CN108977474A - A kind of preparation method of mevastatin - Google Patents
A kind of preparation method of mevastatin Download PDFInfo
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- CN108977474A CN108977474A CN201810361111.3A CN201810361111A CN108977474A CN 108977474 A CN108977474 A CN 108977474A CN 201810361111 A CN201810361111 A CN 201810361111A CN 108977474 A CN108977474 A CN 108977474A
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Abstract
The present invention relates to a kind of preparation method of mevastatin, for the preparation method using Penicillium citrinum as strain, fermented and cultured obtains mevastatin；In the fermentation medium for cultivating the Penicillium citrinum, sodium acetate and/or sodium citrate are added.Preparation method of the present invention effectively improves the production yields of mevastatin, greatly reduces production cost.
Description
Technical field
The present invention relates to a kind of preparation method of mevastatin more particularly to a kind of mevastatin is prepared by fermentation method
Method.
Background technique
Mevastatin (mevastatin) is the suppression of HMG-CoA (3- hydroxy-3-methyl-glutaryl coacetylase) reductase
Preparation (HMG-CoA-RI) quasi-microorganism drug, it can be obtained with inverted bacterium hydroxylating, and new and effective hypolipidemic is general to cut down him
Spit of fland.Mevastatin is there are also many non-effect for reducing fat simultaneously, such as anti-osteoporosis, antitumor.Mevastatin mainly uses Penicillium citrinum
Bacterium (Penicillium citrinum) is produced through deep fermentation.But generally existing mevastatin yield in producing at present
Relatively low, the problems such as production cost is higher.
Summary of the invention
Technology based on the above background, the purpose of the present invention is to provide a kind of preparation methods of mevastatin；The preparation
Method can effectively improve the production yields of mevastatin, to reduce production cost.
For preparation method of the present invention using Penicillium citrinum as strain, fermented and cultured obtains mevastatin；Cultivating the tangerine
In the fermentation medium of mould, sodium acetate and/or sodium citrate are added.
The present invention during the fermentation, adds sodium acetate and/or sodium citrate, can effectively improve the yield of mevastatin；
And after fermentation starts, adds sodium acetate and/or sodium citrate, effect are more preferably more significant.
Wherein, the fermentation medium includes following parts by weight of component: 18-22 parts of sucrose, 3-5 parts of dregs of beans, yeast extract
0.4-0.6 parts, 0.8-1.2 parts of peptone, 0.08-0.12 parts of NaCl, MgSO40.04-0.06 parts, KH2PO4 0.04-0.06
Part, NaNO30.08-0.12 parts, 70-80 parts of water；
Preferably, the fermentation medium includes following parts by weight of component: 20 parts of sucrose, 4 parts of dregs of beans, yeast extract 0.5
Part, 1 part of peptone, 0.1 part of NaCl, MgSO40.05 part, KH2PO40.05 part, NaNO30.1 part, 70-80 parts of water.
Present invention further propose that, the additive amount of the sodium acetate is the 0.05-1.50% (w/w) of the culture medium,
Preferably 0.1-1.0% (w/w), more preferably 0.5-0.7% (w/w).
Wherein, add the sodium acetate time be fermentation after the 0-120 hour, preferably fermentation after 0-72
A hour, the 24-48 hour after more preferably fermenting.
Present invention further propose that, the additive amount of the sodium citrate is the 0.05-1.50% (w/ of the culture medium
W), preferably 0.1-1.2% (w/w), more preferably 0.9-1.1% (w/w).
Wherein, add the sodium citrate time be fermentation after the 0-120 hour, preferably fermentation after 0-
72 hours, the 24-48 hour after more preferably fermenting.
Present invention further propose that, sodium acetate and sodium citrate, the acetic acid are added in the fermentation medium simultaneously
The additive amount of sodium is 0.05-1.50% (w/w), and the additive amount of sodium citrate is 0.05-1.50% (w/w)；
Preferably, the additive amount of the sodium acetate is 0.1-1.0% (w/w), and the additive amount of sodium citrate is 0.1-1.0%
(w/w)；
It is highly preferred that the additive amount of the sodium acetate is 0.5-0.7% (w/w), the additive amount of sodium citrate is 0.5-
0.7% (w/w).
