CN104546744B - A kind of injection bortezomib freeze-dried powder and preparation method thereof - Google Patents
A kind of injection bortezomib freeze-dried powder and preparation method thereof Download PDFInfo
- Publication number
- CN104546744B CN104546744B CN201410840518.6A CN201410840518A CN104546744B CN 104546744 B CN104546744 B CN 104546744B CN 201410840518 A CN201410840518 A CN 201410840518A CN 104546744 B CN104546744 B CN 104546744B
- Authority
- CN
- China
- Prior art keywords
- freeze
- bortezomib
- injection
- preparation
- dried powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of medicine preparations, relate to a kind of injection bortezomib freeze-dried powder and preparation method thereof.Described freeze-dried powder comprises the bortezomib of 1 part and the mannitol of 8 10 parts.Described preparation method utilizes homogenizer high-speed revolution shearing to accelerate the dissolution velocity of medicine, solves the problem that active component bortezomib dissolves difficulty, it is to avoid use the organic solvents such as the tert-butyl alcohol to make up a prescription the final products dissolvent residual caused.Of the present invention simple for process, it is suitable for industrialized production, products obtained therefrom no solvent residue.
Description
Technical field
The present invention relates to field of medicine preparations, particularly a kind of injection bortezomib freeze-dried powder and preparation method thereof.
Background technology
Bortezomib (Bortezomib, PS-341), trade name Bortezomib (Velcade), is by U.S.'s Millennium system
The new type antineoplastic medicine of medicine company research and development.This medicine is by blocking intracellular multiple regulating cell apoptosis and the albumen of signal conduction
The degraded of matter, causes death of neoplastic cells.Numerous studies find, bortezomib is to kinds of tumors, especially in neoplastic hematologic disorder
Multiple myeloma, jacket cell type lymphoma and other B cell type lymphoma, Hodgkin lymphoma have stronger antitumor to live
Property.
The bortezomib dosage form of listing is injection freeze-dried powder the most both at home and abroad, and specification is 3.5mg, contains in prescription
3.5mg active component bortezomib and 35mg mannitol.Its preparation method several patents, wherein patent applications
CN103070835A reports a kind of freeze-dried composition containing bortezomib and preparation method thereof, utilizes and is added with mannitol, uncle
The mixed solvent of butanol, significantly increases the rate of dissolution of bortezomib, simultaneously can be further by the order of addition of material
Improve the rate of dissolution of bortezomib.Utilize nitrogen charging environment not only liquid preparation time to be greatly shortened, and effectively prevent principal agent
Point with the contacting of aerobic environment, reduce final finished has related substance and total miscellaneous content.
Patent application CN103212055A relates to pharmaceutical composition of a kind of bortezomib and preparation method thereof.Institute of the present invention
Containing bortezomib, the tert-butyl alcohol, sodium chloride and excipient, wherein, described bortezomib, tertiary fourth in the pharmaceutical composition stated
The mass ratio of alcohol, sodium chloride and excipient is 1:0.5:1～5:5～20.The interpolation of the tert-butyl alcohol can make bortezomib rapidly
Dissolve, thus quickly and the more stable borate of the polyalcohols excipient reaction formation such as mannitol, solve bortezomib
The stability problem of lyophilized injectable powder itself；And the interpolation of active constituents of medicine sodium chloride, then make its fully ensured that internal just
Normal physiology, biochemical activity and function.
Patent application CN103446068A provides a kind of bortezomib freeze-dried composition and preparation method thereof.Described boron replaces
Assistant rice freeze-dried composition is bortezomib, mannitol, the mixed solution of the tert-butyl alcohol to be sprayed into and form freezing microgranule in liquid nitrogen, then
It is dissolved in water for injection, the freeze-dried freeze-dried composition obtained.
The sample prepared by above-mentioned technique, there is problems in that and 1. need to use organic solvent, such as the tert-butyl alcohol in production process
Deng, finished product all has certain residual, adds drug risk；2. bortezomib is to moisture-sensitive, and injection bortezomib
Solid content only has 38.5mg, easily absorbs the moisture migrated in plug and causes Moisture high UCL, thus affects other indexs of product such as
There are related substance, visible foreign matters etc.；3. bortezomib is oxidizable, and process for preparation causes having related substance to increase with the oxygen reaction in air
Greatly.
