CN103070835B - Freeze-dried composition containing bortezomib and preparation method of freeze-dried composition - Google Patents
Freeze-dried composition containing bortezomib and preparation method of freeze-dried composition Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, in particular to the field of chemical pharmacy, and particularly relates to a freeze-dried composition containing bortezomib and a preparation method of the freeze-dried composition. The freeze-dried composition and the preparation method aim at overcoming main medicine dissolution difficulty and oxygen environment sensitivity in an environment. A mixed solvent comprising mannitol and tert butyl alcohol is used, so that a dissolution rate of bortezomib is increased significantly, and the dissolution rate of bortezomib can be increased further through an addition sequence of materials. A nitrogen filled environment is used, so that liquid preparation time is shortened greatly, the contact of main medicine components with an aerobic environment is avoided effectively, and contents of relevant substances and total impurities in a final finished product are reduced.
Description
Technical field
The invention belongs to medical art, particularly relate to chemical pharmacy field, more specifically relate to a kind of freeze-dried composition containing bortezomib and preparation method thereof.
Background technology
Bortezomib (Bortezomib) is a kind of proteasome inhibitor, and structure is such as formula shown in I.Bortezomib can suppress the class chymase (chymotrypsin-like) of 26S proteasome in mammalian cell active by specificity, sends and has an impact, finally cause cancer cell death to signal a series of in cell.
Bortezomib is the dipeptide boronic acid derivant formed by leucine and phenylalanine, can exist with the trimeric form shown in formula II.In the scope of pH2 ~ 6.5, the dissolubility of bortezomib in water is 3.3 ~ 3.8mg/ml.
Wherein:
Bortezomib (bortezomib) is a kind of dipeptides ylboronic acid compound, it has efficiently single-minded protease inhibitory action, be also referred to as LDP-341 and PS-341 in the past, researched and developed by Millennium Pharmaceuticals company of the U.S. the earliest, and the approval of FDA is obtained May 19 in 2003, with the list marketing of Velcade trade name, Clinical Dosage Form is injection, is used for the treatment of recurrent and Refractory Multiple Myeloma.This product gets permission listing in May, 2004 in Britain, and after the treatment for previously at least having accepted two kinds of therapies is also treated the last time, the multiple myeloma of progress appears in disease.The domestic existing import listing of this product preparation, early than approval listing in 2005, listing producer is Xian-Janssen Pharmaceutical Ltd., and listing specification is 1mg and 3.5mg two specifications.
But, due to bortezomib poorly water-soluble, be easy to oxidation.Therefore in medicine preparation process, there are two large difficult points, one is principal agent indissoluble; Two is easy oxidations, and in finished product, oxidative impurity levels is high.
Therefore, taking bortezomib as the pharmaceutical formulating art of principal agent, be primarily focused on increase bortezomib dissolubility in the formulation always and produce on this two problems of oxidation impurities with avoiding being oxidized in preparation process.Disclose five kinds of anhydrous boron Bortezomib preparations and preparation process thereof in patent US20110230441, in its formulation and technology, use ethanol, propylene glycol and multiple antioxidant thereof to mix as solvent, carry out lyophilizing and prepare finished product.The bortezomib preparation utilizing this technique to prepare employs more organic solvent, and multiple, a large amount of antioxidant.Therefore cause the requirement of finished product freeze temperature harsh, medicine needs long-time lyophilizing under lower freeze temperature, seriously increases preparation difficulty.Meanwhile, organic solvent easily remains in lyophilizing finished product, increases finished product impurity.
Therefore, adopt present preparation technology, preparation process time is long, and finished product its related substances is high; Although multiple anhydrous organic solvent dissolves principal agent add principal agent dissolubility to a certain extent, the freeze-drying process of preparation lyophilizing finished product is long, large to production equipment injury; Residual organic solvent is high simultaneously, and product quality is low.
Summary of the invention
The object of the invention is to overcome principal agent and dissolve difficulty and the problem to oxygen environment sensitive in environment.
In order to realize this goal of the invention, the invention discloses a kind of freeze-dried composition of bortezomib, and the preparation method of this freeze-dried composition, utilize and be added with the tert-butyl alcohol of mannitol and the mixed solvent of water for injection, significantly increase the rate of dissolution of bortezomib, namely can be improved the rate of dissolution of bortezomib by the different orders of addition of material further.Utilize and fill the contact that nitrogen environment effectively prevent principal agent composition and aerobic environment, reduce the related substance of final finished and total assorted content.
