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Production method of tacrolimus

A seed and Streptomyces hygroscopicus technology, applied in the field of biomedicine, can solve problems such as burden, heavy patients, and low yield

Active Publication Date: 2008-10-08
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These patents report the production of tacrolimus with different streptomyces strains, the yield is not very high, the tacrolimus production strains of streptomycessp.MA 6858 mentioned in US5,116,756 patent and streptomyces tsukubaensis mentioned in US5,624,842 , the production of tacrolimus is very low, and the highest concentration of tacrolimus in the fermentation broth is only 37.8mg / L, which leads to high product cost after industrial production and causes a heavy burden to patients

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0013] The screening of example 1 fermentation medium

[0014] Prepare shake flask fermentation medium A, B, C respectively, wherein the composition of the medium is as follows:

[0015] A: Soluble starch 2.0g / L; yeast powder 1.2g / L; glycerin 1.0g / L; corn steep liquor powder 2.5g / L; ammonium sulfate 2.2g / L, K 2 HPO 4 2.1g / L; MnCL 2 0.002g / L; ZnSO 4 0.001g / L; pH 7.4;

[0016] B: soluble starch 2.0g / L; peanut powder 1.2g / L; glycerin 1.0g / L; corn steep liquor powder 2.5g / L; ammonium sulfate 2.2g / L, K 2 HPO 4 2.1g / L; MnCL 2 0.002g / L; ZnSO 4 0.001g / L; pH 7.4;

[0017] C: soluble starch 2.0g / L; yeast powder 1.2g / L; glucose 1.0g / L; corn steep liquor powder 2.5g / L; ammonium sulfate 2.2g / L, K 2 HPO 4 2.1g / L; MnCL 2 0.002g / L; ZnSO 4 0.001g / L; pH 7.4;

[0018] Pour 20 mL of the prepared medium into a 500 mL Erlenmeyer flask, sterilize in an autoclave at 120°C for 15 minutes, insert Streptomyces hygroscopicus (ACCC No.40417) after cooling, and culture at 30°C for 6 days. , m...

example 2

[0021] The screening of example 2 seed culture medium

[0022] Prepare seed medium A, B, and C respectively, wherein the composition of the medium is as follows:

[0023] A: soluble starch 2.5g / L; yeast powder 1.5g / L; glycerin 2.5g / L; corn steep liquor powder 2.5g / L; peanut meal 2.5g / L;, K 2 HPO 4 2.1g / L; MnCL 2 0.0015g / L; ZnSO 4 0.002g / L; pH 7.4;

[0024] B: soluble starch 2.5g / L; peanut powder 1.2g / L; glycerin 1.0g / L; corn steep liquor powder 2.5g / L; peanut meal 2.5g / L; K 2 HPO 4 2.1g / L; MnCL 2 0.0015g / L; ZnSO 4 0.002g / L; pH 7.4;

[0025] C: Soluble starch 2.0g / L; Yeast powder 1.2g / L; Glycerin 2.5g / L; Corn steep liquor dry powder 2.5g / L; K 2 HPO 4 2.1g / L; MnCL 2 0.0015g / L; ZnSO 4 0.002g / L; pH 7.4;

[0026] Pour 20 mL of the prepared medium into a 500 mL Erlenmeyer flask, sterilize in an autoclave at 120°C for 15 minutes, inoculate Streptomyces hygroscopicus (ACCC No. 40417) after cooling, and incubate at 30°C for 3 days. After the culture was over, they were tr...

example 3

[0032] Strain: Streptomyces hygroscopicus (ACCC No.40417)

[0033] Fermentation method: 70L fermenter, batch fermentation

[0034] Fermentation process: 70L fermenter, liquid volume 50L, fermentation temperature controlled at 30°C, air flow rate adjusted to 0.5vvm, fermenter speed to 350rpm, pH, dissolved oxygen and glucose concentrations were recorded after 4 hours of fermentation, and The concentration of the fermentation product tacrolimus was measured after 120 hours of fermentation until the end of 144 hours of fermentation.

[0035] Fermentation results: after the fermentation, the measured concentration of tacrolimus was 250g / L, and the concentration of substrate glucose was 8g / L. The pH dropped from the initial 7.4 to 6.5, and the dissolved oxygen dropped from the initial 100% to 20%.

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PUM

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Abstract

The invention discloses seed medium and fermentation medium for culturing streptomyces hygroscopicus (ACCC No.40417) and a new production method for tacrolimus, and belongs to the biomedical field. Through the microorganism fermentation and culturing, the amount of the dissolved oxygen and the flow acceleration of the substrate during the fermentation process are regulated and controlled, so as to improve the yield of the tacrolimus. The final yield of the tacrolimus can reach 380 mg / L finally, the operation in the overall fermentation process is simple, the concentration of the fermentation product (tacrolimus) in the fermentation liquid is high, the versatile is high, the popularization is easy, and industrialized production can be performed.

Description

Technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a production method of tacrolimus, a potent immunosuppressant of macrolides. Background technique [0002] Over the past ten years, organ transplantation in my country has developed rapidly, ranking first in Asia and second in the world. Immunosuppressant drugs used to reduce rejection after organ transplantation also show rapid growth. The immunosuppressant commonly used to prevent and suppress rejection is cyclosporine, but its use is often accompanied by side effects. The development of new immunosuppressants has become particularly necessary. At present, a new type of immunosuppressant, tacrolimus, is being widely used. [0003] Tacrolimus, also known as FK-506, is a macrolide antibiotic extracted from soil actinomycetes by Fujisawa Pharmaceutical Company of Japan in 1984, and has strong immunosuppressive properties. It is more effective than cyclosporine in preventin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N1/20C12P17/18C12R1/55
Inventor 赵志全刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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