Summary of the invention
The present invention is directed to the defect that above-mentioned technique exists, done lot of experiments and groped, ultimately provide a kind of applicable industry
Metaplasia is produced, is not required to, with organic solvent, products obtained therefrom stay-in-grade injection bortezomib freeze-dried powder and preparation method thereof, lead to
Cross following technical scheme to be achieved:
A kind of injection bortezomib freeze-dried powder, its bortezomib comprising 1 part and the mannitol of 8-10 part.Described
Part is parts by weight.
The preparation method of above-mentioned injection bortezomib freeze-dried powder, comprises the steps:
(1) in dispensing canister, add the water for injection of 60%-80% dose volume, be cooled to 25 DEG C-45 DEG C and lead to wherein
Enter noble gas 30-50 minute；Add recipe quantity bortezomib, use homogenizer high speed shear to clarify to medicinal liquid；
(2) adding recipe quantity mannitol in above-mentioned medicinal liquid, stirring and dissolving, use hydrochloric acid solution regulation pH value is to 3-5, excellent
Selecting pH value is 3-4；Addition water for injection is to full dose, with water 1000-1200 part, medicinal liquid fill after microporous filter membrane aseptic filtration altogether
In cillin bottle, partly add plug, put into lyophilizing in freeze dryer.
(3) freeze-drying curve is: shelf is cooled to-40 ± 2 DEG C before putting into by product in advance, and product keeps shelf temperature after putting into
Degree for-40 ± 2 DEG C 2-4 hour；Vacuum pump starts, and is evacuated to 20 ± 10Pa；It is to slowly warm up to-5 ± 2 DEG C and keeps 10-18
Hour；It is to slowly warm up to 40 ± 2 DEG C and keeps 4-8 hour.
(4) after lyophilizing terminates, in freeze drying box, filling noble gas to pressure is 0.80-0.95 atmospheric pressure, compresses plug,
It is deflated to normal pressure, opens lyophilizing chamber door, take out sample, roll lid pack and get final product.
Preferably, in above-mentioned preparation technology, the water for injection temperature dissolving bortezomib controls at 25 DEG C-35 DEG C；Homogeneous
Machine high speed shear rotating speed is 9000-20000 rev/min.
Described noble gas is the one in nitrogen, carbon dioxide, argon；Plug used use before should through 105 DEG C-
120 DEG C of high temperature dry 2-4 hour to remove wherein moisture.
Process advantage major embodiment of the present invention is in the following areas:
Production process organic solvent-free participates in, products obtained therefrom no solvent residue.Homogenizer high speed shear can be fast by medicine
Speed is pulverized in fine particle, increases the contact area of medicine and water, accelerates the speed of medicine dissolution.This technique Chinese medicine is cut at a high speed
Cut and only need i.e. solubilized clarification in 2-5 minute；Use the organic solvents such as the tert-butyl alcohol to need just can be completely dissolved for 10-20 minute, and have product
Product redissolution post-genomic period, labor protection, dissolvent residual, the series of problems such as difficulty of clearing out a gathering place, therefore this technique is more simple and easy to do, meets
Workshop large-scale production demand.
At utmost reduce contacting of medicine and oxygen, it is to avoid the related substance that has that medicine causes because of oxidation increases.
Dissolve and use before bortezomib noble gas to be passed through in water for injection 30-50 minute, driven away the oxygen in water；Drug solution preparing and
Preservation process makes blanketing with inert gas；Lyophilizing terminates rear filling nitrogen tamponade, above 3 probabilities guaranteeing that medicine is oxidized
It is greatly reduced.
The process of plug and nitrogen filling ensure that in prolonged storage, moisture is within prescribed limit.For solid content
Little product, it is that in plug, moisture migrates in medicine that moisture increases main cause.105 DEG C of-120 DEG C of high temperature of plug are dried by the present invention
Dry 2-4 hour, not remove only the moisture on plug surface, also remove the water of crystallization of plug inner most, reduce plug
The probability of middle water translocation.After filling nitrogen, tamponade also can prevent fine vacuum in bottle from, by moisture inspiration bottle in plug, preventing
Moisture increases.Owing to active component bortezomib is more sensitive to moisture, therefore moisture Control can reduce degraded at reduced levels
The generation of impurity, it is ensured that medicine stability.
Detailed description of the invention
Below by specific embodiment, the present invention is described, below in an example, the various mistakes not described in detail
Journey and method are conventional methods as known in the art.Should correct understanding: embodiments of the invention illustrate that this
Invent and make rather than limitation of the present invention, so the simple of the present invention being transformed also under the method premise of the present invention
Belong to protection scope of the present invention.
