CN108451911A - A kind of preparation method of bortezomib preparation - Google Patents
A kind of preparation method of bortezomib preparation Download PDFInfo
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- CN108451911A CN108451911A CN201810300018.1A CN201810300018A CN108451911A CN 108451911 A CN108451911 A CN 108451911A CN 201810300018 A CN201810300018 A CN 201810300018A CN 108451911 A CN108451911 A CN 108451911A
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- bortezomib
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- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims abstract description 93
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 92
- 239000007788 liquid Substances 0.000 claims abstract description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000000243 solution Substances 0.000 claims abstract description 36
- 238000003756 stirring Methods 0.000 claims abstract description 36
- 239000008215 water for injection Substances 0.000 claims abstract description 35
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 32
- 235000010355 mannitol Nutrition 0.000 claims abstract description 32
- 229930195725 Mannitol Natural products 0.000 claims abstract description 30
- 239000000594 mannitol Substances 0.000 claims abstract description 30
- 238000004108 freeze drying Methods 0.000 claims abstract description 25
- 238000001914 filtration Methods 0.000 claims abstract description 19
- 238000011049 filling Methods 0.000 claims abstract description 15
- 238000005352 clarification Methods 0.000 claims abstract description 10
- 238000009472 formulation Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 238000010792 warming Methods 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 33
- 238000004519 manufacturing process Methods 0.000 abstract description 21
- 239000000843 powder Substances 0.000 abstract description 19
- 239000000047 product Substances 0.000 description 44
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 20
- 230000008569 process Effects 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 238000005259 measurement Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 230000001133 acceleration Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229920001971 elastomer Polymers 0.000 description 4
- 238000007710 freezing Methods 0.000 description 4
- 230000008014 freezing Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000012372 quality testing Methods 0.000 description 4
- PCLIRWBVOVZTOK-UHFFFAOYSA-M 2-(1-methylpyrrolidin-1-ium-1-yl)ethyl 2-hydroxy-2,2-diphenylacetate;iodide Chemical compound [I-].C=1C=CC=CC=1C(O)(C=1C=CC=CC=1)C(=O)OCC[N+]1(C)CCCC1 PCLIRWBVOVZTOK-UHFFFAOYSA-M 0.000 description 3
- PENWAFASUFITRC-UHFFFAOYSA-N 2-(4-chlorophenyl)imidazo[2,1-a]isoquinoline Chemical compound C1=CC(Cl)=CC=C1C1=CN(C=CC=2C3=CC=CC=2)C3=N1 PENWAFASUFITRC-UHFFFAOYSA-N 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 239000004695 Polyether sulfone Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940064457 osmitrol Drugs 0.000 description 2
- 238000010525 oxidative degradation reaction Methods 0.000 description 2
- 229920006393 polyether sulfone Polymers 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- -1 bortezomib tert-butyl alcohol ester Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000009924 canning Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229920005555 halobutyl Polymers 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- 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
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of preparation methods of bortezomib preparation, include the following steps：A) water for injection of 80% or more formula ratio is added into dispensing canister, the mannitol of formula ratio is added under 40 DEG C of temperature conditions below and stirring condition, stirring is to after forming clarification mannitol solution, continue to stir and be added the bortezomib of formula ratio to forming clear solution, water for injection is added to full dose is formulated, obtains bortezomib liquid；B) the bortezomib liquid is obtained into bortezomib preparation through aseptic filtration and freeze-drying.Preparation method provided by the invention enormously simplifies operation requirement and manufacturing cost, and, the impurity content of liquid and freeze-dried powder preparation can be substantially reduced, improve product quality, and gained liquid can relatively be stablized up to holding quality under 8h, meet the follow-up filling equal production times for being up to 8h, is all more advantageous to commercial scale either in terms of operation possibility or in terms of product with stable quality and produces.
Description
Technical field
The present invention relates to pharmaceutical preparations technology field, more particularly to a kind of preparation method of bortezomib preparation.
