CN102793663A - Sustained-release microsphere injection containing antitumor drug (2-methoxyestradiol) - Google Patents
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Abstract
The invention relates to a sustained-release microsphere injection containing an antitumor drug (2-methoxyestradiol), and the sustained-release microsphere injection can be used for effectively solving the problems that a conventional drug delivery system for 2-methoxyestradiol is not ideal in tumor treatment effect and has side effects. The technical scheme adopted for solving the problems is as follows: the sustained-release microsphere injection consists of the following parts by weight percent: 5-50% of sustained-release microspheres and 50-95% of solvent system, or independent sustained-release microsphere. The sustained-release microsphere injection can be used for realizing the purpose that the effect of drug can be sustained for a long time by one-time drug delivery, and overcoming the defects and shortcomings of a conventional 2-methoxyestradiol delivery system; and according to the sustained-release microsphere injection, the effective blood concentration can be maintained in the body for a long time, the dosage amount is only 1/30 that of the conventional drug delivery, the tumor inhibiting efficiency is 62% and is higher than that of the intravenous injection drug delivery by about 45%. The sustained-release microsphere injection can be used for reducing the dosage of the drug (toxic and side effects) and has the obvious advantages of improving the drug therapeutic effect.
Description
Technical field
The present invention relates to medical technical field, a kind of sustained-release microspheres injection that contains antitumor drug 2-methoxyestradiol that particularly the tumor body is interior or tumor body surrounding injection is used.
Background technology
The 2-methoxyestradiol is an estrogen natural metabolite in vivo; Under suitable concentration, have anti-tumor activity widely, have the pharmacological characteristic of time and dose dependent, 2-methoxyestradiol water solublity extreme difference (being about 0.22 μ g/ml); Oral absorption efficient extreme difference; And lack dependency between oral administration post dose and the blood drug level, and oral maximum plasma concentration is all less than 100ng/ml (Jehana James et al.Invest new drugs.25:41-48 (2006), but the external pharmacodynamic study of most tumors cell strain shows; The 2-methoxyestradiol is to most cell strains, like the half-inhibition concentration (IC of breast carcinoma, carcinoma of prostate etc.
50) all greater than μ mol level level (1-10 μ mol level) (H Seeger et al.J steroid biochem and molecular bio. 84:255-257 (2003)), so 2-methoxyestradiol oral administration is not effective form of administration.Given this we have carried out studying (CN200810049466.5 to the parenteral introduction approach of 2-methoxyestradiol in earlier stage; CN200810049465.0, CN2009 10064338.2) obtained the dosage form of intravenously administrable, have safety preferably and higher effective blood drug level.The chemotherapy of considering tumor is generally a kind of auxiliary treatment means; As behind the operative treatment of tumor, need to combine chemotherapy to shift with the whole body of prevention oncocyte; Usually operative site is the source that oncocyte shifts, but conventional administering mode (like oral, intravenous injection) medicine all need pass through transfer in the body, just can reach therapentic part; Though intravenous injection has higher blood medicine and remedy,tissue's substrate concentration, still has only lower blood drug level in the treatment part.If there is a kind of drug-supplying system to have other complex of cooperative effect directly to carry with the 2-methoxyestradiol and with the 2-methoxyestradiol in the part of needs treatment tumor; Make the part that higher drug level arranged; And other fraction medicine concentration of body is extremely low; Reach the purpose that the whole body toxic and side effects that reduces medicine improves curative effect like this, also significantly reduce dosage simultaneously, practice thrift patient treatment expense purpose.
Reduce the dosage purpose in order to reach; People have studied transdermal liniment and the patch (one Chinese patent application number: 2010030115.7) of 2-methoxyestradiol; Though transdermal liniment and patch have advantage aspect the shallow epidermis tumor of treatment; But, also has defective like hepatocarcinoma, pulmonary carcinoma etc. in the profound tumor of treatment.There is the scholar to be injected into polylactic acid-glycollic acid (PLGA) and 2-methoxyestradiol in the silica gel tube of 0.8mm with acetone solution; After drying is removed acetone, hope this doser to be implanted to the part of tumor cell, to reach the purpose of local treatment of tumor through embedding mode; Also there are two defectives in this doser; At first this doser can not biodegradation, must after drug release is accomplished, take out through operation again, cause the clinical treatment poor compliance; Secondly this doser has only a drug release section (and opening of silica gel tube), if the release open end is favourable to oncocyte to treatment, if otherwise then be disadvantageous to treatment, how this just for implanting this doser proposition difficulty; The mode administration that the 3rd this doser can only adopt operation to implant, the common injection system administration that can not adopt (K.G.H.Desai et al.I European Joural of Pharmaceutics and Biopharmaceutics.70:187-198 (2008)).
The growth that the 2-methoxyestradiol suppresses tumor cell has cell cycle property characteristic, only can cell be stoped in G
2/ M the phase; So with 2-methoxyestradiol and other series antineoplastic medicament aperiodic; Be combined with each other through the part of microsphere supported direct injection around inside tumor and tumor like antitumor drug such as nitrogen mustards, metal platinum classes; Can improve tumor treatment efficient like this, the total dosage that reduces medicine is to reduce the toxicity of medicine; In tumor cell, there is a kind of p-glycoprotein; Can to cell, drain into antitumor drug outside the born of the same parents; Antitumor drug and p-glycoprotein inhibitors Combined application generally speaking; Can improve antitumous effect, also be a kind of synergist of antitumor drug, but most of p-glycoprotein inhibitors needs its associating usefulness of very high concentration competence exertion; To such an extent as to the patient is impatient at the toxic and side effects that high concentration is brought, so 2-methoxyestradiol and p-glycoprotein inhibitors are processed the toxic and side effects that a drug-supplying system can significantly reduce p-glycoprotein inhibitors gastrointestinal or whole body administration together.
Summary of the invention
To above-mentioned situation; For overcoming the defective of prior art; The present invention's purpose just provides a kind of sustained-release microspheres injection that contains antitumor drug 2-methoxyestradiol, can effectively solve the present drug-supplying system of 2-methoxyestradiol to the oncotherapy effect undesirable with the problem of side effect is arranged.
The technical scheme that the present invention solves is, a kind of sustained-release microspheres injection that contains antitumor drug 2-methoxyestradiol, by weight percent meter: sustained-release micro-spheres 5-50% and solvent system 50-95% form, or independent sustained-release micro-spheres;
Described sustained-release micro-spheres is by weight percent meter: antitumor active drug 0.5-50% and slow-release auxiliary material 50-99.5% form;
Described antitumor active drug is the 2-methoxyestradiol, or by weight percent meter: 2-methoxyestradiol 5-95% and the complex that can improve other antitumor drug 5-95% of 2-methoxyestradiol antitumous effect;
Described other antitumor drug that can improve 2-methoxyestradiol antitumous effect are in disappear chlormethine, formylmerphalan, chlorambucil, fluorouracil, semustine, nimustine, cyclophosphamide, ifosfamide, cisplatin, carboplatin, oxaliplatin, lobaplatin, iproplatin, paclitaxel, camptothecine, cyclosporin A, verapamil, valspodar (Valspodar), biricodar (Biricodar), his the auspicious Quetta (Tariquidar) any one;
Described slow-release auxiliary material is a polylactic acid, or the copolymer of the lactic acid 10-90% of weight percent meter and hydroxyacetic acid 10-90%, or gathers in 3-hydroxybutyric acid and the polyglycolic acid any one, or any two kinds combination;
The molecular weight peak value of described polylactic acid is a kind of of 1-3 ten thousand, 4-6 ten thousand, 7-10 ten thousand or 11-15 ten thousand;
The molecular weight peak value of the lactic acid 10-90% of described weight percent meter and the copolymer of hydroxyacetic acid 10-90% is a kind of of 1-3 ten thousand, 4-6 ten thousand, 7-10 ten thousand or 11-15 ten thousand;
The molecular weight peak value of the described 3-of gathering hydroxybutyric acid is a kind of of 1-3 ten thousand, 4-6 ten thousand, 7-10 ten thousand or 11-15 ten thousand;
The molecular weight peak value of described polyglycolic acid is a kind of of 2-4 ten thousand, 5-8 ten thousand, 9-12 ten thousand or 13-16 ten thousand;
Described solvent system is a kind of in the xanthan gum of tragacanth, mass concentration 0.1 ~ 2% of chitosan, the mass concentration 0.1 ~ 2% of sanlose, the mass concentration 0.1 ~ 2% of mass concentration 0.5 ~ 3.0%.
A kind of method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol, with weight percent meter: antitumor active drug 0.5-50% and slow-release auxiliary material 50-99.5% mix, after the organic solvent dissolving; With the inorganic micropore glass membrane filtration of film tube type; Collect microsphere, washing, the vacuum drying at room temperature after 48 hours to sustained-release micro-spheres; Packing, subsequent use after the radiation sterilization; Solvent system is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 5-50% and microsphere suspension medium 50-95% suspendible; Described organic solvent is any one in dichloromethane, chloroform or the supercritical fluid carbon dioxide.
A kind of method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol, with weight percent meter: antitumor active drug 0.5-50% and slow-release auxiliary material 50-99.5% add dichloromethane and a spot of water stirs, and forms temporary transient stable water in oil emulsion; The gelatin mixed solution of the polyvinyl alcohol of 1.5-2% and 5-10% is injected into aqueous phase with above-mentioned water in oil emulsion, fast cooling under the high-speed stirred condition; Slowly evacuation is removed dichloromethane; Filter to collect microsphere, washing, the vacuum drying at room temperature after 48 hours to sustained-release micro-spheres; Packing, subsequent use after the radiation sterilization; Solvent system is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 5-50% and microsphere suspension medium 50-95% suspendible.
The described sustained-release microspheres injection that contains antitumor drug 2-methoxyestradiol is used to treat the solid tumor that originates from the people; Like common breast carcinoma, carcinoma of prostate, pulmonary carcinoma, hepatocarcinoma etc.; Administering mode mainly is in the tumor body or the administration of tumor body surrounding injection; Operative site is put in the sustained-release microspheres injection part that also can after the solid tumor operation finishes, will not contain the microsphere suspension medium, the recurrence of tumor behind treatment tumor or the prevention operative treatment.
The realization single administration that the present invention solves is permanently effective; The defective and the deficiency of present 2-methoxyestradiol drug-supplying system have been solved; Can keep effective blood drug concentration (1 ~ 10 μ mol level) for a long time in vivo, pharmaceutical quantities (20mg/kg/30day) has only 1/30 of traditional administration (vein: 20mg/kg/day, totally 30 days); Inhibition efficient to tumor reaches 62%; Be higher than about 45% of intravenous administration, product of the present invention has reduced the dosage (reduction toxic and side effects) of medicine, has significant advantage aspect the raising curative effect of medication.
The specific embodiment
Elaborate below in conjunction with the embodiment specific embodiments of the invention.
Embodiment 1
With weight percent meter: 2-methoxyestradiol 0.5% mixes with slow-release auxiliary material 99.5%, after the dichloromethane dissolving, with the inorganic micropore glass membrane filtration of film tube type; Collect microsphere, washing, the vacuum drying at room temperature after 48 hours to sustained-release micro-spheres; Packing, subsequent use after the radiation sterilization; 0.5 ~ 3.0% sanlose is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; Before the use, with weight percent meter: sustained-release micro-spheres 5% and microsphere suspension medium 95% suspendible; Described slow-release auxiliary material is the polylactic acid of 1-3 ten thousand for the molecular weight peak value.
