CN103070835A - 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 technical field, particularly relate to chemical pharmacy field, more specifically relate to a kind of freeze-dried composition that contains bortezomib and preparation method thereof.
Background technology
Bortezomib (Bortezomib) is a kind of proteasome inhibitor, and structure is suc as formula shown in the I.Bortezomib can specificity suppresses class chymase (chymotrypsin-like) activity of 26S proteasome in the mammalian cell, a series of signal in the cell is sent exert an influence, and finally causes cancer cell death.
Bortezomib is the dipeptides boronic acid derivatives that is formed by leucine and phenylalanine, can exist with the trimeric form shown in the formula II.In pH2 ~ 6.5 scopes, the dissolubility of bortezomib in water is 3.3 ~ 3.8mg/ml.
Wherein:
Bortezomib (bortezomib) is a kind of dipeptides ylboronic acid chemical compound, it has efficient single-minded protease inhibitory action, be also referred to as in the past LDP-341 and PS-341, researched and developed by U.S. Millennium Pharmaceuticals company the earliest, and in the approval of 19 acquisition FDA May 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 was got permission to go on the market in Britain in May, 2004, for the treatment of before at least having accepted two kinds of therapies and after treating the last time, and the multiple myeloma that the disease appearance makes progress.The domestic existing import listing of this product preparation, early than approval listing in 2005, listing producer is Xian-Janssen Pharmaceutical Ltd., the listing specification is 1mg and two specifications of 3.5mg.
But, owing to the bortezomib poorly water-soluble, be easy to oxidation.Therefore in the medicine preparation process, there are two large difficult points, the one, principal agent indissoluble; The 2nd, easy oxidation, oxidation impurities content is high in the finished product.
Therefore, in the medicine preparation field take bortezomib as principal agent, be primarily focused on increases the dissolubility of bortezomib in preparation and avoids that oxidation produces on these two problems of oxidation impurities in the preparation process always.Disclose five kinds of anhydrous borons among the patent US20110230441 for assistant metric system agent and preparation process thereof, in its formulation and technology, used ethanol, propylene glycol and multiple antioxidant thereof to mix as solvent, carried out lyophilizing and prepare finished product.Utilize the bortezomib preparation of this technique preparation to use more organic solvent, and multiple, a large amount of antioxidant.Therefore cause the requirement of finished product freeze temperature harsh, medicine need to long-time lyophilizing under lower freeze temperature, has seriously increased the preparation difficulty.Simultaneously, organic solvent remains in the lyophilizing finished product easily, increases finished product impurity.
Therefore, adopt present preparation technology, preparation process time is long, and the finished product its related substances is high; Although multiple anhydrous organic solvent dissolving principal agent has increased the principal agent dissolubility to a certain extent, the freeze-drying process for preparing the lyophilizing finished product is long, and is large to the production equipment injury; The organic residue amount is high simultaneously, and product quality is low.
Summary of the invention
The object of the invention is to overcome principal agent dissolving difficulty and to the problem of oxygen environment sensitive in the 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, utilization is 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 further improve the rate of dissolution of bortezomib by the difference interpolation order of material.Utilization is filled nitrogen environment and has effectively been avoided contacting of principal agent composition and aerobic environment, has reduced related substance and total assorted content of final finished.
Particularly, the invention discloses following technical scheme:
A kind of freeze-dried composition that contains bortezomib, described freeze-dried composition comprises the active component bortezomib, mannitol and be calculated in mass percent residual quantity and be not higher than 1.5% the tert-butyl alcohol.
Simultaneously, the mass ratio that the invention also discloses described bortezomib, mannitol is 1:(5 ~ 20) the optimum ratio mode.
