive, is unfavorable for injection.
Embodiment 5.
(molecular weight of Polyethylene Glycol is 1500 in amphipathic nature block polymer Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, 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, be mixed with 25% copolymer aquagel.Then average mark install to 5 fill respectively 400,200,100,20 and the container of 2mg isoliquiritigenin in, the sustained-release gel injection of inducing the cancer differentiation that contains 20%, 10%, 5%, 1% and 0.1% isoliquiritigenin of system.Record its gelling temperature and be respectively 37 ℃, 35 ℃, 34 ℃, 33 ℃ and 31.5 ℃.
Embodiment 6.
Measure interior (subcutaneous) release cycle of mice body of the variable concentrations isoliquiritigenin among the embodiment 5, found that be respectively 55 ± 7,48 ± 6,40 ± 8,38 ± 6 days average time (estimating can measure the time in the blood) that discharges in 20%, 10%, 5%, the 1% and 0.1% isoliquiritigenin body.
Embodiment 7.
Induce cancer differentiation slow releasing injection to use more convenient according to the isoliquiritigenin of method " (1) " preparation, 1-5 makes the multiple cancer differentiation slow releasing injection of inducing in conjunction with the embodiments, in gelling temperature and body, discharge to measure find, preferably induce cancer differentiation slow releasing injection to contain concentration, constituent and percentage by weight as follows:
The 0.1%-25% isoliquiritigenin, by the 1-250mg isoliquiritigenin, the 200-260mg amphipathic nature block polymer, 0-70mg mannitol or 0-20mg sorbitol and 690-780 μ 1 solvent are formulated.
More than amphipathic copolymer be Polyethylene Glycol-Vicryl Rapide-Polyethylene Glycol, wherein the molecular weight of Polyethylene Glycol is 800-1200, account for 15% of amphipathic nature block polymer weight, in the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester lactide is 6-9: 1.
Studies show that above-mentioned gelling temperature of inducing cancer to break up sustained-release gel injection is 31 ℃-37 ℃, be 1-9 week release time in the animal body.
Induce the therapeutic effect of cancer differentiation sustained-release gel injection to further specify by following test and treatment embodiment:
Embodiment 8
With the rat is subjects, with 2 * 10
5Individual prostate gland cancer cell subcutaneous injection is in its hypochondrium position, and to grow to diameter be to be divided into four groups behind the 1cm etc. tumor, and what contain 20%, 10%, 0.1% and 0% isoliquiritigenin respectively among the intratumor injection 0.1ml embodiment 5 induces cancer differentiation sustained-release gel injection.Measure gross tumor volume every day, the result shows (table 1), and isoliquiritigenin induces cancer differentiation slow releasing injection can significantly suppress tumor growth, and its tumor-inhibiting action is obvious dose dependent, and is safe and reliable.The operation of intratumor injection slow releasing injection is the most simple and easy to do.
Table 1 isoliquiritigenin sustained-release gel injection is to the tumor-inhibiting action of carcinoma of prostate
Embodiment 9
With the rat is subjects, with 2 * 10
5Individual lung carcinoma cell subcutaneous injection is in its hypochondrium position, and to grow to diameter be to be divided into four groups behind the 1.0cm etc. tumor, and what contain 20%, 10%, 0.1% and 0% isoliquiritigenin respectively among the intratumor injection 0.1ml embodiment 5 induces cancer differentiation sustained-release gel injection.Measure gross tumor volume every day, the result shows (table 2), and isoliquiritigenin induces cancer differentiation slow releasing injection can significantly suppress tumor growth, and its tumor-inhibiting action is obvious dose dependent, and is safe and reliable.The operation of intratumor injection slow releasing injection is the most simple and easy to do.
Table 2 isoliquiritigenin sustained-release gel injection is to the tumor-inhibiting action of pulmonary carcinoma
Generally speaking, used isoliquiritigenin is induced cancer differentiation sustained-release gel injection, and growth all has the obvious suppression effect to kinds of tumor cells, and just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
Embodiment 10
With 60 mices is subjects, with 2 * 10
5Individual hepatoma carcinoma cell subcutaneous injection is subcutaneous in right armpit, and to grow to diameter be it to be divided into four groups at random behind the 1.0cm etc. tumor, and what contain 20%, 10%, 0.1% and 0% isoliquiritigenin respectively among the intratumor injection 0.1ml embodiment 5 induces cancer differentiation sustained-release gel injection.Measure gross tumor volume every day, the result shows (table 3), and isoliquiritigenin induces cancer differentiation slow releasing injection can significantly suppress tumor growth, and its tumor-inhibiting action is obvious dose dependent, and is safe and reliable.The operation of intratumor injection slow releasing injection is the most simple and easy to do.
Table 2 isoliquiritigenin sustained-release gel injection is to the tumor-inhibiting action of hepatocarcinoma
Generally speaking, used isoliquiritigenin is induced cancer differentiation sustained-release gel injection, and growth all has the obvious suppression effect to kinds of tumors, and 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 isoliquiritigenin is characterized in that temperature control sustained-release injection is grouped into by following one-tenth:
A: isoliquiritigenin 0.01%-40%
B: amphipathic copolymer 5%-40%
C: solvent 50%-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 discharge contained isoliquiritigenin and keep the thoughtful several months of active drug concentration numbers in the solid tumor local slow; The viscosity of temperature control sustained-release injection is 10cp-3000cp (5 ℃-30 ℃);
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;
But solvent is selected from distilled water, water for injection, buffer, physiology towards liquid, cell culture fluid, body fluid, tissue fluid for the solution of injection in the body after sterilizing.Wherein, the percentage ratio of solvent in the hydrogel of amphipathic nature block polymer and molten coal composition is 60%-99%.
2. the temperature control sustained-release injection according to claim 1 is characterized in that the percentage by weight of isoliquiritigenin 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 1-15 in the Vicryl Rapide: 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. the temperature control sustained-release injection according to claim 1 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, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, the albumin glue; The drug release regulator is 0-15% in the mass percent 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:
Prepare amphipathic copolymer solution and isoliquiritigenin respectively, packing stores separately, injection is preceding induces cancer differentiation sustained-release gel injection with making behind amphipathic copolymer solution and the abundant mixing of isoliquiritigenin, is stored in low temperature or freezing state then, and use the redissolution back of heating up before using;
The preparation isoliquiritigenin is made medicaments injection earlier, is mixed into a certain amount of amphipathic copolymer then and induces cancer differentiation sustained-release gel injection;-10 ℃ or following storing for future use; Injection in the body after redissolving before using;
Prepare amphipathic copolymer and isoliquiritigenin solution respectively, packing stores separately, injection is preceding induces cancer differentiation sustained-release gel injection with making behind isoliquiritigenin solution and the abundant mixing of amphipathic copolymer, is stored in low temperature or freezing state then, and use the redissolution back of heating up before using;
A certain amount of amphipathic copolymer is mixed with a certain amount of isoliquiritigenin, 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;
A certain amount of amphipathic copolymer is mixed with a certain amount of isoliquiritigenin, pack separately or after the mixing, transport, store, the adding solvent fully mixes and is stored in low temperature to freezing state before clinical practice, use after the preceding intensification of use is redissolved;
The regulator that can add 0-15% in the above method.
8. the temperature control sustained-release injection according to claim 1, it is characterized in that described temperature control sustained-release injection contains following ingredients: the block copolymer solution of 9%-32% contains the 0.005%-30% isoliquiritigenin.
9. the temperature control sustained-release injection according to claim 1, it is characterized in that described temperature control sustained-release injection contains following ingredients: the 0.1%-25% isoliquiritigenin, by the 1-250mg isoliquiritigenin, the 200-260mg amphipathic nature block polymer, 0-70mg mannitol or 0-20mg sorbitol and 690-780 μ l solvent are formulated;
More than amphipathic copolymer be Polyethylene Glycol-Vicryl Rapide-Polyethylene Glycol, wherein the molecular weight of Polyethylene Glycol is 800-1200, account for 20% of amphipathic nature block polymer weight, in the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester lactide is 4-9: 1.
10. described according to Claim 8 temperature control sustained-release injection, it is characterized in that describedly inducing cancer differentiation slow releasing injection to be used for the preparation treatment to comprise 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, the blood vessel cancer, the kindred cancer, lymphatic cancer, 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, the non-hodgkin's lymphoma, application in the medicine of nonsmall-cell lung cancer, can be used as the adjuvant therapy medicaments of operation and chemotherapy, strengthen the treatment medicine of operation and chemotherapy, alleviate its toxicity, can suppress the recurrence or the transfer of tumor.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110812384A (en) * | 2019-12-20 | 2020-02-21 | 江西中医药大学 | New medical application of effective component and derivative thereof in liquorice |
| CN112022797A (en) * | 2020-07-24 | 2020-12-04 | 西安交通大学 | Preparation method of temperature-sensitive plasma active biogel and active biogel |
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2008
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110812384A (en) * | 2019-12-20 | 2020-02-21 | 江西中医药大学 | New medical application of effective component and derivative thereof in liquorice |
| CN112022797A (en) * | 2020-07-24 | 2020-12-04 | 西安交通大学 | Preparation method of temperature-sensitive plasma active biogel and active biogel |
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Application publication date: 20100630 |