CN103446068B - Bortezomib freeze-dried composition and preparation method thereof - Google Patents
Bortezomib freeze-dried composition and preparation method thereof Download PDFInfo
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- CN103446068B CN103446068B CN201310423853.1A CN201310423853A CN103446068B CN 103446068 B CN103446068 B CN 103446068B CN 201310423853 A CN201310423853 A CN 201310423853A CN 103446068 B CN103446068 B CN 103446068B
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Abstract
The invention belongs to field of medicaments, provide a kind of bortezomib freeze-dried composition and preparation method thereof.Described bortezomib freeze-dried composition is sprayed in liquid nitrogen by the mixed solution of bortezomib, mannitol, the tert-butyl alcohol to form freezing microgranule, is then dissolved in water for injection, through the freeze-dried composition that lyophilization obtains.Bortezomib composition quality provided by the invention is better, stability is higher.
Description
Technical field
The invention belongs to field of medicaments, particularly relate to the preparation field of bortezomib, more specifically relate to a kind of bortezomib freeze-dried composition and preparation method thereof.
Background technology
Bortezomib (bortezomib) belongs to dipeptides ylboronic acid compound, it is a kind of new and effective single-minded protease inhibitor, researched and developed by MillenniumPharmaceuticals 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, it is injection.Bortezomib structural formula is as follows:
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.
Bortezomib is a kind of proteasome inhibitor, can the class chymase (chymotrypsin-like) of 26S proteasome in mammalian cell be suppressed active by specificity, signal a series of in cell is sent and has an impact, finally cause cancer cell death.
Bortezomib water solublity is poor, and under slant acidity environmental condition, the dissolubility in water is at about 3.5mg/ml, and the preparation that goes on the market is injection, and therefore in formulation process, the problems of dissolution of principal agent is the difficult point of preparation technology.In addition, bortezomib raw material need be preserved under-20 DEG C of conditions, and it is more responsive to oxygen, oxidizable, temperature is higher or greatly can increase the content of oxidation impurities with air overtime time of contact, but preparation midbody solution stability is better, within 12 hours, aqueous solution impurity still can remain on reduced levels, therefore how to reduce the solid-state life period of bortezomib, as early as possible by material dissolution in solution, have great importance for improving the quality of final preparation.
In conventional bortezomib preparation preparation, when bortezomib dissolves, principal agent becomes the floccule of suspended state to exist, course of dissolution is slower, the long period is needed to dissolve completely, cause solution to complete time of preparation longer, thus cause the rising of oxidative degradation impurity in formulation soln, have impact on the quality of final finished dosage form.Therefore, key prepared by bortezomib preparation is to accelerate the dissolution velocity of raw material in adjuvant solution, and the time of contact of try one's best minimizing and oxygen, thus reach the effect reducing principal agent degraded.
Existing known technology takes comparatively loaded down with trivial details preparation process for the preparation process of bortezomib preparation, not only cause the principal agent course of dissolution time longer, and in long preparation process, make the overlong time that solid-state principal agent contacts with oxygen, greatly increase the generation of oxidation impurities in final finished, reduce the quality of finished product preparation.
Describe in patent US6713446 and first utilize the 97% concentration tert-butyl alcohol of the pure tert-butyl alcohol of 45 of whole recipe quantity DEG C or 35 DEG C to be dissolved by principal agent complete in advance, then add mannitol or mannitol solution mix homogeneously, benefit adds to the full amount of water for injection.According to this patent content, in lab scale research sweeping experiment, main solution is completely clear and bright reaches more than 40 minutes, dissolution time is longer, the time that solid feed contacts with external environment in process for preparation is longer, and degradation impurity increases obviously, affects the quality of final finished dosage form.
Provide a kind of bortezomib freeze-dried powder in patent application CN102784114A, it contains bortezomib, excipient, antioxidant and pH adjusting agent.The preparation that this invention provides, in preparation process, first principal agent and solid-state adjuvant carry out mixed grinding, and the time of causing unstable principal agent to contact with oxygen extends greatly, can cause the increase (see embodiment 7) of degradation impurity, therefore must add antioxidant.But the quality adding antioxidant acquisition product is still poor, and total mixing sees embodiment 8 more than 1%().
summary of the invention:
Dissolve difficulty and principal agent to the problem of oxygen environment sensitive to overcome principal agent, the present invention adopts specific preparation technology, obtains that quality is high, the injection bortezomib freeze-dried composition of good stability.