Simultaneously, also disclose in the present invention the preparation method of the freeze-dried composition that contains bortezomib, concrete preparation process is as follows: at first with the tert-butyl alcohol and water for injection mix homogeneously, obtain mixed solution; Then mannitol is dissolved in the mixed solution, obtains adjuvant solution; Bortezomib is joined in the adjuvant solution, be stirred to fully dissolving; Utilize the tert-butyl alcohol and/or water for injection to complement to the dosing cumulative volume, obtain the preparation midbody solution; The filtration of gained preparation midbody solution, fill, lyophilizing are obtained containing the freeze-dried composition of bortezomib.
As a kind of preferred, preparation process is as follows:
(1) tert-butyl alcohol is heated to 26 ~ 50 ℃, gets the tert-butyl alcohol and inject water to 50% ~ 95% of dosing cumulative volume, mix homogeneously obtains mixed solution;
(2) get mannitol and add in the mixed solution, under 25 ~ 60 ℃ of conditions, be stirred to mannitol and dissolve fully, obtain adjuvant solution;
(3) get bortezomib and add in the adjuvant solution, under 25 ~ 60 ℃ of conditions, be stirred to fully dissolving, add water for injection and/or the tert-butyl alcohol to the dosing cumulative volume, obtain the preparation midbody solution;
(4) step (3) gained midbody solution after filtration, fill, lyophilizing obtain containing the freeze-dried composition of bortezomib.
More preferably, it is as follows to the invention also discloses preparation process:
(1) tert-butyl alcohol is heated to 26 ~ 50 ℃, gets the tert-butyl alcohol of 100 ~ 500 mass parts, inject water to 50% ~ 95% of dosing cumulative volume, mix homogeneously obtains mixed solution;
(2) get in the mannitol adding mixed solution of 5 ~ 20 mass parts, under 25 ~ 60 ℃ of conditions, be stirred to mannitol and dissolve fully, obtain adjuvant solution;
(3) get in the bortezomib adding adjuvant solution of 1 mass parts, under 25 ~ 60 ℃ of conditions, be stirred to fully dissolving, add water for injection and/or the tert-butyl alcohol to the dosing cumulative volume, obtain the preparation midbody solution;
(4) step (3) gained preparation midbody solution after filtration, fill, lyophilizing obtain containing the freeze-dried composition of bortezomib.
Especially, the concentration that the present invention also preferably discloses bortezomib in the preparation midbody solution in above-mentioned preparation method is 0.5 ~ 5mg/ml.
Preferred as the another kind in the preparation; the invention also discloses described preparation process all is under the nitrogen filled protection state; it is specially: at first filled nitrogen 0.5 ~ 2 hour before adding mannitol, then keep the nitrogen filled protection state to preparing freeze-dried composition always.Simultaneously, the invention also discloses and adopt corresponding freeze drying process behind the freeze-dried composition disclosed in this invention, described lyophilizing may further comprise the steps: behind the goods inlet that fill obtains, be cooled to-42 ~-52 ℃ of pre-freezes, kept 1 ~ 5 hour; Open cold-trap, open vacuum; Be warming up to-25 ~-35 ℃ in 3-10 hour, then be incubated 5 ~ 15 hours; Be warming up to-10 ~-20 ℃ in 1 ~ 5 hour, then be incubated 3-10 hour; Be warming up to 25 ~ 45 ℃ in 1-10 minute, then be incubated 3-10 hour.
Further, the invention also discloses described bortezomib with the form adding of trimer and/or monomer.
Simultaneously, because the content of bortezomib also affects the quality of lyophilized formulations to a certain extent in the fill unit, when also disclosing the rear fill of preparation midbody solution filtration especially, the present invention contains bortezomib 0.5 ~ 5mg in each fill unit.
When the fill unit here refers to fill, the volume of each minimum dose product.
The bortezomib pharmaceutical composition that obtains by the present invention has following technique effect compared with prior art:
(1) obviously shortened the time that formulation soln is prepared, can in effective time, finish the preparation of formulation soln, simplified production process, effectively reduced production costs;
(2) keep in the preparation production process filling nitrogen environment, effectively avoided contacting of principal agent and aerobic environment, reduced the generation of oxidation impurities, improved the final products quality;
(3) the final production finished product that obtains by production technology provided by the invention, preparation stability is significantly improved, and has improved the safety of clinical use.
The specific embodiment
Below by specific embodiment the present invention is described; should correct understanding be: embodiments of the invention are to make for the present invention is described; rather than limitation of the present invention, so under method prerequisite of the present invention, simple transformation of the present invention is also belonged to protection scope of the present invention.
In following embodiment, the various process and methods of not describing in detail are conventional methods as known in the art, and not ben reagent, medicine and equipment, vessel etc. are the commercially available prod.
PH value adopts second appendix VI H item of Chinese Pharmacopoeia (version in 2010) pH value algoscopy among the present invention.Second appendix XI H Sterility Test of Chinese Pharmacopoeia (version in 2010) adopted in aseptic detection among the present invention.
Bacterial endotoxin adopts second appendix XI E bacterial endotoxins test of Chinese Pharmacopoeia (version in 2010) among the present invention.
Determination of related substances adopts high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D) to measure among the present invention.The employing octadecylsilane chemically bonded silica is filler (4.6 * 250mm, 5 μ m); Take THF-acetonitrile-water-formic acid as mobile phase A, acetonitrile-water-formic acid is Mobile phase B, adopts the gradient elution mode to measure, and detects wavelength 270nm, 25 ℃ of column temperatures.
Assay adopts high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D) to measure among the present invention.The employing octadecylsilane chemically bonded silica is filler, and employing acetonitrile-water-formic acid is mobile phase, and isocratic elution is measured, and detects wavelength 270nm, 25 ℃ of column temperatures.
The disclosed preparation method of 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 by weighing in the tert-butyl alcohol that the 40mg bortezomib adds 16ml, heated sealed to 45 ℃ is stirred to fully dissolving, and moisturizing adds the mannitol of 400mg, stirring and dissolving, mixed solution aseptic filtration, fill lyophilizing to full dose.
Experimentation and result: the principal agent bortezomib dissolves about 30min, and solution is clear and bright during nearly 40min, and the dosing time is longer.
The maximum list of sample related substance mixes 0.087%, always mixes 0.682%, content 99.1%.
The disclosed preparation method of reference examples 2 US20110230441
Prescription:
Accordingly, preparation technology and result
Prepare the 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 the 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 ℃, it is melted as liquid, take by weighing the 5g tert-butyl alcohol, add water for injection to 50% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 0.5 hour; Take by weighing the mannitol of 1000mg, add in the mixed solution, under 60 ℃ of conditions, be stirred to mannitol and dissolve fully, get adjuvant solution; Take by weighing the 50mg bortezomib and add in the adjuvant solution, under 60 ℃, be stirred to fully dissolving, the supplementary injection water obtains the preparation midbody solution to the dosing cumulative volume, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filter, carry out fill according to the 1ml volume, send into the freeze dryer lyophilizing, obtain the lyophilizing finished product.
Freeze drying process: behind the goods inlet, be cooled to approximately-52 ℃ of pre-freezes, kept this temperature 1 hour; Open cold-trap, open vacuum; Be warming up to-30 ℃ approximately in 10 hours, then kept 5 hours; Be warming up to-15 ℃ approximately in 4 hours, then kept 4 hours; Be warming up to 25 ℃ in 1 minute, then kept 3 hours; Fill the nitrogen tamponade.
Finished product detects to get its content 100.1% through HPLC, and total impurities is 0.315%, and maximum list mixes 0.043%, and 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 ℃, it is melted as liquid, take by weighing the 50g tert-butyl alcohol, add water for injection to 95% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 2 hours; Take by weighing the mannitol of 2500mg, add in the mixed solution, under 50 ℃ of conditions, be stirred to mannitol and dissolve fully, get adjuvant solution; Take by weighing the 500mg bortezomib and add in the adjuvant solution, under 50 ℃, be stirred to fully dissolving, the supplementary injection water obtains the preparation midbody solution to the dosing cumulative volume, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filter, carry out fill according to the 1ml volume, send into the freeze dryer lyophilizing, obtain the lyophilizing finished product.
Freeze drying process: behind the goods inlet, be cooled to approximately-50 ℃ of pre-freezes, kept this temperature 2 hours; Open cold-trap, open vacuum; Be warming up to-30 ℃ approximately in 8 hours, then kept 15 hours; Be warming up to-10 ℃ approximately in 5 hours, then kept 10 hours; Be warming up to 35 ℃ in 5 minutes, then kept 5 hours; Fill the nitrogen tamponade.
Finished product detects to get its content 99.2% through HPLC, and total impurities is 0.293%, and maximum list mixes 0.032%, and 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 ℃, it is melted as liquid, take by weighing the 40g tert-butyl alcohol, add water for injection to 90% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 1 hour; Take by weighing the mannitol of 1750mg, add in the mixed solution, under 40 ℃ of conditions, be stirred to mannitol and dissolve fully, get adjuvant solution; Take by weighing the 175mg bortezomib and add in the adjuvant solution, under 40 ℃, be stirred to fully dissolving, the supplementary injection water obtains the preparation midbody solution to the dosing cumulative volume, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filter, carry out fill according to the 2ml volume, send into the freeze dryer lyophilizing, obtain the lyophilizing finished product.
Freeze drying process: behind the goods inlet, be cooled to approximately-47 ℃ of pre-freezes, kept this temperature 3 hours; Open cold-trap, open vacuum; Be warming up to-25 ℃ approximately in 7 hours, then kept 12 hours; Be warming up to-20 ℃ approximately in 1 hour, then kept 8 hours; Be warming up to 30 ℃ in 3 minutes, then kept 10 hours; Fill the nitrogen tamponade.
Finished product detects to get its content 99.8% through HPLC, and total impurities is 0.237%, and maximum list mixes 0.028%, and 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 ℃, it is melted as liquid, take by weighing the 50g tert-butyl alcohol, add water for injection to 80% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 1 hour; Take by weighing the mannitol of 500mg, add in the mixed solution, under 25 ℃ of conditions, be stirred to mannitol and dissolve fully, get adjuvant solution; Take by weighing the 100mg bortezomib and add in the adjuvant solution, under 25 ℃, be stirred to fully dissolving, the supplementary injection water obtains the preparation midbody solution to the dosing cumulative volume, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filter, carry out fill according to the 0.5ml volume, send into the freeze dryer lyophilizing, obtain the lyophilizing finished product.
Freeze drying process: behind the goods inlet, be cooled to approximately-44 ℃ of pre-freezes, kept this temperature 4 hours; Open cold-trap, open vacuum; Be warming up to-25 ℃ approximately in 5 hours, then kept 10 hours; Be warming up to-15 ℃ approximately in 3 hours, then kept 6 hours; Be warming up to 40 ℃ in 8 minutes, then kept 5 hours; Fill the nitrogen tamponade.
Finished product detects to get its content 99.6% through HPLC, and total impurities is 0.437%, and maximum list mixes 0.054%, and 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 ℃, it is melted as liquid, take by weighing the 15g tert-butyl alcohol, add water for injection to 80% of dosing cumulative volume, mix homogeneously, nitrogen filled protection 1 hour; Take by weighing the mannitol of 1000mg, add in the mixed solution, under 40 ℃ of conditions, be stirred to mannitol and dissolve fully, get adjuvant solution; Take by weighing the 50mg bortezomib and add in the adjuvant solution, under 40 ℃, be stirred to fully dissolving, the supplementary injection water obtains the preparation midbody solution to the dosing cumulative volume, the omnidistance nitrogen filled protection of layoutprocedure; After the detection of preparation midbody solution is qualified, filter, carry out fill according to the 5ml volume, send into the freeze dryer lyophilizing, obtain the lyophilizing finished product.
Freeze drying process: behind the goods inlet, be cooled to approximately-42 ℃ of pre-freezes, kept this temperature 5 hours; Open cold-trap, open vacuum; Be warming up to-35 ℃ approximately in 3 hours, then kept 8 hours; Be warming up to-18 ℃ approximately in 2 hours, then kept 3 hours; Be warming up to 45 ℃ in 10 minutes, then kept 3 hours; Fill the nitrogen tamponade.
Finished product detects to get its content 99.5% through HPLC, and total impurities is 0.482%, and maximum list mixes 0.061%, and finished product pH value 5.9, content and related substance all adopt HPLC to detect.
Embodiment 6:
According to the contrast patent, we have carried out the preparation of comparative examples preparation, and compare research with technical method provided by the present invention, preparation technology and end product quality to preparation are compared, its concrete outcome contrast shows that the preparation method of the new pharmaceutical composition of boronic acid containing chemical compound provided by the invention has larger technical advantage, and concrete outcome sees Table 1:
Table 1 reference examples and embodiment preparation technology are relatively
According to the result of implementation contrast, novel preparation process provided by the invention obviously is better than reference examples preparation technology, can prepare more stable product, has higher producing feasibility.
Embodiment 7:
Concrete operations mode according to above embodiment, can further set forth concrete composition and the preparation process of this pharmaceutical composition, we carry out the accelerated stability investigation to the sample of each group embodiment preparation, can further verify the character of the prepared pharmaceutical composition of the present invention by the data of study on the stability.
We carry out the accelerated stability investigation with the sample of reference examples and embodiment 1～5 preparation under 40 ℃ of conditions, concrete outcome is as shown in table 2:
Table 2 is respectively organized sample acceleration environment stability inferior and is investigated
Can learn, accelerate under the setting-out conditions at 40 ℃, compare with 0 day testing result by the embodiment sample indices of the present invention's preparation do not have significant change according to above result, and reference examples prepares the sample accelerated stability and obviously is worse than the embodiment group.
In the present invention, can learn the concrete preparation process of pharmaceutical composition of the present invention by the concrete operating process of respectively organizing embodiment, investigate and carry out accelerated test by the pharmaceutical composition that each embodiment is obtained, can learn that this pharmaceutical composition can be stablized and preserve 6 months under 40 ℃ of acceleration environments, have good stability.
Claims (10)
1. freeze-dried composition that contains bortezomib, it is characterized in that: described freeze-dried composition contains the active component bortezomib, mannitol and be calculated in mass percent residual quantity and be not higher than 1.5% the tert-butyl alcohol.
2. the freeze-dried composition that contains bortezomib according to claim 1, it is characterized in that: the mass ratio of described bortezomib, mannitol is 1:(5 ~ 20).
3. the preparation method of the freeze-dried composition that contains bortezomib described in the claim 1 or 2 is characterized in that preparation process is as follows: at first with the tert-butyl alcohol and water for injection mix homogeneously, obtain mixed solution; Then mannitol is dissolved in the mixed solution, obtains adjuvant solution; Bortezomib is joined in the adjuvant solution, be stirred to fully dissolving; Utilize the tert-butyl alcohol and/or water for injection to complement to the dosing cumulative volume, obtain the preparation midbody solution; With the filtration of gained preparation midbody solution, fill, lyophilizing, obtain containing the freeze-dried composition of bortezomib.
4. the preparation method that contains the freeze-dried composition of bortezomib according to claim 3 is characterized in that preparation process is as follows:
(1) tert-butyl alcohol is heated to 26 ~ 50 ℃, gets the tert-butyl alcohol and inject water to 50% ~ 95% of dosing cumulative volume, mix homogeneously obtains mixed solution;
(2) get mannitol and add in the mixed solution, under 25 ~ 60 ℃ of conditions, be stirred to mannitol and dissolve fully, obtain adjuvant solution;
(3) get bortezomib and add in the adjuvant solution, under 25 ~ 60 ℃ of conditions, be stirred to fully dissolving, add water for injection and/or the tert-butyl alcohol to the dosing cumulative volume, obtain the preparation midbody solution;
(4) step (3) gained preparation midbody solution after filtration, fill, lyophilizing obtain containing the freeze-dried composition of bortezomib.
5. the preparation method that contains the freeze-dried composition of bortezomib according to claim 3 is characterized in that preparation process is as follows:
(1) tert-butyl alcohol is heated to 26 ~ 50 ℃, gets the tert-butyl alcohol of 100 ~ 500 mass parts, inject water to 50% ~ 95% of dosing cumulative volume, mix homogeneously obtains mixed solution;
(2) get in the mannitol adding mixed solution of 5 ~ 20 mass parts, under 25 ~ 60 ℃ of conditions, be stirred to mannitol and dissolve fully, obtain adjuvant solution;
(3) get in the bortezomib adding adjuvant solution of 1 mass parts, under 25 ~ 60 ℃ of conditions, be stirred to fully dissolving, add water for injection and/or the tert-butyl alcohol to the dosing cumulative volume, obtain the preparation midbody solution;
(4) step (3) gained preparation midbody solution after filtration, fill, lyophilizing obtain containing the freeze-dried composition of bortezomib.
6. the described preparation method that contains the freeze-dried composition of bortezomib of any one in 5 according to claim 3, the concentration that it is characterized in that bortezomib in the preparation midbody solution is 0.5 ~ 5mg/ml.
7. the described preparation method that contains the freeze-dried composition of bortezomib of any one in 5 according to claim 3; it is characterized in that described preparation process all is under the nitrogen filled protection state; it is specially: at first add before the mannitol; mixed solution is filled the nitrogen deoxidation 0.5 ~ 2 hour, then keep the nitrogen filled protection state to preparing freeze-dried composition always.
8. the described preparation method that contains the freeze-dried composition of bortezomib of any one in 5 according to claim 3 is characterized in that described lyophilizing may further comprise the steps: behind the goods inlet that fill obtains, be cooled to-42 ~-52 ℃ of pre-freezes, kept 1 ~ 5 hour; Open cold-trap, open vacuum; Be warming up to-25 ~-35 ℃ in 3-10 hour, then be incubated 5 ~ 15 hours; Be warming up to-10 ~-20 ℃ in 1 ~ 5 hour, then be incubated 3-10 hour; Be warming up to 25 ~ 45 ℃ in 1-10 minute, then be incubated 3-10 hour.
9. the described preparation method that contains the freeze-dried composition of bortezomib of any one in 5 according to claim 3 is characterized in that described bortezomib adds with the form of trimer and/or monomer.
10. the described preparation method that contains the freeze-dried composition of bortezomib of any one in 5 according to claim 3 is characterized in that containing bortezomib 0.5 ~ 5mg in each fill unit during fill after the preparation midbody solution filters.
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Cited By (9)
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| CN103446068A (en) * | 2013-09-17 | 2013-12-18 | 江苏奥赛康药业股份有限公司 | Bortezomib freeze-dried composition and preparation method thereof |
| 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 |
| 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 |
| CN106309385A (en) * | 2016-10-18 | 2017-01-11 | 江苏豪森药业集团有限公司 | Bortezomib freeze-dried powder injection and preparation process thereof |
| WO2017013209A1 (en) | 2015-07-22 | 2017-01-26 | Stada Arzneimittel Ag | Method for producing a bortezomib ester solution |
| 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 |
| 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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| CN106309385A (en) * | 2016-10-18 | 2017-01-11 | 江苏豪森药业集团有限公司 | Bortezomib freeze-dried powder injection and preparation process thereof |
| 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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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. |