Particularly, the invention discloses following technical scheme:
Containing the freeze-dried composition of bortezomib, described freeze-dried composition comprises active component bortezomib, mannitol and be calculated in mass percent residual quantity not higher than 1.5% the tert-butyl alcohol.
Meanwhile, the invention also discloses described bortezomib, the mass ratio of mannitol be 1:(5 ~ 20) optimum ratio mode.
Meanwhile, also disclose the preparation method of the freeze-dried composition containing bortezomib in the present invention, concrete preparation process is as follows: first mixed homogeneously with water for injection by the tert-butyl alcohol, obtains mixed solution; Then mannitol is dissolved in mixed solution, obtains adjuvant solution; Bortezomib is joined in adjuvant solution, be stirred to and dissolve completely; Utilize the tert-butyl alcohol and/or water for injection to complement to dosing cumulative volume, obtain preparation midbody solution; The filtration of gained preparation midbody solution, fill, lyophilizing are obtained the freeze-dried composition containing bortezomib.
Preferred as one, preparation process is as follows:
(1) tert-butyl alcohol is heated to 26 ~ 50 DEG C, get that the tert-butyl alcohol injects water to dosing cumulative volume 50% ~ 95%, mix homogeneously, obtains mixed solution;
(2) getting mannitol adds in mixed solution, under 25 ~ 60 DEG C of conditions, is stirred to mannitol and dissolves completely, obtain adjuvant solution;
(3) getting bortezomib adds in adjuvant solution, is stirred to and dissolves completely under 25 ~ 60 DEG C of conditions, adds water for injection and/or the tert-butyl alcohol to dosing cumulative volume, obtains preparation midbody solution;
(4) step (3) gained midbody solution after filtration, fill, lyophilizing obtain containing bortezomib freeze-dried composition.
More preferably, the invention also discloses preparation process as follows:
(1) tert-butyl alcohol is heated to 26 ~ 50 DEG C, gets the tert-butyl alcohol of 100 ~ 500 mass parts, inject water to 50% ~ 95% of dosing cumulative volume, mix homogeneously, obtain mixed solution;
(2) mannitol getting 5 ~ 20 mass parts adds in mixed solution, under 25 ~ 60 DEG C of conditions, is stirred to mannitol and dissolves completely, obtain adjuvant solution;
(3) bortezomib getting 1 mass parts adds in adjuvant solution, is stirred to and dissolves completely under 25 ~ 60 DEG C of conditions, adds water for injection and/or the tert-butyl alcohol to dosing cumulative volume, obtains preparation midbody solution;
(4) step (3) gained preparation midbody solution after filtration, fill, lyophilizing obtain containing bortezomib freeze-dried composition.
Especially, the concentration that the present invention also preferably discloses bortezomib in preparation midbody solution in above-mentioned preparation method is 0.5 ~ 5mg/ml.
Preferred as the another kind in preparation; the invention also discloses under described preparation process is all in nitrogen filled protection state; it is specially: before adding mannitol, first fill nitrogen 0.5 ~ 2 hour, then keeps nitrogen filled protection state to preparing freeze-dried composition always.Meanwhile, the invention also discloses corresponding freeze drying process after adopting freeze-dried composition disclosed in this invention, described lyophilizing comprises the following steps: after the goods inlet that fill obtains, and is cooled to-42 ~-52 DEG C of pre-freezes, keeps 1 ~ 5 hour; Open cold-trap, open vacuum; Within 3-10 hour, be warming up to-25 ~-35 DEG C, be then incubated 5 ~ 15 hours; Within 1 ~ 5 hour, be warming up to-10 ~-20 DEG C, be then incubated 3-10 hour; Within 1-10 minute, be warming up to 25 ~ 45 DEG C, be then incubated 3-10 hour.
Further, the invention also discloses described bortezomib to add with the form of trimer and/or monomer.
Meanwhile, the content due to bortezomib in fill unit also affects the quality of lyophilized formulations to a certain extent, thus the present invention also particularly disclose preparation midbody solution filter after fill time each fill unit in containing bortezomib 0.5 ~ 5mg.
Here when fill unit refers to fill, the volume of each minimum dose product.