Injection bortezomib freeze-dried composition provided by the invention, described bortezomib freeze-dried composition is sprayed in liquid nitrogen by the mixed solution of bortezomib, mannitol, the tert-butyl alcohol to form freezing microgranule, then water for injection is dissolved in, through the freeze-dried composition that lyophilization obtains; Concrete steps are as follows:
(1) first bortezomib is dissolved in the tert-butyl alcohol, after mix homogeneously, add mannitol, and be mixed to get the mixed solution of bortezomib, mannitol, the tert-butyl alcohol further;
(2) mixed solution obtained in step (1) is sprayed in liquid nitrogen, obtain the freezing microgranule of mixed solution of bortezomib, mannitol, the tert-butyl alcohol;
(3) the freezing microgranule of mixed solution obtained in step (2) is dissolved in water for injection and must treats Solutions in Freeze-drying, and fill, lyophilizing obtain bortezomib freeze-dried composition.
Described step of freeze drying freeze-drying curve is: after the goods inlet that fill obtains, and is cooled to-45 ± 5 DEG C of pre-freezes, keeps 1 ~ 3 hour; Be warming up to-20 ± 5 DEG C, be incubated 2 ~ 3 hours, then be cooled to-45 ± 5 DEG C of insulations 1 ~ 3 hour; Open cold-trap, open vacuum; Baffle temperature is warming up to-25 ~-35 DEG C, then keeps 5 ~ 10 hours; Baffle temperature is warming up to-5 ~ 5 DEG C, then keeps 3-5 hour; Again baffle temperature is warming up to 25 ~ 40 DEG C, then keeps 3-5 hour.
In a preferred embodiment, described compositions its by following technique obtain:
(1) bortezomib is added in the tert-butyl alcohol of 25 ~ 40 DEG C and dissolve, after mix homogeneously, obtain the t-butanol solution containing bortezomib; Then in the t-butanol solution of bortezomib, add mannitol, be uniformly mixed, obtain the mixed solution of bortezomib, mannitol, the tert-butyl alcohol;
(2) by the mixed solution that obtains in step (1) by cryospray device, spray in liquid nitrogen with mist, obtain the freezing microgranule of mixed solution of bortezomib, mannitol, the tert-butyl alcohol;
(3) by the freezing particle dissolution of mixed solution that obtains in step (2) in water for injection, stir 5 ~ 10min under 5 ~ 25 DEG C of conditions, dissolve completely to principal agent, add water for injection to full dose and must treat Solutions in Freeze-drying, fill, according to freeze-drying curve lyophilizing, obtains bortezomib freeze-dried composition.
Above-described freeze-dried composition, each milliliter treats that the ratio of bortezomib in Solutions in Freeze-drying, mannitol, the tert-butyl alcohol is preferably:
Bortezomib 1 ~ 2mg;
Mannitol 10 ~ 20mg;
The tert-butyl alcohol 200 ~ 400mg;
Surplus is water for injection.
Present invention also offers a kind of preparation method of injection bortezomib freeze-dried composition, comprising:
(1) first bortezomib is dissolved in the tert-butyl alcohol, after mix homogeneously, add mannitol, and be mixed to get the mixed solution of bortezomib, mannitol, the tert-butyl alcohol further;
(2) mixed solution obtained in step (1) is sprayed in liquid nitrogen, obtain the freezing microgranule of mixed solution of bortezomib, mannitol, the tert-butyl alcohol;
(3) the freezing microgranule obtained in step (2) is dissolved in water for injection and must treats Solutions in Freeze-drying, and fill, lyophilizing, obtain bortezomib freeze-dried composition;
Described step of freeze drying freeze-drying curve is: after the goods inlet that fill obtains, and is cooled to-45 ± 5 DEG C of pre-freezes, keeps 1 ~ 3 hour; Be warming up to-20 ± 5 DEG C, be incubated 2 ~ 3 hours, then be cooled to-45 ± 5 DEG C of insulations 1 ~ 3 hour; Open cold-trap, open vacuum; Baffle temperature is warming up to-25 ~-35 DEG C, then keeps 5 ~ 10 hours; Baffle temperature is warming up to-5 ~ 5 DEG C, then keeps 3-5 hour; Again baffle temperature is warming up to 25 ~ 40 DEG C, then keeps 3-5 hour.
