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Method for fermentation production of tacrolimus

A tacrolimus and fermenter technology, which is applied in the field of biopharmaceuticals, can solve the problems of heavy burden on patients, low output, high production cost of tacrolimus, etc., and achieve the effect of reducing production cost and shortening the fermentation cycle

Inactive Publication Date: 2017-05-31
WUXI FORTUNE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the traditional fermentation method for preparing tacrolimus has the defect of low yield, which cannot meet the huge demand for tacrolimus, and has the defect of high production cost for preparing tacrolimus, which brings patients Larger burden

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  • Method for fermentation production of tacrolimus

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Embodiment 1

[0024] A method for producing tacrolimus by fermentation, comprising the following steps.

[0025] Step (1), inoculating the Streptomyces on the slant culture medium, and culturing at 26° C. for 15 days.

[0026] In step (2), the mature slant is selected and inoculated on the seed medium, and cultivated on a shaker at 26° C. with a rotation speed of 300 rpm for 50 h. After being inoculated in the fermentation medium according to the inoculum amount of 2%, it is placed in a fermenter for fermentation.

[0027] Step (3), placing the fermenter at 26°C for fermentation. When the fermentation is carried out to 30h, add methanol-containing sodium chloride solution, and when the fermentation is carried out to 50h, add methanol and sodium chloride solution again. The amount of methanol added is 0.01% of the volume of the fermentation liquid in the fermenter. The sodium solution was added in an amount of 0.05% by volume of the fermentation broth in the fermenter. The concentration o...

Embodiment 2

[0034] A method for producing tacrolimus by fermentation, comprising the following steps.

[0035] Step (1), inoculate the Streptomyces on the slant medium, and culture at 30° C. for 9 days.

[0036] Step (2), select the mature slant and inoculate it into the seed liquid medium, cultivate it on a shaking table at 30°C and 200rmp for 40h, inoculate it into the fermentation medium according to 15% of the inoculum amount, and put it into a fermenter for fermentation.

[0037] Step (3), placing the fermenter at 30°C for fermentation. Fermentation is carried out to 20h to add ethanol and potassium chloride solution, and fermentation is carried out to 40h to add ethanol and potassium chloride solution again, the ethanol addition is 0.05% of the volume of the fermentation liquid in the fermenter, the addition of potassium chloride solution 0.5% of the volume of the fermentation broth in the fermenter. The concentration of potassium chloride solution is 2.0mol / L. Fermentation was c...

Embodiment 3

[0045] A method for producing tacrolimus by fermentation, comprising the following steps.

[0046] Step (1), inoculating the Streptomyces on the slant culture medium, and culturing at 28° C. for 12 days.

[0047] Step (2), select the mature slant and inoculate it on the seed liquid medium, cultivate it on a shaker at 28°C and 250rmp for 45h, inoculate it on the fermentation medium according to the inoculum size of 8%, and put it into a fermenter for fermentation.

[0048] Step (3), placing the fermenter at 28° C. for culturing. Add isopropanol and sodium chloride solution when the fermentation is carried out to 24 hours; add isopropanol and sodium chloride solution again when the fermentation is carried out to 48 hours, and the amount of isopropanol added is 0.20% of the volume of the fermentation broth in the fermenter , the added amount of sodium chloride solution is 0.03% of the volume of the fermented liquid in the fermenter. The concentration of sodium chloride solution...

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Abstract

The invention provides a method for fermentation production of tacrolimus. The method comprises the following steps: inoculating streptomycete into an agar slant culture medium, and culturing for 9-15 days at 26-30 DEG C; inoculating mature agar slant on a seed culture medium, culturing for 40-50 hours on a table at 26-30 DEG C at a rotation speed of 200-300rmp, and inoculating into a fermentation culture medium according to an inoculation amount of 2-15%, and putting into a fermentation tank; in different fermentation periods, adding an organic solvent and a salt solution into the fermentation culture medium, and in the whole fermentation process, keeping the dissolved oxygen concentration inside the fermentation tank being greater than a set value in a mode of changing the rotation speed. According to the method, fermentation culture is implemented in an on-batch fermentation mode in the fermentation process of the fermentation tank, the organic solvent and the salt solution are added into the fermentation culture medium in different fermentation periods, the yield of the tacrolimus produced by using the method can be increased by about 20-40% when being compared with that of tacrolimus produced by using a conventional fermentation method, and moreover the fermentation cycle is short and the production cost is relatively low.

Description

technical field [0001] The invention relates to the technical field of biopharmaceuticals, in particular to a method for producing tacrolimus by fermentation. Background technique [0002] Tacrolimus (Tacrolimus, FK506) is a 23-membered macrolide antibiotic produced by fermentation of Streptomyces tsukubaensis. Its molecular formula is C 44 h 69 NO 12 , the structural formula is shown in the following formula (1). [0003] [0004] Tacrolimus can reduce acute and chronic rejection of liver and kidney transplant recipients. The patients who use this product have lower bacterial and viral infection rates than those treated with cyclosporine, especially the drug has a strong hepatotropic effect, and its effect on liver transplantation is 100 times higher than that of cyclosporine, thus greatly reducing the clinical risk. The dose can reduce the original treatment cost by 1 / 3 to 1 / 2. Combination of FK-506 and cyclosporine has obvious synergistic effect, and the effect is...

Claims

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Application Information

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IPC IPC(8): C12P17/18C12R1/465
CPCC12P17/188
Inventor 付静曹峥成梁杨亮游云龙郑缘赵永俊
Owner WUXI FORTUNE PHARMA
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