CN106265536B - Bortezomib pharmaceutical composition and preparation method thereof - Google Patents
Bortezomib pharmaceutical composition and preparation method thereof Download PDFInfo
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
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Abstract
The present invention relates to a kind of pharmaceutical compositions containing bortezomib and preparation method thereof.Pharmaceutical composition of the present invention includes bortezomib, mannitol, meglumine and histidine, substantially increases bortezomib solubility, shortens the drug solution preparing time, stability is more excellent.Present invention process is simple and easy, is suitble to industrialized production.
Description
Technical field
The invention belongs to field of medicine preparations, and in particular to one kind pharmaceutical composition containing bortezomib and preparation method thereof.
Background technique
Bortezomib (Bortezomib), chemical name are [(1R)-3- methyl-1-[[(2S)-1- oxygen-3- phenyl-2-
[(pyrazinecarboxamide) amino] propyl] amino] butyl] boric acid, trade name Bortezomib (Velcade), by U.S. Millennium
The research and development of Pharmaceuticals company.Bortezomib be in mammalian cell 26S proteasome chymotrypsinlike activity can
Retroactive inhibition agent, to multiple types cancer cell have cytotoxicity, at present list dosage form be freeze-dried powder, specification be 1mg and
3.5mg is mainly used for the treatment of multiple bone marrow cancer.
Patent CN103212055B is related to a kind of pharmaceutical composition and preparation method thereof of bortezomib.Invention pharmaceutical composition
Contain bortezomib, the tert-butyl alcohol, sodium chloride and excipient in object, wherein the bortezomib, the tert-butyl alcohol, sodium chloride and figuration
The mass ratio of agent is 1:0.5:1~5:5~20.The tert-butyl alcohol can be such that bortezomib quickly dissolves, so as to more with mannitol etc.
First alcohols excipient reacts to form more stable borate, and then solves bortezomib freeze drying powder injection stability itself and ask
Topic；And the addition of sodium chloride ensure that its normal physiology, biochemical activity and function in vivo.But bortezomib and mannitol
It is formed and still needs to longer time with Nitranitol.
Patent CN102784114A is sufficiently mixed the two by bortezomib and excipient mixed grinding, and injection is added
After water, continuing stirring then has to whole dissolutions to avoid that the methods of heating and ultrasound is used to dissolve bortezomib
Effect avoids the increase of impurity during making up a prescription.
Lyophilized preparation is made using bortezomib and tromethamine in patent CN102292086B, and tromethamine, which has, to be helped
Molten effect, but tromethamine sheet need to be added acid and be adjusted to pH range human-acceptable as alkalinity.
The sample of above-mentioned prescription and technique preparation, there are still following problems: 1. bortezomib is oxidizable, in process for preparation easily
Oxidation reaction occurs, leads to related substance rapid growth；2. bortezomib water solubility is poor, forming Nitranitol with mannitol is needed
The long period is wanted, causing setup time to extend, 3. bortezomib is more sensitive to moisture, and higher moisture in finished product, which is lyophilized, to be influenced
Other indexs of product.
Therefore, it is necessary to developing one kind can be improved bortezomib dissolution time, shorten the drug solution preparing time composition and
The stability of bortezomib can be improved in preparation method, the composition and preparation method, and simple for process, is suitble to industrialization
Production.
Summary of the invention
In order to solve the above-mentioned technical problems, the present invention provides a kind of pharmaceutical composition containing bortezomib and its preparation sides
Method.The first purpose of the invention is to provide a kind of raising bortezomib dissolution time, shorten the drug solution preparing time and can
Improve the bortezomib pharmaceutical composition and preparation method thereof of medicine stability；Another object of the present invention is to provide a kind of technique
It is simple and easy, it is suitble to the preparation method of the pharmaceutical composition containing bortezomib of industrialized production.
Specifically, the present invention is mainly implemented by following scheme:
The present invention provides a kind of stable pharmaceutical composition, the composition includes the bortezomib of effective dose, branch
Support agent mannitol, cosolvent meglumine or or its pharmaceutically acceptable pharmaceutic adjuvant.
Preferably, the weight ratio of the bortezomib and mannitol is 1:5~10.
Preferably, the weight ratio of the bortezomib and meglumine is 1:0.5~0.8, preferably 1:0.5~0.65.
Preferably, the bortezomib pharmaceutical composition also includes stabilizer, wherein stabilizer is selected from histidine, paddy ammonia
Acid or glutathione.
Preferably, the weight ratio of the bortezomib and stabilizer be 1:0.1~1, preferably 0.5~1.
Preferably, in the bortezomib pharmaceutical composition, the weight percent of each component is as follows:
Preferably, in the bortezomib pharmaceutical composition, the weight percent of each component is as follows:
Preferably, in the bortezomib pharmaceutical composition, the weight percent of each component is as follows:
On the other hand, the present invention also provides the preparation methods of bortezomib pharmaceutical composition, comprising the following steps:
(1) bortezomib t-butanol solution is added in aqueous megiumine solution water, stirring to dissolution；
(2) mannitol is added into step (1)；
(3) optionally, stabilizer is added；
(4) water of recipe quantity is added, filtering is filling, freeze-drying.
Preferably, comprising the following steps:
(1) bortezomib t-butanol solution is added in aqueous megiumine solution water, stirring to dissolution；
(2) water for injection for injecting water to 80% recipe quantity is mended, to mannitol is added in step (1), is stirred to molten
Solution；
(3) optionally, stabilizer is added；
(4) water for injection for injecting water to 100% recipe quantity is mended, stirs evenly, obtains intermediate medical fluid；
(5) intermediate medical fluid filters 0.2 μm of filters pressing filter membrane through nitrogen pressure, and dispenses into injection bottle, is freeze-dried, pressure
Plug, rolls lid, packs, obtains bortezomib freeze drying powder injection.
Preferably, the freezing dry process is as follows:
The pre-freeze stage: -45 DEG C keep the temperature 2~4 hours, and -25 DEG C keep the temperature 3~6 hours；
Primary distillation: -30 DEG C are kept for 8~12 hours, and -20 DEG C are kept for 20~26 hours, and -10 DEG C are kept for 3~6 hours, 0 DEG C
It is kept for 4 hours；
Redrying: 30 DEG C are kept for 4~6 hours.
The present invention realizes bortezomib by the way that meglumine is added and by the weight ratio of control bortezomib and meglumine
Quick dissolution；Additionally by the addition that amino acid, the especially histidine such as histidine, glutamic acid or glutathione is added and
The optimization of preparation process substantially increases the stability of the composition of bortezomib.
Specific embodiment
Following embodiment further describes technical solution of the present invention.The embodiment of the present invention is done in order to illustrate the present invention
Out, rather than limiting the invention, thus modify under the premise of method of the invention to technical solution of the present invention or
Equivalent replacement all belongs to the scope of protection of the present invention.
Embodiment 1
Preparation method:
Under room temperature, 1.0g bortezomib is dissolved in the 50mL tert-butyl alcohol, and 0.5g meglumine is dissolved in 100mL water for injection, delays
Slow to be added into bortezomib t-butanol solution, benefit injects water to 800ml, and mannitol 6.0g is added, and stirring is mended to dissolving
1000ml is injected water to, intermediate medical fluid is obtained；Intermediate medical fluid filters 0.2 μm of filters pressing filter membrane through nitrogen pressure, and dispenses 1ml
Into injection bottle, lid is rolled in freeze-drying, tamponade, packs, obtains freeze drying powder injection.Wherein freezing dry process is as follows: pre-freeze
Stage: -45 DEG C keep the temperature 2.5 hours, and -25 DEG C keep the temperature 3 hours；Primary distillation: -30 DEG C are kept for 11 hours, and -20 DEG C of holdings 25.5 are small
When, -10 DEG C are kept for 4 hours, and 0 DEG C is kept for 4 hours；Redrying: 30 DEG C are kept for 5 hours.
Embodiment 2
Preparation method:
Under room temperature, 1.0g bortezomib is dissolved in the 50mL tert-butyl alcohol, and 0.6g meglumine is dissolved in 100mL water for injection, delays
Slow to be added into bortezomib t-butanol solution, benefit injects water to 800ml, and mannitol 8.0g is added, and stirring is mended to dissolving
1000ml is injected water to, intermediate medical fluid is obtained；Intermediate medical fluid filters 0.2 μm of filters pressing filter membrane through nitrogen pressure, and dispenses 1ml
Into injection bottle, lid is rolled in freeze-drying, tamponade, packs, obtains freeze drying powder injection.Freeze-drying process is lyophilized using embodiment 1 is lower
Technique.
Embodiment 3
Preparation method:
Under room temperature, 1.5g bortezomib is dissolved in the 100mL tert-butyl alcohol, and 0.8g meglumine is dissolved in 150mL water for injection, delays
Slow to be added into bortezomib t-butanol solution, benefit injects water to 800ml, and mannitol 8.0g and 0.2g histidine is added,
To dissolving, benefit injects water to 1000ml for stirring, obtains intermediate medical fluid；Intermediate medical fluid filters 0.2 μm of filters pressing through nitrogen pressure
Filter membrane, and 1ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtains freeze drying powder injection.Freeze-drying process is adopted
With the lower lyophilized technique of embodiment 1.
Embodiment 4
Preparation method:
Under room temperature, 1.5g bortezomib is dissolved in the 100mL tert-butyl alcohol, and 0.8g meglumine is dissolved in 150mL water for injection, delays
Slow to be added into bortezomib t-butanol solution, benefit injects water to 800ml, and mannitol 8.0g and 0.7g histidine is added,
To dissolving, benefit injects water to 1000ml for stirring, obtains intermediate medical fluid；Intermediate medical fluid filters 0.2 μm of filters pressing through nitrogen pressure
Filter membrane, and 1ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtains freeze drying powder injection.Freeze-drying process is adopted
With the lower lyophilized technique of embodiment 1.
Embodiment 5
Preparation method:
Under room temperature, 3.5g bortezomib is dissolved in the 200mL tert-butyl alcohol, and 2.1g meglumine is dissolved in 250mL water for injection, delays
Slow to be added into bortezomib t-butanol solution, benefit injects water to 800ml, and mannitol 20.0g and 3.0g histidine is added,
To dissolving, benefit injects water to 1000ml for stirring, obtains intermediate medical fluid；Intermediate medical fluid filters 0.2 μm of filters pressing through nitrogen pressure
Filter membrane, and 1ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtains freeze drying powder injection.Freeze-drying process is adopted
With the lower lyophilized technique of embodiment 1.
Embodiment 6
Preparation method:
Under room temperature, 3.5g bortezomib is dissolved in the 200mL tert-butyl alcohol, and 2.1g meglumine is dissolved in 250mL water for injection, delays
Slow to be added into bortezomib t-butanol solution, benefit injects water to 800ml, and mannitol 22.0g and 3.0g glutamic acid is added,
To dissolving, benefit injects water to 1000ml for stirring, obtains intermediate medical fluid；Intermediate medical fluid filters 0.2 μm of filters pressing through nitrogen pressure
Filter membrane, and 1ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtains freeze drying powder injection.Freeze-drying process is adopted
With the lower lyophilized technique of embodiment 1.
Embodiment 7
Preparation method:
Under room temperature, 3.5g bortezomib is dissolved in the 200mL tert-butyl alcohol, and 1.9g meglumine is dissolved in 250mL water for injection, delays
Slow to be added into bortezomib t-butanol solution, benefit injects water to 800ml, and mannitol 20.0g and 3.0g gluathione is added
Peptide, to dissolving, benefit injects water to 1000ml for stirring, obtains intermediate medical fluid；Intermediate medical fluid filters 0.2 μm of pressure through nitrogen pressure
Filter membrane is filtered, and dispenses 1ml into injection bottle, is freeze-dried, lid is rolled in tamponade, packs, obtains freeze drying powder injection.Freeze-drying process
Using the lower lyophilized technique of embodiment 1.
1 preparation nature of test example is investigated
2 stability of solution of test example is investigated
After sample obtained by embodiment 1-7 is redissolved with 0.9% sodium chloride solution, place 24 hours under room temperature, 2-8
It is placed 72 hours at DEG C, investigates its stability of solution, experimental result is shown in Table 3
By test 2 as can be seen that bortezomib solution of the invention, especially embodiment 3-5 are put at room temperature
Set placed at 24 hours, 2-8 DEG C be within 72 hours it is stable, meet the requirement of injection preparation.
Embodiment 1-7 products obtained therefrom is set 40 DEG C, humidity is placed 6 months under the conditions of being 75%, investigates its stability, is tested
It the results are shown in Table 3
3 stability test result of table
It can be seen that by the above results, embodiment 1-7 bortezomib freeze-dried powder answers that dissolution time is short, moisture is low and is placing
It is basically unchanged in the process；By the way that the addition of stabilizer, especially histidine is added, total miscellaneous and changes of contents is smaller, stability
It is good.
Claims (4)
- It include bortezomib, mannitol and meglumine 1. bortezomib pharmaceutical composition, the bortezomib and mannitol Weight ratio is 1:5~10, and the weight ratio of the bortezomib and meglumine is 1:0.5~0.65, the bortezomib composition It also include stabilizer, the weight ratio of the bortezomib and stabilizer is 1:0.5~1, and the stabilizer is histidine, each component Weight percent it is as follows:Bortezomib 10~15%Mannitol 70~85%Meglumine 5~10%Stabilizer 5~10%.
- 2. the preparation method of bortezomib pharmaceutical composition according to claim 1, comprising the following steps:(1) bortezomib t-butanol solution is added in aqueous megiumine solution water, stirring to dissolution；(2) mannitol is added into step (1)；(3) stabilizer is added；(4) water of recipe quantity is added, filtering is filling, freeze-drying.
- 3. the preparation method of bortezomib pharmaceutical composition according to claim 2, which is characterized in that including following step It is rapid:(1) bortezomib t-butanol solution is added in aqueous megiumine solution water, stirring to dissolution；(2) water for injection for injecting water to 80% recipe quantity is mended, to mannitol is added in step (1), stirring is extremely dissolved；(3) stabilizer is added；(4) water for injection for injecting water to 100% recipe quantity is mended, stirs evenly, obtains intermediate medical fluid；(5) intermediate medical fluid filters 0.2 μm of filters pressing filter membrane through nitrogen pressure, and dispenses into injection bottle, freeze-drying, tamponade, Lid is rolled, packs, obtains bortezomib freeze drying powder injection.
- 4. preparation method according to claim 2, which is characterized in that the freezing dry process is as follows:The pre-freeze stage: -45 DEG C keep the temperature 2 ~ 4 hours, and -25 DEG C keep the temperature 3 ~ 6 hours,Once distillation: -30 DEG C are kept for 8 ~ 12 hours, and -20 DEG C are kept for 20 ~ 26 hours, and -10 DEG C are kept for 3 ~ 6 hours, and 0 DEG C of holding 4 is small When；Redrying: 30 DEG C are kept for 4 ~ 6 hours.
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| CN107260690A (en) * | 2017-06-22 | 2017-10-20 | 江苏豪森药业集团有限公司 | Lyophilized formulations of Decitabine and preparation method thereof |
| JP7423028B2 (en) * | 2017-11-01 | 2024-01-29 | 日医工岐阜工場株式会社 | Lyophilized pharmaceutical composition containing bortezomib |
| CN112741894A (en) * | 2019-10-31 | 2021-05-04 | 江苏恒瑞医药股份有限公司 | Novel echinocandin antifungal agent pharmaceutical composition |
| US11672813B2 (en) * | 2021-09-24 | 2023-06-13 | MAIA Pharmaceuticals, Inc. | Bortezomib compositions |
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|---|---|---|---|---|
| CN101795671A (en) * | 2007-08-21 | 2010-08-04 | 阿尔扎公司 | Liposome compositions for in vivo administration of boronic acid compounds |
| CN102784114A (en) * | 2011-05-14 | 2012-11-21 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder injection and preparation method thereof |
| CN103212055A (en) * | 2013-04-19 | 2013-07-24 | 海南锦瑞制药股份有限公司 | Drug composition of bortezomib and preparation method thereof |
| CN105056205A (en) * | 2015-06-29 | 2015-11-18 | 杭州华东医药集团新药研究院有限公司 | Bortezomib-containing medicinal composition and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101795671A (en) * | 2007-08-21 | 2010-08-04 | 阿尔扎公司 | Liposome compositions for in vivo administration of boronic acid compounds |
| CN102784114A (en) * | 2011-05-14 | 2012-11-21 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder injection and preparation method thereof |
| CN103212055A (en) * | 2013-04-19 | 2013-07-24 | 海南锦瑞制药股份有限公司 | Drug composition of bortezomib and preparation method thereof |
| CN105056205A (en) * | 2015-06-29 | 2015-11-18 | 杭州华东医药集团新药研究院有限公司 | Bortezomib-containing medicinal composition and preparation method thereof |
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