Further, we also disclosed in described preparation method, each milliliter treats that the ratio of bortezomib in Solutions in Freeze-drying, mannitol, the tert-butyl alcohol is preferably:
Bortezomib 1 ~ 2mg;
Mannitol 10 ~ 20mg;
The tert-butyl alcohol 200 ~ 400mg;
Surplus is water for injection.
Bortezomib pharmaceutical composition provided by the invention, without the need to adding antioxidant, prepare by adopting certain technical process and freeze-drying curve, considerably reduce the dissolution time in preparation process, product moisture content is low, impurity content is low, and redissolves rapidly, improves product quality and stability.
Detailed description of the invention
Below by specific embodiment, the present invention is described, below in an example, the various process and methods do not described in detail are conventional methods as known in the art.Should correct understanding: embodiments of the invention are to illustrate that the present invention makes, instead of limitation of the present invention, so also belong to protection scope of the present invention to simple transformation of the present invention under method prerequisite of 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.
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.
embodiment 1:
Prescription
| Bortezomib | 100mg |
| Mannitol | 1000mg |
| The tert-butyl alcohol | 20g |
| Water for injection | Be settled to 100ml |
Preparation technology:
Take the tert-butyl alcohol 20g meeting injection stage requirement of 40 DEG C, add bortezomib 100mg, stir and make the two mix homogeneously, obtain the t-butanol solution containing bortezomib, in above-mentioned solution, add 1000mg mannitol, be uniformly mixed, obtain mixing suspension; Vaporific for mixing suspension spraying in liquid nitrogen is formed freezing microgranule, 90ml is injected water in freezing microgranule, stir about 10min under 5 DEG C of conditions, principal agent dissolves completely, and supplementary water injection is to full dose, and sampling detects intermediate, after intermediate is qualified, fill, is cooled to-40 DEG C of pre-freezes by fill sample, keeps 1 hour; Be warming up to-20 DEG C, be incubated 2 hours, then be cooled to-45 DEG C of insulations 3 hours; Open cold-trap, open vacuum; Within 6 hours, be warming up to-30 DEG C, then keep 30 hours; Within 1 hour, be warming up to 5 DEG C, then keep 4 hours; Within 10 minutes, be warming up to 35 DEG C, then keep 6 hours, obtain final lyophilizing finished product.
Finished product detects through HPLC, content 99.6%, and total impurities is 0.25%, and maximum list is mixed 0.06%.
embodiment 2:
Prescription
| Bortezomib | 200mg |
| Mannitol | 2000mg |
| The tert-butyl alcohol | 40g |
| Water for injection | Be settled to 100ml |
Preparation technology:
Take the tert-butyl alcohol 42g meeting injection stage requirement of 25 DEG C, add bortezomib 200mg, stir and make the two mix homogeneously, obtain the t-butanol solution containing bortezomib, in above-mentioned solution, add 2000mg mannitol, be uniformly mixed, obtain mixing suspension; Vaporific for mixing suspension spraying in liquid nitrogen is formed freezing microgranule, 90ml is injected water in freezing microgranule, stir about 8min under 25 DEG C of conditions, principal agent dissolves completely, and supplementary water injection is to full dose, and sampling detects intermediate, after intermediate is qualified, fill, is cooled to-45 DEG C of pre-freezes by fill sample, keeps 3 hours; Be warming up to-25 DEG C, be incubated 3 hours, then be cooled to-40 DEG C of insulations 3 hours; Open cold-trap, open vacuum; Within 8 hours, will-25 DEG C be warming up to, then keep 10 hours; Within 5 hours, be warming up to-5 DEG C, then keep 8 hours; Within 2 minutes, be warming up to 25 DEG C, then keep 10 hours, obtain final lyophilizing finished product.
Finished product detects through HPLC, content 101.2%, and total impurities is 0.17%, maximum list assorted 0.04%.
embodiment 3:
Prescription
| Bortezomib | 175mg |
| Mannitol | 1750mg |
| The tert-butyl alcohol | 33g |
| Water for injection | Be settled to 100ml |
Preparation technology:
Take the tert-butyl alcohol 33g meeting injection stage requirement of 30 DEG C, add bortezomib 175mg, mix homogeneously, obtain the t-butanol solution containing bortezomib, in above-mentioned solution, add 150mgg mannitol, be uniformly mixed, obtain mixing suspension; Vaporific for mixing suspension spraying in liquid nitrogen is formed freezing microgranule, 90ml is injected water in freezing microgranule, stir about 10min under 25 DEG C of conditions, principal agent dissolves completely, and supplementary water injection is to full dose, and sampling detects intermediate, after intermediate is qualified, fill, is cooled to-50 DEG C of pre-freezes by fill sample, keeps 2 hours; Be warming up to-20 DEG C, be incubated 3 hours, then be cooled to-50 DEG C of insulations 2 hours; Open cold-trap, open vacuum; Within 8 hours, be warming up to-35 DEG C, then keep 25 hours; Within 5 hours, be warming up to 0 DEG C, then keep 6 hours; Within 5 minutes, be warming up to 40 DEG C, then keep 3 hours, obtain final lyophilizing finished product.
Finished product detects through HPLC, content 100.4%, and total impurities is 0.20%, maximum list assorted 0.04%
embodiment 4:
Prescription
| Bortezomib | 200mg |
| Mannitol | 1000mg |
| The tert-butyl alcohol | 33g |
| Water for injection | Be settled to 100ml |
Preparation technology:
Take the tert-butyl alcohol 33g meeting injection stage requirement of 35 DEG C, add bortezomib 200mg, mix homogeneously, obtain the t-butanol solution containing bortezomib, in above-mentioned solution, add 1000mg mannitol, be uniformly mixed, obtain mixing suspension; Vaporific for mixing suspension spraying in liquid nitrogen is formed freezing microgranule, 90ml is injected water in freezing microgranule, stir about 7min under 20 DEG C of conditions, principal agent dissolves completely, and supplementary water injection is to full dose, and sampling detects intermediate, after intermediate is qualified, fill, is cooled to-45 DEG C of pre-freezes by fill sample, keeps 3 hours; Be warming up to-25 DEG C, be incubated 3 hours, then be cooled to-40 DEG C of insulations 2 hours; Open cold-trap, open vacuum; Within 8 hours, be warming up to-25 DEG C, then keep 30 hours; Within 1 hour, be warming up to-5 DEG C, then keep 3 hours; Within 1 minute, be warming up to 30 DEG C, then keep 6 hours, obtain final lyophilizing finished product.
Finished product detects through HPLC, content 99.8%, and total impurities is 0.22%, maximum list assorted 0.06%.
embodiment 5:
Prescription
| Bortezomib | 175mg |
| Mannitol | 2000mg |
| The tert-butyl alcohol | 25g |
| Water for injection | Be settled to 100ml |
Preparation technology:
Take the tert-butyl alcohol 25g meeting injection stage requirement of 35 DEG C, add bortezomib 175mg, mix homogeneously, obtain the t-butanol solution containing bortezomib, in above-mentioned solution, add 1750mg mannitol, be uniformly mixed, obtain suspension; Vaporific for suspension spraying in liquid nitrogen is formed freezing microgranule, 90ml is injected water in freezing microgranule, stir about 5min under 5 DEG C of conditions, principal agent dissolves completely, and supplementary water injection is to full dose, and sampling detects intermediate, after intermediate is qualified, fill, is cooled to-40 DEG C of pre-freezes by fill sample, keeps 1 hour; Be warming up to-15 DEG C, be incubated 2 hours, then be cooled to-45 DEG C of insulations 3 hours; Open cold-trap, open vacuum; Within 4 hours, be warming up to-25 DEG C, then keep 20 hours; Within 5 hours, be warming up to 0 DEG C, then keep 6 hours; Within 5 minutes, be warming up to 35 DEG C, then keep 6 hours, obtain final lyophilizing finished product.
Finished product detects through HPLC, content 99.7%, and total impurities is 0.28%, maximum list assorted 0.07%.
reference examples 1
Prescription:
| Bortezomib | 175mg |
| Mannitol | 1750mg |
| The tert-butyl alcohol | 33g |
| Water for injection | Be settled to 100ml |
Preparation technology's (embodiment 1 with reference to US6713446):
Taking 175mg bortezomib adds in the tert-butyl alcohol of 33g, and heated sealed to 45 DEG C, is stirred to and dissolves completely, and moisturizing, to full dose, adds the mannitol of 1750mg, stirring and dissolving, mixed solution aseptic filtration, fill lyophilizing.
Experimentation and result: 45 DEG C be stirred to dissolve completely need at least 30min, more than 40min time solution just clear and bright, liquid preparation time is longer.
