Method for preparing bendamustine hydrochloride freeze-dried preparation

A technology of bendamustine hydrochloride and freeze-dried preparations, which is applied in the field of preparation of pharmaceutical compositions, can solve problems such as difficult cakes, potential safety hazards, and difficulties in reconstitution, and achieve low organic solvent residues and slow down hydrolysis The effect of speed and low impurity content

Active Publication Date: 2010-12-15
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The above technical solutions all use the organic solvent tert-butanol, which has a relatively high freezing point of 24°C, and the temperature of the pharmaceutical production workshop is controlled at 18-26°C. Under normal production conditions, tert-butanol is prone to icing and crystallization Phenomenon, which seriously hinders the preparation in the normal production process
In addition, since tert-butanol is not recorded in the Pharmacopoeia, there is no pharmaceutical grade tert-butanol available on the market, and tert-butanol is more toxic than ethanol, and there is a safety hazard in using it in injections
Similarly, hydroxypropyl β-cyclodextrin also has safety problems in the preparation of injections, and the main adverse reactions are nephrotoxicity and hemolytic toxicity.
[0010] Among alcohol solvents, ethanol has low toxicity and is the most commonly used pharmaceutical reagent, but the above-mentioned patent CN101119708A believes that high concentration of ethanol produces cakes that are not attractive in appearance and are difficult to redissolve. The dry formulation produces a collapsed cake and is difficult to reconstitute, taking more than 45 minutes to completely dissolve

Method used

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  • Method for preparing bendamustine hydrochloride freeze-dried preparation
  • Method for preparing bendamustine hydrochloride freeze-dried preparation
  • Method for preparing bendamustine hydrochloride freeze-dried preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] Preparation Process:

[0039] Quickly dissolve bendastine hydrochloride in 0.45L of medicinal ethanol, then add it into 1.05L of water for injection in which 42.5g of mannitol has been dissolved, mix well, store at 5°C, filter and sterilize, sub-package, and send to freezer drying machine, freeze-drying to remove ethanol and water, and obtain a freeze-dried preparation of bendamustine hydrochloride.

[0040]The freeze-drying process includes the following steps: sending the subpackaged pre-freeze-drying solution into the freeze-drying box, turning on the freeze-drying machine circulation pump, compressor, and plate cooling valve, and quickly freeze-drying to -45°C, and keeping it for 5 Hours; open the condensation valve and vacuum system, control the vacuum at 20Pa, slowly enter the first drying stage, control the temperature of the freeze-dried sample at -20°C, and dry for 12 hours; quickly enter the second drying stage, and control the temperature of the f...

Embodiment 2

[0042]

[0043] Preparation Process:

[0044] Quickly dissolve bendastine hydrochloride in 0.375L of medicinal ethanol, then add it into 1.125L of water for injection in which 50g of lactose has been dissolved, mix well, store at 8°C, filter and sterilize, sub-package, and send it to a freeze dryer , and freeze-drying to remove ethanol and water to prepare a freeze-dried preparation of bendamustine hydrochloride.

[0045] The freeze-drying process includes the following steps: sending the subpackaged pre-freeze-drying solution into the freeze-drying box, turning on the freeze-drying machine circulation pump, compressor, and plate cooling valve, and quickly freeze-drying to -40°C, keeping the temperature for 6 Hours; open the condensation valve and vacuum system, control the vacuum degree at 20Pa, slowly enter the first drying stage, control the temperature of the freeze-dried sample at -30°C, and dry for 10 hours; quickly enter the second drying stage, and control the tempe...

Embodiment 3

[0047]

[0048] Preparation Process:

[0049] Quickly dissolve bendustine hydrochloride in 0.525L of medicinal ethanol, then add it into 0.975L of water for injection in which 37.5g of mannitol has been dissolved, mix well, store at 3°C, filter and sterilize, subpackage, and send to freezer drying machine, freeze-drying to remove ethanol and water, and obtain a freeze-dried preparation of bendamustine hydrochloride.

[0050] The freeze-drying process includes the following steps: sending the subpackaged pre-freeze-drying solution into the freeze-drying box, turning on the freeze-drying machine circulation pump, compressor, and plate cold valve, and rapidly freeze-drying to -50°C, and keeping it for 4 Hours; open the condensation valve and vacuum system, control the vacuum at 30Pa, slowly enter the first drying stage, control the temperature of the freeze-dried sample at -25°C, and dry for 11 hours; quickly enter the second drying stage, and control the temperature of the fr...

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Abstract

The invention discloses a method for preparing bendamustine hydrochloride freeze-dried preparation. In the method, the bendamustine hydrochloride is dissolved in medicinal ethanol first and then mixed with water-containing solution, and the mixture is stored at low temperature, so long-time contact between the bendamustine hydrochloride and water is prevented, and the hydrolyzation speed of the bendamustine hydrochloride is reduced because of the low-temperature storage. Moreover, for improving the situation that stable freeze-dried preparation with high re-dissolubility and beautiful appearance cannot be obtained by using organic solvent ethanol in the prior art, the inventor, through deep study, finds that the stable freeze-dried preparation with high re-dissolubility and beautiful appearance can be realized by using the safe medicinal ethanol. The bendamustine hydrochloride freeze-dried preparation prepared by the method has the advantages of low impurity content, low organic solvent residue content, high stability, beautiful appearance, high re-dissolubility and applicability to clinical application and industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical composition, and further relates to a preparation method of a bendamustine hydrochloride freeze-dried preparation. Background technique [0002] Bendamustine hydrochloride was first developed in the early 1860s by Ozegowski et al. at the Microbiology Experimental Association of the University of Jena, Germany. It is a bifunctional alkylating agent with a new mechanism of action and has anti-tumor and cell-killing effects. . The anti-tumor and cytocidal effects are mainly due to the cross-linking of DNA single strands and double-links through alkylation, disrupting the function of DNA and DNA synthesis, causing cross-links between DNA and proteins and between proteins and proteins, thereby exerting Antitumor effect. Its structural formula is as follows: [0003] [0004] Bendamustine hydrochloride was first developed in the early 1860s by Ozegowski and his colleagues at the Microbio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/19A61K31/4184A61K47/02A61K47/10A61K47/16A61K47/26A61K47/36A61P35/00
Inventor 卓秋琪曾嘉铨张汉利宝玉荣
Owner 深圳万乐药业有限公司
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