CN110314221B - Freeze-drying process of bortezomib for injection - Google Patents
Freeze-drying process of bortezomib for injection Download PDFInfo
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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 invention discloses a freeze-drying process of bortezomib for injection, which comprises the following steps of (1) pre-freezing; (2) primary drying; (3) resolving and drying; wherein, the pre-freezing comprises the following steps: (1a) cooling the liquid medicine from the normal temperature to-18 to-14 ℃ and keeping the temperature for 1 to 3 hours; (1b) cooling the sample obtained in the step (1a) to-45 to-35 ℃ at a cooling speed of more than or equal to 1.8 ℃/min and keeping for 2-3 h; (1c) heating the sample obtained in the step (1a) to-22 to-20 ℃ and keeping the temperature for 2-4 h; (1d) and (3) cooling the sample obtained in the step (1c) to-45 to-35 ℃ and keeping the temperature for 2-4 hours. According to the bortezomib freeze-drying process, the pre-freezing process and the primary drying are optimized, so that the problems of low freeze-drying efficiency, poor clarity of freeze-dried products, slow re-dissolution, high residual moisture and solvent and the like caused by uneven crystal structures due to surface concentration in the pre-freezing process are effectively solved, and the obtained freeze-dried finished products are excellent in quality in all aspects.
Description
Technical Field
The invention relates to a freeze-drying process, in particular to a freeze-drying process of bortezomib for injection.
Background
Bortezomib is the first proteasome inhibitor (proteasome inhibitor) synthesized globally, can reversibly inhibit 26S proteasome chymotrypsin-like activity in mammalian cells, and can delay and treat multiple myeloma and mantle cell lymphoma exacerbation. In vitro tests prove that bortezomib is cytotoxic to various types of cancer cells. Preclinical in vivo tumor model trials demonstrated that bortezomib was able to delay tumor growth including multiple myeloma.
Bortezomib was first developed by Myogenics in the united states and was purchased by the Millennium pharmaceutical industry (Millennium) in 1999. The millennium pharmaceutical industry followed the continued clinical studies in cooperation with the prosperous life. Bortezomib for injection (NDA:021602) was first approved by the FDA for sale in the united states in 5 months 2003, and was approved for use in multiple myeloma in the same year, and bortezomib acquired a PrixCalien reward in 2005 to demonstrate its breakthrough progress in treating multiple myeloma. In 2006 FDA approved bortezomib for injection for mantle cell lymphoma; bortezomib for injection in 2008 becomes a first-line medicine for treating multiple myeloma.
In 2009, bortezomib for injection approved by Janssen corporation was marketed in china under the trade name velcade (english name:
) The product specification is 3.5mg and 1mg, the administration route is intravenous injection, subcutaneous injection is approved in 2019, and the indications are multiple myeloma and mantle cell lymphoma.
The bortezomib bulk drug is poor in water solubility and extremely sensitive to light, heat and oxygen, and is generally not suitable for being used as a liquid preparation. Most of the prior bortezomib preparations are freeze-dried powder injections, namely, the bortezomib is matched with mannitol serving as an auxiliary material to prepare the freeze-dried preparation. In the preparation process of the preparation, in the state of solution, bortezomib reacts with mannitol to reversibly generate bortezomib mannitol ester, in the freeze drying process, the reaction proceeds towards the direction of generating the bortezomib mannitol ester along with the removal of tert-butyl alcohol and moisture, and finally stable bortezomib mannitol ester is generated for direct injection after clinical redissolution.
The bortezomib serving as a solid raw material medicine is in a tripolymer state and poor in water solubility, partial dissociation occurs in a solvent system, bortezomib mannitol ester is generated through esterification reaction with auxiliary material mannitol along with removal of tert-butyl alcohol and water in a freeze-drying process, and the solubility and the stability of the bortezomib mannitol ester are superior to those of the bortezomib monomer or the bortezomib tripolymer, so that the esterification rate of a finished product directly influences the quality of the product, the design of a freeze-drying process is one of main factors influencing the esterification rate of the finished product, and in addition, the freeze-drying process also directly influences the properties, clarity, redissolution time, tert-butyl alcohol, water, related substances and other key quality attributes of the finished product. Therefore, a proper freeze-drying curve needs to be designed, the prepared structure is loose and complete, the internal structure of the freeze-drying paste is smooth and uniform, and the sublimation channel is free from blockage, so that the variety with high esterification rate is obtained, the storage stability and the use convenience of the product are improved, and the adaptability of a patient and the effectiveness and the safety of the liquid medicine are improved.
The existing bortezomib freeze-drying process mainly comprises three steps: (1) pre-freezing; freezing the liquid medicine to be solid, and providing a drying environment for primary drying; (2) primary drying; removing the solvent in the pre-frozen sample by sublimation; (3) and (3) resolving and drying: further removing water in the product (mainly removing the bound water in the freeze-dried product), and further drying the product to obtain the finished freeze-dried powder preparation. Chinese patent publication No. CN106309385A discloses a bortezomib freeze-drying process using tert-butyl alcohol and water as solvents, which comprises (1) a prefreezing stage: maintaining the temperature at 0 ℃ for 0-4 h, reducing the temperature to-45 ℃, and preserving the temperature for 2-6 h; (2) primary sublimation: keeping the temperature of minus 40 to minus 35 ℃ for 8 to 12 hours, keeping the temperature of minus 35 to minus 30 ℃ for 10 to 22 hours, keeping the temperature of 25 ℃ for 10 to 24 hours, keeping the temperature of 20 to minus 15 ℃ for 4 to 6 hours, keeping the temperature of 10 ℃ for 3 to 6 hours, and keeping the temperature of 0 ℃ for 4 hours; (3) secondary drying: keeping the temperature at 30 ℃ for 4-6 hours; wherein the vacuum degree in the steps (1), (2) and (3) is less than or equal to 0.3 MPa. According to the bortezomib freeze-drying process for injection, in the cooling crystallization process in the step (1), the phenomena of large-particle crystal precipitation, nonuniform crystallization particle size, hard shell on the surface of paste due to solute migration, irregular crystal grain skeleton structure and the like are easy to occur; further causing the phenomena of crack on the surface of the paste body, disintegration and atrophy of the paste body, blocked sublimation process of the solvent and the like in the primary sublimation process of the step (2); not only reduces the freeze-drying efficiency, but also influences the product quality, such as higher water content and solvent residue of the freeze-dried finished product, low esterification rate of the freeze-dried product, long re-dissolving time of the freeze-dried preparation and the like.
