CN102784114A - Bortezomib freeze-dried powder injection and preparation method thereof - Google Patents
Bortezomib freeze-dried powder injection and preparation method thereof Download PDFInfo
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- CN102784114A CN102784114A CN2011101342816A CN201110134281A CN102784114A CN 102784114 A CN102784114 A CN 102784114A CN 2011101342816 A CN2011101342816 A CN 2011101342816A CN 201110134281 A CN201110134281 A CN 201110134281A CN 102784114 A CN102784114 A CN 102784114A
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Abstract
The invention belongs to the technical field of pharmaceuticals, and specifically relates to a bortezomib freeze-dried powder injection and a preparation method thereof. Directed at poor clarity of a redissolved bortezomib preparation, and fast increase of impurities in the bortezomib preparation with standing time, the present invention provides a bortezomib freeze-dried powder injection which includes bortezomib, an excipient, an antioxidant, and a pH adjusting agent. The resulting preparation is good in redissolution with a dissolution time of 29-36 seconds, while the total impurity content of the preparation is not higher than 1.27% after placing for 9 hours at room temperature. The preparation is good in stability, and helps to increase the safety of drug use.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of bortezomib freeze-dried powder and preparation method thereof.
Background technology
(Bortezomib, PS-341), trade name ten thousand Mactra sulcatria Deshayess (Velcade) are the new type antineoplastic medicines by the research and development of U.S. Millennium drugmaker to bortezomib.This medicine causes death of neoplastic cells through the proteinic degraded of multiple regulating cell apoptosis in the blocking-up cell and signal conduction.Discover that in a large number bortezomib is to kinds of tumors, especially the multiple myeloma in the neoplastic hematologic disorder, jacket cell type lymphoma and other B cell type lymphoma, Hodgkin lymphoma have stronger anti-tumor activity.
Yi Wenyuan etc. point out that boric acid peptide class comprises bortezomib (bortezomib, Velcade in " progress of proteasome inhibitor reverse multiple drug resistance of tumor " (" foreign medical science pharmacy fascicle ", in April, 2007, the 34th the 2nd phase of volume)
TM, PS-341), dansyl-phenylalanyl-1eucyl-boronic acid (DFLB) etc., have stronger proteasome inhibitory action than aldehyde peptide class.This type of inhibitor effect is reversible, combine with avtive spot with dissociated speed all slower, long action time is difficult for oxidation deactivation in vivo, metabolic stability.In addition, boric acid peptide analogy aldehyde peptide class has more selectivity, is very weak thiol proteinase inhibitor.Therefore, boric acid peptide class is more satisfactory proteasome inhibitor.Wherein, the PS-341 selectivity is high, and side effect is little, is first proteasome inhibitor that is applied to clinical research.
Chinese invention patent Shen Qing Publication description CN 101094648A discloses the Liposomal formulation of bortezomib (PS-341); Having described boric acid compositions and liposome wraps the polyhydric alcohol that the carries back that takes place to interact and is loaded in the liposome by bag with the form of borate; In one embodiment; The outer covering layer of liposome possess hydrophilic property polymer chain, the malignant tumor that is used for treating the patient.Chinese invention patent Shen Qing Publication description CN 101336893A discloses the slow releasing injection of a kind of bortezomib and topoenzyme inhibitor thereof, and its technical scheme is to contain bortezomib to be made up of sustained-release micro-spheres and solvent with the slow releasing injection of opening up enzyme inhibitor.But the relevant report that does not have the bortezomib freeze-dried powder at present; The listing of import injection powder pin is only arranged, and specification is 1mg and 3.5mg, and clarity is relatively poor but said preparation redissolves the back; And very fast along with increasing the impurity increase standing time, bring certain potential safety hazard to medication.The bortezomib dissolubility is less in addition, is merely about 3mg/mL, and dissolving needs the long period in water.In addition, in process of production for bortezomib is comparatively fast dissolved, adopt heating, method such as ultrasonic usually, yet these methods can cause impurity to increase, and influence medicine stability.
Summary of the invention
Relatively poor in order to solve bortezomib preparation redissolution back clarity; Also in order to solve the bortezomib preparation along with increasing impurity increase problem faster standing time; The invention provides a kind of bortezomib freeze-dried powder, it contains bortezomib, excipient, antioxidant and pH regulator agent.
The present invention has carried out preferably the amount of bortezomib in the bortezomib freeze-dried powder; Preferably, percent meter by weight, the amount of bortezomib is 0.1%-0.3% in the above-mentioned bortezomib freeze-dried powder; More preferably, the amount of bortezomib is 0.1% in the bortezomib freeze-dried powder.
