Process for producing pravastatin on large scale

A pravastatin and process technology, applied in the field of drug preparation, can solve the problems of operating temperature and time affecting product yield and quality, restricting the large-scale production and application of pravastatin, microorganisms that cannot tolerate addition, etc., to achieve improved drug resistance performance and transformation ability, improve production efficiency and output, and realize the effect of resource reuse

Active Publication Date: 2016-08-03
GUANGDONG BLUE TREASURE PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] According to the published patents, the above-mentioned molds, filamentous bacteria, actinomycetes and streptomyces can all convert compatin into pravastatin. Even the low concentration of compestin in the medium, the tolerance concentration of the microbial transformation bacteria to the substrate compestin under the prior art is 0.01-0.05%
Streptomyces defoliate YJ-118 obtained by Li Zhouling et al. (WO98 / 45410) showed higher (0.1-0.5%) substrate resistance, Metkinen (MetkinenNewsMarch2000, MetkinenOy, Finland; reviewedbyManzonianandRollini, 2002, ApplMicrobiolBiotechnol58:555-564) A Streptomyces mutant strain resistant to 3g / L Compactin was also obtained, but its pravastatin yield was not high
WO96 / 40863 discloses the method that actinomycetes madura (Actinomadura) ATCC55678 transforms compatin to produce pravastatin, and Chinese patent CN102757986B discloses that actinomycetes madura is used as a transformation bacterium, and a trace element solution is used in the fermentation process to improve At the same time, it also studied the beneficial effect of controlling the growth temperature of bacteria and the conversion temperature of compatin on the improvement of pravastatin production in the fermentation process. Through this process, the conversion rate of compatin reached more than 70%. The fermented production level of pravastatin is above 18g / L. However, the formula of the trace element solution is complicated, the preparation process is cumbersome, it is easy to cause operational errors, and the cost of raw materials is high, which limits the large-scale production and application of pravastatin
[0007] At the same time, after the fermentation process of using actinomyces madura to transform compatin to produce pravastatin, it is necessary to extract and refine the fermentation broth to obtain the final product. However, the organic solvent used in the process of extracting and refining pravastatin from the fermentation broth , operating temperature and time, etc. will all have an impact on the yield and quality of the product, and there is no complete set of pravastatin production process in the prior art

Method used

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  • Process for producing pravastatin on large scale

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Experimental program
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Embodiment 1

[0041] Embodiment 1, the technique of large-scale production of pravastatin of the present invention

[0042] Specific steps are as follows:

[0043] S1. Fermentation:

[0044] A1. Seed culture: Use a 5L shaker flask to prepare 3L seed medium. The formulation of the seed medium is as follows: glucose 24g / L, yeast extract 22g / L, soybean peptone 6g / L, K 2 HPO 4 ·3H 2 O2g / L, MgSO 4 ·7H 2 00.5g / L and defoamer 1.0g / L, adjust pH7.0; Inoculate Actinomyces madurai in the seed culture medium, cultivate 48 hours at 33~35 DEG C on a shaker after the inoculation, obtain seed liquid;

[0045] A2. Fermentation culture: Prepare 30L fermentation medium with a 50L automatic fermentation tank. The formula of the fermentation medium is as follows: glucose 56g / L, yeast extract 20g / L, soybean peptone 6g / L, K 2 HPO 4 ·3H 2 O1g / L, MgSO 4 ·7H 2 O1g / L, (NH 4 ) 2 SO 4 1g / L, plant extract 4ml / L and defoamer 1.0g / L, adjust the pH to 7.0; inoculate 2.5L of the seed solution obtained from A1 i...

