CN109364030A - A kind of injection bortezomib freeze-dried powder and its preparation process - Google Patents
A kind of injection bortezomib freeze-dried powder and its preparation process Download PDFInfo
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- CN109364030A CN109364030A CN201811641711.1A CN201811641711A CN109364030A CN 109364030 A CN109364030 A CN 109364030A CN 201811641711 A CN201811641711 A CN 201811641711A CN 109364030 A CN109364030 A CN 109364030A
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- China
- Prior art keywords
- bortezomib
- acetonitrile
- freeze
- injection
- dried powder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention provides a kind of injection bortezomib freeze-dried powders, by weight, including following raw material: 0.1-0.3 parts of bortezomib, 3-10 parts of acetonitrile, 1-3 parts of mannitol and 87-94 parts of water.Bulk pharmaceutical chemicals are first completely dissolved in acetonitrile-aqueous solution by preparation process, it is put into auxiliary material mannitol solution again, bortezomib comes into full contact under dissolved state with mannitol solution, it is rapidly formed borate, it solves the problems, such as that bortezomib dissolution of raw material is poor under the premise of consumption of organic solvent is small, improves the stability of intermediate products and preparation.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of injection bortezomib freeze-dried powder.
Background technique
Bortezomib is a kind of new type antineoplastic medicine, trade name Bortezomib (Velcade), by U.S.'s Millennium pharmacy
Company's research and development.The solubility of bortezomib bulk pharmaceutical chemicals in water only has 0.52mg/ml, and the solubility of bulk pharmaceutical chemicals is lower, Bu Nengda
To prescription dosing concentration.Therefore it needs using cosolvent appropriate, and obtain the finished dosage form having good stability on this basis.
Chinese patent CN102784114, a kind of bortezomib freeze-dried powder and preparation method thereof, by by bortezomib with
Excipient mixed grinding makes the two come into full contact with mixing, promotes the dissolution of raw material bortezomib, while antioxidant is added and increases it surely
It is qualitative.Chinese patent CN103142509, composition include bortezomib and amino acid, improve the dissolubility of bortezomib and steady
It is qualitative.Bortezomib, mannitol, the tert-butyl alcohol are sprayed into liquid nitrogen with mist, are formed mixed by Chinese patent CN103446068
It closes solution and freezes particle, overcome the difficult problem of bortezomib dissolution.Chinese patent CN103070835, using addition sweet dew
The pure and mild tert-butyl alcohol improves the solubility of bortezomib.
Although the above patent solves the problems of dissolution of raw material, but still Shortcomings: operating process is many and diverse, when dissolution of raw material
Between it is longer, intermediate products and finished product stability are poor, and organic solvent additive amount is big, and product qualification rate is caused to reduce.
Summary of the invention
In view of the above technical problems, the present invention provides a kind of injection bortezomib freeze-dried powders, solve boron for assistant
The problem of rice dissolution of raw material difference, improves the stability of intermediate products and preparation.
Technical scheme is as follows:
A kind of injection bortezomib freeze-dried powder, by weight, including following raw material:
The present invention also provides the preparation processes of injection bortezomib freeze-dried powder, comprising the following steps:
A, bortezomib is added in 5~30 DEG C of acetonitrile-aqueous solution, stirring clarification obtains material solution；
B, mannitol is taken to be added in 5~30 DEG C of water for injection, stirring clarification obtains auxiliary material solution；
C, material solution is added in auxiliary material solution, 5~10min is stirred at 5~30 DEG C, adds 5~30 DEG C of note
It penetrates with water to 100% recipe quantity, stirs evenly；
D, medical fluid is filling through filtering, and freeze-drying obtains finished product.
Mannitol is applied directly in raw material medicine solution not dissolve.There are esterification, the two exists for mannitol and bulk pharmaceutical chemicals
It is contacted under dissolved state more sufficiently, the speed of esterification can be greatly improved.
Preferably, the step B, volume ratio of the acetonitrile in acetonitrile-aqueous solution are 30-50%.Second under the ratio
The solubility of nitrile-aqueous solution, bortezomib is best, and dissolution time is most short, and intermediate products and finished product stability are best.
Preferably, the material solution account for mixing after medical fluid volume ratio be 10-20%.
It can guarantee that raw material is completely dissolved under this ratio.Material solution ratio is bigger, and intermediate products stability is better；If but
Material solution ratio is greater than 20%, is unfavorable for being lyophilized.
The beneficial effects of the present invention are:
1, the present invention dissolves bortezomib using the acetonitrile-aqueous solution for preparing 30-50% at 5~30 DEG C, and by excellent
Change acetonitrile additional amount and the control with liquid technique, improves the solubility of bortezomib raw material, reduce the dissolution of bortezomib
Time improves the stability of intermediate products.
2, the present invention selects acetonitrile-aqueous solution as solvent, so that bulk pharmaceutical chemicals are after completely dissolution, then puts into auxiliary material sweet dew
In alcoholic solution, bortezomib is come into full contact under dissolved state with mannitol solution, can more be rapidly formed borate, into
One step ensure that the solubility of bortezomib and the stability of intermediate products.