The present invention has carried out preferably the excipient in the bortezomib freeze-dried powder, and preferably, above-mentioned excipient is one or more in mannitol, dextran, lactose, the glucose, and more preferably, excipient is a mannitol.
The present invention has carried out preferably the amount of excipient in the bortezomib freeze-dried powder, preferably, percent meter by weight, the amount of above-mentioned excipient is 3%-10%, more preferably, the amount of excipient is 3%-8%
The present invention has carried out preferably the antioxidant in the bortezomib freeze-dried powder, and preferably, above-mentioned antioxidant is a kind of in sodium sulfite, sodium pyrosulfite, the sodium thiosulfate, and more preferably, antioxidant is sodium sulfite.
The present invention has carried out preferably the amount of antioxidant in the bortezomib freeze-dried powder, preferably, percent meter by weight, the amount of above-mentioned antioxidant is 0.02%-0.1%.
The present invention has carried out preferably the pH regulator agent in the bortezomib freeze-dried powder, and preferably, above-mentioned pH regulator agent is a kind of in sodium hydroxide, sodium carbonate, the sodium bicarbonate; More preferably; The pH regulator agent is a kind of in 0.5mol/L sodium carbonate liquor, 1mol/L sodium hydroxide solution, the 1mol/L sodium bicarbonate solution, more preferably, and pH regulator agent sodium hydroxide; Most preferably be that the pH regulator agent is the 1mol/L sodium hydroxide solution.
The present invention has carried out preferably the pH value of bortezomib freeze-dried powder, preferably, above-mentioned bortezomib freeze-dried powder, pH value be 4.5-6.7, more preferably, pH value is 5.2-6.5.
The present invention also provides preparation bortezomib freeze-dried powder method, and it contains and has the following steps:
A. with bortezomib and excipient, antioxidant mixed grinding 5-10 minute, add the water for injection of 80% recipe quantity, stir, add 0.1% needle-use activated carbon, stirred decarbonization filtering 15 minutes by mass volume ratio until whole dissolvings;
B. filtrating benefit adds to the full amount of water for injection, and stirs, and regulates pH to 4.5-6.7 with the pH regulator agent, and medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in cillin bottle, and the false add plug is put into the freeze dryer lyophilizing;
C. goods are put into the freeze dryer lyophilizing, cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 120-240 minute afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 16-20 hour, improve shelf temperature to 25 ℃ once more; Be incubated 6-10 hour, vacuum maintains 20-30Pa, and the qualified lyophilizing of goods moisture finishes; Freeze drying box backfill nitrogen is to normal pressure, and total head plug outlet rolls lid, packing promptly gets.
Bortezomib can form borate with polyalcohols such as mannitol, glucose, Polyethylene Glycol etc., influences its dissolubility and dissolution velocity.But bortezomib is joined in the polyhydric alcohol solutions can not fast reaction, need to use heating, method such as ultrasonic to accelerate its reaction, and heating can cause the bortezomib degraded, and impurity increases, and ultrasonic time is long also same problem can to occur.The present invention grinds bortezomib and polyalcohols mixed with excipients; Both fully mix in process of lapping; Form uniform suspension after adding water for injection; Stir and all to dissolve in tens minutes, avoided the use of heating, method such as ultrasonic, can effectively avoid the increase of medicine impurity in the process of making up a prescription.The method for preparing of bortezomib freeze-dried powder provided by the present invention can make bortezomib dissolve comparatively fast, and having solved the long medicinal liquid impurity that causes of time of compounding increases problem.
In the pre-freeze stage of freeze-drying process, goods are through reaching the purpose of cooling pre-freeze with shelf heat passage, but tend to cause bottle end temperature that contact with shelf lower; The medicinal liquid skin temperature is higher, and the medicinal liquid top and the bottom form certain thermograde, and this thermograde is big more; Ice-crystal growth speed is slow more; Ice interface propulsive from bottom to top speed is slow more, in the solution solute migration time more sufficient, cause solute to accumulate in the medicinal liquid top layer.Like this, the solute of upper epidermis is more, and density is higher, and bottom then solute is less, short texture, and there is significant difference top and the bottom after the goods lyophilizing, tend to cause problems affect product qualities such as bottom atrophy, middle phantom, top boss, surperficial duricrust.It is thicker that ice-crystal growth speed can cause ice crystal slowly in addition, though easily the lyophilizing solubility is poor, possibly cause problems such as medicine visible foreign matters, particulate matter be defective.The present invention adopts and to cool the temperature to-8 ℃ and be incubated 90 minutes earlier; Be cooled to 120-240 minute method of-40 ℃ of insulations afterwards rapidly and carry out pre-freeze; Medicinal liquid did not also freeze when shelf was cooled to-8 ℃; Thermograde reduced about insulation can make in 90 minutes under this temperature, and solute is evenly distributed in medicinal liquid, and makes products temperature near solidification point.Be cooled to-40 ℃ afterwards rapidly and can make rapid reduction of product temperature reach solidification point, product freezes rapidly, and the ice crystal of formation is tiny, and solubility is good.
To sum up, the present invention has following outstanding advantage with respect to prior art:
It is relatively poor to the invention solves bortezomib preparation redissolution back clarity, and along with increasing impurity increase problem faster standing time.Bortezomib freeze-dried powder provided by the invention, total impurities is little, and solubility and good stability can be found out bortezomib freeze-dried powder provided by the present invention in specific embodiment, and dissolution time is 29～36 seconds; Room temperature was placed after 9 hours, and total impurities content is not higher than 1.27%.
Through a large amount of experiments, the present invention is preferred prescription and each set of dispense ratio of bortezomib freeze-dried powder, the product of gained is the white loose block, and redissolving the back be colourless no turbidity settled solution, and the solution room temperature condition held after the redissolution was stablized in 9 hours.And method for preparing provided by the present invention makes and makes up a prescription more fast and conveniently, and can effectively control the increase of impurity in the process of making up a prescription.
Specific embodiment
Below further set forth the present invention through embodiment, but therefore do not limit the present invention among the described embodiment.
Embodiment 1, bortezomib freeze-dried powder
Take by weighing 3.5g bortezomib, 105g mannitol, 0.7g sodium sulfite, mixed grinding 8 minutes adds 2700mL water for injection, stirs until whole dissolvings, adds the 2.7g needle-use activated carbon, stirs decarbonization filtering 15 minutes.Filtrating is added water for injection to 3500mL, stirs, and regulates pH to 6.0 with the 1mol/L sodium hydroxide solution.Medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in the 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and the false add plug is put into the freeze dryer lyophilizing.
Cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 180 minutes afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 18 hours, improve shelf temperature to 25 ℃ once more; Be incubated 8 hours; Vacuum maintains 25Pa, and the qualified back lyophilizing of goods moisture finishes, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, roll lid, the packing promptly get.
Embodiment 2, bortezomib freeze-dried powder
Take by weighing 3.5g bortezomib, 157.5g dextran, 3.2g sodium pyrosulfite, mixed grinding 5 minutes adds 2700mL water for injection, stirs until whole dissolvings, adds the 2.7g needle-use activated carbon, stirs decarbonization filtering 15 minutes.Filtrating is added water for injection to 3500mL, stirs, and regulates pH to 6.5 with the 1mol/L sodium hydroxide solution.Medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in the 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and the false add plug is put into the freeze dryer lyophilizing.
Cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 120 minutes afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 16 hours, improve shelf temperature to 25 ℃ once more; Be incubated 6 hours; Vacuum maintains 25Pa, and the qualified lyophilizing of goods moisture finishes, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, roll lid, the packing promptly get.
Embodiment 3, bortezomib freeze-dried powder
Take by weighing 3.5g bortezomib, 280g excipient (this excipient is the mixture of mannitol and dextran), 2.6g sodium sulfite, mixed grinding 8 minutes adds 2700mL water for injection; Stirring is until whole dissolvings; Add the 2.7g needle-use activated carbon, stirred decarbonization filtering 15 minutes.Filtrating is added water for injection to 3500mL, stirs, and regulates pH to 6.0 with the 0.5mol/L sodium carbonate liquor.Medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in the 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and the false add plug is put into the freeze dryer lyophilizing.
Cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 200 minutes afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 16 hours, improve shelf temperature to 25 ℃ once more; Be incubated 6 hours; Vacuum maintains 30Pa, and the qualified lyophilizing of goods moisture finishes, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, roll lid, the packing promptly get.
Embodiment 4, bortezomib freeze-dried powder
Take by weighing 10.5g bortezomib, 350g lactose, 3.5g sodium thiosulfate, mixed grinding 5 minutes adds 2700mL water for injection, stirs until whole dissolvings, adds the 2.7g needle-use activated carbon, stirs decarbonization filtering 15 minutes.Filtrating is added water for injection to 3500mL, stirs, and regulates pH to 5.2 with the 1mol/L sodium bicarbonate solution.Medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in the 7mL cillin bottle, and every bottle of fill amount is 5mL, and the false add plug is put into the freeze dryer lyophilizing.
Cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 240 minutes afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 20 hours, improve shelf temperature to 25 ℃ once more; Be incubated 10 hours; Vacuum maintains 25Pa, and the qualified lyophilizing of goods moisture finishes, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, roll lid, the packing promptly get.
Embodiment 5, bortezomib freeze-dried powder
Take by weighing 7g bortezomib, 105g glucose, 3.2g sodium sulfite, mixed grinding 7 minutes adds 2700mL water for injection, stirs until whole dissolvings, adds the 2.7g needle-use activated carbon, stirs decarbonization filtering 15 minutes.Filtrating is added water for injection to 3500mL, stirs, and regulates pH to 6.7 with the 1mol/L sodium hydroxide solution.Medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in the 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and the false add plug is put into the freeze dryer lyophilizing.
Cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 240 minutes afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 20 hours, improve shelf temperature to 25 ℃ once more; Be incubated 10 hours; Vacuum maintains 20Pa, and the qualified lyophilizing of goods moisture finishes, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, roll lid, the packing promptly get.
Embodiment 6, bortezomib freeze-dried powder
Take by weighing 7g bortezomib, 210g excipient (this excipient is the mixture of glucose, lactose and mannitol), 3.2g sodium sulfite, mixed grinding 10 minutes adds 2700mL water for injection; Stirring is until whole dissolvings; Add the 2.7g needle-use activated carbon, stirred decarbonization filtering 15 minutes.Filtrating is added water for injection to 3500mL, stirs, and regulates pH to 4.5 with the 1mol/L sodium hydroxide solution.Medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in the 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and the false add plug is put into the freeze dryer lyophilizing.
Cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 240 minutes afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 20 hours, improve shelf temperature to 25 ℃ once more; Be incubated 10 hours; Vacuum maintains 20Pa, and the qualified lyophilizing of goods moisture finishes, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, roll lid, the packing promptly get.
Embodiment 7, bortezomib freeze-dried powder (Comparative Examples)
Take by weighing 3.5g bortezomib, 35g mannitol, mixed grinding 10 minutes adds 2700mL water for injection, stirs until whole dissolvings, adds the 2.7g needle-use activated carbon, stirs decarbonization filtering 15 minutes.Filtrating is added water for injection to 3500mL, stirs, and medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in the 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and the false add plug is put into the freeze dryer lyophilizing.
Cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 180 minutes afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 20 hours, improve shelf temperature to 25 ℃ once more; Be incubated 8 hours; Vacuum maintains 25Pa, and the qualified lyophilizing of goods moisture finishes, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, roll lid, the packing promptly get.
The product of embodiment 8, bortezomib freeze-dried powder relatively
The comparison of product provided by the present invention (embodiment 1-5) and contrast product (embodiment 7); Total impurities size when main relatively index is placed 0,3,6,9 hour for dissolving the required time (all with the dissolving of 3.5mL sodium chloride injection) and the back room temperature of redissolving fully, the result sees table 1.
The comparison of table 1. product solubility of the present invention, stability and total impurities and reference product
Can be found out that by comparative result product dissolution time provided by the present invention is less than contrast product far away, and redissolve the back total impurities less than contrast product, room temperature is placed in 9 hours related substance and is raise lessly, and stability better.
Embodiment 9, bortezomib freeze-dried powder (Comparative Examples)
Take by weighing 3.5g bortezomib, 105g mannitol, 3.2g sodium sulfite, add 2700mL water for injection, ultrasonic until whole dissolvings, add the 2.7g needle-use activated carbon, stirred decarbonization filtering 15 minutes.Filtrating is added water for injection to 3500mL, stirs, and regulates pH to 6.0 with the 0.5mol/L sodium carbonate liquor.Medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in the 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and the false add plug is put into the freeze dryer lyophilizing.
Goods are put into freeze drying box, be cooled to-40 ℃ of insulations 240 minutes rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 20 hours, improve shelf temperature to 25 ℃ once more; Be incubated 10 hours; Vacuum maintains 25Pa, and the qualified lyophilizing of goods moisture finishes, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, roll lid, the packing promptly get.
The preparation technology's of embodiment 10, bortezomib freeze-dried powder comparison
Preparation technology provided by the present invention and common process (embodiment 9) contrast, and mainly relatively index is dissolved required time (all with the dissolving of 3.5mL sodium chloride injection) fully for make up a prescription front and back total impurities size and products obtained therefrom, and the result sees table 2.
The comparison of table 2 method for preparing of the present invention and common method for preparing
Can be found out that by comparative result the method for preparing provided by the present invention impurity that makes up a prescription in the process raises lessly, the products obtained therefrom dissolution time is less than the common process products obtained therefrom far away.
