CN107090477B - Fermentation method for improving tacrolimus yield - Google Patents
Fermentation method for improving tacrolimus yield Download PDFInfo
- Publication number
- CN107090477B CN107090477B CN201710309551.XA CN201710309551A CN107090477B CN 107090477 B CN107090477 B CN 107090477B CN 201710309551 A CN201710309551 A CN 201710309551A CN 107090477 B CN107090477 B CN 107090477B
- Authority
- CN
- China
- Prior art keywords
- fermentation
- tacrolimus
- dextrin
- fed
- yield
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- 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
- C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms
Abstract
The invention discloses a fermentation method for improving the yield of tacrolimus, which is characterized in that in the conventional tacrolimus fermentation process, adsorption resin and fed-batch complementary dextrin are added, wherein the adsorption resin is added when the fermentation time is 48-60 h, and the volume ratio of the added volume of the adsorption resin to the volume of fermentation liquor is 0.001-0.1: 1; and the fed-batch complementary dextrin begins to be supplemented when the fermentation time is 1-60 h, and the fed-batch speed of the fed-batch complementary dextrin is 0.5-3 g of dextrin per 100ml of fermentation liquor per hour. The fermentation yield of the tacrolimus is obviously improved by the fermentation production process. The invention can improve the fermentation yield of the tacrolimus, and the used adsorption resin can be recycled, thereby realizing the cyclic utilization and further reducing the production cost.
Description
Technical Field
The invention relates to the technical field of tacrolimus production, in particular to a fermentation method for improving the yield of tacrolimus.
Background
Tacrolimus (FK506) is a novel 23-membered macrolide polyketone substance produced by streptomyces, has a strong immunosuppressive effect, has the efficacy which is nearly 100 times higher than that of cyclosporine A (CsA) with wide application, has fewer toxic and side effects than that of the cyclosporine A, and also has the advantages of low mortality, high transplant survival rate, small dependence and the like.
Tacrolimus is widely used for treating autoimmune diseases such as atopic dermatitis, allergic contact dermatitis, psoriasis, lupus erythematosus, lichen planus, vitiligo, Netherton syndrome and host disease inhibition. At present, the medicine is clinically applied to preventing graft rejection reaction after liver or kidney transplantation, and treating the graft rejection reaction which cannot be controlled by applying other immunosuppressive medicines after solid organ transplantation such as liver, pancreas, kidney, heart, lung and the like. However, due to the factors of low fermentation level of tacrolimus, high production cost and the like, many organ transplant patients cannot accept the tacrolimus economically, so that the popularization and application of the tacrolimus are limited to a certain extent.
At present, a series of researches are carried out at home and abroad aiming at the problem of low tacrolimus yield, and from the experimental effect, strain breeding is undoubtedly a method capable of effectively improving the tacrolimus yield. For example: the Wangxuqin and the like adopt a compound mutagenesis method to treat the initial strain streptomyces tsukubaensis to obtain a high-yield strain, and the fermentation yield of the high-yield strain is improved by 73.6 percent compared with the initial strain. Zhengrong et al apply chemical and physical mutagens to mutagenize the strain of Tacrolimus producing strain, and use shikimic acid, pipecolic acid and their corresponding structural analogs as selection pressure to screen out high-yield mutant strain, which has improved fermentation potency by about 2 times. Jung et al increased the tolerance of the strain to the product by gradually increasing the concentration of tacrolimus in the medium, and finally obtained the strain yield reaches 972 mg/L. The method for treating streptomyces producing tacrolimus by using the methods of ultraviolet mutagenesis and resistance screening, such as the Yuan-Hui, obtains 1 strain of high-yield strain, and the 50L pot yield of the strain reaches 918 mg/L.
But the uncertainty of the strain breeding work is high, the working strength is high, and the bred high-yield strains always face the problem of the degradation of the production capacity, so that the hidden trouble of instability is buried for the production of tacrolimus. Therefore, it is necessary to develop a new method for increasing the yield of tacrolimus so as to meet the requirement of practical application.
Disclosure of Invention
The invention aims to provide a fermentation method for improving the yield of tacrolimus, aiming at overcoming the defects in the prior art, so that the fermentation yield of tacrolimus is obviously improved.
The above object of the present invention is achieved by the following technical solutions:
a fermentation method for improving the yield of tacrolimus is characterized in that adsorption resin and fed-batch complementary dextrin are added in the conventional tacrolimus fermentation process, the adsorption resin is added when the fermentation time is 48-60 h, and the volume ratio of the added adsorption resin to the fermentation liquor is 0.001-0.1: 1; and the fed-batch complementary dextrin begins to be supplemented when the fermentation time is 1-60 h, and the fed-batch speed of the fed-batch complementary dextrin is 0.5-3 g of dextrin per 100ml of fermentation liquor per hour.
The invention adopts a novel fermentation process, and adds an effective amount of resin capable of adsorbing tacrolimus in the proper fermentation process, thereby effectively reducing the harmful effect on the thalli of the user caused by the accumulation of tacrolimus; meanwhile, dextrin is fed and supplemented in the fermentation process, so that a fermentation system has sufficient energy, the production period of producing bacteria is prolonged, and the output of tacrolimus is improved.
The adsorption resin is medium-polarity macroporous resin and/or nonpolar macroporous resin.
Preferably, the adsorbent resin includes, but is not limited to, any one or more of XAD16, HP20, HZ801, HZD-3, SP850, and HZ 830. Most preferably, the adsorbent resin is an XAD16 resin.
Preferably, the ratio of the addition volume of the adsorption resin to the volume of the fermentation liquor is 0.03-0.1: 1. Most preferably, the ratio of the added volume of the adsorption resin to the volume of the fermentation broth is 0.1: 1.
Preferably, the fed-batch complementary dextrin is added when the fermentation time is 48-60 h.
Preferably, the feeding speed of the fed-batch dextrin supplement is that 1-2 g of dextrin is added to every 100ml of fermentation liquor per hour. More preferably, the feeding rate of the fed-in complementary dextrin is such that 2g of dextrin per 100ml of fermentation broth per hour is added.
The tacrolimus is obtained by the fermentation production process of the tacrolimus.
Compared with the prior art, the invention has the following beneficial effects:
the fermentation production process of tacrolimus provided by the invention comprises the following improvements: 1) adding an adsorption resin for specifically adsorbing tacrolimus; 2) dextrin is fed during the fermentation process. Adding specific adsorption resin during the fermentation production of tacrolimus, so that the adsorption resin continuously adsorbs the tacrolimus generated during the fermentation before reaching adsorption balance during the fermentation, the concentration of a product in a fermentation liquid is reduced, the feedback inhibition effect during the fermentation of the tacrolimus is solved, the continuous liquid fermentation production of the tacrolimus is realized, and the output of the tacrolimus is improved; on the other hand, the adsorption resin can be reused after regeneration treatment, thereby further reducing the production cost. The fed-batch supplementation of dextrin ensures that a fermentation system has sufficient energy, and the production period of producing bacteria is prolonged, so that the output of tacrolimus is improved. Compared with the existing fermentation method, the fermentation method provided by the invention can greatly improve the yield of the fermentation product tacrolimus, reduces the production cost, and has a very good industrial application prospect.
Detailed Description
The present invention is further explained with reference to specific embodiments, which are described in detail and specific, but not to be construed as limiting the scope of the invention, and all technical solutions obtained by equivalents or equivalent changes should be included in the scope of the claims of the present invention.
In the following examples and comparative examples, all the raw materials used were commercially available products.
Example 1
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. Adding XAD16 resin after culturing for 48 hours, wherein the volume ratio of the resin to the fermentation broth is 0.1:1, simultaneously feeding dextrin, and feeding dextrin at a speed of 0.5g dextrin per 100ml fermentation broth per hour. And continuing culturing for 170h, and finishing fermentation. The obtained fermentation solution was filtered with a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently eluted with 2 volumes of acetone solution, and the content of tacrolimus in the eluted solution was measured by HPLC, and found to be 1022 mg/L.
Example 2
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. Adding XAD16 resin after culturing for 48 hours, wherein the volume ratio of the resin to the fermentation broth is 0.1:1, simultaneously feeding dextrin, and feeding dextrin at a speed of 2g per 100ml fermentation broth per hour. And continuing culturing for 170h, and finishing fermentation. The obtained fermentation solution was filtered with a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently resolved with 2 volumes of acetone solution, and the content of tacrolimus in the resolved solution was measured by HPLC, and found to be 1248 mg/L.
Example 3
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. After 60 hours of incubation, HP20 resin was added at a resin volume to broth volume ratio of 0.001:1, and dextrin supplementation was started with the addition of 1g dextrin per 100ml broth per hour. And continuing culturing for 170h, and finishing fermentation. The obtained fermentation solution was filtered with a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently eluted with 2 volumes of acetone solution, and the content of tacrolimus in the eluted solution was measured by HPLC, and found to be 663 mg/L.
Example 4
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. And adding HZ801 resin after culturing for 48 hours, wherein the volume ratio of the resin to the fermentation broth is 0.03:1, and simultaneously feeding and supplementing dextrin at a feeding speed of 3g of dextrin per 100ml of fermentation broth per hour. And continuing culturing for 170h, and finishing fermentation. The obtained fermentation solution was filtered with a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently resolved with 2-fold volume of acetone solution, and the content of tacrolimus in the resolved solution was measured by HPLC, and found to be 779 mg/L.
Example 5
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. After 1 hour of culture, dextrin was fed in at a rate of 0.5 g/hr per 100ml of fermentation broth. Adding SP850 resin when culturing for 48h, wherein the volume ratio of the resin to the fermentation liquid is 0.03: 1. And continuing culturing for 170h, and finishing fermentation. The obtained fermentation solution was filtered with a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently resolved with 2 volumes of acetone solution, and the content of tacrolimus in the resolved solution was measured by HPLC, and found to be 713 mg/L.
Example 6
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. And adding HZD-3 resin after culturing for 48 hours, wherein the volume ratio of the resin to the fermentation broth is 0.1:1, and simultaneously feeding and supplementing dextrin at a feeding speed of 0.5g dextrin per 100ml of fermentation broth per hour. And continuing culturing for 170h, and finishing fermentation. The obtained fermentation solution was filtered with a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently resolved with 2 volumes of acetone solution, and the content of tacrolimus in the resolved solution was measured by HPLC, and found to be 983 mg/L.
Example 7
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. After 48 hours of culture, HZ830 resin is added, the volume ratio of the resin to the fermentation broth is 0.1:1, and dextrin is fed at a rate of 0.5g dextrin per 100ml fermentation broth per hour. And continuing culturing for 170h, and finishing fermentation. The obtained fermentation solution was filtered using a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently resolved with 2 volumes of acetone solution, and the content of tacrolimus in the resolved solution was measured using HPLC, and found to be 921 mg/L.
Comparative example 1
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. Culturing for 170h, and finishing fermentation. The fermentation solution was filtered through a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently eluted with 2 volumes of acetone solution, and the content of tacrolimus in the eluted solution was measured by HPLC, which showed 492 mg/L.
Comparative example 2
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. Adding XAD16 resin after culturing for 48 hours, wherein the volume ratio of the resin to the fermentation liquid is 0.1:1, continuing culturing for 170 hours, and ending the fermentation. The fermentation solution was filtered through a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently eluted with 2 volumes of acetone solution, and the content of tacrolimus in the eluted solution was measured by HPLC, which gave a result of 873 mg/L.
Comparative example 3
Preparing fermentation medium, adjusting pH to 7.8, subpackaging in triangular flask, and sterilizing at 121 deg.C for 20 min. Inoculating the fermentation seed liquid according to the inoculation amount of 10% of the volume of the culture medium. The culture conditions were: the culture temperature was 28 ℃, the stirring speed was 200rpm, and the aeration rate was 1.0V/V.min. After 48 hours of culture, dextrin supplementation was started, and 2g of dextrin was added per 100ml of fermentation broth per hour. And continuing culturing for 170h, and finishing fermentation. The obtained fermentation solution was filtered with a filter cloth, and the adsorption resin and mycelia containing tacrolimus were collected and sufficiently resolved with 2 volumes of acetone solution, and the content of tacrolimus in the resolved solution was measured by HPLC, and found to be 603 mg/L.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that are within the spirit and principle of the present invention are intended to be included therein.
Claims (1)
1. A fermentation method for improving the yield of tacrolimus is characterized in that in the conventional tacrolimus fermentation process, adsorption resin XAD16 and supplemented dextrin are added in a fed-batch manner, the adsorption resin is added when the fermentation time is 48 hours, and the volume ratio of the added adsorption resin to the volume of fermentation liquor is 0.1: 1; and the fed-batch complementary dextrin begins to be supplemented when the fermentation time is 48 hours, and 2g of dextrin is added into every 100ml of fermentation liquor at the fed-batch speed of the fed-batch complementary dextrin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710309551.XA CN107090477B (en) | 2017-05-04 | 2017-05-04 | Fermentation method for improving tacrolimus yield |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710309551.XA CN107090477B (en) | 2017-05-04 | 2017-05-04 | Fermentation method for improving tacrolimus yield |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107090477A CN107090477A (en) | 2017-08-25 |
| CN107090477B true CN107090477B (en) | 2021-08-27 |
Family
ID=59638034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710309551.XA Active CN107090477B (en) | 2017-05-04 | 2017-05-04 | Fermentation method for improving tacrolimus yield |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107090477B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1856500A (en) * | 2003-07-24 | 2006-11-01 | 特瓦药厂私人有限公司 | Method of purifying macrolides |
| CN1876822A (en) * | 2005-06-06 | 2006-12-13 | 上海市农药研究所 | Tacrolimus generation strain and production method thereof |
| EP2185714A1 (en) * | 2007-08-17 | 2010-05-19 | Genotech Co., Ltd | Method of extraction and yield-up of tricyclo compounds by adding a solid adsorbent resin as their carrier in fermentation medium |
-
2017
- 2017-05-04 CN CN201710309551.XA patent/CN107090477B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1856500A (en) * | 2003-07-24 | 2006-11-01 | 特瓦药厂私人有限公司 | Method of purifying macrolides |
| CN1876822A (en) * | 2005-06-06 | 2006-12-13 | 上海市农药研究所 | Tacrolimus generation strain and production method thereof |
| EP2185714A1 (en) * | 2007-08-17 | 2010-05-19 | Genotech Co., Ltd | Method of extraction and yield-up of tricyclo compounds by adding a solid adsorbent resin as their carrier in fermentation medium |
Non-Patent Citations (4)
| Title |
|---|
| Sangwon Jung et al..Strain development of Streptomyces sp. for tacrolimus production using sequential adaptation.《Journal of Industrial Microbiology & Biotechnology》.2009,第36卷(第12期),第1467页摘要部分，第1468页左栏第二段. * |
| Strain development of Streptomyces sp. for tacrolimus production using sequential adaptation;Sangwon Jung et al.;《Journal of Industrial Microbiology & Biotechnology》;20090913;第36卷(第12期);第1467页摘要部分 * |
| 他克莫司工程菌的构建及初步发酵工艺优化;王亚等;《中国医药工业杂志》;20160218;第47卷(第2期);第156页左栏倒数第1段、第2段，右栏第一段、图3 * |
| 王亚等.他克莫司工程菌的构建及初步发酵工艺优化.《中国医药工业杂志》.2016,第47卷(第2期),第152页摘要部分，第156页左栏倒数第1段、第2段，右栏第一段、图3. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107090477A (en) | 2017-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112359002B (en) | Streptomyces albus and application thereof in production of epsilon-polylysine | |
| JP5804719B2 (en) | Industrial production method of (S) -1,1,1-trifluoro-2-propanol | |
| CN107090477B (en) | Fermentation method for improving tacrolimus yield | |
| CN106434823B (en) | Fermentation method of cephalosporin C | |
| CN107435057B (en) | Method for producing hydroxyproline by adopting escherichia coli JL-HYP fermentation | |
| CN107058414B (en) | Method for preparing L-alanine | |
| CN106868079B (en) | Culture medium for fermenting polymyxin B sulfate and method for producing polymyxin B sulfate through fermentation | |
| KR102013010B1 (en) | Strain producing turanose and uses thereof | |
| CN109266707B (en) | Method for preparing polysialic acid | |
| CN111253408A (en) | Antibiotic pactamide G, preparation method thereof and application thereof in preparation of antibacterial drugs | |
| CN113774002B (en) | Bacillus amyloliquefaciens culture medium and application thereof | |
| CN106520871B (en) | Method for producing A40926 by fermentation method | |
| KR100240696B1 (en) | Arylalkanoic acid resolution | |
| KR101716879B1 (en) | Method Producing Daptomycin Using Decanoyl Glyceride | |
| CN110564789B (en) | Method for producing L-theanine by using escherichia coli fermentation | |
| CN110872338B (en) | Indole diterpenoid compound and preparation method and application thereof | |
| CN108315375B (en) | Production method of oxidized nicotinamide adenine dinucleotide phosphate | |
| JP6857022B2 (en) | Manufacturing method of organic acid | |
| CN114437963B (en) | Streptomyces olive and application thereof in biosynthesis of vanillin | |
| JP2016202073A (en) | Method for producing fumarate | |
| WO2017160042A1 (en) | L-histidine producing corynebacterium glutamicum variant and method for producing l-histidine, using same | |
| CN116200297B (en) | High-yield tetrahydropyrimidine salt-addicted single island bacillus cereus and culture method and application thereof | |
| CN109504729B (en) | Fermentation method of vancomycin | |
| CN113930346B (en) | Application of marine-derived aspergillus and fermentation product thereof in mango anthracnose resistance | |
| CN112646854B (en) | Echinocandin B synthetic medium and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 510663 1 Pinnacle Road, Luogang District, Guangzhou, Guangdong Applicant after: Guangzhou Institute of Microbiology Co.,Ltd. Applicant after: GUANGZHOU MEDCAN PHARMATECH Ltd. Applicant after: SOUTH CHINA University OF TECHNOLOGY Address before: 510663 1 Pinnacle Road, Luogang District Science City, Guangzhou, Guangdong Applicant before: GUANGDONG INSTITUTE OF MICROBIOLOGY Applicant before: GUANGZHOU MEDCAN PHARMATECH Ltd. Applicant before: SOUTH CHINA University OF TECHNOLOGY |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 510663 No.1 jiantashan Road, Huangpu District, Guangzhou City, Guangdong Province Patentee after: Guangzhou Institute of Microbiology Group Co.,Ltd. Patentee after: GUANGZHOU MEDCAN PHARMATECH Ltd. Patentee after: SOUTH CHINA University OF TECHNOLOGY Address before: 510663 1 Pinnacle Road, Luogang District, Guangzhou, Guangdong Patentee before: Guangzhou Institute of Microbiology Co.,Ltd. Patentee before: GUANGZHOU MEDCAN PHARMATECH Ltd. Patentee before: SOUTH CHINA University OF TECHNOLOGY |