Embodiment 1
(1) adding 2.4L water for injection in dispensing canister, water temperature keeps 45 DEG C, is passed through nitrogen wherein 30 minutes；Add
3.5g bortezomib, uses homogenizer high speed shear (rotating speed 9000 revs/min) to clarify to medicinal liquid；
(2) in above-mentioned medicinal liquid, add 35g mannitol, stirring and dissolving, use 0.1mol/L hydrochloric acid solution regulation pH value extremely
5.0, addition water for injection is to 3.5L, and medicinal liquid fill after microporous filter membrane aseptic filtration, in cillin bottle, partly adds plug (plug warp
105 DEG C dry 4 hours), put into lyophilizing in freeze dryer.
(3) freeze-drying curve is: shelf is cooled to-40 DEG C before putting into by product in advance, and product keeps shelf temperature after putting into
For-40 DEG C 2 hours；Vacuum pump starts, and is evacuated to 20Pa；It is to slowly warm up to-5 DEG C and keeps 10 hours；It is to slowly warm up to 40
DEG C and keep 4 hours.
(4) after lyophilizing terminates, in freeze drying box, filling nitrogen to pressure is 0.80 atmospheric pressure, compresses plug, is often deflated to
Pressure, opens lyophilizing chamber door, takes out sample, rolls lid pack and get final product.
Embodiment 2
(1) adding 2.8L water for injection in dispensing canister, water temperature keeps 35 DEG C, is passed through carbon dioxide 40 points wherein
Clock；Add 3.5g bortezomib, use homogenizer high speed shear (rotating speed 12000 revs/min) to clarify to medicinal liquid；
(2) in above-mentioned medicinal liquid, add 35g mannitol, stirring and dissolving, use 0.1mol/L hydrochloric acid solution regulation pH value extremely
3.0, addition water for injection is to 3.5L, and medicinal liquid fill after microporous filter membrane aseptic filtration, in cillin bottle, partly adds plug (plug warp
110 DEG C dry 3 hours), put into lyophilizing in freeze dryer.
(3) freeze-drying curve is: shelf is cooled to-40 DEG C before putting into by product in advance, and product keeps shelf temperature after putting into
For-40 DEG C 4 hours；Vacuum pump starts, and is evacuated to 20Pa；It is to slowly warm up to-5 DEG C and keeps 15 hours；It is to slowly warm up to 40
DEG C and keep 6 hours.
(4) after lyophilizing terminates, in freeze drying box, filling nitrogen to pressure is 0.90 atmospheric pressure, compresses plug, is often deflated to
Pressure, opens lyophilizing chamber door, takes out sample, rolls lid pack and get final product.
Embodiment 3
(1) adding 2.6L water for injection in dispensing canister, water temperature keeps 30 DEG C, is passed through argon wherein 50 minutes；Add
3.5g bortezomib, uses homogenizer high speed shear (rotating speed 16000 revs/min) to clarify to medicinal liquid；
(2) in above-mentioned medicinal liquid, add 35g mannitol, stirring and dissolving, use 0.1mol/L hydrochloric acid solution regulation pH value extremely
4.5, addition water for injection is to 3.5L, and medicinal liquid fill after microporous filter membrane aseptic filtration, in cillin bottle, partly adds plug (plug warp
120 DEG C dry 2 hours), put into lyophilizing in freeze dryer.
(3) freeze-drying curve is: shelf is cooled to-40 DEG C before putting into by product in advance, and product keeps shelf temperature after putting into
For-40 DEG C 3 hours；Vacuum pump starts, and is evacuated to 20Pa；It is to slowly warm up to-5 DEG C and keeps 15 hours；It is to slowly warm up to 40
DEG C and keep 6 hours.
(4) after lyophilizing terminates, in freeze drying box, filling nitrogen to pressure is 0.95 atmospheric pressure, compresses plug, is often deflated to
Pressure, opens lyophilizing chamber door, takes out sample, rolls lid pack and get final product.
