CN106755168A - A kind of method of fermenting and producing tacrolimus fermentation - Google Patents
A kind of method of fermenting and producing tacrolimus fermentation Download PDFInfo
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- CN106755168A CN106755168A CN201611065060.7A CN201611065060A CN106755168A CN 106755168 A CN106755168 A CN 106755168A CN 201611065060 A CN201611065060 A CN 201611065060A CN 106755168 A CN106755168 A CN 106755168A
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
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Abstract
The invention provides a kind of method of fermenting and producing tacrolimus, including streptomycete is inoculated in slant medium, is cultivated 9~15 days at 26~30 DEG C；Ripe inclined plane inoculating is selected on seed culture medium, at 26~30 DEG C, 40~50h is cultivated under 200~300rmp of rotating speed on shaking table, fermentation tank is inserted after being inoculated in fermentation medium by 2~15% inoculum concentration；In the different time periods of fermenting, to addition organic solvent and salting liquid in fermentation medium, and in whole fermentation process, the dissolved oxygen concentration in fermentation tank is maintained to be maintained on setting value by way of changing rotating speed.In the present invention, fermented and cultured is carried out by the way of batch fermentation during ferment tank, and add organic solvent and salting liquid in the different phase of fermentation is to fermentation medium, preparing the tacrolimus present invention relative to traditional fermentation method can improve the yield about 20~40% of tacrolimus, and fermentation period is short, production cost is relatively low.
Description
Technical field
The present invention relates to biological pharmacy technical field, more particularly to a kind of method of fermenting and producing tacrolimus.
Background technology
Tacrolimus (Tacrolimus, FK506) is sent out by streptomyces tsukubaensis (streptomyces tsukubaensis)
A kind of 23 membered macrolide antibiotic that ferment is produced, its molecular formula C44H69NO12, shown in structural formula such as following formula (1).
Tacrolimus can reduce the acute and chronic rejection of liver renal allograft recipient.With the patient of this product, bacterium and virus are felt
Dye rate is also low compared with ciclosporin in treating person, and especially the medicine has stronger close liver property, higher than cyclosporine to effect of liver transfer operation by 100
Times, thus greatly reduce Clinical practice dosage, it is possible to decrease former medical expense 1/3~1/2.FK-506 and cyclosporin share tool
There is obvious synergy, effect is more preferable.Tacrolimus cannot be only used for preventing the generation of immune response, it may also be used for treatment is
The immune response of generation and autoimmune disease, to preventing the immune response of organ transplant and the treatment of autoimmune disease
It is significant.
Since being found from tacrolimus, basis and clinical research are carried out to tacrolimus both at home and abroad, in 1994 by the U.S.
Food and Drug Administration (FDA) approval listing.Current clinical practice is in the graft after prevention liver or kidney transplantation operation
Rejection.Tacrolimus is with other immunodepressant such as rapamycin and cyclosporin etc. to appeared in prevention of organ transplant
Rejection there is good effect, it is and stronger than cyclosporin (CsA) 100 times in clinical effectiveness immunosuppressant activity,
Be thus able to substantially reduce Clinical practice dosage, while adverse reaction liquid is substantially reduced, and can reduce medical expense he gram
Department is widely used in atopic dermatitis (AD), allergia contact dermatitis, psoriasis, lupus erythematosus (SLE), leucoderma, flat
The treatment of the autoimmune disease such as flat liver moss and Nethenton.At present, traditional fermentation method prepares tacrolimus and there is yield not
Defect high, it is impossible to meet the great demand to tacrolimus, and in the presence of the production cost for preparing tacrolimus defect higher,
This brings larger burden with regard to patient.
In view of this, it is necessary to which the method to producing tacrolimus by fermentation method in the prior art is improved, with solution
Certainly above mentioned problem.
The content of the invention
It is an object of the invention to disclose a kind of method of fermenting and producing tacrolimus, it is used to reduce preparing using fermentation method
The production cost of tacrolimus, shortens fermentation period.
For achieving the above object, the invention provides a kind of method of fermenting and producing tacrolimus, including following step
Suddenly：
Step (1), streptomycete is inoculated in slant medium, is cultivated 9~15 days at 26~30 DEG C；
Step (2), select ripe inclined plane inoculating on seed culture medium, at 26~30 DEG C, under 200~300rmp of rotating speed
40~50h is cultivated on shaking table, fermentation tank is inserted after being inoculated in fermentation medium by 2~15% inoculum concentration；
Step (3), fermentation tank is placed in 26~30 DEG C at fermented, added when fermentation is carried out to 20~30h organic
Solvent and salting liquid, add organic solvent and salting liquid again when fermentation is carried out to 40~50h, treat fermentation carry out to 70~
Supplemented medium is carried out during 80h, and in whole fermentation process, the dissolved oxygen in fermentation tank is maintained by way of changing rotating speed
Concentration is maintained on setting value；
Step (4), the zymotic fluid to being obtained through step (3) carry out separation and Extraction, obtain final product tacrolimus.
As a further improvement on the present invention, the slant medium composition in the step (1) is：Brewer's wort powder 10~
20g/L, yeast extract 3~8g/L of powder, 5~15g/L of glucose and 18~22g/L of agar composition；The pH of the slant medium is in
6.0~8.0.
As a further improvement on the present invention, the seed culture medium composition in the step (2) is：Cornstarch 5~
15g/L, 5~15g/L of corn pulp, 10~20g/L of glucose, 5~15g/L of dusty yeast, 1~5g/L of calcium carbonate are constituted；It is described oblique
The pH of face culture medium is in 6.0~8.0.
As a further improvement on the present invention, the fermentation medium composition in the step (2) is：Cornstarch 45~
55g/L, 5~15g/L of dusty yeast, 5~15g/L of corn pulp, corn oil 5~15g/L, K2HPO41~5g/L, KH2PO41~5g/
L and 1~5g/L of calcium carbonate is constituted；The pH of the fermentation medium is in 6.0~8.0.
As a further improvement on the present invention, the addition of salting liquid is the zymotic fluid in fermentation tank in the step (3)
Volume 0.05%~0.5%；The addition of organic solvent is the 0.01~0.05% of the volume of the zymotic fluid in fermentation tank.
As a further improvement on the present invention, the salting liquid in the step (3) is selected from sodium chloride solution or potassium chloride
Solution, the organic solvent is selected from methyl alcohol, ethanol or isopropanol；The concentration of the salting liquid is 1.0~5.0mol/L.
As a further improvement on the present invention, the supplemented medium composition in the step (3) is：Cornstarch 50~
80g/L, 10~20g/L of dusty yeast, 0.3~0.6g/L of calcium carbonate are constituted；The pH of the supplemented medium is in 6.0~7.0.
As a further improvement on the present invention, the tank pressure of fermentation tank is 0.01~0.05MPa, ventilation in the step (3)
It is 0.5~1.5VVM to measure, and the dissolved oxygen concentration of Preliminary fermentation tank is 100%, the dissolved oxygen concentration in fermentation process in fermentation tank
Setting value be 25%.
Compared with prior art, the beneficial effects of the invention are as follows：In the present invention, using in batches during ferment tank
The mode of fermentation carries out fermented and cultured, and adds organic solvent and salting liquid in the different phase of fermentation is to fermentation medium,
Preparing the tacrolimus present invention relative to traditional fermentation method can improve the yield about 20~40% of tacrolimus, and fermentation week
Phase is also shorter, so as to reduce the production cost of tacrolimus.
Specific embodiment
With reference to each implementation method, the present invention is described in detail, but it should explanation, these implementation methods are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according in these implementation method institutes works energy, method or structure
Equivalent transformation or replacement, belong within protection scope of the present invention.
Unless there is specified otherwise in specification, component, the raw material in each embodiment in the present invention are pure using analysis
Rank.In addition, " g " in each embodiment is unit of weight " gram "；" h " is chronomere's " hour "；" ml " is volume unit " milli
Rise "；" room temperature " is 23 DEG C." VVM " is throughput unit (air volume/culture volume/min), and is specially single
(usually per minute) is passed into the gas volume of round (such as " fermentation tank ") in the time of position." g/L " is in culture medium
The content unit of each component.
Embodiment one：
A kind of method of fermenting and producing tacrolimus, comprises the following steps.
Step (1), streptomycete is inoculated in slant medium, is cultivated 15 days at 26 DEG C.
Step (2), select ripe inclined-plane and carry out being inoculated in seed culture medium, at 26 DEG C, under rotating speed 300rpm on shaking table
Carry out culture 50h.It is inoculated in be inserted in fermentation tank after fermentation medium by 2% inoculum concentration and is fermented.
Step (3), fermentation tank is placed in 26 DEG C at fermented.Waiting to ferment carries out to 30h adding the sodium chloride containing methyl alcohol
Solution, adds methyl alcohol and sodium chloride solution again when fermentation is carried out to 50h, and the addition of methyl alcohol is the zymotic fluid in fermentation tank
Volume 0.01%, the addition of sodium chloride solution is the 0.05% of the volume of the zymotic fluid in fermentation tank.Sodium chloride solution
Concentration be 1.0mol/L.Feed-batch culture is carried out when fermentation is carried out to 80h.In whole fermentation process, fermentation tank tank pressure is
0.01MPa, throughput 0.5VVM, the dissolved oxygen concentration of Preliminary fermentation tank is 100%.Meanwhile, during the fermentation by changing
The mode of rotating speed maintains the dissolved oxygen concentration in fermentation tank to be maintained at more than 25%, and tank is put after fermentation 90h, and zymotic fluid is obtained.
Step (4), the zymotic fluid to being obtained through step (3) carry out separation and Extraction, obtain final product tacrolimus.In the present embodiment
In, separation and Extraction can be carried out by recrystallization to the tacrolimus in zymotic fluid.
Each group in slant medium is divided into (unit：g/L)：Brewer's wort powder 10, yeast extract powder 3, glucose 5, agar 18,
Balance of water；The pH of slant medium is in 6.0.
Each group in seed culture medium is divided into (unit：g/L)：Cornstarch 5, corn pulp 5, glucose 10, dusty yeast 5,
Calcium carbonate 1, balance of water；The pH of seed culture medium is in 6.0.
Each group in fermentation medium is divided into (unit：g/L)：Cornstarch 45, dusty yeast 5, corn pulp 5, corn oil 5,
K2HPO41, KH2PO41, calcium carbonate 1, balance of water；The pH of fermentation medium is in 6.0.
Supplemented medium each group is divided into (unit：g/L)：Cornstarch 50, dusty yeast 10, calcium carbonate 0.3, balance of water.
The pH of supplemented medium is in 6.0.
Embodiment two：
A kind of method of fermenting and producing tacrolimus, comprises the following steps.
Step (1), streptomycete is inoculated in slant medium, is cultivated 9 days at 30 DEG C.
Step (2), select ripe inclined-plane and carry out being inoculated in seed liquid culture medium, at 30 DEG C, trained on shaking table under 200rmp
40h is supported, is inoculated in be inserted in fermentation tank after fermentation medium by 15% inoculum concentration and is fermented.
Step (3), fermentation tank is placed in 30 DEG C at fermented.Fermentation carries out to 20h adding ethanol and Klorvess Liquid,
Fermentation carries out adding ethanol and Klorvess Liquid again to 40h, and ethanol addition is the volume of the zymotic fluid in fermentation tank
0.05%, the addition of Klorvess Liquid is the 0.5% of the volume of the zymotic fluid in fermentation tank.The concentration of Klorvess Liquid is
2.0mol/L.Fermentation carries out to 70h carrying out feed-batch culture.In whole fermentation process, fermentation tank tank pressure is 0.05MPa, ventilation
Amount 1.5VVM, the dissolved oxygen concentration of Preliminary fermentation tank is 100%.Meanwhile, tieed up by way of changing rotating speed during the fermentation
Hold the dissolved oxygen concentration in fermentation tank and be maintained at more than 25%, tank is put after fermentation 100h, zymotic fluid is obtained.
In the present embodiment, the bottom of fermentation tank is provided with agitating device, and agitating device is driven by servomotor, to control
The rotating speed of agitating device.The speed setting range of speeds of agitating device is 180~400rpm.Improving rotating speed can improve in fermentation tank
Dissolved oxygen concentration, reducing rotating speed can reduce dissolved oxygen concentration in fermentation tank.Servomotor in controller, for example single-chip microcomputer or
Under the control of person PLC, by the dissolved oxygen concentration measured by set sensor from fermentation tank, to automatically control servo electricity
The rotating speed of machine, so as to automatically control the rotating speed of the agitating device set by fermenter base, so as to by way of changing rotating speed
The dissolved oxygen concentration in fermentation tank is maintained to be maintained at more than 25%.
Step (4), the zymotic fluid to being obtained through step (3) carry out separation and Extraction, obtain final product tacrolimus.
Each group in slant medium is divided into (unit：g/L)：Brewer's wort powder 20, yeast extract powder 8, glucose 15, agar
22, balance of water；The pH of slant medium is in 8.0.
Each group in seed culture medium is divided into (unit：g/L)：Cornstarch 15, corn pulp 15, glucose 20, dusty yeast
15, calcium carbonate 5, balance of water；The pH of seed culture medium is in 8.0.
Each group in fermentation medium is divided into (unit：g/L)：Cornstarch 55, dusty yeast 15, corn pulp 15, corn oil
15, K2HPO45, KH2PO45, calcium carbonate 5, balance of water；The pH of fermentation medium is in 8.0.
Each group in supplemented medium is divided into (unit：g/L)：Cornstarch 80, dusty yeast 20, calcium carbonate 0.6 is balance of
Water；The pH of supplemented medium is in 6.4.
Embodiment three：
A kind of method of fermenting and producing tacrolimus, comprises the following steps.
Step (1), streptomycete is inoculated in slant medium, is cultivated 12 days at 28 DEG C.
Step (2), select ripe inclined-plane and carry out being inoculated in seed liquid culture medium, at 28 DEG C, trained on shaking table under 250rmp
45h is supported, is inoculated in be inserted in fermentation tank after fermentation medium by 8% inoculum concentration and is fermented.
Step (3), fermentation tank is placed in 28 DEG C at cultivated.Fermentation adds isopropanol and sodium chloride when carrying out to 24h
Solution；Fermentation is carried out to isopropanol and sodium chloride solution is added during 48h again, and isopropanol addition is the zymotic fluid in fermentation tank
Volume 0.20%, the addition of sodium chloride solution is the 0.03% of the volume of the zymotic fluid in fermentation tank.Sodium chloride solution
Concentration be 5.0mol/L.
Fermentation is carried out to carrying out feed-batch culture during 75h.In whole fermentation process, fermentation tank tank pressure is 0.03MPa, ventilation
Amount 1.0VVM, the dissolved oxygen concentration of Preliminary fermentation tank is 100%.Meanwhile, tieed up by way of changing rotating speed during the fermentation
Hold the dissolved oxygen concentration in fermentation tank and be maintained at more than 25%, tank is put after fermentation 96h, zymotic fluid is obtained.
Step (4), the zymotic fluid to being obtained through step (3) carry out separation and Extraction, obtain final product tacrolimus.
Each group in slant medium is divided into (unit：g/L)：Brewer's wort powder 15, yeast extract powder 5, glucose 10, agar
20, the pH of slant medium is in 6.5.
Each group in seed culture medium is divided into (unit：g/L)：Cornstarch 10, corn pulp 10, glucose 15, dusty yeast
10, calcium carbonate 3, balance of water；The pH of seed culture medium is in 6.5.
Each group in fermentation medium is divided into (unit：g/L)：Cornstarch 50, dusty yeast 10, corn pulp 10, corn oil
10, K2HPO43, KH2PO43, calcium carbonate 3, balance of water；The pH of fermentation medium is in 6.5.
Each group in supplemented medium is divided into (unit：g/L)：Cornstarch 60, dusty yeast 15, calcium carbonate 0.4 is balance of
Water；The pH of supplemented medium is in 7.0.
Those listed above is a series of to be described in detail only for feasibility implementation method of the invention specifically
Bright, they simultaneously are not used to limit the scope of the invention, all equivalent implementations made without departing from skill spirit of the present invention
Or change should be included within the scope of the present invention.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be in other specific forms realized.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires to be limited rather than described above, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each implementation method is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that for clarity, those skilled in the art should
Specification an as entirety, the technical scheme in each embodiment can also be formed into those skilled in the art through appropriately combined
May be appreciated other embodiment.
Claims (8)
1. a kind of method of fermenting and producing tacrolimus, it is characterised in that comprise the following steps：
Step (1), streptomycete is inoculated in slant medium, is cultivated 9~15 days at 26~30 DEG C；
Step (2), ripe inclined plane inoculating is selected on seed culture medium, at 26~30 DEG C, in shaking table under 200~300rmp of rotating speed
40~50h of upper culture, fermentation tank is inserted after being inoculated in fermentation medium by 2~15% inoculum concentration；
Step (3), fermentation tank is placed in 26~30 DEG C at fermented, add organic solvent when fermentation is carried out to 20~30h
And salting liquid, organic solvent and salting liquid are added again when fermentation is carried out to 40~50h, when fermentation is carried out to 70~80h
Supplemented medium is carried out, and in whole fermentation process, the dissolved oxygen concentration in fermentation tank is maintained by way of changing rotating speed
It is maintained on setting value；
Step (4), the zymotic fluid to being obtained through step (3) carry out separation and Extraction, obtain final product tacrolimus.
2. method according to claim 1, it is characterised in that the slant medium composition in the step (1) is：Malt
Juice 10~20g/L of powder, yeast extract 3~8g/L of powder, 5~15g/L of glucose and 18~22g/L of agar composition；The inclined-plane culture
The pH of base is in 6.0~8.0.
3. method according to claim 1, it is characterised in that the seed culture medium composition in the step (2) is：Corn
5~15g/L of starch, 5~15g/L of corn pulp, 10~20g/L of glucose, 5~15g/L of dusty yeast, 1~5g/L of calcium carbonate are constituted；
The pH of the slant medium is in 6.0~8.0.
4. method according to claim 1, it is characterised in that the fermentation medium composition in the step (2) is：Corn
45~55g/L of starch, 5~15g/L of dusty yeast, 5~15g/L of corn pulp, corn oil 5~15g/L, K2HPO41~5g/L,
KH2PO41~5g/L and 1~5g/L of calcium carbonate is constituted；The pH of the fermentation medium is in 6.0~8.0.
5. method according to claim 1, it is characterised in that the addition of salting liquid is fermentation tank in the step (3)
In zymotic fluid volume 0.05%~0.5%；The addition of organic solvent is the volume of the zymotic fluid in fermentation tank
0.01~0.05%.
6. method according to claim 5, it is characterised in that the salting liquid in the step (3) is selected from sodium chloride solution
Or Klorvess Liquid, the organic solvent is selected from methyl alcohol, ethanol or isopropanol；The concentration of the salting liquid be 1.0~
5.0mol/L。
7. method according to claim 1, it is characterised in that the supplemented medium composition in the step (3) is：Corn
50~80g/L of starch, 10~20g/L of dusty yeast, 0.3~0.6g/L of calcium carbonate are constituted；The pH of the supplemented medium in 6.0~
7.0。
8. method according to claim 1, it is characterised in that in the step (3) tank pressure of fermentation tank be 0.01~
0.05MPa, throughput is 0.5~1.5VVM, and the dissolved oxygen concentration of Preliminary fermentation tank is 100%, in fermentation process in fermentation tank
Dissolved oxygen concentration setting value be 25%.
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| CN201611065060.7A CN106755168A (en) | 2016-11-28 | 2016-11-28 | A kind of method of fermenting and producing tacrolimus fermentation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107557403A (en) * | 2017-10-31 | 2018-01-09 | 无锡福祈制药有限公司 | A kind of method for improving sirolimus fermentation yield |
| CN107722038A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of method of purification of the epimer of tacrolimus 8 |
| CN108220359A (en) * | 2018-01-29 | 2018-06-29 | 天津大学 | The method for promoting FK506 yield using chemistry triggering agent |
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| CN103695496A (en) * | 2013-12-05 | 2014-04-02 | 成都雅途生物技术有限公司 | Method for producing tacrolimus by fermentation |
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| CN101407779A (en) * | 2008-11-18 | 2009-04-15 | 南京工业大学 | Streptomycete and use thereof in tacrolimus production by multi-stage fermentation |
| CN101851653A (en) * | 2010-05-17 | 2010-10-06 | 上海交通大学 | Fermentation production method of validamycin A |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107557403A (en) * | 2017-10-31 | 2018-01-09 | 无锡福祈制药有限公司 | A kind of method for improving sirolimus fermentation yield |
| CN107722038A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of method of purification of the epimer of tacrolimus 8 |
| CN108220359A (en) * | 2018-01-29 | 2018-06-29 | 天津大学 | The method for promoting FK506 yield using chemistry triggering agent |
| CN108220359B (en) * | 2018-01-29 | 2021-12-21 | 天津大学 | Method for increasing FK506 yield by using chemical trigger |
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