Disclosure of Invention
The invention aims to overcome the defects of low bortezomib freeze-drying efficiency and poor quality of the obtained freeze-dried finished product in the prior art, and provides a freeze-drying process of bortezomib for injection, wherein the freeze-drying process improves the freeze-drying efficiency, and the obtained freeze-dried finished product has lower water content, tertiary butanol and the like and better re-solubility.
In order to achieve the above purpose, the invention provides the following technical scheme:
a freeze-drying process of bortezomib for injection comprises the following steps: (1) pre-freezing; (2) primary drying; (3) resolving and drying; wherein, the pre-freezing of the step (1) comprises the following steps:
(1a) reducing the temperature of the liquid medicine from normal temperature to-18 to-14 ℃, and keeping the temperature for 1 to 3 hours at the temperature of-18 to-14 ℃;
(1b) cooling the sample obtained in the step (1a) to-45 to-35 ℃ at a cooling speed of more than or equal to 1.8 ℃/min, and keeping the temperature for 2-3 h at the temperature of-45 to-35 ℃;
(1c) raising the temperature of the sample obtained in the step (1b) to-22 to-20 ℃ at a temperature rise speed of 0.4 to 0.8 ℃/min, and keeping the temperature for 1 to 3 hours at the temperature of-22 to-20 ℃;
(1d) and (3) reducing the temperature of the sample obtained in the step (1c) to-45 to-35 ℃ at a cooling speed of more than or equal to 1.8 ℃/min, and keeping the temperature for 2-4 h at the temperature of-45 to-35 ℃.
Wherein, the liquid medicine in (1a) is a liquid preparation for preparing bortezomib freeze-dried powder preparation, the solvent system of the liquid preparation is tert-butyl alcohol-water solution, and the excipient is mannitol.
The improvement of the freeze-drying process of the bortezomib for injection is the pre-freezing process in the step (1), and the steps (2), (3) and (4) are the prior art processes, which are not described again. Wherein,
in the step (1a), the temperature of the liquid medicine is reduced to be near the crystallization temperature (-18 to-14 ℃), and the liquid medicine is kept at the temperature for 1-3 hours, so that the crystallization-free supercooled liquid with relatively uniform temperature distribution and small temperature difference among all parts can be obtained, and a good crystallization environment is provided for obtaining crystal particles with uniform quality and a good crystal grain framework structure in the crystallization process in the step (1 b). The step (1b) is a pre-freezing crystallization process, the temperature reduction end point of the pre-freezing crystallization is controlled to be-45 ℃ to-35 ℃, the temperature reduction end point is 10 ℃ to 20 ℃ lower than the liquid medicine eutectic point of-22 ℃, the precipitated crystal grain structure can be completely frozen, and the risks of bottle spraying, melting, collapse, caking and the like of products in the primary drying process of the pre-freezing sample can be effectively reduced. Meanwhile, in the step (1b), the crystallization process is rapidly cooled at a speed of more than or equal to 1.8 ℃/min, so that not only can a crystal structure with fine and uniform crystal grain diameter and good crystal grain skeleton structure be obtained, but also the risk of forming compact hard shells on the surface of the paste body by the solute caused by the migration degree of the solute in the crystallization process can be reduced, further the sublimation resistance of the primary drying solvent is reduced, and the primary drying efficiency is improved; the step (1c) is a pre-freezing annealing step, the annealing process in the step (1c) raises the temperature of the liquid medicine from the pre-freezing final temperature to a temperature between the eutectic point and the glass transition temperature of the liquid medicine (the eutectic point Tc of the liquid medicine is-12 ℃ and the glass transition temperature Tg of the liquid medicine is-32 ℃), so that the crystal obtained in the step (1b) can be strengthened, the structure of the crystal is more uniform, the disintegration temperature of the product can be increased, and the probability of low-temperature disintegration of the product in a primary drying process is reduced. The step (1d) is to lower the temperature after annealing, and the same function as the step (1b) is not described herein again. According to the bortezomib freeze-drying process, the matching of low-temperature balance (namely the step (1a)), rapid cooling crystallization (the steps (1b) and (1d)) and a cooling crystallization process annealing process (the step (1c)) is adopted in the pre-freezing stage, so that crystal particles with uniform quality and a good crystal grain framework structure can be obtained, the formation of large crystal grains in the pre-freezing process can be effectively reduced, and the problems of poor clarity after product re-dissolution, long re-dissolution time, low primary drying efficiency, high moisture and solvent residues of a dried product, low esterification rate and the like caused by the phenomena of nonuniform crystallization, solute migration and the like are avoided, and the quality of the finished freeze-dried powder preparation is better.
Preferably, in the step (1a), the temperature of the liquid medicine is reduced from the normal temperature to-18 to-14 ℃ at a cooling rate of 4.6 to 5.6 ℃/min. In the pre-cooling process, the liquid medicine is in a liquid state, and the rapid cooling is favorable for shortening the pre-freezing time and reducing the production cost.
Preferably, in the step (1a), the temperature of the liquid medicine is reduced from normal temperature to-15 to-18 ℃, and the liquid medicine is kept at the temperature of-15 to-18 ℃ for 1 to 3 hours. When the liquid medicine pre-cooling end point is-15 to-18 ℃, the cooling crystallization effect in the step (1b) is better, and the finally obtained crystal grains have better quality.
Preferably, in the step (1b), the temperature of the sample obtained in the step (1a) is reduced to-37 to-35 ℃. The eutectic point of the liquid medicine is about-22 ℃, and the sample is pre-cooled to-37 to-35 ℃ and kept for 2 to 3 hours; the heat transfer of all parts of the sample crystallization can be guaranteed to be even, the hardness difference of all parts of the pre-frozen sample crystallization framework is small, the stress is even, the sample can be guaranteed to be completely frozen, a good environment is provided for the subsequent drying stage, and the finally obtained freeze-dried powder injection has better quality.
Preferably, in the step (1b), the sample obtained in the step (1a) is cooled at a cooling rate of 2.3-2.7 ℃/min. The crystal grains obtained at the cooling speed of 2.3-2.7 ℃/min have better quality.
Preferably, in the step (1c), the temperature of the sample obtained in the step (1b) is raised at a temperature raising rate of 0.5 to 0.7 ℃/min.
Preferably, in the step (1c), the temperature of the sample obtained in the step (1b) is increased to-21 to-20 ℃, and the sample is kept at-21 to-20 ℃ for 1 to 2 hours.
Preferably, in the step (1d), the temperature of the sample obtained in the step (1c) is reduced to-45 to-38 ℃, and the sample is kept at-45 to-38 ℃ for 2 to 3 hours.
Preferably, in the step (1d), the sample obtained in the step (1c) is cooled at a cooling rate of 2.3-2.7 ℃/min. The crystal grains obtained at the cooling speed of 2.3-2.7 ℃/min have better quality.
As a preferable embodiment of the present invention, the primary drying of step (2) comprises the steps of:
(2a) under the condition that the vacuum degree is 0.15-0.25 mbar, the temperature of the sample obtained in the step (1b) is increased to-33-30 ℃ at the temperature increasing speed of 1-7.5 ℃/h, and the sample is kept for 18-20 h under the condition of-33-30 ℃;
(2b) heating the sample obtained in the step (2a) to-25 to-20 ℃ at a heating rate of 0.7 to 1.8 ℃/h under the condition that the vacuum degree is 0.15 to 0.25mbar, and keeping the temperature for 3 to 5h under the condition of-25 to-20 ℃;
(2c) under the condition that the vacuum degree is 0.15-0.25 mbar, the temperature of the sample obtained in the step (2b) is increased to-15-10 ℃ at the temperature increasing speed of 5-10 ℃/h, and the sample is kept for 3-5 h under the condition of-15-10 ℃;
(2d) and (3) heating the sample obtained in the step (2c) to-5-0 ℃ at a heating rate of 5-7.5 ℃/h under the condition that the vacuum degree is 0.5-1 mbar, and keeping the temperature for 1-3 h under the condition of-5-0 ℃.
According to the freeze-drying process of the bortezomib for injection, the primary drying process in the step (2) is divided into four stages, and process parameters are adjusted according to different stages of the sample and the content of tert-butyl alcohol and water in the sample: (1) the cooperation relation of drying temperature, rate of rise and vacuum three in the accurate control drying process, and then control tert-butyl alcohol and the gaseous flux of flowing in the lotion skeleton of water sublimation in-process, can avoid unit volume freeze-drying lotion gaseous flux too big to lead to spouting bottle phenomenon in the drying process to take place, can improve sublimation efficiency again, shorten drying process time, improve the finished product rate of esterification, reduction in production cost. (2) And precisely controlling the temperature rise end point of each stage, so that the temperature of the temperature rise end point of each stage is lower than the disintegration temperature of the sample. (disintegration temperature is increased with the increase of the drying degree of the product, for example, the disintegration temperature of the first stage of primary drying is-27.4 ℃ to-25.8 ℃, and the temperature rise end point of the stage is-33 ℃ to-30 ℃, the disintegration temperature of the sample is taken as the node temperature of gradient temperature rise in the primary drying process, which can scientifically and reasonably shorten the drying time and reduce the production cost, and can reduce the risk of product collapse caused by overhigh temperature. (3) the efficiency of primary drying and the drying quality of the sample are improved by accurately controlling the change of vacuum degrees of different stages, namely, the primary drying early stage has a large amount of solvents in the product and the temperature of the product is lower, the sublimation of the solvent of the product in the stage has lower dependence on heat conduction, the invention utilizes higher vacuum degree to carry out sublimation drying on the product, can improve the drying rate of the product and better control the flux of freeze-dried paste in unit, the phenomena of bottle spraying, collapse, melting and the like of the product in the drying process are reduced; in the later stage of primary drying, when the sample approaches the end point of primary drying (i.e., step (2e)), the temperature is the main factor affecting the sublimation efficiency of the product. At this time, by reducing the vacuum degree of the drying environment and adding an inert heat transfer medium (such as nitrogen), the heat transfer efficiency can be improved, the heat conduction of the sample is promoted to be more uniform, and the sublimation of solvents such as moisture is facilitated. The one-time drying process adopts a gradient heating drying mode, accurately controls the process parameters such as temperature, heating rate, vacuum degree and the like of each stage in stages, has no phenomena of bottle spraying, collapse and atrophy in the freeze-drying process, has lower content of the tertiary butanol in the sample, and can obtain the freeze-dried product with intact framework and moisture content of less than or equal to 1.5 wt.% at the end point of one-time drying.
Preferably, in the step (2a), the temperature of the sample obtained in the step (1d) is increased to-31 to-30 ℃, and the sample is kept at-31 to-30 ℃ for 18 to 20 hours.
Preferably, in the step (2a), the temperature of the sample obtained in the step (1d) is raised at a temperature raising speed of 1-2.5 ℃/h.
Preferably, in the step (2b), the temperature of the sample obtained in the step (2a) is increased to-23 to-20 ℃, and the sample is kept at-23 to-20 ℃ for 3 to 4 hours.
Preferably, in the step (2b), the temperature of the sample obtained in the step (2a) is raised at a temperature raising rate of 1-1.8 ℃/h.
Preferably, in the step (2c), the temperature of the sample obtained in the step (2b) is increased to-12 to-10 ℃, and the sample is kept for 3-5 hours under the conditions of-12 to-10.
Preferably, in the step (2c), the temperature of the sample obtained in the step (2b) is increased at a temperature increasing rate of 8-10 ℃/h.
Preferably, in the step (2d), the temperature of the sample obtained in the step (2c) is raised to-3-0 ℃, and the sample is kept at-3-0 ℃ for 1-3 h.
Preferably, in the step (2d), the temperature of the sample obtained in the step (2c) is increased at a temperature increasing rate of 5-6 ℃/h.
Preferably, the steps (2a) - (2c) are dried by heating under the condition that the vacuum degree is 0.18-0.22 mbar.
Preferably, the step (2d) is dried by heating under the condition that the vacuum degree is 0.6-0.9 mbar.
In a preferred embodiment of the present invention, the desorption drying in step (3) comprises the steps of: (3a) heating the sample obtained in the step (2) to 25-27 ℃ under the condition that the vacuum degree is 0.5-1 mbar; keeping the temperature for 1 to 3 hours at the temperature of 25 to 27 ℃. In the analytic drying process, the low vacuum degree and the higher drying temperature are matched, so that the bound water in the product can be removed to the greatest extent, a better crystal grain skeleton structure is kept, and the moisture content in the finally prepared bortezomib freeze-dried preparation can be as low as 0.5 wt.% or less. Meanwhile, the vacuum degree is set to be 0.5-1 mbar, and compared with the primary drying stage, the inert heat transfer medium is added, so that the drying efficiency can be effectively improved.
Preferably, the degree of vacuum in the step (3a) is 0.8-1 mbar.
Preferably, in the step (3a), the temperature of the sample obtained in the step (2) is increased to 25-27 ℃; keeping the temperature for 1 to 3 hours at the temperature of 25 to 27 ℃.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the bortezomib freeze-drying process, the matching of low-temperature balance (namely the step (1a)), rapid cooling crystallization (the steps (1b) and (1d)) and a cooling crystallization process annealing process (the step (1c)) is adopted in the pre-freezing stage, so that crystal particles with uniform quality and a good crystal grain framework structure can be obtained, the formation of large crystal grains in the pre-freezing process can be effectively reduced, and the problems of poor clarity after product re-dissolution, long re-dissolution time, low primary drying efficiency, high moisture and solvent residues of a dried product, low esterification rate and the like caused by the phenomena of nonuniform crystallization, solute migration and the like are avoided, and the quality of the finished freeze-dried powder preparation is better.
2. In the primary drying process in the step (2), a gradient heating drying mode is adopted, the process parameters such as temperature, heating rate and vacuum degree of each stage are accurately controlled in stages, the phenomena of bottle spraying, collapse and atrophy are avoided in the freeze-drying process, the content of the tertiary butanol in the sample is lower, and the freeze-dried product with a complete crystal grain skeleton and the moisture content of less than or equal to 1.5 wt.% can be obtained at the primary drying end point.
3. In the analysis drying process in the step (3), through the cooperation of low vacuum degree and drying temperature, the bound water in the product can be removed to the greatest extent, a better crystal grain skeleton structure is kept, and the moisture content in the finally prepared bortezomib freeze-dried preparation can be as low as 0.5 wt.% or less. Meanwhile, the vacuum degree is set to be 0.5-1 mbar, and compared with the primary drying stage, the heat transfer medium is added, so that the drying efficiency can be effectively improved.
Description of the drawings:
fig. 1 is a schematic view of the microstructure of the finished lyophilized preparation obtained in example 1 under an electron microscope.
Fig. 2 is a schematic view of the microstructure of the finished lyophilized preparation obtained in comparative example 1 under an electron microscope.
FIG. 3 shows the samples obtained in the examples and comparative examples, and the reference formulation in the original research
A clarity contrast chart after redissolution (photographed by visual examination under 1000 lx-3000 lx); wherein, the identification reference information shown in fig. 3 is as follows;
1-clarity test pictures of samples prepared in example 1;
2-clarity test picture of sample prepared in example 2;
3-clarity test pictures of samples prepared in example 3;
VELCADE-PROGROUP REFERENCE PREPARATION
A clarity detection picture;
4-clarity test picture of sample prepared in comparative example 1;
5-clarity test picture of sample prepared in comparative example 2;
6-clarity test picture of sample prepared in comparative example 3;
7-clarity test picture of sample prepared in comparative example 4;
8-clarity test picture of sample prepared in comparative example 5.
Detailed Description
The present invention will be described in further detail with reference to test examples and specific embodiments. It should be understood that the scope of the above-described subject matter is not limited to the following examples, and any techniques implemented based on the disclosure of the present invention are within the scope of the present invention.
The liquid medicine treated by each example and comparative example of the invention consists of the following prescription:
| components | Dosage of |
| Bortezomib | 3.336mg (as boron)The amount of the Zomi monomer is 3.5mg) |
| Mannitol | 35mg |
| Tert-butyl alcohol | 1.09g |
| Water for injection | Adding to 3.5ml |
*: the tert-butyl alcohol and the water for injection are almost completely removed in the freeze drying process
Example 1
The lyophilization process of bortezomib for injection of example 1, comprising the steps of:
(1) pre-freezing:
(1a) cooling the liquid medicine from the normal temperature to-15 ℃ at a cooling rate of 4.6-5.6 ℃/min, and keeping the temperature at-15 ℃ for 2 h;
(1b) cooling the sample obtained in the step (1a) to-35 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 2.5 hours at-35 ℃;
(1c) heating the sample obtained in the step (1b) to-21 ℃ at a heating speed of 0.5-0.7 ℃/min, and keeping the temperature for 2 hours at-21 ℃;
(1d) cooling the sample obtained in the step (1c) to-38 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 3 hours at-38 ℃;
(2) primary drying:
(2a) heating the sample obtained in the step (1d) to-31 ℃ at a heating rate of 1-2.5 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 19h at-31 ℃;
(2b) heating the sample obtained in the step (2a) to-22 ℃ at a heating rate of 1-1.8 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-22 ℃;
(2c) heating the sample obtained in the step (2b) to-12 ℃ at a heating rate of 8-10 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-12 ℃;
(2d) heating the sample obtained in the step (2c) to-2 ℃ at a heating rate of 5-6 ℃/h under the condition that the vacuum degree is 0.8mbar, and keeping the temperature for 2h under the condition of-2 ℃;
(3) and (3) resolving and drying:
(3a) heating the sample obtained in the step (2) to 26 ℃ under the condition that the vacuum degree is 0.8 mbar; the temperature is kept at 26 ℃ for 2 h.
Example 2
The lyophilization process of bortezomib for injection of example 2, comprising the steps of:
(1) pre-freezing:
(1a) cooling the liquid medicine from the normal temperature to-14 ℃ at a cooling rate of 4.6-5.6 ℃/min, and keeping the temperature at-14 ℃ for 3 hours;
(1b) cooling the sample obtained in the step (1a) to-45 ℃ at a cooling speed of 1.8-3.1 ℃/min, and keeping the temperature for 3h at-45 ℃.
(1c) Heating the sample obtained in the step (1b) to-22 ℃ at a heating speed of 0.4-0.8 ℃/min, and keeping the temperature for 3 hours at-22 ℃.
(1d) Cooling the sample obtained in the step (1c) to-35 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 4h at-35 ℃.
(2) Primary drying:
(2a) heating the sample obtained in the step (1b) to-33 ℃ at a heating rate of 1-7.5 ℃/h under the condition that the vacuum degree is 0.15mbar, and keeping the temperature for 20h under the condition of-33 ℃;
(2b) heating the sample obtained in the step (2a) to-25 ℃ at a heating rate of 0.7-1.8 ℃/h under the condition that the vacuum degree is 0.15mbar, and keeping the temperature for 5h under the condition of-25 ℃;
(2c) heating the sample obtained in the step (2b) to-15 ℃ at a heating rate of 5-10 ℃/h under the condition that the vacuum degree is 0.15mbar, and keeping the temperature for 5h under the condition of-15 ℃;
(2d) heating the sample obtained in the step (2c) to 0 ℃ at a heating rate of 5-7.5 ℃/h under the condition that the vacuum degree is 1mbar, and keeping the temperature for 3h under the condition of-17 ℃;
(3) and (3) resolving and drying:
(3a) heating the sample obtained in the step (2) to 27 ℃ under the condition that the vacuum degree is 1 mbar; the temperature is kept at 27 ℃ for 3 h.
Example 3
The lyophilization process of bortezomib for injection of embodiment 3, comprising the steps of:
(1) pre-freezing:
(1a) cooling the liquid medicine from the normal temperature to-18 ℃ at a cooling rate of 4.6-5.6 ℃/min, and keeping the temperature at-18 ℃ for 1 h;
(1b) cooling the sample obtained in the step (1a) to-40 ℃ at a cooling speed of 1.8-3.1 ℃/min, and keeping the temperature for 2h at-40 ℃.
(1c) Heating the sample obtained in the step (1b) to-20 ℃ at a heating speed of 0.4-0.8 ℃/min, and keeping the temperature for 1h at-20 ℃.
(1d) And (3) cooling the sample obtained in the step (1c) to-45 ℃ at a cooling speed of 1.8-3.1 ℃/min, and keeping the temperature for 2h at-45 ℃.
(2) Primary drying:
(2a) heating the sample obtained in the step (1b) to-30 ℃ at a heating rate of 1-7.5 ℃/h under the condition that the vacuum degree is 0.25mbar, and keeping the temperature for 18h under the condition of-30 ℃;
(2b) heating the sample obtained in the step (2a) to-20 ℃ at a heating rate of 0.7-1.8 ℃/h under the condition that the vacuum degree is 0.25mbar, and keeping the temperature for 3h under the condition of-20 ℃;
(2c) heating the sample obtained in the step (2b) to-10 ℃ at a heating rate of 5-10 ℃/h under the condition that the vacuum degree is 0.25mbar, and keeping the temperature for 3h under the condition of-10 ℃;
(2d) heating the sample obtained in the step (2c) to-5 ℃ at a heating rate of 5-7.5 ℃/h under the condition that the vacuum degree is 0.5mbar, and keeping the temperature for 1h under the condition of-5 ℃;
(3) and (3) resolving and drying:
(3a) heating the sample obtained in the step (2) to 25 ℃ under the condition that the vacuum degree is 0.5 mbar; keeping at 25 ℃ for 1 h.
Comparative example 1
The freeze-drying process of bortezomib for injection of comparative example 1, comprising the steps of:
(1) pre-freezing:
(1a) cooling the liquid medicine from the normal temperature to-15 ℃ at a cooling rate of 4.6-5.6 ℃/min, and keeping the temperature at-15 ℃ for 2 h;
(1b) cooling the sample obtained in the step (1a) to-35 ℃ at a cooling speed of 0.1-0.3 ℃/min, and keeping the temperature for 2.5 hours at-35 ℃;
(1c) heating the sample obtained in the step (1b) to-21 ℃ at a heating speed of 0.5-0.7 ℃/min, and keeping the temperature for 2 hours at-21 ℃;
(1d) cooling the sample obtained in the step (1c) to-38 ℃ at a cooling speed of 0.1-0.3 ℃/min, and keeping the temperature for 3 hours at-38 ℃;
(2) primary drying:
(2a) heating the sample obtained in the step (1d) to-31 ℃ at a heating rate of 1-2.5 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 19h at-31 ℃;
(2b) heating the sample obtained in the step (2a) to-22 ℃ at a heating rate of 1-1.8 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-22 ℃;
(2c) heating the sample obtained in the step (2b) to-12 ℃ at a heating rate of 8-10 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-12 ℃;
(2d) heating the sample obtained in the step (2c) to-2 ℃ at a heating rate of 5-6 ℃/h under the condition that the vacuum degree is 0.8mbar, and keeping the temperature for 2h under the condition of-2 ℃;
(3) and (3) resolving and drying:
(3a) heating the sample obtained in the step (2) to 26 ℃ under the condition that the vacuum degree is 0.8 mbar; the temperature is kept at 26 ℃ for 2 h.
Comparative example 2
The lyophilization process of bortezomib for injection of comparative example 2, comprising the steps of:
(1) pre-freezing:
(1a) cooling the liquid medicine from the normal temperature to-15 ℃ at a cooling rate of 4.6-5.6 ℃/min, and keeping the temperature at-15 ℃ for 2 h;
(1b) cooling the sample obtained in the step (1a) to-35 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 2.5 hours at-35 ℃;
(1c) heating the sample obtained in the step (1b) to-21 ℃ at a heating speed of 0.5-0.7 ℃/min, and keeping the temperature for 2 hours at-21 ℃;
(1d) cooling the sample obtained in the step (1c) to-38 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 3 hours at-38 ℃;
(2) primary drying:
(2a) heating the sample obtained in the step (1d) to-31 ℃ at a heating rate of 1-2.5 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 19h at-31 ℃;
(2b) heating the sample obtained in the step (2a) to-22 ℃ at a heating rate of 1-1.8 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-22 ℃;
(2c) heating the sample obtained in the step (2b) to-12 ℃ at a heating rate of 8-10 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-12 ℃;
(2d) heating the sample obtained in the step (2c) to-2 ℃ at a heating rate of 5-6 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 2h under the condition of-2 ℃;
(3) and (3) resolving and drying:
(3a) heating the sample obtained in the step (2) to 26 ℃ under the condition that the vacuum degree is 0.2 mbar; the temperature is kept at 26 ℃ for 2 h.
Comparative example 3
The lyophilization process of bortezomib for injection of comparative example 3, comprising the steps of:
(1) pre-freezing:
(1a) cooling the liquid medicine from the normal temperature to-15 ℃ at a cooling rate of 4.6-5.6 ℃/min, and keeping the temperature at-15 ℃ for 2 h;
(1b) cooling the sample obtained in the step (1a) to-35 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 2.5 hours at-35 ℃;
(1c) heating the sample obtained in the step (1b) to-21 ℃ at a heating speed of 0.5-0.7 ℃/min, and keeping the temperature for 2 hours at-21 ℃;
(1d) cooling the sample obtained in the step (1c) to-38 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 3 hours at-38 ℃;
(2) primary drying:
(2a) heating the sample obtained in the step (1d) to-31 ℃ at a heating rate of 10-15 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 19h under the condition of-31 ℃;
(2b) heating the sample obtained in the step (2a) to-22 ℃ at a heating rate of 5-8 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-22 ℃;
(2c) heating the sample obtained in the step (2b) to-12 ℃ at a heating rate of 8-10 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-12 ℃;
(2d) heating the sample obtained in the step (2c) to-2 ℃ at a heating rate of 5-6 ℃/h under the condition that the vacuum degree is 0.8mbar, and keeping the temperature for 2h under the condition of-2 ℃;
(3) and (3) resolving and drying:
(3a) heating the sample obtained in the step (2) to 26 ℃ under the condition that the vacuum degree is 0.8 mbar; the temperature is kept at 26 ℃ for 2 h.