Embodiment 4
(1) adding 2.4L water for injection in dispensing canister, water temperature keeps 25 DEG C, is passed through nitrogen wherein 45 minutes；Add
3.5g bortezomib, uses homogenizer high speed shear (rotating speed 20000 revs/min) to clarify to medicinal liquid；
(2) in above-mentioned medicinal liquid, add 35g mannitol, stirring and dissolving, use 0.1mol/L hydrochloric acid solution regulation pH value extremely
3.9, addition water for injection is to 3.5L, and medicinal liquid fill after microporous filter membrane aseptic filtration, in cillin bottle, partly adds plug (plug warp
110 DEG C dry 4 hours), put into lyophilizing in freeze dryer.
(3) freeze-drying curve is: shelf is cooled to-40 DEG C before putting into by product in advance, and product keeps shelf temperature after putting into
For-40 DEG C 4 hours；Vacuum pump starts, and is evacuated to 20Pa；It is to slowly warm up to-5 DEG C and keeps 18 hours；It is to slowly warm up to 40
DEG C and keep 8 hours.
(4) after lyophilizing terminates, in freeze drying box, filling nitrogen to pressure is 0.90 atmospheric pressure, compresses plug, is often deflated to
Pressure, opens lyophilizing chamber door, takes out sample, rolls lid pack and get final product.
Embodiment 5 (comparative example)
The tert-butyl alcohol is heated to 40 DEG C so that it is melt as liquid, weighs the 15g tert-butyl alcohol, mend that to inject water to dosing total
The 80% of volume, mix homogeneously, nitrogen filled protection 1 hour；Weigh the mannitol of 1000mg, add in mixed solution, at 40 DEG C of bars
Under part, stirring is completely dissolved to mannitol, obtains adjuvant solution；Weigh 50mg bortezomib and add in adjuvant solution, at 40 DEG C,
Stirring, to being completely dissolved, adds water for injection to dosing cumulative volume, obtains preparation midbody solution, and configuration process whole process nitrogen charging is protected
Protect；After the detection of preparation midbody solution is qualified, filter, carry out fill according to 5ml volume, send into freeze dryer lyophilizing, it is thus achieved that lyophilizing
Finished product.
Freeze drying process: after goods inlet, is cooled to about-42 DEG C of pre-freezes, keeps this temperature 5 hours；Open cold-trap, open vacuum；3
Hour it is warming up to about-35 DEG C, then keeps 8 hours；Within 2 hours, it is warming up to about-18 DEG C, then keeps 3 hours；Within 10 minutes, it is warming up to
45 DEG C, then keep 3 hours；Nitrogen charging tamponade.
Test example 1
Being put by embodiment 1-5 products obtained therefrom and place 24 months under room temperature condition, investigate its stability, experimental result see table:
Table 1 injection bortezomib long-term shelf-stability experimental result
By above-mentioned experimental result it can be seen that embodiment 1-4 products obtained therefrom at moisture, turbidity, visible foreign matters, have related substance
Aspect is better than embodiment 5 products obtained therefrom, and preparation technology products obtained therefrom steady quality of the present invention is described, indices is outstanding.
Claims (6)
1. the preparation method of an injection bortezomib freeze-dried powder, it is characterised in that injection bortezomib freeze-dried powder
Comprise each component of following parts by weight: the bortezomib of 1 part and the mannitol of 8-10 part；Its preparation method comprises following step
Rapid:
(1) in dispensing canister, add the water for injection of 60%-80% dose volume, be cooled to 25 DEG C-45 DEG C, be passed through wherein
Noble gas 30-50 minute；Add recipe quantity bortezomib, use homogenizer high speed shear to clarify to medicinal liquid；
(2) in above-mentioned medicinal liquid, add recipe quantity mannitol, stirring and dissolving, use hydrochloric acid solution regulation pH value to 3-5, add
Water for injection is to full dose, and with water 1000-1200 part altogether, medicinal liquid fill after microporous filter membrane aseptic filtration, in cillin bottle, partly adds
Plug, put into lyophilizing in freeze dryer；
(3) freeze-drying curve is: in advance shelf is cooled to-40 ± 2 DEG C, and product keeps shelf temperature to be-40 ± 2 DEG C after putting into,
It is incubated 2-4 hour；Vacuum pump starts, and is evacuated to 20 ± 10Pa；It is to slowly warm up to-5 ± 2 DEG C and keeps 10-18 hour；Slow
Slowly it is warming up to 40 ± 2 DEG C and keeps 4-8 hour；
(4) after lyophilizing terminates, in freeze drying box, filling noble gas to pressure is 0.80-0.95 atmospheric pressure, compresses plug, puts
Gas, to normal pressure, opens lyophilizing chamber door, takes out sample, rolls lid pack and get final product.
2. the preparation method of injection bortezomib freeze-dried powder as claimed in claim 1, it is characterised in that dissolve boron for assistant
The water for injection temperature of rice is 25 DEG C-35 DEG C.