Embodiment 2
With weight percent meter: antitumor active drug 30% mixes with slow-release auxiliary material 70%, after the chloroform dissolving, with the inorganic micropore glass membrane filtration of film tube type; Collect microsphere, washing, the vacuum drying at room temperature after 48 hours to sustained-release micro-spheres; Packing, subsequent use after the radiation sterilization; 0.1 ~ 2% chitosan is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; Before the use, with weight percent meter: sustained-release micro-spheres 30% and microsphere suspension medium 70% suspendible; Described antitumor active drug is: by weight percent meter: the complex of 2-methoxyestradiol 5% and paclitaxel 95%; Described slow-release auxiliary material is lactic acid 10-90% and the copolymer of hydroxyacetic acid 10-90% of the weight percent meter of 4-6 ten thousand for the molecular weight peak value.
Embodiment 3
With weight percent meter: antitumor active drug 50% mixes with slow-release auxiliary material 50%; After the supercritical fluid carbon dioxide dissolving,, collect microsphere with the inorganic micropore glass membrane filtration of film tube type; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; 0.1 ~ 2% tragacanth is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; Before the use, with weight percent meter: sustained-release micro-spheres 50% and microsphere suspension medium 50% suspendible; Described antitumor active drug is by weight percent meter: the complex of 2-methoxyestradiol 95% and Ta Rui Quetta 5%; Described slow-release auxiliary material for the molecular weight peak value be 7-10 ten thousand gather the 3-hydroxybutyric acid.
Embodiment 4
With weight percent meter: antitumor active drug 0.5% adds dichloromethane with slow-release auxiliary material 99.5% and a spot of water stirs, form temporary transient stable water in oil emulsion, and 1.5% polyvinyl alcohol and 5% gelatin mixed solution are under stirring condition; Above-mentioned water in oil emulsion is injected into aqueous phase, fast cooling, slowly evacuation is removed dichloromethane; Filter to collect microsphere, washing, the vacuum drying at room temperature after 48 hours to sustained-release micro-spheres; Packing, subsequent use after the radiation sterilization; 0.1 ~ 2% xanthan gum is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 5% and microsphere suspension medium 95% suspendible; Described antitumor active drug is: by weight percent meter: the complex of 2-methoxyestradiol 5% and carboplatin 95%; Described slow-release auxiliary material is the polyglycolic acid of 9-12 ten thousand for the molecular weight peak value.
Embodiment 5
With weight percent meter: antitumor active drug 30% adds dichloromethane with slow-release auxiliary material 70% and a spot of water stirs, form temporary transient stable water in oil emulsion, and 2% polyvinyl alcohol and 10% gelatin mixed solution are under stirring condition; Above-mentioned water in oil emulsion is injected into aqueous phase, fast cooling, slowly evacuation is removed dichloromethane; Filter to collect microsphere, washing, the vacuum drying at room temperature after 48 hours to sustained-release micro-spheres; Packing, subsequent use after the radiation sterilization; 0.5 ~ 3.0% sanlose is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 30% and microsphere suspension medium 70% suspendible; Described antitumor active drug is by weight percent meter: the complex of 2-methoxyestradiol 50% and fluorouracil 50%; Described slow-release auxiliary material is the polylactic acid of 7-10 ten thousand for the molecular weight peak value.
Embodiment 6
With weight percent meter: antitumor active drug 50% adds dichloromethane with slow-release auxiliary material 50% and a spot of water stirs, form temporary transient stable water in oil emulsion, and 1.5% polyvinyl alcohol and 10% gelatin mixed solution are under stirring condition; Above-mentioned water in oil emulsion is injected into aqueous phase, fast cooling, slowly evacuation is removed dichloromethane; Filter to collect microsphere, washing, the vacuum drying at room temperature after 48 hours to sustained-release micro-spheres; Packing, subsequent use after the radiation sterilization; 0.1 ~ 2% tragacanth is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 50% and microsphere suspension medium 50% suspendible; Described antitumor active drug is for by weight percent meter: the complex of the 2-methoxyestradiol 95% and the chlormethine 5% that disappears; Described slow-release auxiliary material for the molecular weight peak value be 2-4 ten thousand gather the 3-hydroxybutyric acid.