The bortezomib pharmaceutical composition obtained by the present invention compared with prior art, has following technique effect:
(1) obviously shorten the time of formulation soln preparation, the preparation of formulation soln can be completed in effective time, simplify production process, effectively reduce production cost;
(2) keep in formulation manufacturing processes filling nitrogen environment, effectively prevent the contact of principal agent and aerobic environment, decrease the generation of oxidation impurities, improve final products quality;
(3) by the final production finished product that production technology provided by the invention obtains, preparation stability is significantly improved, and improves the safety of Clinical practice.
Detailed description of the invention
Below by specific embodiment, the present invention is described; should correct understanding: embodiments of the invention are to illustrate that the present invention makes; instead of limitation of the present invention, so under method prerequisite of the present invention, also protection scope of the present invention is belonged to simple transformation of the present invention.
Below in an example, the various process and methods do not described in detail are conventional methods as known in the art, and not ben reagent, medicine and equipment, vessel etc. are commercially available prod.
In the present invention, pH value adopts Chinese Pharmacopoeia (version in 2010) second annex VI H item pH value algoscopy.In the present invention, Sterility testing adopts Chinese Pharmacopoeia (version in 2010) second annex Ⅺ H Sterility Test.
In the present invention, bacterial endotoxin adopts Chinese Pharmacopoeia (version in 2010) second annex Ⅺ E bacterial endotoxins test.
In the present invention, determination of related substances adopts high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D) to measure.Employing octadecylsilane chemically bonded silica is filler (4.6 × 250mm, 5 μm); With THF-acetonitrile-water-formic acid for mobile phase A, acetonitrile-water-formic acid is Mobile phase B, adopts gradient elution mode to measure, determined wavelength 270nm, column temperature 25 DEG C.
In the present invention, assay adopts high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D) to measure.Employing octadecylsilane chemically bonded silica is filler, and adopt acetonitrile-water-formic acid to be mobile phase, isocratic elution measures, determined wavelength 270nm, column temperature 25 DEG C.
Preparation method disclosed in reference examples 1 US6713446
Prescription:
| Bortezomib | 40mg |
| Mannitol | 400mg |
| The tert-butyl alcohol | 16ml |
| Water for injection | Be settled to 40ml |
| Make altogether | 40 |
Preparation technology: take 40mg bortezomib and add in the tert-butyl alcohol of 16ml, heated sealed to 45 DEG C, is stirred to and dissolves completely, moisturizing, to full dose, adds the mannitol of 400mg, stirring and dissolving, mixed solution aseptic filtration, fill lyophilizing.
Experimentation and result: principal agent bortezomib dissolves at about 30min, and during nearly 40min, solution is clear and bright, and liquid preparation time is longer.
The maximum list of sample related substance assorted 0.087%, always mixes 0.682%, content 99.1%.
Preparation method disclosed in reference examples 2 US20110230441
Prescription:
Accordingly, preparation technology and result
Prepare lyophilizing sample according to above prescription and technique, not only freeze-drying time is longer, and formability is poor, and each sample organic residue content is higher, and sample impurity content is high.
Embodiment 1
Prescription:
| Bortezomib | 50mg |
| Mannitol | 1000mg |
| The tert-butyl alcohol | 5g |
| Water for injection | Be settled to 100ml |
Preparation technology: the tert-butyl alcohol is heated to 26 DEG C, makes it melt as liquid state, takes the 5g tert-butyl alcohol, mends and injects water to 50% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 0.5 hour; Take the mannitol of 1000mg, add in mixed solution, under 60 DEG C of conditions, be stirred to mannitol and dissolve completely, obtain adjuvant solution; Taking 50mg bortezomib adds in adjuvant solution, at 60 DEG C, is stirred to and dissolves completely, add water for injection to dosing cumulative volume, obtain preparation midbody solution, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filters, carry out fill according to 1ml volume, send into freeze dryer lyophilizing, obtain lyophilizing finished product.
Freeze drying process: after goods inlet, is cooled to about-52 DEG C of pre-freezes, keeps this temperature 1 hour; Open cold-trap, open vacuum; Within 10 hours, be warming up to about-30 DEG C, then keep 5 hours; Within 4 hours, be warming up to about-15 DEG C, then keep 4 hours; Within 1 minute, be warming up to 25 DEG C, then keep 3 hours; Fill nitrogen tamponade.