Background technology
Bortezomib (Bortezomib) is yellow solid chemicals, and trade name Bortezomib (Velcade) is a kind of anti-swollen
Tumor medicine can be used for the treatment of relapsed or stubborn jacket cell lymph cancer.Currently, commercially available bortezomib preparation is mainly both at home and abroad
Injectable lyophilised powder, due to the excellent effect in anticancer aspect, have become anti-cancer field consumption and demand it is larger one
Class medicament.
However, bortezomib is degradable, by conditions such as high temperature, high humidity, illumination, acid, alkali, oxidations to bortezomib
Factors affecting stability is studied, the results showed that：It slightly degrades under the conditions of 40 DEG C of high temperature, illumination or alkali, and 60
It can significantly degrade under DEG C high temperature, oxidizing condition；The oxidative degradation impurity of bortezomib has Impurity C1With Impurity C2,
Further oxidation impurities Impurity M and Impurity N, Impurity C1With Impurity C2It hydrolyzes under the high temperature conditions
Generating impurity Impurity D, Impurity D, further hydrolysis generates impurity A under the high temperature conditions；
The actual conditions information of the above impurity is generated referring to following table：
The route for generating the above impurity is as follows：
In addition, bortezomib has 3 isomers, including isomer impurities Impurity E, Impurity F and
ImpurityG.With reference to 42 standard detections of USP drafts volumn, the chromatogram of any of the above impurity is referring to Fig. 1, each impurity chromatography
Information is referring to following table：
Due to bortezomib degradable formation impurity under numerous conditions, therefore in the process for preparing bortezomib preparation
In, it is easy to impurity is generated, formulation products quality is influenced, keeps formulation products stability poor, therefore, process for preparation is difficult control
System, and how to improve the quality of bortezomib preparation and quality stability also becomes the technical barrier of this field for a long time.
In the past, the preparation method of bortezomib freeze dried powder mainly accordingly changed by using t-butanol solution for solvent
The quality stability of kind bortezomib solution coordinates control oxidative degradation in conjunction with nitrogen charging.However, to belong to the 3rd class molten for the tert-butyl alcohol
Agent, residual limit are 5000ppm, need to recycle a large amount of solvents in production process, handle, cost is very high, and the party
Method may will produce a small amount of slightly water-soluble bortezomib tert-butyl alcohol ester impurity, there is also redissolved after freeze-drying, solution generates opalescence, no
The problems such as dissolubility particle is unqualified, it is also necessary to the conditions such as harsh control reactant form, reactant addition sequence, solution temperature,
Preparation process requires excessively harsh complexity, manufacturing cost also higher.
Based on this, prior art generally use following manner prepares bortezomib preparation (referring to CN104546744A)：With
Water for injection is solvent, and first bortezomib is suspended after obtaining bortezomib suspension under the conditions of nitrogen charging, then with mannitol at
Ester forms solution, finally improves quality stability in conjunction with pH is adjusted.Although this method avoids using organic solvent, also avoid
The possibility that tert-butyl alcohol class impurity generates, still, there is still a need for stringent control reactant addition sequence, nitrogen charging conditions for this method
With the conditions such as solution temperature and adjusting pH, it is desirable that complicated, manufacturing cost is higher, but to the improvement of product quality stability
Not apparent enough, scale industrial production and product quality stability cannot reach preferable improvement.Therefore, prepared by exploitation
Simply, the preparation method that at low cost and product quality is high and stability is good becomes this field urgent problem to be solved.
Invention content
In view of this, the purpose of the present invention is to provide a kind of preparation method of bortezomib preparation, preparation of the invention
Simply, at low cost, and can preferably improve product quality and quality stability.
