A kind of fermentation method that improves tacrolimus production

A technology of tacrolimus and fermentation method, applied in the field of tacrolimus production, can solve the problems of high uncertainty in strain selection and breeding, degradation of production capacity of high-yield strains, unstable tacrolimus production, and the like, Achieve good industrial application prospects, reduce production costs, and prolong the production cycle.

Active Publication Date: 2021-08-27
广州市微生物研究所集团股份有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the uncertainty and work intensity of strain selection is high, and the high-yield strains bred are always facing the problem of degradation in production capacity, which has laid a hidden danger for the production of tacrolimus.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Prepare the fermentation medium, adjust the pH to 7.8, pack into Erlenmeyer flasks, and sterilize at 121°C for 20 minutes, then set aside. Add the fermented seed solution according to the inoculum size of 10% medium volume. The culture conditions are: culture temperature 28° C., stirring speed 200 rpm, ventilation 1.0 V / V·min. After cultivating for 48 hours, add XAD 16 resin, the volume ratio of resin volume to fermentation broth is 0.1:1, and at the same time, start to feed supplementary dextrin, and add 0.5g dextrin per 100ml fermentation broth per hour at a flow rate. Continue to cultivate until 170h, and end the fermentation. Use a filter cloth to filter the obtained fermentation broth, collect the adsorption resin and mycelium containing tacrolimus, fully analyze it with 2 times the volume of acetone solution, use HPLC to detect the content of tacrolimus in the analysis solution, and the result is 1022mg / L .

Embodiment 2

[0023] Prepare the fermentation medium, adjust the pH to 7.8, pack into Erlenmeyer flasks, and sterilize at 121°C for 20 minutes, then set aside. Add the fermented seed solution according to the inoculum size of 10% medium volume. The culture conditions are: culture temperature 28° C., stirring speed 200 rpm, ventilation 1.0 V / V·min. After cultivating for 48 hours, add XAD 16 resin, the ratio of resin volume to fermentation broth volume is 0.1:1, and start to add dextrin at the same time, and add 2g dextrin per 100ml fermentation broth per hour at the flow rate. Continue to cultivate until 170h, and end the fermentation. Use a filter cloth to filter the obtained fermentation broth, collect the adsorption resin and mycelium containing tacrolimus, fully analyze it with 2 times the volume of acetone solution, use HPLC to detect the content of tacrolimus in the analysis solution, and the result is 1248mg / L .

Embodiment 3

[0025] Prepare the fermentation medium, adjust the pH to 7.8, pack into Erlenmeyer flasks, and sterilize at 121°C for 20 minutes, then set aside. Add the fermented seed solution according to the inoculum size of 10% medium volume. The culture conditions are: culture temperature 28° C., stirring speed 200 rpm, ventilation 1.0 V / V·min. After cultivating for 60 hours, add HP20 resin, the ratio of resin volume to fermentation broth volume is 0.001:1, and at the same time start to feed and supplement dextrin, and add 1g of dextrin per 100ml of fermentation broth per hour at a flow rate. Continue to cultivate until 170h, and end the fermentation. Use a filter cloth to filter the obtained fermentation broth, collect the adsorption resin and mycelium containing tacrolimus, fully analyze it with 2 times the volume of acetone solution, use HPLC to detect the content of tacrolimus in the analysis solution, and the result is 663mg / L .

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Abstract

The invention discloses a fermentation method for improving tacrolimus production. During the conventional tacrolimus fermentation process, an adsorption resin is added and dextrin is added in a stream. The adsorption resin is added when the fermentation time is 48h to 60h. The volume ratio of the added volume of the adsorption resin to the volume of the fermentation broth is 0.001 to 0.1:1; the supplementary dextrin is added when the fermentation time is 1h to 60h, and the flow rate of the supplementary dextrin is added at a rate of Add 0.5 to 3 g of dextrin per 100 ml of fermentation broth per hour. Through this fermentation production process, the fermentation yield of tacrolimus is significantly improved. The invention can improve the fermentation yield of tacrolimus, and the used adsorption resin can be recovered to realize recycling and further reduce the production cost.

Description

technical field [0001] The invention relates to the technical field of tacrolimus production, in particular to a fermentation method for increasing tacrolimus production. Background technique [0002] Tacrolimus (FK506) is a new type of 23-membered macrolide polyketide produced by Streptomyces, which has a strong immunosuppressive effect, and its efficacy is better than that of cyclosporin A (Cyclosporin A), which is widely used. , CsA) is nearly 100 times higher than cyclosporin A, and has fewer side effects than cyclosporine A, and has the advantages of low mortality, high transplant survival rate, and less dependence. [0003] Tacrolimus is widely used in the treatment of autoimmune diseases such as atopic dermatitis, allergic contact dermatitis, psoriasis, lupus erythematosus, lichen planus, vitiligo, Nethenton syndrome and host-suppressive diseases. It is currently clinically used to prevent graft rejection after liver or kidney transplantation, and to treat graft reje...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P17/18C12R1/465
CPCC12P17/188
Inventor 秦鹏梁淑娃谢鹏黄魁英刘广宇梁宏基劳逸俊
Owner 广州市微生物研究所集团股份有限公司
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