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Preparation with bortezomib as active ingredient and preparation method thereof

A technology of bortezomib and active ingredients, which is applied in the field of freeze-dried powder preparations and its preparation, can solve the problems of slow dissolution rate of bortezomib, poor clarity, and poor water solubility of bortezomib, and achieve long preparation time and preparation The effect of stabilizing and reducing the hidden dangers of medication

Active Publication Date: 2017-05-17
YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] An object of the present invention is to provide a preparation with bortezomib as the active ingredient, which solves the problems of poor water solubility of bortezomib and poor clarity after reconstitution of lyophilized products, while avoiding the use of tert-butanol and taking into account Solubility and Stability of Bortezomib
[0011] Another object of the present invention is to provide a kind of freeze-dried powder preparation with bortezomib as active ingredient, to solve the problem of slow dissolution rate in the preparation process of bortezomib, improve the stability of bortezomib preparation, and related substances reduce to a lower level

Method used

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  • Preparation with bortezomib as active ingredient and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0037] Weigh 35g of mannitol and dissolve in 1600ml (80% of the full prescription) of hot water for injection, stir until completely dissolved, add 3.2g of activated carbon for needles, keep warm, stir for 15 minutes, filter and decarbonize, cool to 15°C, and set aside .

[0038] Under the protection of nitrogen, weigh bortezomib and dissolve it in 3.5g, and dissolve it with 14ml of 5M hydrochloric acid solution (it can be dissolved after standing), then slowly add the bortezomib solution dropwise into the aqueous solution for injection containing mannitol under stirring, And ultrasonic 3min, can be completely dissolved.

[0039] Then add activated carbon for needles to a content of 0.05w / v%, stir for 10 minutes, and decarbonize by filtration. Add water for injection to the filtrate to 2000ml (full prescription), stir evenly, and adjust the pH to 3.46.

[0040] Finally, the freeze-dried powder injection was prepared as follows: filter with a 0.22 μm filter membrane, fill in ...

Embodiment 2

[0043] Weigh 17g of mannitol and dissolve it in 1600ml (80% of the full prescription) of hot water for injection, stir until completely dissolved, add 5g of activated carbon for needles, keep warm, stir for 15 minutes, filter and decarbonize, and cool to 15 under the protection of nitrogen. ℃, spare.

[0044] Under the protection of nitrogen, weigh bortezomib and dissolve it in 3.5g, and dissolve it with 140ml of 0.1M sodium hydroxide solution, then add the bortezomib solution into the aqueous solution for injection containing mannitol under stirring, and stir to make it uniform.

[0045] Then add activated carbon for needles to a content of 0.1w / v%, stir for 15 minutes, and filter for decarbonization. Add water for injection to the obtained filtrate to 2000ml (that is, the full prescription), stir evenly, and adjust the pH to 5.45.

[0046] Finally, the freeze-dried powder injection was prepared as follows: filter with a 0.22 μm filter membrane, fill in vials, each bottle co...

Embodiment 3

[0049] Weigh 70g of mannitol and dissolve it in 1200ml (60% of the full prescription) of hot water for injection, stir until completely dissolved, filter, cool to 15°C under nitrogen protection, and set aside.

[0050] Under the protection of nitrogen, weigh bortezomib and dissolve it in 3.5 g, and dissolve it with 450 ml of absolute ethanol; add the bortezomib solution to the aqueous solution for injection containing mannitol under stirring, and stir to make it uniform.

[0051] Add water for injection to the filtrate to 2000ml (full prescription), stir evenly, and adjust the pH to 4.25. Filter with a 0.22 μm filter membrane, fill in vials, each bottle contains bortezomib 3.5 mg, half-stoppered, and freeze-dry in a lyophilizer according to the following process: plate temperature drops to -25°C, and keep warm for 120 minutes , then lowered to -45°C, and maintained for 120 minutes, pre-vacuumized, the plate temperature rose to -35°C, kept for 15 hours, then raised to 25°C, kep...

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Abstract

A preparation taking bortezomib as an active composition contains bortezomib, a solubilizer and an excipient, wherein the excipient is one or more selected from mannitol, low-molecular dextran, lactose, sorbitol and glucose. The provided preparation taking bortezomib as the active composition has good redissolving property and the total impurity content less than 0.4%, the problem that the dissolving speed is slow during bortezomib preparation is solved, the stability of the bortezomib preparation is improved, and related substances are reduced to a relatively low level (the total related substances content is less than 0.7% after acceleration is performed at 40 DEG C for 3 months).

Description

technical field [0001] The invention relates to a pharmaceutical composition, in particular to a freeze-dried powder preparation with bortezomib as an active ingredient and a preparation method thereof. Background technique [0002] Bortezomib, whose chemical name is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl)amino] Propyl] amino] butyl] boronic acid (CAS: 179324-69-7), a proteasome inhibitor first developed by Millennium Pharmaceuticals in the United States and marketed in May 2003, is used for the treatment of relapsed and refractory Treated multiple myeloma. Bortezomib is unstable to acid and alkali, easy to be oxidized and decomposed, and also easy to hydrolyze (CN103142509), and it is relatively sensitive to heat, so terminal sterilization process is not suitable. Therefore, it is difficult to make it into injection water injection, and mostly adopt aseptic freeze-dried powder injection. [0003] Velcade is a common trade name for bortezomib preparat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/19A61K47/26A61K47/36A61K31/69A61K38/05A61P35/00
Inventor 郑璐吴斌邹华生姚书扬张益波高苇
Owner YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA