A kind of lyophilization process of bortezomib for injection

A technology for bortezomib and injection, applied in the field of freeze-drying technology, can solve the problems of poor quality of freeze-dried finished products, low freeze-drying efficiency, low resolubility, etc., and avoid uneven crystallization, long reconstitution time, ester The effect of low conversion rate

Active Publication Date: 2020-09-04
SICHUAN HUIYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The object of the present invention is to overcome the above-mentioned deficiencies of the low freeze-drying efficiency of bortezomib existing in the prior art and the poor quality of the resulting freeze-dried product, and provide a freeze-drying process of bortezomib for injection. While improving the freeze-drying efficiency, the obtained freeze-dried finished product has lower residual water and tert-butanol, and better resolubility

Method used

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  • A kind of lyophilization process of bortezomib for injection
  • A kind of lyophilization process of bortezomib for injection
  • A kind of lyophilization process of bortezomib for injection

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Effect test

Embodiment 1

[0066] The lyophilization process of the bortezomib for injection of embodiment 1 comprises the following steps:

[0067] (1) Pre-freezing:

[0068] (1a) Lower the liquid medicine from room temperature to -15°C at a cooling rate of 4.6-5.6°C / min, and keep at -15°C for 2 hours;

[0069] (1b) Cool the sample obtained in step (1a) to -35°C at a cooling rate of 2.3-2.7°C / min, and keep it at -35°C for 2.5h;

[0070] (1c) heating the sample obtained in step (1b) to -21°C at a heating rate of 0.5-0.7°C / min, and keeping it at -21°C for 2 hours;

[0071] (1d) Cool the sample obtained in step (1c) to -38°C at a cooling rate of 2.3-2.7°C / min, and keep it at -38°C for 3 hours;

[0072] (2) Once dry:

[0073] (2a) Under the condition of vacuum degree of 0.2mbar, the temperature of the sample obtained in step (1d) is raised to -31°C at a heating rate of 1-2.5°C / h, and kept at -31°C for 19h;

[0074] (2b) Under the condition of a vacuum degree of 0.2mbar, the temperature of the sampl...

Embodiment 2

[0080] The freeze-drying process of the bortezomib for injection of embodiment 2 comprises the following steps:

[0081] (1) Pre-freezing:

[0082] (1a) Lower the liquid medicine from room temperature to -14°C at a cooling rate of 4.6-5.6°C / min, and keep at -14°C for 3 hours;

[0083] (1b) Cool the sample obtained in step (1a) to -45°C at a cooling rate of 1.8-3.1°C / min, and keep at -45°C for 3h.

[0084] (1c) Heat the sample obtained in step (1b) to -22°C at a heating rate of 0.4-0.8°C / min, and keep at -22°C for 3h.

[0085] (1d) Cool the sample obtained in step (1c) to -35°C at a cooling rate of 2.3-2.7°C / min, and keep at -35°C for 4h.

[0086] (2) Once dry:

[0087] (2a) Under the condition of vacuum degree of 0.15mbar, the temperature of the sample obtained in step (1b) is raised to -33°C at a heating rate of 1-7.5°C / h, and kept at -33°C for 20h;

[0088] (2b) Under the condition of vacuum degree of 0.15mbar, the temperature of the sample obtained in step (2a) is r...

Embodiment 3

[0094] The lyophilization process of the bortezomib for injection of embodiment 3 comprises the following steps:

[0095] (1) Pre-freezing:

[0096] (1a) Lower the liquid medicine from room temperature to -18°C at a cooling rate of 4.6-5.6°C / min, and keep at -18°C for 1 hour;

[0097] (1b) Cool the sample obtained in step (1a) to -40°C at a cooling rate of 1.8-3.1°C / min, and keep at -40°C for 2h.

[0098] (1c) Heat the sample obtained in step (1b) to -20°C at a heating rate of 0.4-0.8°C / min, and keep it at -20°C for 1 hour.

[0099] (1d) Cool the sample obtained in step (1c) to -45°C at a cooling rate of 1.8-3.1°C / min, and keep at -45°C for 2h.

[0100] (2) Once dry:

[0101] (2a) Under the condition of a vacuum degree of 0.25mbar, the temperature of the sample obtained in step (1b) is raised to -30°C at a heating rate of 1-7.5°C / h, and kept at -30°C for 18h;

[0102] (2b) Under the condition of a vacuum degree of 0.25mbar, the temperature of the sample obtained in ste...

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Abstract

The invention discloses a freeze-drying technology of bortezomib for injection. The freeze-drying technology comprises the steps of (1) pre-freezing; (2) primary drying; (3) resolution drying, whereinthe step of pre-freezing comprises the following sub-steps that (1a) the temperature of medicine liquid is lowered to -18--14 DEG C from room temperature and kept for 1-3 hours; (1b) the sample obtained in the sub-step (1a) is cooled to -45--35 DEG C at the cooling speed higher than or equal to 1.8 DEG C / min, and the temperature is kept for 2-3 hours; (1c) the sample obtained in the sub-step (1b)is heated to -22--20 DEG C, and the temperature is kept for 2-4 hours; (1d) the sample obtained in the sub-step (1c) is cooled to -45--35 DEG C, and the temperature is kept for 2-4 hours. According to the freeze-drying technology for the bortezomib, by optimizing the pre-freezing process and the primary drying process, the problems are effectively solved that in the pre-freezing process, due to surface concentration and a non-uniform crystalline structure, the freeze-drying efficiency is low, and a freeze-dried product is poor in clarity, slow in redissolution and high in water and solvent residue rate and the like, and the freeze-dried product is excellent in quality in various aspects.

Description

technical field [0001] The invention relates to a freeze-drying process, in particular to a freeze-drying process of bortezomib for injection. Background technique [0002] Bortezomib is the world's first synthetic proteasome inhibitor (proteasome inhibitor), which can reversibly inhibit the chymotrypsin-like activity of 26S proteasome in mammalian cells, and can delay and treat the progression of multiple myeloma and mantle cell lymphoma. In vitro experiments have demonstrated that bortezomib is cytotoxic to various types of cancer cells. In vivo experiments in preclinical tumor models demonstrated that bortezomib can delay the growth of tumors, including multiple myeloma. [0003] Bortezomib was first developed by Myogenics in the United States and was acquired by Millennium in 1999. After that, Millennium Pharmaceuticals cooperated with Johnson & Johnson to continue clinical research. In May 2003, the FDA first approved bortezomib for injection (NDA: 021602) to be mark...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/05A61K9/19A61K47/10A61P35/00F26B5/06
CPCA61K9/0019A61K9/19A61K38/05A61K47/10A61P35/00F26B5/06
Inventor 余俐佳丁兆胡和平杨仁明
Owner SICHUAN HUIYU PHARMA
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