Wherein, the time for adding the sodium acetate and sodium citrate is the 0-120 hour after fermentation, is preferably fermented
The 0-72 hour afterwards, the 40-55 hour after more preferably fermenting.
Sodium acetate and sodium citrate are added in the fermentation medium of penicillium citrinum (Penicillium citrinum),
The yield of mevastatin can be significantly improved, the raising of yield is up to 17%；Its most suitable additive amount, most suitable addition time are respectively as follows:
0-72 hours addition weight percent are the sodium acetate of the 0.10-1.00% of fermentation medium；0-72 hours addition weight percents
Than the sodium citrate of the 0.10-1.00% for fermentation medium.
Wherein, the fermentation process that this field routine can be used in the fermentation condition of the culture is selected, and the present invention is preferred
It uses following fermentation condition: under conditions of pH value is 20-30 DEG C for 5.5-6.5, temperature, being fermented with the revolving speed of 200-300rpm
Culture 200-260 hours；
Preferably, under conditions of pH value is 6.0, temperature is 24 ± 1 DEG C, with the revolving speed of 240-260rpm, fermented and cultured
220-250 hours.
In preparation method of the present invention, it is seeded to before fermentation medium to also typically include strain is seeded to seed culture
Preculture is carried out in base, then the seed liquor obtained after culture is inoculated in fermentation medium again, then carries out fermented and cultured.
The preculture specifically: Penicillium citrinum strain is seeded in seed culture medium, 24-26 DEG C at a temperature of, with
The revolving speed culture of 150-300rpm 96-120 hours.
Preferably, Penicillium citrinum seed liquor obtained after preculture is seeded to fermented and cultured by the inoculum concentration of 10-20%
In base.
The present invention provides a kind of preferred embodiment, the preparation method specifically: Penicillium citrinum strain is seeded to seed
Preculture is carried out in culture medium, is seeded to seed liquor is obtained after preculture in fermentation medium by the inoculum concentration of 10-20%,
Under conditions of pH value is 5.5-6.5, temperature is 20-30 DEG C, with the revolving speed of 240-260rpm, fermented and cultured 220-250 hours；?
The 0-72 hour after fermentation adds sodium acetate and/or the lemon of 0.10-1.00% (w/w) into the fermentation medium
Sour sodium；
Most preferably add the sodium acetate and/or sodium citrate of 0.9-1.1% (w/w).
In preparation method of the present invention, the step for carrying out separating-purifying after fermenting to fermentation liquid is normally also included
Suddenly.Such as fermentation liquid is filtered, extract, be concentrated, crystallize, is dried, to obtain mevastatin finished product.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described.It should be understood that following embodiment is merely to illustrate this
Invention is not for limiting the scope of the invention.
Unless otherwise indicated, % used in following embodiment is weight percentage.
The Penicillium citrinum strain that following embodiment uses derives from Beijing University's medicine Chongqing Daxin Pharmaceutical Co., Ltd strain
Center.The Penicillium citrinum seed liquor used in following embodiment obtains as follows: by penicillium citrinum (Penicillium
Citrinum) inclined-plane (i.e. strain) is inoculated in shake-flask seed culture medium, 25 ± 1 DEG C at a temperature of, shaking speed 250rpm,
Period 96-120 hour is to get Penicillium citrinum seed liquor.
The fermentation medium weight percent that following embodiment uses are as follows: sucrose 20%, dregs of beans 4%, yeast extract
0.5%, peptone 1%, NaCl 0.1%, MgSO40.05%, KH2PO40.05%, NaNO30.1%, surplus is water.
The assay of mevastatin is detected using HPLC in following embodiment.
Embodiment 1
The present embodiment provides a kind of preparation method of mevastatin, specifically: by penicillium citrinum seed liquor by 10-20%'s
Inoculum concentration is seeded in fermentation medium, under conditions of pH value is 6.0, temperature is 24 ± 1 DEG C, with the revolving speed of 250rpm, hair
Ferment culture 220 hours；
The 0th hour (when just starting fermentation) after fermentation, into the fermentation medium, addition accounts for the hair
The sodium acetate that ferment culture medium weight ratio is 0.05%.
Embodiment 2-6
The present embodiment provides a kind of preparation methods of mevastatin, and the addition of sodium acetate is only that with the difference of embodiment 1
Amount is different, respectively 0.10%, 0.30%, 0.60%, 1.00%, 1.50%.
As control the content of embodiment 1-6 mevastatin is measured by sampling, such as in fermentation medium not add sodium acetate
Following table:
Table 1
By the result of table 1 as it can be seen that addition sodium acetate can significantly improve the biosynthesis of mevastatin in the fermentation medium,
Preferred additive amount range is 0.10-1.00%.
Embodiment 7
The present embodiment provides a kind of preparation method of mevastatin, specifically: by penicillium citrinum seed liquor by 10-20%'s
Inoculum concentration is seeded in fermentation medium, under conditions of pH value is 6.0, temperature is 24 ± 1 DEG C, with the revolving speed of 250rpm, hair
Ferment culture 250 hours；
The 0th hour (when just starting fermentation) after fermentation, into the fermentation medium, addition accounts for the hair
The sodium acetate that ferment culture medium weight ratio is 0.6%.
Embodiment 8-12
The present embodiment provides a kind of preparation methods of mevastatin, and the addition of sodium acetate is only that with the difference of embodiment 7
Time is different, the 24th, 48,72,96,120 hour after respectively fermenting.
The content of embodiment 7-12 mevastatin is measured by sampling as control in fermentation medium not add sodium acetate,
It is as follows:
Table 2
From the result of table 2 as it can be seen that beauty can be significantly improved by adding sodium acetate into fermentation medium at fermentation 0-120 hours
The biosynthesis of statin is cut down, it is preferred to add the time as 0-72 hours after fermentation.
Embodiment 13
The present embodiment provides a kind of preparation method of mevastatin, specifically: by penicillium citrinum seed liquor by 10-20%'s
Inoculum concentration is seeded in fermentation medium, under conditions of pH value is 6.0, temperature is 24 ± 1 DEG C, with the revolving speed of 250rpm, hair
Ferment culture 230 hours；
The 0th hour (when just starting fermentation) after fermentation, into the fermentation medium, addition accounts for the hair
The sodium citrate that ferment culture medium weight ratio is 0.05%.
Embodiment 14-18
The present embodiment provides a kind of preparation method of mevastatin, the difference with embodiment 13 is only that adding for sodium citrate
Dosage is different, respectively 0.10%, 0.30%, 0.60%, 1.00%, 1.50%.
Fermentation medium not add sodium citrate is measured by sampling embodiment 13-18 content, is as follows: as control
Table 3
By the result of table 3 as it can be seen that the biology that addition sodium citrate can significantly improve mevastatin in the fermentation medium closes
At preferred additive amount range is 0.10-1.00%.
Embodiment 19
The present embodiment provides a kind of preparation method of mevastatin, specifically: by penicillium citrinum seed liquor by 10-20%'s
Inoculum concentration is seeded in fermentation medium, under conditions of pH value is 6.0, temperature is 24 ± 1 DEG C, with the revolving speed of 250rpm, hair
Ferment culture 240 hours；
The 0th hour (when just starting fermentation) after fermentation, into the fermentation medium, addition accounts for the hair
The sodium citrate that ferment culture medium weight ratio is 1%.
Embodiment 20-24
The present embodiment provides a kind of preparation method of mevastatin, the difference with embodiment 19 is only that adding for sodium citrate
24th, 48,72,96,120 hours different between added-time, after respectively fermenting.
Containing for embodiment 19-24 mevastatin is measured by sampling as control in fermentation medium not add sodium citrate
Amount, is as follows:
Table 4
From the result of table 4 as it can be seen that adding sodium citrate into fermentation medium at fermentation 0-120 hours can significantly improve
The biosynthesis of mevastatin, preferred addition time are 0-72 hours after fermentation.
Embodiment 25
The present embodiment provides a kind of preparation method of mevastatin, specifically: by penicillium citrinum seed liquor by 10-20%'s
Inoculum concentration is seeded in fermentation medium, under conditions of pH value is 6.0, temperature is 24 ± 1 DEG C, with the revolving speed of 250rpm, hair
Ferment culture 240 hours；
The 0th hour (when just starting fermentation) after fermentation, into the fermentation medium, while addition accounts for institute
Stating fermentation medium weight ratio is 0.05% sodium acetate and 0.05% sodium citrate.
Embodiment 26-30
The present embodiment provides a kind of preparation method of mevastatin, the difference with embodiment 25 is only that, sodium acetate and lemon
The additive amount of lemon acid sodium is different, respectively 0.10%, 0.30%, 0.60%, 1.00%, 1.50% sodium acetate and citric acid
Sodium；
Fermentation medium not add sodium citrate and sodium acetate is measured by sampling embodiment 25-30 U.S.A and cuts down as control
The content of statin, is as follows:
Table 5
By the result of table 5 as it can be seen that U.S.A can be significantly improved and cut down by adding sodium acetate and sodium citrate simultaneously in the fermentation medium
The biosynthesis of statin, preferred dosage range are the 0.10-1.00% of fermentation medium
Embodiment 31
The present embodiment provides a kind of preparation method of mevastatin, specifically: by penicillium citrinum seed liquor by 10-20%'s
Inoculum concentration is seeded in fermentation medium, under conditions of pH value is 6.0, temperature is 24 ± 1 DEG C, with the revolving speed of 250rpm, hair
Ferment culture 250 hours；
The 0th hour (when just starting fermentation) after fermentation, into the fermentation medium, while addition accounts for institute
Stating fermentation medium weight ratio is 0.6% sodium acetate and 0.6% sodium citrate.
Embodiment 32-36
The present embodiment provides a kind of preparation method of mevastatin, the difference with embodiment 31 is only that, is added while being added
Add sodium acetate and sodium citrate time difference, the 24th, 48,72,96,120 hour after respectively fermenting.
Embodiment 31-36 is measured by sampling as control medium in fermentation medium sodium citrate and sodium acetate is not added
The content of mevastatin, is as follows:
Table 6
From the result of table 6 as it can be seen that adding sodium acetate and sodium citrate simultaneously into fermentation medium at fermentation 0-120 hours
The biosynthesis of mevastatin can be significantly improved, the preferred addition time is 0-72 hours.
Comparative example 1
Preparation and condition of culture of this comparative example with embodiment 1-6 are completely the same, and difference is only that, sodium acetate is replaced
For sodium formate.Influence of the sodium formate additive amount to mevastatin yield is as follows:
Table 7
Comparative example 2
Preparation and condition of culture of this comparative example with embodiment 1-6 are completely the same, and difference is only that, sodium acetate is replaced
For sodium propionate.Influence of the sodium propionate additive amount to mevastatin yield is as follows:
Table 8
Although above having used general explanation, specific embodiment and test, the present invention is made to retouch in detail
It states, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Range.
Claims (10)
1. a kind of preparation method of mevastatin, using Penicillium citrinum as strain, fermented culture obtains mevastatin, and feature exists
In, in the fermentation medium for cultivating the Penicillium citrinum, addition sodium acetate and/or sodium citrate.
2. preparation method according to claim 1, which is characterized in that the fermentation medium includes following parts by weight group
Point: 18-22 parts of sucrose, 3-5 parts of dregs of beans, 0.4-0.6 parts of yeast extract, 0.8-1.2 parts of peptone, 0.08-0.12 parts of NaCl,
MgSO40.04-0.06 parts, KH2PO40.04-0.06 parts, NaNO30.08-0.12 parts, 70-80 parts of water；
Preferably, the fermentation medium includes following parts by weight of component: 20 parts of sucrose, 4 parts of dregs of beans, 0.5 part of yeast extract, egg
1 part of white peptone, 0.1 part of NaCl, MgSO40.05 part, KH2PO40.05 part, NaNO30.1 part, 70-80 parts of water.
3. preparation method according to claim 1 or 2, which is characterized in that the additive amount of the sodium acetate is the culture
The 0.05-1.50% (w/w) of base, preferably 0.1-1.0% (w/w), more preferably 0.5-0.7% (w/w).
4. preparation method according to claim 1-3, which is characterized in that add the time of the sodium acetate as hair
The 0-120 hour after ferment, the 0-72 hour after preferably fermenting, the 24-48 hour after more preferably fermenting.
5. preparation method according to claim 1-4, which is characterized in that the additive amount of the sodium citrate is institute
State the 0.05-1.50% (w/w) of culture medium, preferably 0.1-1.2% (w/w), more preferably 0.9-1.1% (w/w).
6. preparation method according to claim 1-5, which is characterized in that the time for adding the sodium citrate is
The 0-120 hour after fermentation, the 0-72 hour after preferably fermenting, 24-48 after more preferably fermenting are small
When.
7. preparation method according to claim 1-6, which is characterized in that added simultaneously in the fermentation medium
Sodium acetate and sodium citrate, the time for adding the sodium acetate and sodium citrate is the 0-120 hour after fermentation, the second
The additive amount of sour sodium is 0.05-1.50% (w/w), and the additive amount of sodium citrate is 0.05-1.50% (w/w)；
The 0-72 hour after preferably fermenting, the additive amount of the sodium acetate are 0.1-1.0% (w/w), sodium citrate
Additive amount is 0.1-1.0% (w/w)；
The 40-55 hour after more preferably fermenting, the additive amount of the sodium acetate are 0.5-0.7% (w/w), sodium citrate
Additive amount be 0.5-0.7% (w/w).
8. preparation method according to claim 1-7, which is characterized in that the condition of the culture are as follows: in pH value
Under conditions of being 20-30 DEG C for 5.5-6.5, temperature, with the revolving speed of 200-300rpm, fermented and cultured 200-260 hours；
Preferably, under conditions of pH value is 6.0, temperature is 24 ± 1 DEG C, with the revolving speed of 240-260rpm, fermented and cultured 220-
250 hours.
9. preparation method according to claim 1-8, which is characterized in that further include before being seeded to fermentation medium
Strain is seeded in seed culture medium and carries out preculture；
Preferably, the preculture specifically: Penicillium citrinum strain is seeded in seed culture medium, 24-26 DEG C at a temperature of,
With revolving speed culture 96-120 hours of 150-300rpm；
It is highly preferred that the Penicillium citrinum seed liquor after the preculture is seeded in fermentation medium by the inoculum concentration of 10-20%.
10. -9 described in any item preparation methods according to claim 1, which is characterized in that Penicillium citrinum strain is seeded to seed
Preculture is carried out in culture medium, is seeded to seed liquor is obtained after preculture in fermentation medium by the inoculum concentration of 10-20%,
Under conditions of pH value is 5.5-6.5, temperature is 20-30 DEG C, with the revolving speed of 240-260rpm, fermented and cultured 220-250 hours；?
The 0-72 hour after fermentation adds the sodium acetate and/or citric acid of 0.1-1.0% (w/w) into the fermentation medium
Sodium；
Preferably add the sodium acetate and/or sodium citrate of 0.9-1.1% (w/w).
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1953233A1 (en) * | 2007-02-02 | 2008-08-06 | LEK Pharmaceuticals d.d. | Fermentation process for preparing pravastatin |
| CN103865809A (en) * | 2014-03-10 | 2014-06-18 | 福州大学 | Novel anti-tumor application of penicillium enol B1 from penicillium citrinum |
-
2018
- 2018-04-20 CN CN201810361111.3A patent/CN108977474A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1953233A1 (en) * | 2007-02-02 | 2008-08-06 | LEK Pharmaceuticals d.d. | Fermentation process for preparing pravastatin |
| CN103865809A (en) * | 2014-03-10 | 2014-06-18 | 福州大学 | Novel anti-tumor application of penicillium enol B1 from penicillium citrinum |
Non-Patent Citations (3)
| Title |
|---|
| AHMAD,A. ET AL: "Screening of nutrient parameters for mevastatin production by Penicillium citrinum MTCC 1256 under submerged fermentation using the Plackett-Burman design", 《J PHARM BIOALLIED SCI.》 * |
| 张怡: "基于代谢途径的前体对美伐他汀生物合成的影响", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
| 胡一峰等: "美伐他汀发酵菌种筛选和发酵条件优化", 《浙江化工》 * |
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Application publication date: 20181211 |