CN102206694A - Slow-release composition containing capric acid - Google Patents
Slow-release composition containing capric acid Download PDFInfo
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- CN102206694A CN102206694A CN201110085101XA CN201110085101A CN102206694A CN 102206694 A CN102206694 A CN 102206694A CN 201110085101X A CN201110085101X A CN 201110085101XA CN 201110085101 A CN201110085101 A CN 201110085101A CN 102206694 A CN102206694 A CN 102206694A
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- Prior art keywords
- capric acid
- slow releasing
- releasing composition
- daptomycin
- fermentation
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Abstract
The invention belongs to the field of biomedicine, and relates to a slow-release composition containing capric acid, particularly application of a slow-release composition containing capric acid in preparation of Daptomycin by fermentation. A certain amount of the slow-release composition containing capric acid can be supplemented at a specific time in the Daptomycin fermentation and production process, thereby synthesizing the Daptomycin. The invention reduces the number of times of shake flask fermentation and material supplementation, and lowers the probability of microbiological contamination; the slow-release capric acid reduces the toxicity for bacteria, and ensures good growth conditions for bacteria; and compared with the traditional batch-by-batch material supplementation method, the unit of the shake flask fermentation is increased by 4.1-5.8 times.
Description
Technical field
The invention belongs to biomedicine field, related to a kind of slow releasing composition that contains capric acid, relate in particular to a kind of application of slow releasing composition in the method for fermentative preparation daptomycin that contains capric acid.
Background technology
Daptomycin (Daptomycin) (chemical formula one is the chemical formula of daptomycin) is to extract a cyclic ester peptide matters that obtains in streptomycete (S.reseosporus) fermented liquid, it not only has novel chemical structure, and its binding mode is also with arbitrary to have got permission microbiotic different: it can destroy the bacterial cell membrane function in many aspects, kills gram positive organism thus rapidly.The daptomycin decapacitation acts on outside most of clinical relevant gram positive organisms, the more important thing is external still to have a strong active to being resistance isolated strains such as X-1497 (Methicillin), vancomycin and Linezolid.
Chemical formula one
At present, daptomycin mainly is by fermentative Production, and needs in process of production to add the precursor substance capric acid, yet adding of capric acid need be controlled within the certain level, when the capric acid excessive concentration, cognition makes thalli growth be subjected to certain inhibition before the high toxicity; And capric acid concentration is when low, and under-supply, the daptomycin synthetic ratio is low.Lu Wenyu etc. are at " capric acid resistant mutant strain stream adds the fermentative Production daptomycin " (University Of Tianjin's journal, 2006, the 39th phase, the 20-24 page or leaf) discloses in the fermentor tank production of 7.5L, adopt the technology of continuous flow feeding to eliminate the restraining effect of precursor, the daptomycin of preparation gained is tired and is 210mg/L.Surplus three grade that continues is in " Streptomyces roseosporus NRRL113789 produces the fermention medium optimization of daptomycin precursor A21978C " (Anhui agricultural sciences, 2008, the 36th the 19th phase of volume, the 7974-7976 page or leaf) discloses in the literary composition in shake flask fermentation by optimizing fermention medium and improved daptomycin output, the fermentation unit of final A21978C component is 60mg/mL, does not disclose related data for the daptomycin behind the A21978C bio-modification.
To sum up can learn, the pertinent literature that shake flask fermentation prepares daptomycin is not disclosed at present, and add capric acid in the shake flask fermentation process owing to can not realize automatization trace flow feeding continuously, generally adopt repeatedly feed supplement, so not only cause the fermentation microbiological contamination easily, and because the capric acid excessive concentration suppresses thalli growth, thereby make fermentation unit lower.
Summary of the invention
The invention provides a kind of slow releasing composition that contains capric acid, percentage ratio meter by weight, it contains the component of following significant quantity: capric acid 3.0～10.0%, ethanol 3.0～8.0%, stearic acid 0.5～1.0%, polyoxyethylene glycol 1.0～2.0%, agar powder 1.0～2.0%, water 77.0～91.5%; More preferably capric acid 6%, ethanol 6%, stearic acid 0.7%, polyoxyethylene glycol (PEG) 1.1%, agar powder 1.2%, water 85%.