3, loosely, in process of vacuum drying, moisture and organic solvent are or not injection bortezomib freeze-drying muffin itself
It is disconnected to be removed, the disturbance of sample muffin internal gas flow is caused, organic solvent usage amount more large disturbances are more violent, are easy to keep muffin broken
It is broken, spray bottle.The present invention improves the solubility of bortezomib and the stability of intermediate products by the control with liquid technique, reduces
Organic solvent usage amount, the disturbance of muffin internal gas flow is small, and muffin is non-breakable and spray bottle, product qualification rate are high.
Specific embodiment
In order to it is clearer, explain purpose of the present invention technical solution in detail, below by related embodiment to this hair
It is bright to be described further.Following embodiment is only to illustrate implementation method of the invention, does not limit protection of the invention
Range.
Embodiment 1
A kind of injection bortezomib freeze-dried powder, by weight, including following raw material:
Embodiment 2
A kind of injection bortezomib freeze-dried powder, by weight, including following raw material:
Embodiment 3
A kind of injection bortezomib freeze-dried powder, by weight, including following raw material:
Embodiment 4
The preparation process of injection bortezomib freeze-dried powder of the present invention, comprising the following steps:
A, bortezomib is added in 5 DEG C of acetonitrile-aqueous solution, stirring clarification obtains material solution；
B, mannitol is taken to be added in 5 DEG C of water for injection, stirring clarification obtains auxiliary material solution；
C, material solution is added in auxiliary material solution, stirs 10min at 5 DEG C, add 5 DEG C of water for injection extremely
100% recipe quantity, stirs evenly；
D, medical fluid is filling through filtering, and freeze-drying obtains finished product.
Volume ratio of the acetonitrile in acetonitrile-aqueous solution is 30%.
The material solution account for mixing after medical fluid volume ratio be 10%, auxiliary material solution account for mixing after medical fluid volume ratio
Example is 90%.
Embodiment 5
The preparation process of injection bortezomib freeze-dried powder of the present invention, comprising the following steps:
A, bortezomib is added in 5~30 DEG C of acetonitrile-aqueous solution, stirring clarification obtains material solution；
B, mannitol is taken to be added in 5~30 DEG C of water for injection, stirring clarification obtains auxiliary material solution；
C, material solution is added in auxiliary material solution, 5~10min is stirred at 5~30 DEG C, adds 5~30 DEG C of note
It penetrates with water to 100% recipe quantity, stirs evenly；
D, medical fluid is filling through filtering, and freeze-drying obtains finished product.
Volume ratio of the acetonitrile in acetonitrile-aqueous solution is 40%.
The material solution account for mixing after medical fluid volume ratio be 15%, auxiliary material solution account for mixing after medical fluid volume ratio
Example is 85%.
Embodiment 6
The preparation process of injection bortezomib freeze-dried powder of the present invention, comprising the following steps:
A, bortezomib is added in 5~30 DEG C of acetonitrile-aqueous solution, stirring clarification obtains material solution；
B, mannitol is taken to be added in 5~30 DEG C of water for injection, stirring clarification obtains auxiliary material solution；
C, material solution is added in auxiliary material solution, 5~10min is stirred at 5~30 DEG C, adds 5~30 DEG C of note
It penetrates with water to 100% recipe quantity, stirs evenly；
D, medical fluid is filling through filtering, and freeze-drying obtains finished product.
Volume ratio of the acetonitrile in acetonitrile-aqueous solution is 50%.
The material solution account for mixing after medical fluid volume ratio be 20%, auxiliary material solution account for mixing after medical fluid volume ratio
Example is 80%.
Bortezomib is insoluble in water, therefore organic solvent is added in medical fluid prescription to increase bortezomib solubility.Experiment choosing
The organic solvent system taken is respectively ethyl alcohol, the tert-butyl alcohol, acetonitrile and isopropanol, i.e. selection alcohol-water；Tertiary butanol and water；Acetonitrile-
Water；Four groups of mixed systems of isopropanol-water detect the dissolution situation and stability of bortezomib at room temperature respectively.
1 bortezomib of table solubility and dissolution time in different organic phase-water
Stability of 2 bortezomib of table in different organic phase-water
As it can be seen that dissolution and stability of the bortezomib in acetonitrile-aqueous solution system be all it is optimal, further experiment obtains
Out, there is preferable solubility using the acetonitrile-water system of 30-50%, be suitable for present invention process, most preferably 50%
Acetonitrile-aqueous solution system, solubility is best, and dissolution time is most short, and intermediate products and finished product stability are best.
Saturation solubility of 3 bortezomib of table in acetonitrile-water system at room temperature
| Composition | Saturation solubility |
| 30% acetonitrile-water | 6.72mg/mL |
| 40% acetonitrile-water | 15.47mg/mL |
| 50% acetonitrile-water | 27.34mg/mL |
After the product that present invention process is obtained is placed 3 months, each achievement data, commercially available bortezomib freeze-dried powder are detected
As reference preparation, testing result is shown in Table 4.By the control and optimization to liquid technique is matched, the stability of product of the present invention is obtained
Better than reference preparation.