3. the preparation method of injection bortezomib freeze-dried powder as claimed in claim 2, it is characterised in that homogenizer is at a high speed
Shear rotating speed and be 9000-20000 rev/min.
4. the preparation method of the injection bortezomib freeze-dried powder as described in claim 2-3 is arbitrary, it is characterised in that described
Noble gas is the one in nitrogen, carbon dioxide, argon.
5. the preparation method of injection bortezomib freeze-dried powder as claimed in claim 4, it is characterised in that plug used makes
Dry 2-4 hour through 105 DEG C-120 DEG C with front.
6. the preparation method of injection bortezomib freeze-dried powder as claimed in claim 5, it is characterised in that step 2) in
The pH value of regulation solution is 3-4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410840518.6A CN104546744B (en) | 2014-12-30 | 2014-12-30 | A kind of injection bortezomib freeze-dried powder and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410840518.6A CN104546744B (en) | 2014-12-30 | 2014-12-30 | A kind of injection bortezomib freeze-dried powder and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104546744A CN104546744A (en) | 2015-04-29 |
| CN104546744B true CN104546744B (en) | 2016-11-16 |
Family
ID=53064528
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410840518.6A Active CN104546744B (en) | 2014-12-30 | 2014-12-30 | A kind of injection bortezomib freeze-dried powder and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104546744B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108451911B (en) * | 2018-04-04 | 2020-05-22 | 重庆惠源医药有限公司 | Preparation method of bortezomib preparation |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784114B (en) * | 2011-05-14 | 2016-03-02 | 山东新时代药业有限公司 | A kind of bortezomib freeze-dried powder and preparation method thereof |
| CN103446068B (en) * | 2013-09-17 | 2015-12-23 | 江苏奥赛康药业股份有限公司 | Bortezomib freeze-dried composition and preparation method thereof |
-
2014
- 2014-12-30 CN CN201410840518.6A patent/CN104546744B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104546744A (en) | 2015-04-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101623285B (en) | Cefmetazole sodium medicament and preparation method thereof | |
| CN102784114B (en) | A kind of bortezomib freeze-dried powder and preparation method thereof | |
| CN104546744B (en) | A kind of injection bortezomib freeze-dried powder and preparation method thereof | |
| CN102228444B (en) | N(2)-L-alanyl-L-glutamine preparation for injection and preparation method thereof | |
| CN1994461A (en) | Lyophilization process of glutathione for injection | |
| CN101297809B (en) | Preparation of cefoperazone and sulbactam sodium mixed powder | |
| CN103446068B (en) | Bortezomib freeze-dried composition and preparation method thereof | |
| CN110464846A (en) | A kind of Meloxicam composition, preparation and the preparation method and application thereof | |
| CN102423484B (en) | Stable cetrorelix medicinal composition and preparation method thereof | |
| CN102302462B (en) | Gemcitabine hydrochloride lyophilized preparation | |
| CN102579372B (en) | Gemcitabine hydrochloride lyophilized composition and preparation method thereof | |
| CN102755325B (en) | Cefoxitin sodium medicinal composition, powder injection and preparation method thereof | |
| CN103494779B (en) | Andrographolide powder preparation for injection and preparation method thereof | |
| CN104414982B (en) | A kind of bortezomib freeze drying powder injection and preparation method thereof | |
| CN103070823A (en) | Aseptic packaging method of large volume injection | |
| CN109364030A (en) | A kind of injection bortezomib freeze-dried powder and its preparation process | |
| CN103212058A (en) | Composition containing antifungal drug and lactate buffering agent | |
| CN103271878A (en) | Ceftezole sodium agent and preparation method thereof | |
| CN103301123A (en) | Preparation method for controlling pH (Potential of Hydrogen) of amoxicillin sodium/sulbactam sodium | |
| CN106176637A (en) | Lyophilized formulations of bortezomib and preparation method thereof | |
| KR101779676B1 (en) | Methods for manufacturing dialysate chemical formulations | |
| CN102429860A (en) | Double-cavity bag packed cefpirome sulfate injection and preparation method thereof | |
| CN102429863A (en) | Azithromycin injection packed by double-cavity bag and preparation method thereof | |
| CN107773538B (en) | Stable picoplatin sterile lyophilized powder and preparation process thereof | |
| CN103263436B (en) | Disodium adenosine triphosphate and magnesium chloride composition for injection, and freeze-dried powder injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |