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Method for preparing high-purity daptomycin

A daptomycin, high-purity technology, applied in the field of preparation of high-purity daptomycin, can solve the problems of daptomycin difficult to achieve large-scale production, no post-industrial extraction technology, no good industrial production strains, etc. , achieve the effect of shortening the process cycle, stable sample yield and low toxicity

Active Publication Date: 2013-02-13
NCPC NEW DRUG RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these two patented technologies simplify the process and reduce the cost, it is still difficult to realize industrial production
Daptomycin is difficult to achieve large-scale production, one is because there is no good industrial production strain, and the other is because there is no suitable post-industrial extraction technology

Method used

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  • Method for preparing high-purity daptomycin
  • Method for preparing high-purity daptomycin

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Take 100 L of daptomycin fermentation broth with a fermentation unit of 1960 μg / mL, add 3000 g of perlite as a filter aid to the above fermentation broth, stir for 1 hour, and then plate and frame filter to obtain daptomycin filtrate. Introduce the daptomycin filtrate into a macroporous resin D312 column (loading capacity: 20L) at a flow rate of 40L / h for adsorption and enrichment. The flow rate was controlled at 10 L / h, and the collection was started when the concentration of daptomycin in the desorbed liquid detected by HPLC was higher than 200 μg / mL, and the collection was stopped when the concentration was lower than 200 μg / mL. The collected desorbed solution was concentrated under reduced pressure until the concentration of daptomycin was 120 g / L to obtain a concentrated solution of daptomycin. Then slowly add acetone of 7 times the volume of the concentrated solution for crystallization, filter the crystallized solution, and dry at 45°C to obtain 195 g of crude da...

Embodiment 2

[0028] 10 L of daptomycin fermentation broth with a fermentation unit of 2060 μg / mL was used, and 100 g of perlite was added to the fermentation broth as a filter aid, stirred for 30 minutes and then vacuum filtered to obtain a daptomycin filtrate. This daptomycin filtrate is introduced into a macroporous resin LX-50 column with a loading capacity of 2000mL at a flow rate of 4L / h for adsorption and enrichment. After the adsorption is completed, it is washed with methanol aqueous solution with a volume concentration of 30%, and then washed with a volume concentration of 30%. 70% methanol aqueous solution was used for desorption, and the desorption flow rate was controlled at 1 L / h. When the concentration of daptomycin in the desorption liquid detected by HPLC was higher than 200 μg / mL, the desorption liquid was collected, and when the concentration was lower than 200 μg / mL, the collection was stopped. Concentrate the above desorption solution under reduced pressure at 50°C until...

Embodiment 3

[0031] Take 10 L of daptomycin fermentation broth with a fermentation unit of 2300 μg / mL, add 200 g of diatomaceous earth as a filter aid to the fermentation broth, stir for 30 minutes, and then vacuum filter to obtain daptomycin filtrate. The filtrate was introduced into a macroporous resin D113 column with a capacity of 2000mL at a flow rate of 4L / h for adsorption and enrichment. After the adsorption was completed, it was first washed with 40% ethanol aqueous solution, and then desorbed with 75% ethanol aqueous solution. The desorption flow rate was controlled at 1L / h h, when the concentration of daptomycin in the desorbed solution detected by HPLC was higher than 200 μg / mL, the collection was started, and when the concentration was lower than 200 μg / mL, the collection was stopped. After the desorption is completed, the collected desorption liquid is concentrated under reduced pressure to a concentration of 110 g / L of daptomycin, and then slowly add isopropanone in an amount ...

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Abstract

The invention discloses a method for preparing high-purity daptomycin. The method includes steps of crude extraction and fine extraction on filtrate of daptomycin fermentation liquor, wherein the crude extraction includes guiding the daptomycin filtrate into large-pore adsorption resins for adsorbing, desorbing the resins which are saturated in adsorbing through strippant in gradient mode, then performing decompressed concentration, crystallization and drying on the stripping liquid to obtain crude daptomycin; and the fine extraction includes dissolving the crude daptomycin through polar solvents, filling the obtained dissolving solution into a polymer nanometer microsphere pillar for chromatographic separation, performing gradient eluting on the polymer nanometer microshpere pillar through elution agents, collecting the elution solution with the high performance liquid chromatography (HPLC) content larger than or equal to 98.5%, and performing decompressed concentration, crystallization and drying on the eluting solution to obtain daptomycin products with the preparation purity higher than 98.5%. The method for preparing high-purity daptomycin is easy and convenient to operate, stable in yield, low in cost and suitable for producing the daptomycin products in industrial scale production mode.

Description

technical field [0001] The invention relates to the technical field of industrial microorganisms, in particular to a preparation method of high-purity daptomycin. Background technique [0002] Daptomycin is a member of the lipopeptide family, which belongs to the ring ten lipopeptide structure group, and is fermented by Streptomyces roseosporus. It is currently the world's first successfully developed ring lipopeptide antibiotic. Daptomycin has a novel structure and a unique bactericidal mechanism. It can destroy the function of bacterial cell membranes in many aspects and kill Gram-positive bacteria. effective for a long time. The chemical formula of daptomycin is C 72 h 101 N 17 o 26 , the molecular weight is 1620.67, and its structural formula is as follows: [0003] [0004] Daptomycin was discovered by Eli Lilly and Company in the late 1980s. In 1997, Cubist obtained the global exclusive right to develop, produce and sell daptomycin. After six years of in vitr...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/16C07K1/14
Inventor 段宝玲张雪霞任风芝李晓露朱秀良李宁陈书红成晓迅林毅王海燕李丽红张艳立董爱华
Owner NCPC NEW DRUG RES & DEV
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