The Detection of Stability of 4 bortezomib freeze-dried powder long term storage of table
The present invention also controls acetonitrile residual solvent usage amount by the adjustment to lyophilization cycle, and lyophilized technique includes following
Step:
A, feeding: the freeze dryer that feeding to plate layer temperature is 4~6 DEG C；
B, it freezes: 4~6 DEG C of room temperature of freeze-drying, 10~15min of product pre-freeze；
- 55~-50 DEG C are cooled to, 3~4h of product pre-freeze；
- 12~-8 DEG C are warming up to, 5~6h of product pre-freeze；
- 55~-50 DEG C are cooled to, 3~4h of product pre-freeze；
C, lyophilization: adjusting the temperature to -50~-40 DEG C, under vacuum condition, keeps 10~12h；
- 2~2 DEG C, under vacuum condition are warming up to, 10~12h is kept；
D, desorbing and drying: adjusting the temperature to 35~45 DEG C, under vacuum condition, keeps 5~6h.
Since the fusing point of acetonitrile is lower, acetonitrile is moved to the upper layer of ice crystal after melting, and reduces in sublimation process resistance simultaneously
It avoids acetonitrile and is wrapped in crystal and can not extract out, the effective residual for controlling organic solvent；Meanwhile annealing also changes crystalline substance
The size and form of body effectively raise drying efficiency, improve the outer of finished product so that the gap formed after dry is more uniform
See the stability with finished product；During lyophilization, since the saturated vapour pressure of acetonitrile is larger, lower drying temperature is first used
Most acetonitrile is removed, then carries out staged heating and adjustment vacuum degree, the rate of sublimation of held stationary is effective less
The disturbance of muffin internal gas flow, muffin is non-breakable and spray bottle.
Preferably, the vacuum degree of the lyophilization is 100 μ bar, and the vacuum degree of desorbing and drying is 200 μ bar.
Preferably, the freezing step is cooled to -55~-50 DEG C in 100~120min, rises in 100~120min
Temperature is cooled to -55~-50 DEG C to -12~-8 DEG C in 100~120min.
Preferably, the lyophilization is warming up to -50~-40 DEG C in 25~35min, -2~2 is warming up in 5-6h
℃。
Preferably, the desorbing and drying are warming up to 35~45 DEG C in 100~120min.
Lyophilized technique of the invention increases annealing steps, and finished product molding is more preferable, improves the stability of freeze-drying finished product.
Meanwhile additional amount, the temperature of annealing process and lyophilization cycle and the stair like control strategy of vacuum degree by controlling acetonitrile, further
Solve the problems, such as that spray bottle, qualification rate are higher.
A specific embodiment of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.
Claims (4)
1. a kind of injection bortezomib freeze-dried powder, which is characterized in that by weight, including following raw material:
2. the preparation process of injection bortezomib freeze-dried powder according to claim 1, which is characterized in that including following step
It is rapid:
A, bortezomib is added in 5~30 DEG C of acetonitrile-aqueous solution, stirring clarification obtains material solution；
B, mannitol is taken to be added in 5~30 DEG C of water for injection, stirring clarification obtains auxiliary material solution；
C, material solution is added in auxiliary material solution, 5~10min is stirred at 5~30 DEG C, adds 5~30 DEG C of injection
Water is stirred evenly to 100% recipe quantity；
D, medical fluid is filling through filtering, and freeze-drying obtains finished product.
3. the preparation process of injection bortezomib freeze-dried powder according to claim 2, which is characterized in that the step A,
Volume ratio of the acetonitrile in acetonitrile-aqueous solution is 30-50%.
4. the preparation process of injection bortezomib freeze-dried powder according to claim 2, which is characterized in that the step C,
Material solution account for mixing after medical fluid volume ratio be 10-20%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811641711.1A CN109364030B (en) | 2018-12-29 | 2018-12-29 | Bortezomib freeze-dried powder injection for injection and preparation process thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811641711.1A CN109364030B (en) | 2018-12-29 | 2018-12-29 | Bortezomib freeze-dried powder injection for injection and preparation process thereof |
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| Publication Number | Publication Date |
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| CN109364030A true CN109364030A (en) | 2019-02-22 |
| CN109364030B CN109364030B (en) | 2020-05-05 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110314221A (en) * | 2019-06-29 | 2019-10-11 | 四川汇宇制药有限公司 | A kind of lyophilized technique of injection bortezomib |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108078931A (en) * | 2017-12-12 | 2018-05-29 | 健进制药有限公司 | A kind of bendamustine hydrochloride freeze-dried powder pin and preparation method thereof |
-
2018
- 2018-12-29 CN CN201811641711.1A patent/CN109364030B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108078931A (en) * | 2017-12-12 | 2018-05-29 | 健进制药有限公司 | A kind of bendamustine hydrochloride freeze-dried powder pin and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110314221A (en) * | 2019-06-29 | 2019-10-11 | 四川汇宇制药有限公司 | A kind of lyophilized technique of injection bortezomib |
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| CN109364030B (en) | 2020-05-05 |
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