Finished product detects to obtain its content 100.1% through HPLC, and total impurities is 0.315%, and maximum list assorted 0.043%, finished product pH value 5.9, content and related substance all adopt HPLC to detect.
Embodiment 2
Prescription:
| Bortezomib | 500mg |
| Mannitol | 2500mg |
| The tert-butyl alcohol | 50g |
| Water for injection | Be settled to 100ml |
Preparation technology: the tert-butyl alcohol is heated to 50 DEG C, makes it melt as liquid state, takes the 50g tert-butyl alcohol, mends and injects water to 95% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 2 hours; Take the mannitol of 2500mg, add in mixed solution, under 50 DEG C of conditions, be stirred to mannitol and dissolve completely, obtain adjuvant solution; Taking 500mg bortezomib adds in adjuvant solution, at 50 DEG C, is stirred to and dissolves completely, add water for injection to dosing cumulative volume, obtain preparation midbody solution, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filters, carry out fill according to 1ml volume, send into freeze dryer lyophilizing, obtain lyophilizing finished product.
Freeze drying process: after goods inlet, is cooled to about-50 DEG C of pre-freezes, keeps this temperature 2 hours; Open cold-trap, open vacuum; Within 8 hours, be warming up to about-30 DEG C, then keep 15 hours; Within 5 hours, be warming up to about-10 DEG C, then keep 10 hours; Within 5 minutes, be warming up to 35 DEG C, then keep 5 hours; Fill nitrogen tamponade.
Finished product detects to obtain its content 99.2% through HPLC, and total impurities is 0.293%, and maximum list assorted 0.032%, finished product pH value 5.6, content and related substance all adopt HPLC to detect.
Embodiment 3
Prescription:
| Bortezomib | 175mg |
| Mannitol | 1750mg |
| The tert-butyl alcohol | 40g |
| Water for injection | Be settled to 100ml |
Preparation technology: the tert-butyl alcohol is heated to 40 DEG C, makes it melt as liquid state, takes the 40g tert-butyl alcohol, mends and injects water to 90% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 1 hour; Take the mannitol of 1750mg, add in mixed solution, under 40 DEG C of conditions, be stirred to mannitol and dissolve completely, obtain adjuvant solution; Taking 175mg bortezomib adds in adjuvant solution, at 40 DEG C, is stirred to and dissolves completely, add water for injection to dosing cumulative volume, obtain preparation midbody solution, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filters, carry out fill according to 2ml volume, send into freeze dryer lyophilizing, obtain lyophilizing finished product.
Freeze drying process: after goods inlet, is cooled to about-47 DEG C of pre-freezes, keeps this temperature 3 hours; Open cold-trap, open vacuum; Within 7 hours, be warming up to about-25 DEG C, then keep 12 hours; Within 1 hour, be warming up to about-20 DEG C, then keep 8 hours; Within 3 minutes, be warming up to 30 DEG C, then keep 10 hours; Fill nitrogen tamponade.
Finished product detects to obtain its content 99.8% through HPLC, and total impurities is 0.237%, and maximum list assorted 0.028%, finished product pH value 5.4, content and related substance all adopt HPLC to detect.
Embodiment 4
Prescription:
| Bortezomib | 100mg |
| Mannitol | 500mg |
| The tert-butyl alcohol | 50g |
| Water for injection | Be settled to 100ml |
Preparation technology: the tert-butyl alcohol is heated to 40 DEG C, makes it melt as liquid state, takes the 50g tert-butyl alcohol, mends and injects water to 80% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 1 hour; Take the mannitol of 500mg, add in mixed solution, under 25 DEG C of conditions, be stirred to mannitol and dissolve completely, obtain adjuvant solution; Taking 100mg bortezomib adds in adjuvant solution, at 25 DEG C, is stirred to and dissolves completely, add water for injection to dosing cumulative volume, obtain preparation midbody solution, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filters, carry out fill according to 0.5ml volume, send into freeze dryer lyophilizing, obtain lyophilizing finished product.
Freeze drying process: after goods inlet, is cooled to about-44 DEG C of pre-freezes, keeps this temperature 4 hours; Open cold-trap, open vacuum; Within 5 hours, be warming up to about-25 DEG C, then keep 10 hours; Within 3 hours, be warming up to about-15 DEG C, then keep 6 hours; Within 8 minutes, be warming up to 40 DEG C, then keep 5 hours; Fill nitrogen tamponade.
Finished product detects to obtain its content 99.6% through HPLC, and total impurities is 0.437%, and maximum list assorted 0.054%, finished product pH value 5.7, content and related substance all adopt HPLC to detect.
Embodiment 5
Prescription:
| Bortezomib | 50mg |
| Mannitol | 1000mg |
| The tert-butyl alcohol | 15g |
| Water for injection | Be settled to 100ml |
Preparation technology: the tert-butyl alcohol is heated to 40 DEG C, makes it melt as liquid state, takes the 15g tert-butyl alcohol, mends and injects water to 80% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 1 hour; Take the mannitol of 1000mg, add in mixed solution, under 40 DEG C of conditions, be stirred to mannitol and dissolve completely, obtain adjuvant solution; Taking 50mg bortezomib adds in adjuvant solution, at 40 DEG C, is stirred to and dissolves completely, add water for injection to dosing cumulative volume, obtain preparation midbody solution, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filters, carry out fill according to 5ml volume, send into freeze dryer lyophilizing, obtain lyophilizing finished product.
Freeze drying process: after goods inlet, is cooled to about-42 DEG C of pre-freezes, keeps this temperature 5 hours; Open cold-trap, open vacuum; Within 3 hours, be warming up to about-35 DEG C, then keep 8 hours; Within 2 hours, be warming up to about-18 DEG C, then keep 3 hours; Within 10 minutes, be warming up to 45 DEG C, then keep 3 hours; Fill nitrogen tamponade.
Finished product detects to obtain its content 99.5% through HPLC, and total impurities is 0.482%, and maximum list assorted 0.061%, finished product pH value 5.9, content and related substance all adopt HPLC to detect.
Embodiment 6:
According to contrast patent, We conducted the preparation of comparative examples preparation, and carry out comparative study with technical method provided by the present invention, the preparation technology of preparation and end product quality are compared, the preparation method of the new pharmaceutical composition of its concrete outcome contrast display boronic acid containing compound provided by the invention has larger technical advantage, and concrete outcome is in table 1:
Table 1 reference examples and embodiment preparation technology compare
According to result of implementation contrast, novel preparation process provided by the invention is obviously better than reference examples preparation technology, can prepare more stable product, has higher producing feasibility.
Embodiment 7:
According to the concrete operations mode of above embodiment, concrete composition and the preparation process of this pharmaceutical composition can be set forth further, we carry out accelerated stability investigation to sample prepared by each group of embodiment, can be verified the character of pharmaceutical composition prepared by the present invention by the data of study on the stability further.
Sample prepared by reference examples and embodiment 1 ~ 5 is carried out accelerated stability investigation by us under 40 DEG C of conditions, and concrete outcome is as shown in table 2:
Table 2 respectively group sample acceleration environment stability inferior is investigated
Can learn according to above result, under accelerating setting-out condition at 40 DEG C, the embodiment sample indices prepared by the present invention, compared with 0 day testing result, does not have significant change, and reference examples is prepared sample accelerated stability and is obviously worse than embodiment group.
In the present invention, the concrete preparation process of pharmaceutical composition of the present invention can be learnt by the operating process of each group of concrete embodiment, and carry out accelerated test investigation by the pharmaceutical composition obtained each embodiment, can learn that this pharmaceutical composition can stablize preservation 6 months under 40 DEG C of acceleration environments, have good stability.
Claims (4)
1., containing the freeze-dried composition of bortezomib, it is characterized in that: described freeze-dried composition contains active component bortezomib, mannitol and be calculated in mass percent residual quantity not higher than 1.5% the tert-butyl alcohol; The mass ratio of described bortezomib, mannitol is 1:(5 ~ 20); Its preparation process is as follows,
(1) tert-butyl alcohol is heated to 26 ~ 50 DEG C, get that the tert-butyl alcohol injects water to dosing cumulative volume 50% ~ 95%, mix homogeneously, obtains mixed solution;
(2) getting mannitol adds in mixed solution, under 25 ~ 60 DEG C of conditions, is stirred to mannitol and dissolves completely, obtain adjuvant solution;
(3) getting bortezomib adds in adjuvant solution, is stirred to and dissolves completely under 25 ~ 60 DEG C of conditions, adds water for injection and/or the tert-butyl alcohol to dosing cumulative volume, obtains preparation midbody solution;
(4) step (3) gained preparation midbody solution after filtration, fill, lyophilizing obtain containing bortezomib freeze-dried composition
In described preparation midbody solution, the concentration of bortezomib is 0.5 ~ 5mg/ml;
Under described preparation process is all in nitrogen filled protection state, it is specially: before first adding mannitol, mixed solution is filled nitrogen deoxidation 0.5 ~ 2 hour, then keeps nitrogen filled protection state to preparing freeze-dried composition always;
Described lyophilizing comprises the following steps: after the goods inlet that fill obtains, and is cooled to-42 ~-52 DEG C of pre-freezes, keeps 1 ~ 5 hour; Open cold-trap, open vacuum; Within 3-10 hour, be warming up to-25 ~-35 DEG C, be then incubated 5 ~ 15 hours; Within 1 ~ 5 hour, be warming up to-10 ~-20 DEG C, be then incubated 3-10 hour; Within 1-10 minute, be warming up to 25 ~ 45 DEG C, be then incubated 3-10 hour.
2. the preparation method of the freeze-dried composition containing bortezomib according to claim 1, is characterized in that preparation process is as follows:
(1) tert-butyl alcohol is heated to 26 ~ 50 DEG C, gets the tert-butyl alcohol of 100 ~ 500 mass parts, inject water to 50% ~ 95% of dosing cumulative volume, mix homogeneously, obtain mixed solution;
(2) mannitol getting 5 ~ 20 mass parts adds in mixed solution, under 25 ~ 60 DEG C of conditions, is stirred to mannitol and dissolves completely, obtain adjuvant solution;
(3) bortezomib getting 1 mass parts adds in adjuvant solution, is stirred to and dissolves completely under 25 ~ 60 DEG C of conditions, adds water for injection and/or the tert-butyl alcohol to dosing cumulative volume, obtains preparation midbody solution;
(4) step (3) gained preparation midbody solution after filtration, fill, lyophilizing obtain containing bortezomib freeze-dried composition.
3., according to the preparation method of the freeze-dried composition containing bortezomib described in claim 2, it is characterized in that described bortezomib adds with the form of trimer and/or monomer.
4., according to the preparation method of the freeze-dried composition containing bortezomib described in claim 2, after it is characterized in that the filtration of preparation midbody solution, during fill, in each fill unit, contain bortezomib 0.5 ~ 5mg.
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| 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 |
| CN103446068B (en) * | 2013-09-17 | 2015-12-23 | 江苏奥赛康药业股份有限公司 | Bortezomib freeze-dried composition 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 |
| 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 |
| 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 |
| EP3120837A1 (en) * | 2015-07-22 | 2017-01-25 | Stada Arzneimittel Ag | Ready-to-use solution of bortezomib |
| CN107224569A (en) * | 2016-03-26 | 2017-10-03 | 复旦大学 | Water-soluble Pharmaceutical composition of a kind of bortezomib and its production and use |
| CN106309385B (en) * | 2016-10-18 | 2018-02-06 | 江苏豪森药业集团有限公司 | Bortezomib freeze drying powder injection and its preparation technology |
| CN114053391A (en) * | 2021-12-17 | 2022-02-18 | 瀚晖制药有限公司 | Freeze-dried bortezomib preparation and freeze-drying process thereof |
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| EA201170527A1 (en) * | 2008-10-01 | 2011-10-31 | Др. Редди'С Лабораторис Лтд. | PHARMACEUTICAL COMPOSITIONS, INCLUDING BORONIC ACID COMPOUNDS |
| MX2011007192A (en) * | 2009-01-09 | 2011-10-04 | Sun Pharma Advanced Res Co Ltd | Bortezumib containing pharmaceutical composition. |
| EP2238973A1 (en) * | 2009-04-07 | 2010-10-13 | Cephalon France | Lyophilized preparations of proteasome inhibitors |
| WO2012047845A1 (en) * | 2010-10-05 | 2012-04-12 | App Pharmaceuticals | Bortezomib formulations stabilised with boric |
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Address after: 211112 No. 699, Science Construction Road, Nanjing Jiangning Academy of Sciences, Nanjing, Jiangsu Province Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 No. 699, Science Construction Road, Nanjing Jiangning Academy of Sciences, Nanjing, Jiangsu Province Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |