CN102784114B - A kind of bortezomib freeze-dried powder and preparation method thereof - Google Patents
A kind of bortezomib freeze-dried powder and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to medical art, be specifically related to a kind of bortezomib freeze-dried powder and preparation method thereof.After redissolving for bortezomib preparation, the poor and bortezomib preparation of clarity is 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 adjusting agent, gained preparation solubility is good, dissolution time is 29 ~ 36 seconds, and after said preparation room temperature places 9 hours simultaneously, total impurities content is not higher than 1.27%, there is good stability, contribute to increasing drug safety.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of bortezomib freeze-dried powder and preparation method thereof.
Background technology
Bortezomib (Bortezomib, PS-341), trade name Bortezomib (Velcade) is the new type antineoplastic medicine researched and developed by Millennium drugmaker of the U.S..This medicine, by blocking the degraded of the protein of multiple regulating cell apoptosis and intracellular signaling in cell, causes death of neoplastic cells.Large quantity research finds, bortezomib is to kinds of tumors, and the multiple myeloma especially in 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 in " progress of proteasome inhibitor reverse multiple drug resistance of tumor " (" foreign medical science pharmacy fascicle ", in April, 2007, the 34th volume the 2nd phase), and boric acid peptide class comprises bortezomib (bortezomib, Velcade
tM, PS-341), dansyl-phenylalanyl-1eucyl-boronicacid (DFLB) etc., than aldehyde peptide class, there is stronger proteasome inhibitory action.This type of inhibitor reversible action, is combined with the speed of dissociating all comparatively slow, long action time in vivo, not easily oxidation deactivation, metabolic stability with avtive spot.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, PS-341 selectivity is high, and side effect is little, is first proteasome inhibitor being applied to clinical research.
Chinese invention patent application Publication Specification CN101094648A discloses the Liposomal formulation of bortezomib (PS-341), be loaded in liposome with the form of borate by bag after the polyhydric alcohol describing boric acid compositions and liposome package-contained interacts, in one embodiment, liposome has the outer covering layer of hydrophilic polymer chain, is used for the treatment of the malignant tumor in patient.Chinese invention patent application Publication Specification CN101336893A discloses the slow releasing injection of a kind of bortezomib and topoenzyme inhibitor thereof, and its technical scheme is be made up of sustained-release micro-spheres and solvent containing bortezomib and the slow releasing injection opening up enzyme inhibitor.But do not have the relevant report of bortezomib freeze-dried powder at present, only have import injection powder pin to go on the market, specification is 1mg and 3.5mg, but after said preparation redissolution, clarity is poor, and very fast along with increasing impurity increase standing time, bring certain potential safety hazard to medication.Bortezomib dissolubility is less in addition, is only about 3mg/mL, and dissolving in water needs the long period.In addition, in process of production in order to make bortezomib comparatively fast dissolve, usually adopt heating, the method such as ultrasonic, but these methods can cause impurity to increase, and affect medicine stability.
Summary of the invention
Poor in order to solve the rear clarity of bortezomib preparation redissolution, also in order to solve 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 adjusting agent.
The present invention carries out preferably to the amount of bortezomib in bortezomib freeze-dried powder, preferably, percentage, in above-mentioned bortezomib freeze-dried powder, the amount of bortezomib is 0.1%-0.3%, more preferably, in bortezomib freeze-dried powder, the amount of bortezomib is 0.1%.
The present invention carries out preferably to the excipient in bortezomib freeze-dried powder, and preferably, above-mentioned excipient is one or more in mannitol, dextran, lactose, glucose, and more preferably, excipient is mannitol.
The present invention carries out preferably the amount of excipient in bortezomib freeze-dried powder, and preferably, percentage, the amount of above-mentioned excipient is 3%-10%, and more preferably, the amount of excipient is 3%-8%
The present invention carries out preferably the antioxidant in bortezomib freeze-dried powder, and preferably, above-mentioned antioxidant is the one in sodium sulfite, sodium pyrosulfite, sodium thiosulfate, more preferably, antioxidant is sodium sulfite.
The present invention carries out preferably the amount of antioxidant in bortezomib freeze-dried powder, and preferably, percentage, the amount of above-mentioned antioxidant is 0.02%-0.1%.
The present invention to carry out preferably to the pH adjusting agent in bortezomib freeze-dried powder, preferably, above-mentioned pH adjusting agent is the one in sodium hydroxide, sodium carbonate, sodium bicarbonate, more preferably, pH adjusting agent is the one in 0.5mol/L sodium carbonate liquor, 1mol/L sodium hydroxide solution, 1mol/L sodium bicarbonate solution, more preferably, and pH adjusting agent sodium hydroxide, most preferably, pH adjusting agent is 1mol/L sodium hydroxide solution.
The present invention carries out preferably to 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.
Present invention also offers and prepare bortezomib freeze-dried powder method, it contains following steps:
A. by bortezomib and excipient, antioxidant mixed grinding 5-10 minute, add the water for injection of 80% recipe quantity, stir until all dissolve, add 0.1% needle-use activated carbon by mass volume ratio, stir 15 minutes, decarbonization filtering;
B. filtrate benefit adds to the full amount of water for injection, and stirs, and regulate pH to 4.5-6.7 by pH adjusting agent, medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in cillin bottle, and false add plug, puts into freeze dryer lyophilizing;
C. goods are put into freeze dryer lyophilizing, first cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulation 120-240 minute afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature is to-10 DEG C, and insulation 16-20 hour, improves shelf temperature to 25 DEG C again, insulation 6-10 hour, vacuum maintains 20-30Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure, total head plug outlet, rolls lid, packs and get final product.
Bortezomib can form borate with polyalcohols as mannitol, glucose, Polyethylene Glycol etc., affects its dissolubility and dissolution velocity.But being joined by bortezomib in polyhydric alcohol solutions can not fast reaction, need to use heating, the method such as ultrasonic accelerates its reaction, and heating can cause bortezomib to be degraded, impurity increases, and ultrasonic time is long also there will be same problem.Bortezomib and polyalcohols mixed with excipients grind by the present invention, both fully mix in process of lapping, uniform suspension is formed after adding water for injection, stir and can all dissolve for tens minutes, avoid the use of heating, the method such as ultrasonic, effectively can avoid the increase of medicine impurity in the process of making up a prescription.The preparation method of bortezomib freeze-dried powder provided by the present invention, can make bortezomib dissolve comparatively fast, and solving the long medicinal liquid impurity caused of time of compounding increases problem.
In the pre-freeze stage of freeze-drying process, goods are by reaching the object of pre-freeze of lowering the temperature with the heat trnasfer of shelf, but often cause temperature at the bottom of the bottle contacted with shelf lower, medicinal liquid skin temperature is higher, and medicinal liquid top and the bottom form certain thermograde, and this thermograde is larger, ice-crystal growth speed is slower, the speed that ice interface advances from bottom to top is slower, and in solution, the solute migration time is more sufficient, causes solute to be gathered in 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 after goods lyophilizing, there is significant difference top and the bottom, often causes the problems affect product qualities such as bottom atrophy, middle phantom, top boss, surface crust.Ice-crystal growth speed can cause ice crystal thicker slowly in addition, although easily lyophilizing solubility is poor, and the problem such as medicine visible foreign matters, particulate matter may be caused defective.The present invention adopts and first cools the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulations method of 120-240 minute afterwards and carry out pre-freeze, when shelf is cooled to-8 DEG C, medicinal liquid does not also freeze, insulation can make upper and lower thermograde reduce for 90 minutes at such a temperature, solute is evenly distributed in medicinal liquid, and makes products temperature close to solidification point.Be cooled to rapidly-40 DEG C afterwards product temperature can be made to reduce rapidly reach solidification point, product flash freeze, the ice crystal of formation is tiny, and solubility is good.
To sum up, the present invention, relative to prior art, has following outstanding advantage:
After the invention solves the redissolution of bortezomib preparation, clarity is poor, and along with increasing impurity increase problem faster standing time.Bortezomib freeze-dried powder provided by the invention, total impurities is little, solubility and good stability, can find out bortezomib freeze-dried powder provided by the present invention in a particular embodiment, and dissolution time is 29 ~ 36 seconds; After room temperature places 9 hours, total impurities content is not higher than 1.27%.
By a large amount of experiments, the formula of the present invention is preferred bortezomib freeze-dried powder and each component proportion, the product of gained is white loose block, be colourless without turbidity settled solution after redissolving, and under the solution room temperature condition after redissolution, placement 9 hours is stable.And preparation method provided by the present invention makes to make up a prescription more fast and convenient, and effectively can control the increase of impurity in the process of making up a prescription.
Specific embodiment
Set forth the present invention further by the following examples, but therefore do not limit the present invention in described embodiment.
Embodiment 1, bortezomib freeze-dried powder
Take 3.5g bortezomib, 105g mannitol, 0.7g sodium sulfite, mixed grinding 8 minutes, adds 2700mL water for injection, stirs until all dissolve, adds 2.7g needle-use activated carbon, stir 15 minutes, decarbonization filtering.Filtrate benefit injects water to 3500mL, stirs, and regulates pH to 6.0 with 1mol/L sodium hydroxide solution.Medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and false add plug puts into freeze dryer lyophilizing.
First cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulations 180 minutes afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature, to-10 DEG C, is incubated 18 hours, again improves shelf temperature to 25 DEG C, be incubated 8 hours, vacuum maintains 25Pa, and the qualified rear lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, rolls lid, packs and get final product.
Embodiment 2, bortezomib freeze-dried powder
Take 3.5g bortezomib, 157.5g dextran, 3.2g sodium pyrosulfite, mixed grinding 5 minutes, adds 2700mL water for injection, stirs until all dissolve, adds 2.7g needle-use activated carbon, stir 15 minutes, decarbonization filtering.Filtrate benefit injects water to 3500mL, stirs, and regulates pH to 6.5 with 1mol/L sodium hydroxide solution.Medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and false add plug puts into freeze dryer lyophilizing.
First cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulations 120 minutes afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature, to-10 DEG C, is incubated 16 hours, again improves shelf temperature to 25 DEG C, be incubated 6 hours, vacuum maintains 25Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, rolls lid, packs and get final product.
Embodiment 3, bortezomib freeze-dried powder
Take 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, stir until all dissolve, add 2.7g needle-use activated carbon, stir 15 minutes, decarbonization filtering.Filtrate benefit injects water to 3500mL, stirs, and regulates pH to 6.0 with 0.5mol/L sodium carbonate liquor.Medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and false add plug puts into freeze dryer lyophilizing.
First cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulations 200 minutes afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature, to-10 DEG C, is incubated 16 hours, again improves shelf temperature to 25 DEG C, be incubated 6 hours, vacuum maintains 30Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, rolls lid, packs and get final product.
Embodiment 4, bortezomib freeze-dried powder
Take 10.5g bortezomib, 350g lactose, 3.5g sodium thiosulfate, mixed grinding 5 minutes, adds 2700mL water for injection, stirs until all dissolve, adds 2.7g needle-use activated carbon, stir 15 minutes, decarbonization filtering.Filtrate benefit injects water to 3500mL, stirs, and regulates pH to 5.2 with 1mol/L sodium bicarbonate solution.Medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in 7mL cillin bottle, and every bottle of fill amount is 5mL, and false add plug puts into freeze dryer lyophilizing.
First cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulations 240 minutes afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature, to-10 DEG C, is incubated 20 hours, again improves shelf temperature to 25 DEG C, be incubated 10 hours, vacuum maintains 25Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, rolls lid, packs and get final product.
Embodiment 5, bortezomib freeze-dried powder
Take 7g bortezomib, 105g glucose, 3.2g sodium sulfite, mixed grinding 7 minutes, adds 2700mL water for injection, stirs until all dissolve, adds 2.7g needle-use activated carbon, stir 15 minutes, decarbonization filtering.Filtrate benefit injects water to 3500mL, stirs, and regulates pH to 6.7 with 1mol/L sodium hydroxide solution.Medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and false add plug puts into freeze dryer lyophilizing.
First cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulations 240 minutes afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature, to-10 DEG C, is incubated 20 hours, again improves shelf temperature to 25 DEG C, be incubated 10 hours, vacuum maintains 20Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, rolls lid, packs and get final product.
Embodiment 6, bortezomib freeze-dried powder
Take 7g bortezomib, 210g excipient (this excipient is the mixture of glucose, lactose and mannitol), 3.2g sodium sulfite, mixed grinding 10 minutes, add 2700mL water for injection, stir until all dissolve, add 2.7g needle-use activated carbon, stir 15 minutes, decarbonization filtering.Filtrate benefit injects water to 3500mL, stirs, and regulates pH to 4.5 with 1mol/L sodium hydroxide solution.Medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and false add plug puts into freeze dryer lyophilizing.
First cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulations 240 minutes afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature, to-10 DEG C, is incubated 20 hours, again improves shelf temperature to 25 DEG C, be incubated 10 hours, vacuum maintains 20Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, rolls lid, packs and get final product.
Embodiment 7, bortezomib freeze-dried powder (comparative example)
Take 3.5g bortezomib, 35g mannitol, mixed grinding 10 minutes, adds 2700mL water for injection, stirs until all dissolve, adds 2.7g needle-use activated carbon, stir 15 minutes, decarbonization filtering.Filtrate benefit injects water to 3500mL, and stir, medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and false add plug puts into freeze dryer lyophilizing.
First cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulations 180 minutes afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature, to-10 DEG C, is incubated 20 hours, again improves shelf temperature to 25 DEG C, be incubated 8 hours, vacuum maintains 25Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, rolls lid, packs and get final product.
The product of embodiment 8, bortezomib freeze-dried powder compares
Product provided by the present invention (embodiment 1-5) compares with contrast product (embodiment 7), main Comparative indices is that after dissolving required time (all dissolving with 3.5mL sodium chloride injection) completely and redissolving, room temperature places 0,3,6,9 little total impurities sizes constantly, the results are shown in Table 1.
Table 1. product solubility of the present invention, stability and total impurities compare with reference product
As can be seen from comparative result, product dissolution time provided by the present invention is far less than contrast product, and after redissolving, total impurities is less than contrast product, and room temperature is placed related substance in 9 hours and raised less, and stability is better.
Embodiment 9, bortezomib freeze-dried powder (comparative example)
Take 3.5g bortezomib, 105g mannitol, 3.2g sodium sulfite, add 2700mL water for injection, ultrasonic until all dissolve, add 2.7g needle-use activated carbon, stir 15 minutes, decarbonization filtering.Filtrate benefit injects water to 3500mL, stirs, and regulates pH to 6.0 with 0.5mol/L sodium carbonate liquor.Medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in 7mL cillin bottle, and every bottle of fill amount is 3.5mL, and false add plug puts into freeze dryer lyophilizing.
Goods are put into freeze drying box, be cooled to rapidly-40 DEG C of insulations 240 minutes, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature, to-10 DEG C, is incubated 20 hours, again improves shelf temperature to 25 DEG C, be incubated 10 hours, vacuum maintains 25Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure.Total head plug outlet, rolls lid, packs and get final product.
The comparison of the preparation technology of embodiment 10, bortezomib freeze-dried powder
Preparation technology provided by the present invention and common process (embodiment 9) contrast, main Comparative indices dissolves required time (all dissolving with 3.5mL sodium chloride injection) completely for make up a prescription front and back total impurities size and products obtained therefrom, the results are shown in Table 2.
Table 2 preparation method of the present invention compares with common preparation method
As can be seen from comparative result, the preparation method provided by the present invention impurity in process that makes up a prescription raises less, and products obtained therefrom dissolution time is far less than common process products obtained therefrom.
Claims (5)
1. a bortezomib freeze-dried powder, it is characterized in that, supplementary material for the preparation of this freeze-dried powder consists of bortezomib, excipient, antioxidant, pH adjusting agent and water for injection, percentage, the amount of described bortezomib is 0.1%-0.3%, the amount of excipient is 3%-10%, the amount of antioxidant is 0.02%-0.1%, all the other are water for injection, and described antioxidant is the one in sodium sulfite, sodium pyrosulfite, sodium thiosulfate.
2. bortezomib freeze-dried powder according to claim 1, is characterized in that, described excipient is one or more in mannitol, dextran, lactose, glucose.
3. bortezomib freeze-dried powder according to claim 1, is characterized in that, described pH adjusting agent is the one in sodium hydroxide, sodium carbonate, sodium bicarbonate.
4. bortezomib freeze-dried powder according to claim 1, is characterized in that, its pH value is 4.5-6.7.
5. prepare a method for bortezomib freeze-dried powder as claimed in claim 1, it is characterized in that, it contains following steps:
A. by bortezomib and excipient, antioxidant mixed grinding 5-10 minute, add the water for injection of 80% recipe quantity, stir until all dissolve, add 0.1% needle-use activated carbon by mass volume ratio, stir 15 minutes, decarbonization filtering;
B. filtrate benefit adds to the full amount of water for injection, and stirs, and regulate pH to 4.5-6.7 by pH adjusting agent, medicinal liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and fill is in cillin bottle, and false add plug, puts into freeze dryer lyophilizing;
C. goods are put into freeze dryer lyophilizing, first cool the temperature to-8 DEG C and be incubated 90 minutes, be cooled to rapidly-40 DEG C of insulation 120-240 minute afterwards, evacuation is started after cold-trap is cooled to-40 DEG C, slow raising shelf temperature is to-10 DEG C, and insulation 16-20 hour, improves shelf temperature to 25 DEG C again, insulation 6-10 hour, vacuum maintains 20-30Pa, and the qualified lyophilizing of goods moisture terminates, and freeze drying box backfill nitrogen is to normal pressure, total head plug outlet, rolls lid, packs and get final product.
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| AU2013227219A1 (en) | 2012-03-02 | 2014-10-23 | Dr. Reddy's Laboratories Limited | Pharmaceutical compositions comprising boronic acid compounds |
| CN103070835B (en) * | 2013-01-31 | 2015-01-07 | 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 |
| CN103142509B (en) * | 2013-03-06 | 2018-01-02 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of injection bortezomib pharmaceutical composition |
| CN103212055B (en) * | 2013-04-19 | 2014-11-05 | 海南锦瑞制药股份有限公司 | Drug composition of bortezomib and preparation method thereof |
| CN104414982B (en) * | 2013-08-28 | 2018-06-22 | 山东新时代药业有限公司 | A kind of bortezomib freeze drying powder injection and preparation method thereof |
| CN103505424B (en) * | 2013-10-09 | 2015-03-11 | 哈药集团技术中心 | Preparation method for bortezomib for injection |
| CN104586776B (en) * | 2013-10-30 | 2017-05-17 | 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 |
| CN103720666B (en) * | 2013-12-16 | 2015-11-25 | 亿腾药业（泰州）有限公司 | A kind of preparation method of injection bortezomib lyophilized formulations |
| CN104546744B (en) * | 2014-12-30 | 2016-11-16 | 山东新时代药业有限公司 | A kind of injection bortezomib freeze-dried powder 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 |
| US10314880B2 (en) * | 2015-08-06 | 2019-06-11 | Ftf Pharma Private Limited | Composition comprising bortezomib |
| CN106265536B (en) * | 2016-08-24 | 2019-01-11 | 江苏豪森药业集团有限公司 | Bortezomib pharmaceutical composition and preparation method thereof |
| CN108451911B (en) * | 2018-04-04 | 2020-05-22 | 重庆惠源医药有限公司 | Preparation method of bortezomib preparation |
| CN109453125B (en) * | 2018-12-29 | 2020-05-05 | 健进制药有限公司 | Freeze-drying process of bortezomib freeze-dried powder injection for injection |
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| CN101094648A (en) * | 2004-11-05 | 2007-12-26 | 阿尔扎公司 | Liposomal formulation of bortezomib (ps-341) |
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| WO2010114982A2 (en) * | 2009-04-03 | 2010-10-07 | Cephalon, Inc. | Lyophilization cakes of proteasome inhibitors |
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