CN108753878A - The fermentation process of micafen sodium intermediate - Google Patents
The fermentation process of micafen sodium intermediate Download PDFInfo
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- CN108753878A CN108753878A CN201810536318.XA CN201810536318A CN108753878A CN 108753878 A CN108753878 A CN 108753878A CN 201810536318 A CN201810536318 A CN 201810536318A CN 108753878 A CN108753878 A CN 108753878A
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- fermentation
- soybean lecithin
- zymotic fluid
- methyl hexadecanoate
- fermentation process
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
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- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
The invention discloses a kind of fermentation process of completely new FR901379.Methyl hexadecanoate is added as FR901379 fatty acid side chain precursor substances in this method in FR901379 fermentation process, promotes the biosynthesis of FR901379.It is introduced and the immiscible soybean lecithin of reaction solution in zymotic fluid simultaneously.Methyl hexadecanoate is in addition to as fermentation precursor, also it reduces gas-liquid together as the carrier of oxygen in fermentation system with soybean lecithin and passes oxygen resistance, solve the problems, such as that prior art fermentation process dissolved oxygen is insufficient, the fermentation yield for improving FR901379, reduces production cost.
Description
Technical field
The present invention relates to field of microbial fermentation, and in particular to the preparation of antimycotic fermentation semisynthetic drug precursor, more
More particularly to the fermentation process of micafen sodium intermediate FR901379.
Background technology
In recent years, since immunocompromised patient increases year by year, fungal infection incidence is significantly raised, especially deep fungal
The incidence and case fatality rate of infection dramatically increase.Echinocandin class antibiotic is that one group found the 1970s naturally produces
Object has similar ring type polypeptide core and different fatty acid side chains, can inhibit fungal cell wall β -1 noncompetitively,
The activity of 3- glucan synthases, to reach antimycotic purpose.Compared with conventional antifungal drug, such drug, which has, to be made
With mechanism uniqueness, toxic side effect is low, and has very strong antibacterial activity to some azoles and the drug resistant fungi of amphotericin B, is
The common drug of clinical treatment deep fungal infection at present.This kind of drug of FDA approveds listing includes Caspofungin
(Caspofungin), mikafen (Micafungin) and anidulafungin (Anidulafungin).Mikafen pharmaceutical salts are
Micafen sodium.
FR901379 is the important precursor for synthesizing mikafen class drug, is obtained after mutated by C.empetri
Superior strain fermentation gained.FR901379 obtains mikafen parent nucleus FR179642 after removing side chain by deacylase,
FR179642 is by being chemically modified to obtain micafen sodium.
The structure of FR901379 is as follows：
USP5502033, EP0431350A1 are disclosed using Coleophoma empetri F-11899 fermenting and producings
The process of FR901379, fermentation medium include basic carbon nitrogen source, inorganic salts, unit 100mg/L.CN201010571797.2
Disclose a kind of culture medium using Coleophoma empetri F-11899 fermenting and producings FR901379, optimize carbon source and
Organic nitrogen source, unit are increased to 300~400mg/L.But in the technology of existing fermenting and producing FR901379, however it remains due to
The growth characteristics of der Pilz in zymotic fluid, zymotic fluid viscosity is excessively high, and oxygen transmission effect is poor, and dissolved oxygen is relatively low, to inhibit bacterium
Body cometabolism, the problem for causing FR901379 fermentation units relatively low.
201010571797.2 provide one kind gives birth to for bacterial strain Coleophoma empetri F-11899 or its variant
The fermentation medium of FR901379 is produced, the fermentation medium contains carbon source, organic nitrogen source, inorganic salts and metal ion.Fermentation
Potency is 300~400mg/L.
201611019780.X provides a kind of culture medium and its method of fermenting and producing FR901379, the group of the culture medium
As fructose, corn protein powder, casein, Yeast protein peptone, magnesium sulfate, dipotassium hydrogen phosphate, calcium carbonate, antifoaming agent, water, into one
Step includes adding fructose and hydrogen peroxide during the fermentation, and by the improvement to fermentation medium, the yield of FR901379 is higher,
Unit reaches 3.0~3.4g/L.But the nutrition of this method zymotic fluid is excessively abundant, it is big to put tank Fungal biodiversity, isolates and purifies into
This is higher.
Based on to expanding production, the needs of cost are reduced, in the production field of mikafen, it is still desirable to more preferably
The fermentation process of FR901379.
Invention content
The purpose of the present invention is to provide a kind of fermentation process of completely new FR901379.This method is fermented in FR901379
Methyl hexadecanoate is added in the process as FR901379 fatty acid side chain precursor substances, promotes the biosynthesis of FR901379.Together
When in zymotic fluid introduce with the immiscible soybean lecithin of reaction solution.Methyl hexadecanoate in addition to as fermentation precursor, also and greatly
Beans lecithin reduces gas-liquid and passes oxygen resistance, it is molten to solve prior art fermentation process together as the carrier of oxygen in fermentation system
The problem of hypoxgia, improves the fermentation yield of FR901379, reduces production cost.
The bacterium source that the present invention uses is Coleophoma empetri F-11899.The invention is realized in this way：
1) preparation of fermentation medium, is carried out using condition well known to those skilled in the art, it may for example comprise but be not limited to
Fermentation medium disclosed in 201010571797.2.
2) bacterial strain Coleophoma empetri seed culture fluids, are inoculated in fermentation medium to ferment.
3), after 24~72h of fermented and cultured, added into zymotic fluid 3~10% mass volume ratios methyl hexadecanoate and
Soybean lecithin mixture.In the methyl hexadecanoate and soybean lecithin mixture, mass volume ratio shared by soybean lecithin
It is 10~30%.
4), when ferment 160h after, when the concentration of FR901379 no longer increases, fermentation ends.
By the method for the invention, FR901379 puts tank concentration up to 3.24-3.51g/L, and cost is relatively low.
Specific embodiment
It present invention will be described in detail below.However, the present invention may be embodied as many different forms,
And it is not necessarily limited in embodiment described herein, and it is to make disclosure to provide the purpose in these embodiments
More completely with comprehensively.Agents useful for same and raw material, except providing preparation method, remaining is commercially available.Unless otherwise defined,
Otherwise the meaning and the normally understood meaning of claim theme technical field personnel that all scientific and technical terminologies have herein
It is identical.
Embodiment 1
Cultured seed is transferred to 120 DEG C of sterilizing 30min postcoolings of 30L to 24-26 DEG C with 5% (v/v) ratio
In fermentation medium, which forms, and quality (g)/volume (L) ratio is：Glucose 50, cottonseed meal 20, yeast powder
10, peptone 10, magnesium sulfate 2, dipotassium hydrogen phosphate 1, calcium carbonate 4, antifoaming agent 1, remaining is water.
24-26 DEG C of temperature is controlled in fermentation process, ventilatory capacity 1VVM, initial speed 150rpm regulate and control rotating speed 150 in the process
Dissolved oxygen is set to be not less than 20% between~600rpm.
Methyl hexadecanoate and soybean lecithin are configured to solution according to mass volume ratio shared by soybean lecithin for 20%
It is for use after 120 DEG C of sterilizing 30min.
After fermented and cultured 48h, methyl hexadecanoate and the soybean lecithin that 8% mass volume ratio is added into zymotic fluid are mixed
Close object.
Fermentation period is 8 days, measures FR901379 and puts a concentration of 3.51g/L of tank.
Embodiment 2
Cultured seed is transferred to 120 DEG C of sterilizing 30min postcoolings of 30L to 24-26 DEG C with 5% (v/v) ratio
In fermentation medium, which forms, and quality (g)/volume (L) ratio is：Glucose 50, cottonseed meal 20, yeast powder
10, peptone 10, magnesium sulfate 2, dipotassium hydrogen phosphate 1, calcium carbonate 4, antifoaming agent 1, remaining is water.
24-26 DEG C of temperature is controlled in fermentation process, ventilatory capacity 1VVM, initial speed 150rpm regulate and control rotating speed 150 in the process
Dissolved oxygen is set to be not less than 20% between~600rpm.
Methyl hexadecanoate and soybean lecithin are configured to solution according to mass volume ratio shared by soybean lecithin for 10%
It is for use after 120 DEG C of sterilizing 30min.
After fermented and cultured 48h, the methyl hexadecanoate and soybean lecithin of 10% mass volume ratio are added into zymotic fluid
Mixture.
Fermentation period is 8 days, measures FR901379 and puts a concentration of 3.24g/L of tank.
Embodiment 3
Cultured seed is transferred to 120 DEG C of sterilizing 30min postcoolings of 30L to 24-26 DEG C with 5% (v/v) ratio
In fermentation medium, which forms, and quality (g)/volume (L) ratio is：Glucose 50, cottonseed meal 20, yeast powder
10, peptone 10, magnesium sulfate 2, dipotassium hydrogen phosphate 1, calcium carbonate 4, antifoaming agent 1, remaining is water.
24-26 DEG C of temperature is controlled in fermentation process, ventilatory capacity 1VVM, initial speed 150rpm regulate and control rotating speed 150 in the process
Dissolved oxygen is set to be not less than 20% between~600rpm.
Methyl hexadecanoate and soybean lecithin are configured to solution according to mass volume ratio shared by soybean lecithin for 30%
It is for use after 120 DEG C of sterilizing 30min.
After fermented and cultured 48h, methyl hexadecanoate and the soybean lecithin that 3% mass volume ratio is added into zymotic fluid are mixed
Close object.
Fermentation period is 8 days, measures FR901379 and puts a concentration of 3.43g/L of tank.
Embodiment 4
Cultured seed is transferred to 120 DEG C of sterilizing 30min postcoolings of 30L to 24-26 DEG C with 5% (v/v) ratio
In fermentation medium, which forms, and quality (g)/volume (L) ratio is：Glucose 50, cottonseed meal 20, yeast powder
10, peptone 10, magnesium sulfate 2, dipotassium hydrogen phosphate 1, calcium carbonate 4, antifoaming agent 1, remaining is water.
24-26 DEG C of temperature is controlled in fermentation process, ventilatory capacity 1VVM, initial speed 150rpm regulate and control rotating speed 150 in the process
Dissolved oxygen is set to be not less than 20% between~600rpm.
Methyl hexadecanoate and soybean lecithin are configured to solution according to mass volume ratio shared by soybean lecithin for 15%
It is for use after 120 DEG C of sterilizing 30min.
After fermented and cultured 48h, methyl hexadecanoate and the soybean lecithin that 5% mass volume ratio is added into zymotic fluid are mixed
Close object.
Fermentation period is 8 days, measures FR901379 and puts a concentration of 3.30g/L of tank.
Claims (5)
1. a kind of fermentation process of FR901379, this method is that palm fibre is added into zymotic fluid during fermenting FR901379
Palmitic acid acid methyl esters and soybean lecithin mixture.
2. the method as described in claim 1, this method are：
1), the preparation of fermentation medium；
2) bacterial strain Coleophoma empetri seed culture fluids, are inoculated in fermentation medium to ferment；
3), after 24~72h of fermented and cultured, methyl hexadecanoate and soybean lecithin mixture are added into zymotic fluid；
4), when ferment 160h after, when the concentration of FR901379 no longer increases, fermentation ends.
3. the matter of methyl hexadecanoate and soybean lecithin mixture is added into zymotic fluid for method as claimed in claim 1 or 2
It is 3~10% to measure volume ratio.
4. method as claimed in claim 1 or 2, in methyl hexadecanoate and soybean lecithin mixture, shared by soybean lecithin
Mass volume ratio is 10~30%.
5. the group of method as claimed in claim 2, fermentation medium becomes：Glucose, cottonseed meal, yeast powder, peptone,
Magnesium sulfate, dipotassium hydrogen phosphate, calcium carbonate, antifoaming agent, water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810536318.XA CN108753878A (en) | 2018-05-30 | 2018-05-30 | The fermentation process of micafen sodium intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810536318.XA CN108753878A (en) | 2018-05-30 | 2018-05-30 | The fermentation process of micafen sodium intermediate |
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| Publication Number | Publication Date |
|---|---|
| CN108753878A true CN108753878A (en) | 2018-11-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201810536318.XA Withdrawn CN108753878A (en) | 2018-05-30 | 2018-05-30 | The fermentation process of micafen sodium intermediate |
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| CN (1) | CN108753878A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111876366A (en) * | 2020-08-14 | 2020-11-03 | 卓和药业集团有限公司 | Fermentation method of micafungin sodium intermediate FR901379 |
| CN112111408A (en) * | 2020-09-04 | 2020-12-22 | 杭州华东医药集团新药研究院有限公司 | Micafungin precursor WF11899A production strain and fermentation method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102876745A (en) * | 2011-07-14 | 2013-01-16 | 北大方正集团有限公司 | Method for production of lipstatin through fermentation |
| CN106399431A (en) * | 2016-11-28 | 2017-02-15 | 无锡福祈制药有限公司 | Preparation method of micafungin precursor |
| CN108085354A (en) * | 2016-11-21 | 2018-05-29 | 重庆乾泰生物医药有限公司 | A kind of culture medium and its method of fermenting and producing FR901379 |
-
2018
- 2018-05-30 CN CN201810536318.XA patent/CN108753878A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102876745A (en) * | 2011-07-14 | 2013-01-16 | 北大方正集团有限公司 | Method for production of lipstatin through fermentation |
| CN108085354A (en) * | 2016-11-21 | 2018-05-29 | 重庆乾泰生物医药有限公司 | A kind of culture medium and its method of fermenting and producing FR901379 |
| CN106399431A (en) * | 2016-11-28 | 2017-02-15 | 无锡福祈制药有限公司 | Preparation method of micafungin precursor |
Non-Patent Citations (1)
| Title |
|---|
| 胡必杰 等: "《SIFIC医院感染防控用品使用指引 2014-2015年》", 31 May 2014 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111876366A (en) * | 2020-08-14 | 2020-11-03 | 卓和药业集团有限公司 | Fermentation method of micafungin sodium intermediate FR901379 |
| CN112111408A (en) * | 2020-09-04 | 2020-12-22 | 杭州华东医药集团新药研究院有限公司 | Micafungin precursor WF11899A production strain and fermentation method |
| CN112111408B (en) * | 2020-09-04 | 2022-03-01 | 杭州华东医药集团新药研究院有限公司 | Micafungin precursor WF11899A production strain and fermentation method |
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Application publication date: 20181106 |
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