Sample size 99.1%, always mixes 0.69%, maximum list assorted 0.15%.
reference examples 2
Prescription:
| Bortezomib | 175mg |
| Mannitol | 1750mg |
| Sodium sulfite | 35mg |
| Water for injection | Be settled to 100ml |
Preparation technology's (embodiment 1 with reference to CN102784114A):
Take the bortezomib of recipe quantity, mannitol and sodium sulfite, mixed grinding 8 minutes, injects and uses water 80ml, is stirred to whole dissolving, adds 135mg needle-use activated carbon, stirs 15 minutes, and decarburization is filtered.Filtrate benefit injects water to 100ml, stirs, and regulates pH to 6.0. Pharmaceutical through 0.22 μm of microporous filter membrane aseptic filtration with 1mol/L sodium hydroxide solution, fill is in cillin bottle, false add plug, puts into freeze dryer lyophilizing, obtains finished product (freeze-drying curve is as CN102784114A embodiment 1).
Experimentation and result: be stirred to all dissolve need at least 25min, more than 35min time solution just clear and bright, liquid preparation time is longer.
Sample size 99.4%, always mixes 1.05%, maximum list assorted 0.18%.
reference examples 3
Prescription:
| Bortezomib | 175mg |
| Mannitol | 1750mg |
| Sodium sulfite | 35mg |
| The tert-butyl alcohol | 33g |
| Water for injection | Be settled to 100ml |
Preparation technology's (embodiment 1 with reference to CN102784114A):
Take the bortezomib of recipe quantity, mannitol and sodium sulfite, mixed grinding 8 minutes, abrasive material adds in the tert-butyl alcohol of recipe quantity, is stirred to whole dissolving, adds 135mg needle-use activated carbon, stirs 15 minutes, and decarburization is filtered.Filtrate benefit injects water to 100ml, stirs, and regulates pH to 6.0. Pharmaceutical through 0.22 μm of microporous filter membrane aseptic filtration with 1mol/L sodium hydroxide solution, fill is in cillin bottle, false add plug, puts into freeze dryer lyophilizing, obtains finished product (freeze-drying curve is as CN102784114A embodiment 1).
Experimentation and result: be stirred to all dissolve need at least 15min, more than 20min time solution just clear and bright, liquid preparation time is longer.
Sample size 99.5%, always mixes 0.82%, maximum list assorted 0.16%.
embodiment 6 freeze-drying prods character observation
To each embodiment and reference examples product, detect probation moisture, product appearance respectively, dissolve with 3.5ml sodium chloride injection, record dissolves required time completely, and detects the impurity content after dissolving completely, the results are shown in Table 1:
Table 1: each example product investigates result
| Investigation project | Product appearance | Moisture | The redissolution time |
| Embodiment 1 | White chunks or loose powder | 0.68% | 21 seconds |
| Embodiment 2 | White chunks or loose powder | 1.12% | 23 seconds |
| Embodiment 3 | White chunks or loose powder | 0.75% | 19 seconds |
| Embodiment 4 | White chunks or loose powder | 0.81% | 24 seconds |
| Embodiment 5 | White chunks or loose powder | 0.88% | 25 seconds |
| Reference examples 1 | White particle sprills | 0.84% | 85 seconds |
| Reference examples 2 | White chunks thing | 1.89% | 40 seconds |
| Reference examples 3 | White chunks thing | 1.78% | 35 seconds |
embodiment 7 study on the stability
Prepare lyophilizing finished product by the preparation technology of various embodiments of the present invention and reference examples, the sample of preparation is carried out 40 DEG C and accelerate setting-out contrast investigation, measure and record its impurity and content, concrete outcome is in table 2:
Show 2:40 DEG C to accelerate to investigate result
Learnt by the study on the stability result of embodiment and reference examples product, product provided by the invention, not only 0 day quality is apparently higher than reference examples sample, and under 40 DEG C of conditions, accelerate placement 6 months, related substance still remains at low levels.Therefore can illustrate that bortezomib medical composition quality provided by the invention is higher, stability better, there is higher clinical and using value.
The above is the specific embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
Claims (3)
1. bortezomib freeze-dried composition, is characterized in that: described bortezomib freeze-dried composition is by bortezomib, manna
The mixed solution of alcohol, the tert-butyl alcohol sprays in liquid nitrogen and forms freezing microgranule, is then dissolved in water for injection, through the freeze-dried composition that lyophilization obtains; Concrete steps are as follows:
(1) first bortezomib is dissolved in the tert-butyl alcohol, after mix homogeneously, add mannitol, and be mixed to get the mixed solution of bortezomib, mannitol, the tert-butyl alcohol further;
(2) mixed solution obtained in step (1) is sprayed in liquid nitrogen, obtain the freezing microgranule of mixed solution of bortezomib, mannitol, the tert-butyl alcohol;
(3) the freezing microgranule of mixed solution obtained in step (2) is dissolved in water for injection and must treats Solutions in Freeze-drying, and fill, lyophilizing, obtain bortezomib freeze-dried composition;
Described step of freeze drying freeze-drying curve is: after the goods inlet that fill obtains, and is cooled to-45 ± 5 DEG C of pre-freezes, and maintenance 1 ~ 3 is little
Time; Be warming up to-20 ± 5 DEG C, be incubated 2 ~ 3 hours, then be cooled to-45 ± 5 DEG C of insulations 1 ~ 3 hour; Open cold-trap, open vacuum; Baffle temperature is warming up to-25 ~-35 DEG C, then keeps 5 ~ 10 hours; Baffle temperature is warming up to-5 ~ 5 DEG C, then keeps 3-5 hour; Again baffle temperature is warming up to 25 ~ 40 DEG C, then keeps 3-5 hour;
Each milliliter treats that the ratio of bortezomib in Solutions in Freeze-drying, mannitol, the tert-butyl alcohol is:
Bortezomib 1 ~ 2mg;
Mannitol 10 ~ 20mg;
The tert-butyl alcohol 200 ~ 400mg;
Surplus is water for injection.
2. bortezomib freeze-dried composition as claimed in claim 1, it is characterized in that, concrete steps are as follows: boron replaces by (1)
Assistant rice adds in the tert-butyl alcohol of 25 ~ 40 DEG C and dissolves, and after mix homogeneously, obtains the t-butanol solution containing bortezomib; Then in the t-butanol solution of bortezomib, add mannitol, be uniformly mixed, obtain the mixed solution of bortezomib, mannitol, the tert-butyl alcohol;
(2) mixed solution obtained in step (1) is sprayed in liquid nitrogen with mist, obtain the freezing microgranule of mixed solution of bortezomib, mannitol, the tert-butyl alcohol;
(3) by the freezing particle dissolution of mixed solution that obtains in step (2) in water for injection, stir under 5 ~ 25 DEG C of conditions
5 ~ 10min, dissolves completely to principal agent, adds water for injection to full dose and must treat Solutions in Freeze-drying, fill, according to freeze-drying curve lyophilizing, obtains bortezomib freeze-dried composition.
3. a preparation method for bortezomib freeze-dried composition, is characterized in that step is as follows:
(1) first bortezomib is dissolved in the tert-butyl alcohol, after mix homogeneously, add mannitol, and be mixed to get the mixed solution of bortezomib, mannitol, the tert-butyl alcohol further;
(2) mixed solution obtained in step (1) is sprayed in liquid nitrogen, obtain the freezing microgranule of mixed solution of bortezomib, mannitol, the tert-butyl alcohol;
(3) the freezing microgranule of mixed solution obtained in step (2) is dissolved in water for injection and must treats Solutions in Freeze-drying, and fill, lyophilizing, obtain bortezomib freeze-dried composition;
Described step of freeze drying freeze-drying curve is: after the goods inlet that fill obtains, and is cooled to-45 ± 5 DEG C of pre-freezes, keeps 1 ~ 3 hour; Be warming up to-20 ± 5 DEG C, be incubated 2 ~ 3 hours, then be cooled to-45 ± 5 DEG C of insulations 1 ~ 3 hour; Open cold-trap, open vacuum; Baffle temperature is warming up to-25 ~-35 DEG C, then keeps 5 ~ 10 hours; Baffle temperature is warming up to-5 ~ 5 DEG C, then keeps 3-5 hour; Again baffle temperature is warming up to 25 ~ 40 DEG C, then keeps 3-5 hour;
Each milliliter treats that the ratio of bortezomib in Solutions in Freeze-drying, mannitol, the tert-butyl alcohol is:
Bortezomib 1 ~ 2mg;
Mannitol 10 ~ 20mg;
The tert-butyl alcohol 200 ~ 400mg;
Surplus is water for injection.
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| 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 |
| 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 |
| JP7423028B2 (en) * | 2017-11-01 | 2024-01-29 | 日医工岐阜工場株式会社 | Lyophilized pharmaceutical composition containing bortezomib |
| 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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| 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 |
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| 微粉化技术提高水不溶性药物溶解度;陈鹏等;《化学通报》;20071231(第10期);766-771页 * |
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