The present invention also provides the preparation method of this slow releasing composition, and its step is as follows:
Aseptic condition down will
Mixed solution splashes in 0～10 ℃ of aseptic dimethyl silicone oil, makes sustained-release dropping pill;
The present invention also provides the application of this slow releasing composition in the method for fermentative preparation daptomycin, promptly in the liquid nutrient medium that contains assimilable carbon, nitrogenous source and inorganic salt, carry out under the aerobic fermentation condition, at specified time a certain amount of slow releasing composition that contains capric acid is added in the nutrient solution, thereby improve the daptomycin combined coefficient.The method of fermentative preparation daptomycin provided by the present invention comprises following steps:
A. Streptomyces roseosporus is inoculated on the slant medium, in 30 ℃ of aerobic cultivations 10 days;
B. the bacterium that step a is cultivated is inoculated on the 20-50ml liquid seed culture medium in 28-32 ℃, 220rpm shaking culture 30-48h;
C. the bacterium that b is cultivated is inoculated in the fermention medium by inoculum size 2-10%, and 30 ℃, 220rpm shaking culture 8 days;
D. cultivate 20-48h from inoculation fermentation and begin to add the slow releasing composition that contains capric acid, every liter of fermented liquid is per hour added the slow releasing composition that contains the 0.1-0.4ml capric acid, and every interval 24-72h adds once, and 204h finishes until fermentation;
E. adopt Tianjin, island LC-20A liquid chromatograph to detect daptomycin, add precursor after every interval 24h sampling detect;
F. 24h microscopy after the feed supplement for the first time, during fermentation ends, the relative biomass of the centrifugal survey of 3000rpm.
The present invention has carried out preferably the slant culture based formulas among the step a, and preferably, slant medium consists of among the above-mentioned steps a: yeast extract 4g/L, malt extract 10g/L, glucose 4g/L, agar 15g/L.
The present invention has carried out preferably the seed culture based formulas among the step b, and preferably, seed culture medium consists of among the above-mentioned steps b: dextrin 20g/L, peptone 10g/L, yeast extract 3g/L, K
2HPO
40.1g/L, NaCl 0.2g/L.
The present invention has carried out preferably the fermentative medium formula among the step c, and preferably, fermention medium consists of among the above-mentioned steps c: dextrin 30g/L, glucose 6g/L, soyflour 15g/L, yeast powder 4g/L, FeSO
47H
2O 0.5g/L, K
2HPO
40.2g/L, MgSO
47H
2O 0.1g/L.
The present invention has carried out preferably the time of origin of adding of slow releasing composition, preferably, above-mentionedly cultivates 20～36h from inoculation fermentation and begins to add the slow releasing composition that contains capric acid.
Carried out the pitch time that the present invention adds slow releasing composition preferably, preferably, above-mentioned every interval 24～48h adds the slow releasing composition that once contains capric acid.
The present invention has carried out preferably the additional amount of slow releasing composition, and preferably above-mentioned, every liter of fermented liquid is per hour added the slow releasing composition that contains the 0.15-0.3ml capric acid.
The present invention compared with prior art has following outstanding advantage:
(1) adds the slow releasing composition that contains capric acid provided by the invention in the process of fermentative preparation daptomycin, reduce the number of times of adding of capric acid, greatly reduce the microbiological contamination probability;
(2) because the slow releasing composition that contains capric acid provided by the invention, it is a kind of sustained-release materials, slow release by capric acid, alleviated in the fermenting process capric acid to the toxicity of thalline, guaranteed that thalline growth conditions in building-up process is good, 24h microscopy after the feed supplement for the first time, visible mycelia is thicker, longer, color depth; During fermentation ends, the fermented liquid thickness;
(3) improved the fermentation unit that shakes bottle preparation daptomycin greatly, tiring of fermentative preparation daptomycin of the present invention is increased to 101.7mg/L, is up to 137.1mg/L, and the method for preparing daptomycin than traditional zymotic improves 4.1-5.8 doubly.