The present invention tests as follows:
Get different tumor cell lines, be inoculated in the nude mice oxter, treat that the tumor piece grows into size and is 100mm
3About, around the tumor piece, be radial hexagonal configuration local injection the invention described above product with syringe; Every nude mice is pressed the 0.4mg dose ejection and implants as injection groups, measures the tumor volume every day, raises after 30 days; Put to death nude mice, measurement volumes and weight are calculated tumor control rate; Set the former medicine nude mice of 2-methoxyestradiol gastric infusion group or intravenous administration group simultaneously and organize as the positive, measure the 2-methoxyestradiol simultaneously tumor cell line is compared as the experiment in vitro group in external 72h inhibition efficient, the result sees table 1.
Tumor control rate=inhibition rate of tumor growth=(C-T)/C
Wherein, the average tumor of the negative matched group of C heavy (volume); T is the average tumor of administration group heavy (volume).
Table 1 result of the test synopsis
In the table:
SK-N-SH: HNB's cell strain; RAW 264.7: mice is huge has a liking for the glucagonoma cell strain; A549: people's non-small cell lung cancer cell strain; 4T1: mouse mastopathy cell strain; NCL-H1299: people's non-small cell JEG-3; PC-3: Human Prostate Cancer Cells strain; NCL-H1755: human hepatoma cell strain
Above-mentioned test; Through repeated multiple times; All obtained identical or akin result, the method for preparing of the sustained-release microspheres injection through testing surperficial 2-methoxyestradiol of the present invention has operability, and the sustained-release microspheres injection entrapment efficiency of the 2-methoxyestradiol of preparation is higher; The microsphere size has syringeability preferably, can bring benefit to clinical practice; The dosage of the sustained-release microspheres injection topical of 2-methoxyestradiol has only 1/30 of conventional dosage (oral or injection) simultaneously; And the interior antitumous effect of object obviously is superior to the oral or drug administration by injection of similar medicine; It is consistent that the fundamental sum medicine suppresses efficient at external cell; It is thus clear that product of the present invention has reduced the dosage (reduction toxic and side effects) of medicine, has significant advantage aspect the raising curative effect of medication.
Claims (10)
1. a sustained-release microspheres injection that contains antitumor drug 2-methoxyestradiol is characterized in that, by weight percent meter: sustained-release micro-spheres 5-50% and solvent system 50-95% form, or independent sustained-release micro-spheres;
Described sustained-release micro-spheres is by weight percent meter: antitumor active drug 0.5-50% and slow-release auxiliary material 50-99.5% form;
Described antitumor active drug is the 2-methoxyestradiol, or by weight percent meter: 2-methoxyestradiol 5-95% and the complex that can improve other antitumor drug 5-95% of 2-methoxyestradiol antitumous effect;
Described other antitumor drug that can improve 2-methoxyestradiol antitumous effect are in chlormethine, formylmerphalan, chlorambucil, fluorouracil, semustine, nimustine, cyclophosphamide, ifosfamide, cisplatin, carboplatin, oxaliplatin, lobaplatin, iproplatin, paclitaxel, camptothecine, cyclosporin A, verapamil, valspodar, biricodar, his the auspicious Quetta any one of disappearing;
Described slow-release auxiliary material is a polylactic acid, or the copolymer of the lactic acid 10-90% of weight percent meter and hydroxyacetic acid 10-90%, or gathers in 3-hydroxybutyric acid and the polyglycolic acid any one, or any two kinds combination;
The molecular weight peak value of described polylactic acid is a kind of of 1-3 ten thousand, 4-6 ten thousand, 7-10 ten thousand or 11-15 ten thousand;
The molecular weight peak value of the lactic acid 10-90% of described weight percent meter and the copolymer of hydroxyacetic acid 10-90% is a kind of of 1-3 ten thousand, 4-6 ten thousand, 7-10 ten thousand or 11-15 ten thousand;
The molecular weight peak value of the described 3-of gathering hydroxybutyric acid is a kind of of 1-3 ten thousand, 4-6 ten thousand, 7-10 ten thousand or 11-15 ten thousand;
The molecular weight peak value of described polyglycolic acid is a kind of of 2-4 ten thousand, 5-8 ten thousand, 9-12 ten thousand or 13-16 ten thousand;
Described solvent system is a kind of in the xanthan gum of tragacanth, mass concentration 0.1 ~ 2% of chitosan, the mass concentration 0.1 ~ 2% of sanlose, the mass concentration 0.1 ~ 2% of mass concentration 0.5 ~ 3.0%.
2. the described method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol of claim 1 is characterized in that, with weight percent meter: antitumor active drug 0.5-50% and slow-release auxiliary material 50-99.5% mix; After the organic solvent dissolving,, collect microsphere with the inorganic micropore glass membrane filtration of film tube type; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; Solvent system is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 5-50% and microsphere suspension medium 50-95% suspendible; Described organic solvent is any one in dichloromethane, chloroform or the supercritical fluid carbon dioxide.
3. the method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol according to claim 2 is characterized in that, with weight percent meter: 2-methoxyestradiol 0.5% mixes with slow-release auxiliary material 99.5%; After the dichloromethane dissolving,, collect microsphere with the inorganic micropore glass membrane filtration of film tube type; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; 0.5 ~ 3.0% sanlose is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 5% and microsphere suspension medium 95% suspendible; Described slow-release auxiliary material is the polylactic acid of 1-3 ten thousand for the molecular weight peak value.
4. the method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol according to claim 2 is characterized in that, with weight percent meter: antitumor active drug 30% mixes with slow-release auxiliary material 70%; After the chloroform dissolving,, collect microsphere with the inorganic micropore glass membrane filtration of film tube type; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; 0.1 ~ 2% chitosan is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 30% and microsphere suspension medium 70% suspendible; Described antitumor active drug is: by weight percent meter: the complex of 2-methoxyestradiol 5% and paclitaxel 95%; Described slow-release auxiliary material is lactic acid 10-90% and the copolymer of hydroxyacetic acid 10-90% of the weight percent meter of 4-6 ten thousand for the molecular weight peak value.
5. the method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol according to claim 2 is characterized in that, with weight percent meter: antitumor active drug 50% mixes with slow-release auxiliary material 50%; After the supercritical fluid carbon dioxide dissolving,, collect microsphere with the inorganic micropore glass membrane filtration of film tube type; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; 0.1 ~ 2% tragacanth is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 50% and microsphere suspension medium 50% suspendible; Described antitumor active drug is by weight percent meter: the complex of 2-methoxyestradiol 95% and Ta Rui Quetta 5%; Described slow-release auxiliary material for the molecular weight peak value be 7-10 ten thousand gather the 3-hydroxybutyric acid.
6. the described method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol of claim 1 is characterized in that, with weight percent meter: antitumor active drug 0.5-50% and slow-release auxiliary material 50-99.5% add dichloromethane and a spot of water stirs; Form temporary transient stable water in oil emulsion, the gelatin mixed solution of the polyvinyl alcohol of 1.5-2% and 5-10% is injected into aqueous phase with above-mentioned water in oil emulsion under stirring condition; Fast cooling, slowly evacuation is removed dichloromethane, filters and collects microsphere; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; Solvent system is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 5-50% and microsphere suspension medium 50-95% suspendible.
7. the method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol according to claim 6 is characterized in that, with weight percent meter: antitumor active drug 0.5% adds dichloromethane with slow-release auxiliary material 99.5% and a spot of water stirs; Form temporary transient stable water in oil emulsion, 1.5% polyvinyl alcohol and 5% gelatin mixed solution are injected into aqueous phase with above-mentioned water in oil emulsion under stirring condition; Fast cooling, slowly evacuation is removed dichloromethane, filters and collects microsphere; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; 0.1 ~ 2% xanthan gum is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 5% and microsphere suspension medium 95% suspendible; Described antitumor active drug is: by weight percent meter: the complex of 2-methoxyestradiol 5% and carboplatin 95%; Described slow-release auxiliary material is the polyglycolic acid of 9-12 ten thousand for the molecular weight peak value.