Embodiment 2

[0059] Embodiment 2, the technique of large-scale production of pravastatin of the present invention

[0060] Specific steps are as follows:

[0061] S1. Fermentation:

[0062] A1. Seed culture: Use a 5L shaker flask to prepare 3L seed medium. The formulation of the seed medium is as follows: glucose 26g / L, yeast extract 20g / L, soybean peptone 8g / L, K 2 HPO 4 ·3H 2 O1g / L, MgSO 4 ·7H 2 O1g / L and defoamer 1.0g / L, adjust pH7.2; Inoculate Actinomyces madurai in the seed culture medium, after the inoculation, cultivate at 33~35 DEG C on a shaker for 72 hours to obtain the seed liquid;

[0063] A2. Fermentation culture: Prepare 30L fermentation medium with a 50L automatic fermentation tank. The formula of the fermentation medium is as follows: glucose 60g / L, yeast extract 24g / L, soybean peptone 8g / L, K 2 HPO 4 ·3H 2 O2g / L, MgSO 4 ·7H 2 O0.5g / L, (NH 4 ) 2 SO 4 2g / L, plant extract 8ml / L and defoamer 1.0g / L, adjust the pH to 7.2; inoculate 2.5L of the seed solution obtaine...

Embodiment 3

[0077] Embodiment 3, the technique of large-scale production of pravastatin of the present invention

[0078] Specific steps are as follows:

[0079] S1. Fermentation:

[0080] A1. Seed culture: Use a 5L shaker flask to prepare 3L seed medium. The formula of the seed medium is as follows: glucose 25g / L, yeast extract 20g / L, soybean peptone 7g / L, K 2 HPO 4 ·3H 2 O1g / L, MgSO 4 ·7H 2 00.5g / L and defoamer 1.0g / L, adjust pH7.0; Inoculate Actinomyces madurai in the seed culture medium, cultivate 72 hours in shaking table at 33~35 ℃ after the inoculation, obtain seed liquid;

[0081] A2. Fermentation culture: prepare 30L fermentation medium with 50L automatic fermentation tank, the formula of fermentation medium is as follows: glucose 58g / L, yeast extract 22g / L, soybean peptone 7g / L, K 2 HPO 4 ·3H 2 O1g / L, MgSO 4 ·7H 2 O0.5g / L, (NH 4 ) 2 SO 4 1g / L, plant extract 6ml / L and antifoaming agent 1.0g / L, adjust the pH to 7.0; inoculate 2.5L of the seed solution obtained from A1...

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Abstract

The invention discloses a process for producing pravastatin on a large scale. The process comprises the steps of fermenting, extracting and refining, wherein a plant extracting solution composed of an exocarpium benincasae extracting solution and a water melon peel extracting solution is used in the fermentation process, drug resistance and the conversion capacity of microorganisms to the substrate compactin and the fermentation level of pravastatin are effectively improved, the yield of pravastatin is increased, and in the steps of extracting and refining, the pH value of the solution, types and dosage of organic solvent, extracting time and temperature, cooling operation and crystallization time are controlled strictly to ensure the yield and purity of pravastatin. The process is stable, cost is low, and large-scale industrial production of pravastatin is achieved.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a process for large-scale production of pravastatin. Background technique [0002] Pravastatin is a 3-hydroxy 3-methylglutaryl-CoA reductase inhibitor, initially used to treat hyperlipidemia and familial hypercholesterolemia, and later the indications continued to expand, it can slow down the development of atherosclerosis, reduce Coronary atherosclerotic lesions and clinical cardiovascular events. [0003] The production of pravastatin is usually obtained by a two-step fermentation process, although there are also reports or patents (WO99 / 10499, WO2007 / 147827, US6,274,360 and EP1,266,967) describing that the method for one-step fermentation can be used to produce pravastatin, but due to technical For reasons such as complexity and production efficiency, the industrial production of pravastatin is still based on two-step fermentation. [0004] The two-step fermenta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/62C12N1/20C12N1/38C07C67/48C07C67/52C07C67/56C07C69/33C12R1/03
CPCC07C67/48C07C67/52C07C67/56C12N1/20C12N1/38C12P7/62C07C69/33
Inventor 徐会根罗定军黄智勇陈继敏李耀荣熊志叶家雄
Owner GUANGDONG BLUE TREASURE PHARMA
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