Claims (9)
1. a bortezomib freeze-dried powder is characterized in that, it contains bortezomib, excipient, antioxidant and pH regulator agent.
2. bortezomib freeze-dried powder according to claim 1 is characterized in that, percent meter by weight, and the amount of the bortezomib that it contains is 0.1%-0.3%.
3. bortezomib freeze-dried powder according to claim 1 is characterized in that, described excipient is one or more in mannitol, dextran, lactose, the glucose.
4. according to claim 1 or 3 described bortezomib freeze-dried powders, it is characterized in that, percent meter by weight, the amount of the excipient that it contains is 3%-10%.
5. bortezomib freeze-dried powder according to claim 1 is characterized in that, described antioxidant is a kind of in sodium sulfite, sodium pyrosulfite, the sodium thiosulfate.
6. according to claim 1 or 5 described bortezomib freeze-dried powders, it is characterized in that, percent meter by weight, the amount of the antioxidant that it contains is 0.02%-0.1%.
7. bortezomib freeze-dried powder according to claim 1 is characterized in that, described pH regulator agent is a kind of in sodium hydroxide, sodium carbonate, the sodium bicarbonate.
8. bortezomib freeze-dried powder according to claim 1 is characterized in that, its pH value is 4.5-6.7.
9. a method for preparing bortezomib freeze-dried powder as claimed in claim 1 is characterized in that, it contains and has the following steps:
A. with bortezomib and excipient, antioxidant mixed grinding 5-10 minute, add the water for injection of 80% recipe quantity, stir, add 0.1% needle-use activated carbon, stirred decarbonization filtering 15 minutes by mass volume ratio until whole dissolvings;
B. filtrating benefit adds to the full amount of water for injection, and stirs, and regulates pH to 4.5-6.7 with the pH regulator agent, and medicinal liquid is through 0.22 μ m microporous filter membrane aseptic filtration, and fill is in cillin bottle, and the false add plug is put into the freeze dryer lyophilizing;
C. goods are put into the freeze dryer lyophilizing, cool the temperature to-8 ℃ and be incubated 90 minutes earlier, be cooled to-40 ℃ of insulations 120-240 minute afterwards rapidly, cold-trap begins evacuation after being cooled to-40 ℃; Slowly improve shelf temperature to-10 ℃, be incubated 16-20 hour, improve shelf temperature to 25 ℃ once more; Be incubated 6-10 hour, vacuum maintains 20-30Pa, and the qualified lyophilizing of goods moisture finishes; Freeze drying box backfill nitrogen is to normal pressure, and total head plug outlet rolls lid, packing promptly gets.
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| CN103070835A (en) * | 2013-01-31 | 2013-05-01 | 江苏奥赛康药业股份有限公司 | Freeze-dried composition containing bortezomib and preparation method of freeze-dried composition |
| CN103142509A (en) * | 2013-03-06 | 2013-06-12 | 石药集团中奇制药技术（石家庄）有限公司 | Bortezomib pharmaceutic composition for injection |
| CN103212055A (en) * | 2013-04-19 | 2013-07-24 | 海南锦瑞制药股份有限公司 | Drug composition of bortezomib and preparation method thereof |
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| CN103505424A (en) * | 2013-10-09 | 2014-01-15 | 哈药集团技术中心 | Preparation method for bortezomib for injection |
| CN103720666A (en) * | 2013-12-16 | 2014-04-16 | 亿腾药业（泰州）有限公司 | Preparation method for bortezomib freeze-dried preparation for injection |
| CN104414982A (en) * | 2013-08-28 | 2015-03-18 | 山东新时代药业有限公司 | Freeze-dried bortezomib powder injection and preparation method thereof |
| CN104546744A (en) * | 2014-12-30 | 2015-04-29 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder for injection and preparation method thereof |
| CN104586776A (en) * | 2013-10-30 | 2015-05-06 | 扬子江药业集团上海海尼药业有限公司 | Preparation taking bortezomib as active composition and preparation method thereof |
| CN105056205A (en) * | 2015-06-29 | 2015-11-18 | 杭州华东医药集团新药研究院有限公司 | Bortezomib-containing medicinal composition and preparation method thereof |
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| CN108451911A (en) * | 2018-04-04 | 2018-08-28 | 重庆惠源医药有限公司 | A kind of preparation method of bortezomib preparation |
| CN109453125A (en) * | 2018-12-29 | 2019-03-12 | 健进制药有限公司 | A kind of lyophilized technique of injection bortezomib freeze-dried powder |
| US10314880B2 (en) * | 2015-08-06 | 2019-06-11 | Ftf Pharma Private Limited | Composition comprising bortezomib |
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