8. the method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol according to claim 6 is characterized in that, with weight percent meter: antitumor active drug 30% adds dichloromethane with slow-release auxiliary material 70% and a spot of water stirs; Form temporary transient stable water in oil emulsion, 2% polyvinyl alcohol and 10% gelatin mixed solution are injected into aqueous phase with above-mentioned water in oil emulsion under stirring condition; Fast cooling, slowly evacuation is removed dichloromethane, filters and collects microsphere; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; 0.5 ~ 3.0% sanlose is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 30% and microsphere suspension medium 70% suspendible; Described antitumor active drug is by weight percent meter: the complex of 2-methoxyestradiol 50% and fluorouracil 50%; Described slow-release auxiliary material is the polylactic acid of 7-10 ten thousand for the molecular weight peak value.
9. the method for preparing that contains the sustained-release microspheres injection of antitumor drug 2-methoxyestradiol according to claim 6 is characterized in that, with weight percent meter: antitumor active drug 50% adds dichloromethane with slow-release auxiliary material 50% and a spot of water stirs; Form temporary transient stable water in oil emulsion, 1.5% polyvinyl alcohol and 10% gelatin mixed solution are injected into aqueous phase with above-mentioned water in oil emulsion under stirring condition; Fast cooling, slowly evacuation is removed dichloromethane, filters and collects microsphere; Washing; The vacuum drying at room temperature after 48 hours to sustained-release micro-spheres, packing, subsequent use after the radiation sterilization; 0.1 ~ 2% tragacanth is obtained the microsphere suspension medium through 0.22 μ m filtering with microporous membrane, packing, subsequent use behind the pressure sterilizing; During use, with weight percent meter: sustained-release micro-spheres 50% and microsphere suspension medium 50% suspendible; Described antitumor active drug is for by weight percent meter: the complex of the 2-methoxyestradiol 95% and the chlormethine 5% that disappears; Described slow-release auxiliary material for the molecular weight peak value be 2-4 ten thousand gather the 3-hydroxybutyric acid.
10. any described sustained-release microspheres injection that contains antitumor drug 2-methoxyestradiol of claim 1 or 2-9 is being treated tumor or the application of the back tumor recurrence medicine that prevents to perform the operation.
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| CN105456200A (en) * | 2015-12-08 | 2016-04-06 | 郑州大学 | Preparation method and application of nanoparticle microsphere for improving oral bioavailability of poorly soluble drugs |
| CN107412161A (en) * | 2017-05-22 | 2017-12-01 | 河南科技大学 | A kind of methoxyestradiol intravenous injection of self-emulsifying 2 and preparation method thereof |
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| CN1857201A (en) * | 2006-03-06 | 2006-11-08 | 济南帅华医药科技有限公司 | Slow released anticancer injection with both blood vessel inhibitor and its synergist |
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2012
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857201A (en) * | 2006-03-06 | 2006-11-08 | 济南帅华医药科技有限公司 | Slow released anticancer injection with both blood vessel inhibitor and its synergist |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105456200A (en) * | 2015-12-08 | 2016-04-06 | 郑州大学 | Preparation method and application of nanoparticle microsphere for improving oral bioavailability of poorly soluble drugs |
| CN105456200B (en) * | 2015-12-08 | 2018-08-21 | 郑州大学 | A kind of preparation method and application for the nano mciroball improving insoluble drug oral administration biaavailability |
| CN107412161A (en) * | 2017-05-22 | 2017-12-01 | 河南科技大学 | A kind of methoxyestradiol intravenous injection of self-emulsifying 2 and preparation method thereof |
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| CN102793663B (en) | 2014-09-17 |
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