The present invention provides a kind of preparation methods of bortezomib preparation, include the following steps：
A) water for injection of 80% or more formula ratio is added into dispensing canister, in 40 DEG C of temperature conditions and stirring bar below
The mannitol of formula ratio is added under part, to after forming clarification mannitol solution, the boron for continuing to stir and be added formula ratio replaces for stirring
Rice is helped to clear solution is formed, water for injection is added to full dose is formulated, obtains bortezomib liquid；
B) the bortezomib liquid is obtained into bortezomib preparation through aseptic filtration, filling and freeze-drying.
Preferably, the water for injection of 85% formula ratio is added into dispensing canister.
Preferably, after water for injection being added into dispensing canister, the temperature of water for injection is down to 40 DEG C or less and is carried out subsequently
It prepares, and maintains the temperature of solution in dispensing canister during subsequent formulation at 40 DEG C or less.
Preferably, the temperature is 25 DEG C or less.
Preferably, the temperature is 5~15 DEG C.
Preferably, it is freeze-dried to water content≤1.0%.
Preferably, the freeze-drying curve of the freeze-drying is：Product is first kept the temperature 2~4 hours at -43~-47 DEG C；It
After be evacuated to 2~8Pa, then be warming up to -27~-23 DEG C and keep 15~18 hours；Finally it is warming up to 48~52 DEG C again and protects
It holds 4~8 hours.
Preferably, it in the step b), after freeze, is also tied cover seal.
The present invention provides a kind of preparation methods of bortezomib preparation, include the following steps：A) it is added into dispensing canister
The mannitol of formula ratio is added in the water for injection of 80% or more formula ratio under 40 DEG C of temperature conditions below and stirring condition,
Stirring continues to stir and be added the bortezomib of formula ratio to forming clear solution, then add to after forming clarification mannitol solution
Enter water for injection to full dose is formulated, obtains bortezomib liquid；B) the spray Bortezomib liquid is dry through aseptic filtration and freezing
It is dry, obtain bortezomib preparation.Water and mannitol are first mixed to form Osmitrol in preparation method provided by the invention,
And solution temperature is controlled at 40 DEG C hereinafter, then addition bortezomib is molten to clarification is formed under lasting stirring turbulent-flow conditions again
Liquid adds the water for injection of surplus, obtains bortezomib liquid；Follow-up aseptic filtration and freeze-drying are carried out again, obtain boron
Bortezomib freeze-dried powder preparation.The cooperation in the protective gas condition such as inflated with nitrogen is needed to get off surely in the previous preparation method in this field
Fixed output quota quality fills protective gas and has become the necessary requirement for preparing bortezomib preparation substantially, or even needs to adjust pH value
Stabilized product quality and high shear Homogenization are assisted, and process for preparation of the present invention and filling whole process are all not necessarily to nitrogen charging, prepare
Process, also without high shear Homogenization, greatly reduces operation requirement and complexity, while dropping significantly without pH value is adjusted
Low manufacturing cost, and in the case where excluding nitrogen charging condition, the present invention is by specific manner of formulation, than matching under previous nitrogen charging
The mode of system achieves better product quality and stability, is more advantageous to commercial scale production.
Impurity is difficult control in bortezomib preparation process for preparation, therefore its impurity content is difficult to decrease and keeps stability,
Reduction by 0.01% is extremely difficult, and the improvement for preparation quality has been compared with much progress, and test result shows according to the present invention
Preparation method, impurity content can reduce by 0.02% or more, hence it is evident that the impurity content for reducing liquid and freeze-dried powder preparation carries
High product quality；Moreover, gained liquid can meet up to keeping quality to stablize relatively under 8h up to the follow-up filling of 8h
Etc. production processes, provide necessary guarantee to meet the product commercial scale production cycle.
Description of the drawings
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
The embodiment of invention for those of ordinary skill in the art without creative efforts, can also basis
The attached drawing of offer obtains other attached drawings.
Fig. 1 is bortezomib impurity chromatogram；
Fig. 2 is the preparation flow figure of embodiment 1.
Specific implementation mode
The present invention provides a kind of preparation methods of bortezomib preparation, include the following steps：
A) water for injection of 80% or more formula ratio is added into dispensing canister, in 40 DEG C of temperature conditions and stirring bar below
The mannitol of formula ratio is added under part, to after forming clarification mannitol solution, the boron for continuing to stir and be added formula ratio replaces for stirring
Rice is helped to clear solution is formed, water for injection is added to full dose is formulated, obtains bortezomib liquid；
B) the bortezomib liquid is obtained into bortezomib preparation through aseptic filtration and freeze-drying.
Water and mannitol are first mixed to form Osmitrol in preparation method provided by the invention, then continued again
It stirs and bortezomib is added under turbulent-flow conditions to clear solution is formed, add the water for injection of surplus, obtain bortezomib medicine
Liquid；Follow-up aseptic filtration and freeze-drying are carried out again, obtain bortezomib freeze-dried powder preparation.In the previous preparation method in this field
Typically first by bortezomib mixed with water obtain solution after mixed again with mannitol, and whole need in protections such as inflated with nitrogen
The cooperation of gas condition is got off stabilized product quality, is filled protective gas and is had become the indispensable item for preparing bortezomib preparation substantially
Part, and first mixing water with mannitol in process for preparation of the present invention, then mixed with bortezomib, through applicants have found that, lead to
Cross above-mentioned specific batch mixing sequence so that bortezomib can quickly be reacted with mannitol after being added, and avoided high temperature and dropped with oxidation
Solution so that whole process greatly reduces operation without still having excellent product quality and quality stability in the case of nitrogen charging
It is required that and complexity, while greatly reducing manufacturing cost, be more advantageous to commercial scale production.
According to the present invention, the water for injection of 80% or more formula ratio is first added into dispensing canister, in 40 DEG C of temperature below
The mannitol of formula ratio is added under condition and stirring condition, stirring continues to stir and be added to after forming clarification mannitol solution
The bortezomib of formula ratio adds water for injection to full dose is formulated, obtains bortezomib liquid to clear solution is formed.
In the present invention, the water for injection of 80% or more formula ratio is added into dispensing canister, 85% formula ratio is preferably added
Water for injection.
After water for injection is added, the mannitol of formula ratio is added under 40 DEG C of temperature conditions below and stirring condition, stirs
It mixes to formation and clarifies mannitol solution.
Wherein, 40 DEG C of temperature conditions below include following manner：Before water for injection is added into dispensing canister first
Water for injection is down to 40 DEG C and still maintains 40 DEG C or less hereinafter, being added during dispensing canister and subsequent formulation；Or to making up a prescription
After water for injection is added in tank, then the temperature of water for injection is down to 40 DEG C or less and carries out subsequent formulations, and maintains subsequent formulation
In the process in dispensing canister the temperature of solution at 40 DEG C or less；To reduce Operating Complexity, it is preferred to use the latter.In the present invention,
The temperature is preferably 25 DEG C hereinafter, further preferably 5~15 DEG C, within this temperature range, can further improve product
Quality and quality stability.
The operation that mannitol is added carries out under conditions of with stirring, specially：Before mannitol is added
Start to stir, the liquid in dispensing canister made to form turbulence state, mannitol, while lasting stirring are added under the stirring condition,
To obtain clear mannitol solution.
In the present invention, after forming clear mannitol solution, continue the bortezomib for stirring and being added formula ratio, stirs
To after forming clear solution, water for injection is added to full dose is formulated, obtains bortezomib liquid.Wherein, water for injection is added
Process to formula full dose preferably carries out under agitation, that is, after bortezomib is added and forms clear solution, continues to stir
Operation is added water for injection and mends to formula full dose, to obtain bortezomib liquid while stirring.
It is carried out under continuous agitation in the above-mentioned entire process for preparation of the present invention, wherein the design parameter item stirred
Part is not particularly limited, and can be adaptively adjusted according to the volume size of dispensing canister, and liquid can be made to form turbulent flow.
It is after obtaining bortezomib liquid, the bortezomib liquid is dry through aseptic filtration and freezing according to the present invention
It is dry, obtain bortezomib preparation.