Embodiment
Further specify the present invention by the following examples, but these embodiment do not limit the present invention in any way.
Embodiment 1: the preparation method who contains the slow releasing composition of capric acid
| ? | Capric acid (%) | Ethanol (%) | Stearic acid (%) | Polyoxyethylene glycol (%) | Agar powder (%) | Water (%) |
| Composition 1 | 3 | 3 | 0.5 | 1.0 | 1.0 | 91.5 |
| Composition 2 | 10 | 8 | 1.0 | 2.0 | 2.0 | 77.0 |
| Composition 3 | 6 | 6 | 0.7 | 1.1 | 1.2 | 85.0 |
Embodiment 2: the preparation of fermention medium
Slant medium (g/L): yeast extract 4, malt extract 10, glucose 4, agar 15 becomes feed liquid by formulated, transfers pH7.2,121 ℃ of sterilization 30min;
Seed culture medium (g/L): dextrin 20, peptone 10, yeast extract 3, K
2HPO
40.1 NaCl 0.2, becomes feed liquid by formulated, transfers pH7.0,121 ℃ of sterilization 30min;
Fermentative medium formula (g/L): dextrin 30, glucose 6, soyflour 15, yeast powder 4, FeSO
47H
2O 0.5, K
2HPO
40.2, MgSO
47H
2O 0.1, becomes feed liquid by formulated, transfers pH7.2,121 ℃ of sterilization 30min.
Embodiment 3: add capric acid fermentative preparation daptomycin
A. Streptomyces roseosporus NRRL11379 is inoculated on the slant medium, in 30 ℃ of aerobic cultivations 10 days;
B. the bacterium that step a is cultivated is inoculated on the 30ml seed culture medium, in 30 ℃, 220rpm shaking culture 48h;
C. the bacterium that b is cultivated is inoculated in the fermention medium by inoculum size 8%, 30 ℃, 220rpm shaking culture 8 days;
D. cultivate 36h from fermentation and begin to add capric acid, every liter of fermented liquid is once added the mixed solution (contain capric acid and ethanol in this mixed solution, and its weight ratio being 1: 1) that contains the 3.6ml capric acid, and every interval 24h adds once, and 204h finishes until fermentation, adds altogether 6 times;
E. adopt Tianjin, island LC-20A liquid chromatograph to detect daptomycin, add capric acid after every interval 24h sampling detect the 20.1mg/L of fermentation ends daptomycin unit;
F. 24h microscopy after the feed supplement for the first time: mycelia is thin, and painted light, fracture is serious; During fermentation ends, fermented liquid is rare, and the relative biomass of the centrifugal survey of 3000rpm is 12%.
Embodiment 4: the method for preparing daptomycin
Steps d begins to add the slow releasing composition that contains capric acid for cultivating 36h from fermentation, and every liter of fermented liquid is once added the slow releasing composition that contains the 7.2ml capric acid, and every interval 48h adds once, and 204h finishes until fermentation, adds altogether 3 times.
All the other steps are with embodiment 3.
Adopt Tianjin, island LC-20A liquid chromatograph to detect daptomycin, add slow releasing composition after every interval 24h sampling detect the 133.6mg/L of fermentation ends daptomycin unit; 24h microscopy after the feed supplement for the first time: mycelia is thicker, and is longer, color depth; During fermentation ends, the fermented liquid thickness, the relative biomass of the centrifugal survey of 3000rpm is 21%.
Embodiment 5: the method for preparing daptomycin
Steps d begins to add the slow releasing composition that contains capric acid for cultivating 36h from fermentation, and every liter of fermented liquid is once added the slow releasing composition that contains the 10.8ml capric acid, and every interval 72h adds once, and 204h finishes until fermentation, adds altogether 2 times.
All the other steps are with embodiment 3.
Adopt Tianjin, island LC-20A liquid chromatograph to detect daptomycin, add slow releasing composition after every interval 24h sampling detect the 101.7mg/L of fermentation ends daptomycin unit; 24h microscopy after the feed supplement for the first time: mycelia is thin, and is longer, painted shallow, the mycelia fracture; During fermentation ends, fermented liquid is than thickness, and the relative biomass of the centrifugal survey of 3000rpm is 19%.
Embodiment 6: the method for preparing daptomycin
Steps d begins to add the slow releasing composition that contains capric acid for cultivating 30h from fermentation, and every liter of fermented liquid is once added the slow releasing composition that contains the 5.4ml capric acid, and every interval 36h adds once, and 204h finishes until fermentation, adds altogether 4 times.
All the other steps are with embodiment 3.
Adopt Tianjin, island LC-20A liquid chromatograph to detect daptomycin, add slow releasing composition after every interval 24h sampling detect the 137.1mg/L of fermentation ends daptomycin unit; 24h microscopy after the feed supplement for the first time: mycelia is thicker, and is longer, color depth; During fermentation ends, the fermented liquid thickness, the relative biomass of the centrifugal survey of 3000rpm is 22%.
Embodiment 7: the method for preparing daptomycin
Steps d begins to add the slow releasing composition that contains capric acid for cultivating 20h from fermentation, and every liter of fermented liquid is once added the slow releasing composition that contains the 3.2ml capric acid, and every interval 32h adds once, and 204h finishes until fermentation, adds altogether 5 times.
All the other steps are with embodiment 3.
Adopt Tianjin, island LC-20A liquid chromatograph to detect daptomycin, add slow releasing composition after every interval 24h sampling detect the 135.3mg/L of fermentation ends daptomycin unit; 24h microscopy after the feed supplement for the first time: mycelia is thicker, and is longer, color depth; During fermentation ends, the fermented liquid thickness, the relative biomass of the centrifugal survey of 3000rpm is 21%.
Embodiment 8: the method for preparing daptomycin
Steps d begins to add the slow releasing composition that contains capric acid for cultivating 36h from fermentation, and every liter of fermented liquid is once added the slow releasing composition that contains the 14.4ml capric acid, and every interval 48h adds once, and 204h finishes until fermentation, adds altogether 3 times.
All the other steps are with embodiment 3.
Adopt Tianjin, island LC-20A liquid chromatograph to detect daptomycin, add slow releasing composition after every interval 24h sampling detect the 135.2mg/L of fermentation ends daptomycin unit; 24h microscopy after the feed supplement for the first time: mycelia is thicker, and is longer, color depth; During fermentation ends, the fermented liquid thickness, the relative biomass of the centrifugal survey of 3000rpm is 22%.
Embodiment 9: the method for preparing daptomycin
Steps d begins to add the slow releasing composition that contains capric acid for cultivating 48h from fermentation, and every liter of fermented liquid is once added the slow releasing composition that contains the 9.6ml capric acid, and every interval 24h adds once, and 204h finishes until fermentation, adds altogether 5 times.
All the other steps are with embodiment 3.
Adopt Tianjin, island LC-20A liquid chromatograph to detect daptomycin, add slow releasing composition after every interval 24h sampling detect the 134.9mg/L of fermentation ends daptomycin unit; 24h microscopy after the feed supplement for the first time: mycelia is thicker, and is longer, color depth; During fermentation ends, the fermented liquid thickness, the relative biomass of the centrifugal survey of 3000rpm is 20%.
Claims (9)
1. slow releasing composition that contains capric acid is characterized in that: percentage ratio meter by weight, and it contains the component of following significant quantity: capric acid 3.0 ~ 10.0%, ethanol 3.0 ~ 8.0%, stearic acid 0.5 ~ 1.0%, polyoxyethylene glycol 1.0 ~ 2.0%, agar powder 1.0 ~ 2.0%, water 77.0 ~ 91.5%.
2. slow releasing composition according to claim 1 is characterized in that: percentage ratio meter by weight, it contains the component of following significant quantity: capric acid 6%, ethanol 6%, stearic acid 0.7%, polyoxyethylene glycol (PEG) 1.1%, agar powder 1.2%, water 85%.
3. method for preparing slow releasing composition as claimed in claim 1 or 2 is characterized in that it may further comprise the steps:
The sustained-release dropping pill for preparing is inhaled the oil that goes to the surface with aseptic paper, and cryopreservation.
4. method for preparing daptomycin is characterized in that it comprises following steps:
A. Streptomyces roseosporus is inoculated on the slant medium, in 30 ℃ of aerobic cultivations 8-10 days;
B. the bacterium that step a is cultivated is inoculated on the 20-50ml liquid seed culture medium in 28-32 ℃, 220rpm shaking culture 36-50h;
C. the bacterium that b is cultivated is inoculated in the fermention medium by inoculum size 2-10%, and 30 ℃, 220rpm shaking culture 8-10 days;
D. cultivate 20-48h from inoculation fermentation and begin to add slow releasing composition as claimed in claim 1 or 2, every interval 24-72h adds once, until fermentation ends.
5. method according to claim 4 is characterized in that slant medium consists of among the step a: yeast extract 4 g/L, malt extract 10 g/L, glucose 4 g/L, agar 15 g/L.
6. method according to claim 4 is characterized in that seed culture medium consists of among the step b: dextrin 20 g/L, peptone 10 g/L, yeast extract 3 g/L, K
2HPO
40.1 g/L, NaCl 0.2 g/L.
7. method according to claim 4 is characterized in that fermention medium consists of among the step c: dextrin 30 g/L, glucose 6 g/L, soyflour 15 g/L, yeast powder 4 g/L, FeSO
4 .7H
2O 0.5 g/L, K
2HPO
40.2 g/L, MgSO
4 .7H
2O 0.1 g/L.
8. method according to claim 4 is characterized in that cultivating 20h ~ 36h from inoculation fermentation in the steps d begins to add slow releasing composition as claimed in claim 1 or 2.
9. method according to claim 4 is characterized in that every interval 24h in the steps d ~ 48h adds slow releasing composition once as claimed in claim 1 or 2.
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| CN 201110085101 CN102206694B (en) | 2011-04-06 | 2011-04-06 | Slow-release composition containing capric acid |
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|---|---|---|---|
| CN 201110085101 CN102206694B (en) | 2011-04-06 | 2011-04-06 | Slow-release composition containing capric acid |
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| CN102206694B CN102206694B (en) | 2013-10-16 |
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Cited By (2)
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|---|---|---|---|---|
| CN102703551A (en) * | 2012-06-27 | 2012-10-03 | 中国药科大学 | Novel method for adding decanoic acid in fermentation process of daptomycin |
| CN102796680A (en) * | 2012-07-04 | 2012-11-28 | 鲁南新时代生物技术有限公司 | Streptomyces roseosporus and method for producing daptomycin by utilizing combined precursor |
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|---|---|---|---|---|
| CN102703551A (en) * | 2012-06-27 | 2012-10-03 | 中国药科大学 | Novel method for adding decanoic acid in fermentation process of daptomycin |
| CN102796680A (en) * | 2012-07-04 | 2012-11-28 | 鲁南新时代生物技术有限公司 | Streptomyces roseosporus and method for producing daptomycin by utilizing combined precursor |
| CN102796680B (en) * | 2012-07-04 | 2018-06-05 | 鲁南新时代生物技术有限公司 | A kind of Streptomyces roseosporus and its method for producing Daptomycin using precursor is combined |
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| Publication number | Publication date |
|---|---|
| CN102206694B (en) | 2013-10-16 |
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Effective date of registration: 20151218 Address after: Shandong province Linyi city Feixian County North Ring Road No. 1 Patentee after: Lunan New Era Biological Technology Co., Ltd. Address before: 273400 Shandong city of Linyi province Feixian County North Ring Road No. 1 Patentee before: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. |