Comparative example 4
The lyophilization process of bortezomib for injection of comparative example 4, comprising the steps of:
(1) pre-freezing:
(1a) cooling the liquid medicine from the normal temperature to-15 ℃ at a cooling rate of 4.6-5.6 ℃/min, and keeping the temperature at-15 ℃ for 2 h;
(1b) cooling the sample obtained in the step (1a) to-38 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 3 hours at-38 ℃.
(2) Primary drying:
(2a) heating the sample obtained in the step (1d) to-31 ℃ at a heating rate of 1-2.5 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 19h at-31 ℃;
(2b) heating the sample obtained in the step (2a) to-22 ℃ at a heating rate of 1-1.8 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-22 ℃;
(2c) heating the sample obtained in the step (2b) to-12 ℃ at a heating rate of 8-10 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 4h under the condition of-12 ℃;
(2d) heating the sample obtained in the step (2c) to-2 ℃ at a heating rate of 5-6 ℃/h under the condition that the vacuum degree is 0.8mbar, and keeping the temperature for 2h under the condition of-2 ℃;
(3) and (3) resolving and drying:
(3a) heating the sample obtained in the step (2) to 26 ℃ under the condition that the vacuum degree is 0.8 mbar; the temperature is kept at 26 ℃ for 2 h.
Comparative example 5
(1) Pre-freezing:
(1a) cooling the liquid medicine from the normal temperature to-15 ℃ at a cooling rate of 4.6-5.6 ℃/min, and keeping the temperature at-15 ℃ for 2 h;
(1b) cooling the sample obtained in the step (1a) to-35 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 2.5 hours at-35 ℃.
(1c) Heating the sample obtained in the step (1b) to-21 ℃ at a heating speed of 0.5-0.7 ℃/min, and keeping the temperature for 2 hours at-21 ℃.
(1d) And (3) cooling the sample obtained in the step (1c) to-38 ℃ at a cooling speed of 2.3-2.7 ℃/min, and keeping the temperature for 3 hours at-38 ℃.
(2) Primary drying:
(2a) heating the sample obtained in the step (1d) to-12 ℃ at a heating rate of 1-10 ℃/h under the condition that the vacuum degree is 0.2mbar, and keeping the temperature for 27h under the condition of-12 ℃;
(2b) heating the sample obtained in the step (2a) to-2 ℃ at a heating rate of 5-6 ℃/h under the condition that the vacuum degree is 0.8mbar, and keeping the temperature for 2h under the condition of-2 ℃;
(3) and (3) resolving and drying:
(3a) heating the sample obtained in the step (2) to 26 ℃ under the condition that the vacuum degree is 0.8 mbar; the temperature is kept at 26 ℃ for 2 h.
Experimental results and analysis:
the samples obtained in the step (3) of the respective examples and comparative examples are detected and analyzed, the experimental data are shown in the table 1, and the reference preparation in the original research is added
As a control test sample (
-china, specification: 3.5 mg; the validity period is as follows: month 1 2021, lot number: IBZWL 00; the certificate holder: Janssen-Cilag International N.V.).
TABLE 1
Referring to the above experimental data, the results of the experimental data are as follows:
1. the products obtained in examples 1 to 3 are superior to those obtained in comparative examples 1 to 5 in properties, clarity and color of redissolving solution, freeze-drying behavior (bottle spraying rate), moisture, tert-butanol residue, redissolving time, and related substances.
2. Compared with the freeze-dried product in the embodiment 1, the solvent residue (particularly tertiary butanol) is obviously increased, the redissolution time is obviously prolonged, the clarity is poor, the esterification rate is reduced to a certain extent, and the product has the phenomenon of atrophy.
3. Compared with the freeze-dried product in the example 1, the solvent residue of the comparative example 2 is obviously increased, the turbidity of the liquid after redissolution is slightly increased and the esterification rate is greatly reduced compared with the example 1.
4. Compared with the freeze-dried product in the embodiment 1, the comparative example 3 has the bottle spraying phenomenon in the freeze-drying process, the dissolution residue is obviously increased, the redissolution time of the freeze-dried product is also obviously prolonged, the clarity is deteriorated, the esterification rate is greatly reduced, and the product has the atrophy phenomenon.
5. Compared with the freeze-dried product in the embodiment 1, the comparative example 4 has the advantages that the phenomenon of severe bottle spraying exists in the freeze-drying process, the dissolution residue is obviously increased, the redissolution time of the freeze-dried product is also obviously prolonged, the clarity is poor, the esterification rate is greatly reduced, and the product has the phenomenon of atrophy.
6. Compared with the freeze-dried product in the embodiment 1, the comparative example 5 has the phenomena of bottle spraying in the freeze-drying process, obvious increase of the dissolution residue, obvious prolongation of the redissolution time of the freeze-dried product, serious deterioration of the clarity, obvious reduction of the esterification rate, atrophy of the product, melting at the bottom and the like.
In conclusion, the invention carries out optimization design from each link of pre-freezing to primary drying, the quality indexes of the freeze-dried finished product in the aspects of freeze-drying behavior (bottle spraying phenomenon), product skeleton structure, dissolution residue (water and tert-butyl alcohol), redissolution time, clarity of the liquid medicine after redissolution, esterification rate, related substances and the like are all obviously improved, the obtained freeze-dried product has stable quality, and particularly, the clarity is better than that of a reference preparation
Referring to the drawings, FIG. 1 is a schematic view of the microstructure of the freeze-dried product obtained in example 1 observed under an electric microscope. FIG. 1 shows that the freeze-dried product obtained in example 1 has uniform crystal grains and forms a uniform lamellar skeleton structure. FIG. 2 is a schematic view of the microstructure of the freeze-dried product obtained in comparative example 1 observed under an electric microscope. Fig. 2 shows that the freeze-dried product obtained in comparative example 1 has larger grains and local melting phenomenon, and is shown as a particle aggregation skeleton structure formed by larger crystals. FIG. 3 shows examples 1 to 3, comparative examples 1 to 5 and reference preparations
The clarity conditions after redissolution (observed under 1000 lx-3000 lx illumination condition of a clarity instrument) show that the clarity of the examples 1-3 is less than 0.5#, which is slightly superior to that of the reference preparation
(clarity 0.5#), whereas the comparative example clarity is slightly worse,the quality of the bortezomib freeze-dried powder injection for injection obtained by the freeze-drying process is better.
Claims (7)
1. A freeze-drying process of bortezomib for injection comprises the following steps: (1) pre-freezing; (2) primary drying; (3) resolving and drying; the method is characterized in that the pre-freezing in the step (1) comprises the following steps:
(1a) cooling the liquid medicine from the normal temperature to-18 to-14 ℃, and keeping the liquid medicine at the temperature of-18 to-14 ℃ for 1 to 3 hours;
(1b) cooling the sample obtained in the step (1a) to-45 to-35 ℃ at a cooling speed of 2.3 to 2.7 ℃/min, and keeping the sample at the temperature of-45 to-35 ℃ for 2 to 3 hours;
(1c) heating the sample obtained in the step (1b) to-22 to-20 ℃ at a heating speed of 0.4 to 0.8 ℃/min, and keeping the temperature for 1 to 3 hours at the temperature of-22 to-20 ℃;
(1d) reducing the temperature of the sample obtained in the step (1c) to-45 to-35 ℃ at a cooling speed of 2.3 to 2.7 ℃/min, and keeping the sample at the temperature of-45 to-35 ℃ for 2 to 4 hours;
the primary drying of the step (2) comprises the following steps:
(2a) heating the sample obtained in the step (1b) to-33 to-30 ℃ at a heating speed of 1 to 7.5 ℃/h under the condition that the vacuum degree is 0.15 to 0.25mbar, and keeping the temperature for 18 to 20h under the conditions of-33 to-30 ℃;
(2b) heating the sample obtained in the step (2a) to-25 to-20 ℃ at a heating speed of 0.7 to 1.8 ℃/h under the condition that the vacuum degree is 0.15 to 0.25mbar, and keeping the temperature for 3 to 5 hours under the conditions of-25 to-20 ℃;
(2c) heating the sample obtained in the step (2b) to-15 to-10 ℃ at a heating speed of 5 to 10 ℃/h under the condition that the vacuum degree is 0.15 to 0.25mbar, and keeping the temperature for 3 to 5h under the condition of-15 to-10 ℃;
(2d) heating the sample obtained in the step (2c) to-5-0 ℃ at a heating rate of 5-7.5 ℃/h under the condition that the vacuum degree is 0.5-1 mbar, and keeping the temperature for 1-3 h under the condition of-5-0 ℃;
the bortezomib comprises the following components:
The desorption drying in the step (3) comprises the following steps: (3a) heating the sample obtained in the step (2) to 25-27 ℃ under the condition that the vacuum degree is 0.5-1 mbar; keeping the temperature for 1 to 3 hours at the temperature of 25 to 27 ℃.
2. The lyophilization process of bortezomib for injection as claimed in claim 1, wherein: in the step (1a), the temperature of the liquid medicine is reduced to-15 to-18 ℃ from normal temperature, and the liquid medicine is kept for 1 to 3 hours under the conditions of-15 to-18 ℃.
3. The lyophilization process of bortezomib for injection as claimed in claim 1, wherein: in the step (1b), the temperature of the sample obtained in the step (1a) is reduced to-37 to-35 ℃.
4. The lyophilization process of bortezomib for injection as claimed in claim 1, wherein: in the step (2a), the sample obtained in the step (1d) is heated at a heating rate of 1-2.5 ℃/h.
5. The lyophilization process of bortezomib for injection as claimed in claim 1, wherein: in the step (2b), the sample obtained in the step (2a) is heated at a heating rate of 1-1.8 ℃/h.
6. The lyophilization process of bortezomib for injection as claimed in claim 1, wherein: in the step (2c), the sample obtained in the step (2b) is heated at a heating rate of 8-10 ℃/h.
7. The lyophilization process of bortezomib for injection as claimed in claim 1, wherein: heating and drying the steps (2a) - (2c) under the condition that the vacuum degree is 0.18-0.22 mbar; and (2d) heating and drying under the condition that the vacuum degree is 0.6-0.9 mbar.
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| CN103585018A (en) * | 2013-11-01 | 2014-02-19 | 北京阜康仁生物制药科技有限公司 | New freeze-drying method for reduced glutathione for injection |
| CN106310217A (en) * | 2015-06-16 | 2017-01-11 | 北京济美堂医药研究有限公司 | Freeze-drying process for preparation of bortezomib for injection |
| JP2017218399A (en) * | 2016-06-06 | 2017-12-14 | 富士製薬工業株式会社 | Lyophilized preparation containing bortezomib and method for producing the same |
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| CN106309385B (en) * | 2016-10-18 | 2018-02-06 | 江苏豪森药业集团有限公司 | Bortezomib freeze drying powder injection and its preparation technology |
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