The present invention is not particularly limited the aseptic filtration, operates and carries out according to this field routine aseptic filtration,
Particulate matter and sterilizing can be removed by the aseptic filtration.As in one embodiment, using including 0.45 μm of aperture
Filter and aperture be 0.22 μm two-stage filter form sterilization and filtration system carry out aseptic filtration；In the filter
The type of filter membrane is not particularly limited, using this field conventional filtration film, such as polyether sulfone (i.e. PES).
The present invention preferably also carries out filling after sterile filtration this.The present invention is not particularly limited the filling mode,
It is carried out according to this field routine canning means, such as the filling bortezomib solution into 10ml cillin bottles at room temperature
3.5ml, halogenated butyl rubber plug are partly jumped a queue.
It is described it is filling after be freeze-dried, preferably freeze drying of the present invention to water content≤1.0%.The freezing is dry
It is dry to be carried out in freeze dryer.The present invention is not particularly limited the actual conditions parameter of the freeze-drying, can reach 1.5%
Water content below.In one embodiment, following freeze-drying curve can be used：First product is kept the temperature at -43~-47 DEG C
2~4 hours；It is evacuated to 2~8Pa later, then is warming up to -27~-23 DEG C and is kept for 15~18 hours；It is finally warming up to 48 again
~52 DEG C and keep 4~8 hours.After the freeze-drying, bortezomib freeze-dried powder preparation is formed.It was freeze-dried above-mentioned
Shelf is preferably first cooled to -43~-47 DEG C and places product again by Cheng Zhong, and product continues to above-mentioned low temperature after being put into freeze dryer.
After above-mentioned entire freeze-drying, rubber plug is compressed, normal pressure is deflated to, you can takes out sample.
The present invention is preferably also tied cover seal after the freeze-drying, described to tie cover seal according to this field routine
Operation requires to carry out.
The present invention provides a kind of preparation methods of bortezomib preparation, include the following steps：A) it is added into dispensing canister
The mannitol of formula ratio is added in the water for injection of 80% or more formula ratio under 40 DEG C of temperature conditions below and stirring condition,
Stirring continues to stir and be added the bortezomib of formula ratio to forming clear solution, then add to after forming clarification mannitol solution
Enter water for injection to full dose is formulated, obtains bortezomib liquid；B) the bortezomib liquid is dry through aseptic filtration and freezing
It is dry, obtain bortezomib preparation.Preparation method provided by the invention is without nitrogen charging and adjusts the operations such as pH, enormously simplifies operation
It is required that and manufacturing cost, overcome the problem of this field existing harsh complexity of process for preparation for a long time；Moreover, being grasped simplifying
Make after being required with condition, not only without reducing product quality, the impurity of liquid and freeze-dried powder preparation can also be substantially reduced instead
Content improves product quality, and gained liquid can meet the follow-up filling up to 8h up to keeping quality to stablize relatively under 8h
The production times such as dress are all more advantageous to commercial scale life either in terms of operation possibility or in terms of product with stable quality
Production.
For a further understanding of the present invention, the preferred embodiment of the invention is described with reference to embodiment, still
It should be appreciated that these descriptions are only the feature and advantage further illustrated the present invention, rather than to the claims in the present invention
Limitation.In following embodiment, quality testing is carried out with reference to USP draft volumn42 standard detecting methods.
Embodiment 1
2975mL waters for injection are added into dispensing canister, water temperature is down to 25 DEG C, and stirring makes water for injection form turbulent flow and adds
Enter 35g mannitol, until after forming clarification mannitol solution, 3.5g bortezomibs are added under continuous stirring, until after solution clarification
Water for injection is added to 3500mL, is stirred evenly, bortezomib liquid (being denoted as Y-1) is obtained.
By gained bortezomib liquid after sterilization and filtration system aseptic filtration, component is filling in cillin bottle, and half adds glue
Plug.The filling product of gained are put into freeze dryer and are lyophilized, freeze-drying curve is：Shelf is cooled to -45 ± 2 DEG C, product be put into after in -
3 hours are kept the temperature at 45 ± 2 DEG C；Start vacuum pump later and be evacuated to 5 ± 3Pa, then is to slowly warm up to -25 ± 2 DEG C and keeps 16
Hour；It is last to be to slowly warm up to 50 ± 2 DEG C again and kept for 5 hours.After freeze-drying, rubber plug is compressed, is deflated to normal pressure, opens and freezes
Dry machine box door takes out sample, ties cover seal, obtains bortezomib formulation products (being denoted as Z-1).The preparation flow of the present embodiment is joined
It is the preparation flow figure of the present embodiment according to Fig. 2, Fig. 2.
Comparative example 1
2.4L waters for injection are added into dispensing canister, water temperature is kept for 25 DEG C, is passed through nitrogen thereto 45 minutes；3.5g is added
Bortezomib is clarified using homogenizer high speed shear (20000 revs/min of rotating speed) to liquid；35g mannitol is added later, stirs
Dissolving is mixed, pH value is adjusted to 3.9 using 0.1mol/L hydrochloric acid solutions, water for injection is added to 3.5L, obtains liquid and (is denoted as DY-
1)。
Gained liquid is filling in cillin bottle after micropore filtering film aseptic filtration, after half adds rubber plug, it is put into freeze dryer
Middle freeze-drying, freeze-drying curve are：Shelf is cooled to -40 DEG C by product in advance before being put into, and product keeps shelf temperature after being put into be -40
4 hours at DEG C；Vacuum pump startup, is evacuated to 20Pa, is to slowly warm up to -5 DEG C and is kept for 18 hours；It is to slowly warm up to 40 later
DEG C and keep 8 hours.After freeze-drying, filling nitrogen compresses rubber plug to 0.90 atmospheric pressure of pressure in freeze drying box, is deflated to often
Pressure opens freeze-drying chamber door, takes out sample, pricks lid pack up to freeze-dried powder preparation product (being denoted as DZ-1).
Respectively liquid Y-1, the formulation products Z-1 to bortezomib active constituent (i.e. API), embodiment 1 before preparation and
Liquid DY-1, the formulation products DZ-1 of comparative example 1 carry out quality testing, detect the intermediate liquid in production process and preparation production
The qualitative character of product, as a result referring to table 1.
The quality measurements of table 1 embodiment 1 and comparative example 1
Note：In table 1~5, ImpA indicates ImpurityA impurity components described previously, ImpD, ImpC1、ImpC2、ImpE、
The rest may be inferred by ImpM and ImpN；Unkown is non-principal component, " ND " expression " being not detected ", RLD standard reference preparations.
By the above test result it is found that preparation method (comparative example 1) compared with the prior art, preparation method of the invention
Obtained liquid and freeze-dried powder preparation can be substantially reduced impurity content, improve product quality.In addition, compared to RLD, this hair
The quality of bright freeze dried powder is also obviously improved, and the problem of avoid organic solvent residual.
Embodiment 2, comparative example 2
Bortezomib liquid is prepared according to the preparation process of embodiment 1, obtains sample detection (note after bortezomib liquid 8h
For Y8-2)；
Bortezomib liquid is prepared according to the preparation process of comparative example 1, obtains sample detection (note after bortezomib liquid 8h
For DY8-2).
The quality measurements of sample Y8-2 and DY8-2 are detected referring to table 2.
The quality measurements of table 2 embodiment 2 and comparative example 2
| Detect sample | ImpA | ImpD | ImpC1 | ImpC2 | ImpM | ImpN | ImpE | Unkown | Total amount |
| Y-1 | ND | 0.01% | 0.05% | 0.01% | ND | 0.02% | 0.03% | ND | 0.12% |
| Y8-2 | 0.02% | 0.01% | 0.06% | 0.02% | ND | 0.01% | 0.03% | ND | 0.15% |
| DY-1 | ND | 0.01% | 0.07% | 0.02% | ND | 0.01% | 0.03% | ND | 0.14% |
| DY8-2 | 0.04% | 0.03% | 0.10% | 0.02% | ND | 0.01% | 0.05% | 0.05% | 0.29% |
The liquid retention time is the necessary guarantee of product commercial scale production cycle, by the above test result it is found that existing
There is liquid made from the preparation method of technology after placing 8h, impurity content obviously increases, and quality stability is poor；And compare it
Under, liquid made from preparation method according to the invention is after placing 8h, and impurity content variation is smaller, i.e. quality of liquid medicine stability
It greatly improves, disclosure satisfy that the follow-up filling production up to 8h, be more advantageous to scale commodity production.
Embodiment 3, comparative example 3
Accelerated test is carried out to bortezomib formulation products made from embodiment 1, acceleration environment is：40 DEG C of temperature, humidity
For RH75%, the time is respectively 1 month (being denoted as Z-4a) and 2 months (being denoted as Z-4b), and product quality is detected after acceleration.
Accelerated test is carried out to bortezomib formulation products made from comparative example 1, acceleration environment is：40 DEG C of temperature, humidity
For RH75%, the time is respectively 1 month (being denoted as D-4a) and 2 months (being denoted as D-4b), and product quality is detected after acceleration.
The quality measurements of embodiment 3 (detect sample Z-4 series) and comparative example 3 (it is serial to detect sample D-4) referring to
Table 3.
The quality measurements of table 3 embodiment 3 and comparative example 3
| Detect sample | ImpA | ImpD | ImpC1 | ImpC2 | ImpM | ImpN | ImpE | Unkown | Total amount |
| Z-1 | ND | 0.01% | 0.05% | 0.01% | ND | 0.02% | 0.03% | ND | 0.12% |
| Z-4a | 0.03% | 0.07% | 0.04% | 0.02% | ND | 0.01% | 0.03% | ND | 0.20% |
| Z-4b | 0.05% | 0.11% | 0.06% | 0.03% | ND | 0.02% | 0.03% | ND | 0.30% |
| DZ-1 | ND | 0.01% | 0.08% | 0.02% | ND | 0.01% | 0.03% | ND | 0.15% |
| DZ-4a | 0.06% | 0.08% | 0.05% | 0.02% | ND | 0.01% | 0.04% | 0.03% | 0.29% |
| DZ-4b | 0.11% | 0.13% | 0.06% | 0.02% | ND | 0.02% | 0.03% | ND | 0.37% |
By the above test result it is found that freeze dried powder made from the preparation method according to the prior art, after accelerated experiment,
Product impurity content dramatically increases, and quality stability and reliability are poor；In contrast, preparation method according to the invention is made
Freeze dried powder quality stability and reliability be obviously improved.
Embodiment 4~6
Embodiment 4：Bortezomib liquid and bortezomib freeze dried powder product are prepared according to the preparation process of embodiment 1,
Unlike, process for preparation temperature is 15 DEG C, and gained liquid is denoted as Y-4, and gained formulation products are denoted as Z-4.
Embodiment 5：Bortezomib liquid and bortezomib freeze dried powder product are prepared according to the preparation process of embodiment 1,
Unlike, process for preparation temperature is 5 DEG C, and gained liquid is denoted as Y-5, and gained formulation products are denoted as Z-5.
Embodiment 6：Bortezomib liquid and bortezomib freeze dried powder product are prepared according to the preparation process of embodiment 1,
Unlike, process for preparation temperature is 40 DEG C, and gained liquid is denoted as Y-6, and gained formulation products are denoted as Z-6.
Liquid and preparation to embodiment 4~6 carry out quality testing, as a result referring to table 4.
The quality measurements of 4 embodiment 4~6 of table
By the above test result it is found that process for preparation according to the invention, when temperature is down to 5~15 DEG C, gained liquid
It can be further obviously improved with the product quality of freeze dried powder.
Embodiment 7
Bortezomib liquid and bortezomib freeze dried powder product are prepared according to the preparation process of embodiment 1, unlike,
Controlled at 15 DEG C, the water for injection for accounting for total water volume 90% is first added, finally mends again to formula full dose.
Embodiment 8
Bortezomib liquid and bortezomib freeze dried powder product are prepared according to the preparation process of embodiment 1, unlike,
Controlled at 5 DEG C, the water for injection for accounting for total water volume 90% is first added, finally mends again to formula full dose.
Liquid and preparation to embodiment 7~8 carry out quality testing, as a result referring to table 5.
The quality measurements of 5 embodiment 7~8 of table
Principle and implementation of the present invention are described for specific case used herein, and above example is said
The bright method and its core concept for being merely used to help understand the present invention, including best mode, and but also this field is appointed
What technical staff can put into practice the present invention, including manufacture and use any device or system, and implement the method for any combination.
It should be pointed out that for those skilled in the art, it without departing from the principle of the present invention, can also be right
Some improvement and modification can also be carried out by the present invention, these improvement and modification are also fallen within the protection scope of the claims of the present invention.This hair
The range of bright patent protection is defined by the claims, and may include those skilled in the art it is conceivable that other implementation
Example.If these other embodiments, which have, is similar to the structural element of claim character express, or if they include with
Equivalent structural elements of the character express of claim without essence difference, are wanted then these other embodiments should also be included in right
In the range of asking.
Claims (8)
1. a kind of preparation method of bortezomib preparation, which is characterized in that include the following steps：
A) water for injection of 80% or more formula ratio is added into dispensing canister, under 40 DEG C of temperature conditions below and stirring condition
The mannitol of formula ratio is added, stirring continues the bortezomib for stirring and being added formula ratio to after forming clarification mannitol solution
To clear solution is formed, water for injection is added to full dose is formulated, obtains bortezomib liquid；
B) the bortezomib liquid is obtained into bortezomib preparation through aseptic filtration, filling and freeze-drying.
2. preparation method according to claim 1, which is characterized in that the injection of 85% formula ratio is added into dispensing canister
Water.
3. preparation method according to claim 1, which is characterized in that after water for injection is added into dispensing canister, will inject
It is down to 40 DEG C or less with the temperature of water and carries out subsequent formulation, and the temperature of solution in dispensing canister during subsequent formulation is maintained to exist
40 DEG C or less.
4. preparation method according to claim 1 or 3, which is characterized in that the temperature is 25 DEG C or less.
5. preparation method according to claim 4, which is characterized in that the temperature is 5~15 DEG C.
6. preparation method according to claim 1, which is characterized in that freeze-drying to water content≤1.0%.
7. preparation method according to claim 1 or 6, which is characterized in that the freeze-drying curve of the freeze-drying is：First will
Product keeps the temperature 2~4 hours at -43~-47 DEG C；It is evacuated to 2~8Pa later, then is warming up to -27~-23 DEG C and keeps 15
~18 hours；It is last to be warming up to 48~52 DEG C again and kept for 4~8 hours.
8. preparation method according to claim 1, which is characterized in that in the step b), after freeze, also into
Row ties cover seal.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002059130A1 (en) * | 2001-01-25 | 2002-08-01 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Formulation 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 |
| CN104546744A (en) * | 2014-12-30 | 2015-04-29 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder for injection and preparation method thereof |
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2018
- 2018-04-04 CN CN201810300018.1A patent/CN108451911B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002059130A1 (en) * | 2001-01-25 | 2002-08-01 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Formulation 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 |
| CN104546744A (en) * | 2014-12-30 | 2015-04-29 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder for injection and preparation method thereof |
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| 徐焕焕等: "叔丁醇在难溶性药物硼替佐米冻干粉针剂制备中的应用", 《中国新药杂志》 * |
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