WO2004005275A1 - Fed batch solid state fermentation for the production of hmg-coa reductase inhibitors - Google Patents
Fed batch solid state fermentation for the production of hmg-coa reductase inhibitors Download PDFInfo
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- WO2004005275A1 WO2004005275A1 PCT/IN2002/000145 IN0200145W WO2004005275A1 WO 2004005275 A1 WO2004005275 A1 WO 2004005275A1 IN 0200145 W IN0200145 W IN 0200145W WO 2004005275 A1 WO2004005275 A1 WO 2004005275A1
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- 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
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
Definitions
- the present invention provides a novel method for producing compound of formula I, its acid form or any salt form, where Rj . is H or CH 3 , by solid state fermentation using fed-batch technique by culturing microorganisms capable of producing the compound of formula I.
- Formula I US 6,197,560 disclosed a method for producing lovastatin by a microorganism by a fermentation process involving submerged technique with feeding.
- US 6,165,757 disclosed a submerged fermentation process for producing an HMG-CoA reductase inhibitor such as lovastatin or compactin, in particular, relating to a process wherein at least part of the assimilable nitrogen source and, optionally, the carbon source is provided continuously or intermittently to the culture medium.
- WO 99/19458 disclosed a submerged fermentation of Aspergilfus terreus for production of lovastatin.
- US 5,691,173 disclosed a novel microorganism, Penicillium adametzioides and a process of using the microorganism to produce compactin, the process consisting of fermentation in a nutrient medium.
- WO 00/37665 disclosed synthesizing a natural product from fungi by immobilizing spores onto a support which are exposed to nutrient media in a submerged or bioreactor system producing natural products such as antibiotics or growth regulators from fungi, especially, mevastatin.
- Producing biological compounds by fermentation, especially fed batch fermentation, in submerged fermentation process is an expensive procedure, as the demand for purified water and clean steam (for sterilization) can be high, the process is generally labor intensive, requiring skilled workers at all levels of production. The cost of high grade nutrients and other ingredients necessary for culture media can be high.
- the present invention provides a novel method for increasing the fermentation yields of compound of formula I, its free acid form or any salt form, wherein Ri is either H or CH 3 .
- the invention provides a fermentation process in which the compound of formula I, its acid form or any salt form, is produced on solid nutritious matrix.
- the fermentation is carried out in fed-batch mode to increase the productivity/yields of the final product.
- the fermentation is also carried out in a contained bio- reactor.
- solid state fermentation or "solid state cultivation”, sometimes referred to as “semi-solid state fermentation” as used herein, means the process of fermenting microorganisms on a solid medium that provides anchorage points for the microorganisms in the absence of any freely flowing substance.
- the amount of water in the solid medium can be any amount of water.
- the solid medium could be almost dry, or it could be slushy.
- solid state fermentation and “semi-solid state fermentation” are interchangeable.
- Feed-batch fermentation or “fed-batch technique”: The term fed-batch fermentation as used herein, means a fermentation process carried out where substrate or nutrients are added in small increments as the fermentation progresses.
- the substrate or nutrient is added in small increment that would encourage the production of secondary metabolites because some secondary metabolite production is inhibited by high concentrations of substrate or substrates, so this method would encourage the production of such metabolites.
- Supplement of nutrients at a time when the initially fed nutrient are consumed by the microorganisms or culture also help in providing more energy to the microorganism which in turn increases the overall production of the secondary metabolites.
- Bioreactor means a device capable of holding fermentation media inoculated with microorganism and carrying out the process of solid state fermentation in a contained manner.
- a bioreactor can be used to grow any microorganism capable of growing under specified conditions in a contained environment.
- Some examples of microorganisms capable of growing in a bioreactor are fungi, yeast and bacteria. Particularly preferred microorganisms are fungi.
- the present invention discloses a process for production of compound of formula I, its acid form or any salt form, by culturing a microorganism capable of producing such compound on solid nutrient matrix wherein, the nutrients are fed in adequate quantities so that the production of the product increases significantly.
- the instant invention discloses a process for the manufacture of compound of formula I, its acid form or any salt form, wherein Ri is either CH 3 or H, by fed batch solid substrate fermentation to enhance productivity comprising: - mixing solid substrate medium with a microbial strain capable of producing compound of formula I, feeding nutrient in the course of fermentation and incubating the mixture to obtain compound of formula I.
- the microbial strain used for solid substrate fermentation is Aspergillus terreus for the production of compound of formula I, its free acid or any salt form, when Ri is CH 3 .
- the microbial strain used for solid substrate fermentation is Penicillium sp for the production of compound of formula I, its free acid or any salt form, when Ri is H.
- the solid substrate for fermentation is selected from wheat bran, wheat rawa, broken wheat, boiled rice, rice bran, rice rawa, beaten rice, maize bran, maize grits, oat bran, bagasse, tapioca residue, soya grits, soya flakes, rice flakes, ceramic beads, glass beads or a mixture of two or more of these.
- the nutrient feeding for fed-batch fermentation is done at the beginning of the fermentation or throughout the fermentation.
- the nutrient feeding for fed-batch fermentation is done with the carbon : nitrogen ratio in the feed maintained between 15 :1 to 100
- the nutrient feeding for fed-batch fermentation is done with the carbon : nitrogen ratio in the feed maintained between 15 : 1 to 50 : 1.
- the carbon feed for fed-batch fermentation is selected from glucose, sucrose, starch (maize, wheat, tapioca, potato), modified starch, maltose, malto-dextrin, soyabean oil, acetate or a mixture of one or more of these.
- the nitrogen feed for fed-batch fermentation is selected from ammonium sulphate, ammonium nitrate, sodium nitrate, bacteriological peptone, yeast extract, casein hydrolyzate, soy peptone, soy flour, cotton seed flour, corn steep liquor or a mixture of one or more of these.
- the nutrient for feeding is selected from a carbon source, nitrogen source or any other source capable of enhancing the production of Formula I.
- the fist aspect of invention is production of compound of formula I, its acid form or any salt form, wherein R x is CH 3 .
- the compound is obtained by culturing Aspergillus terreus on solid nutrient matrix e.g. wheat bran. The culture is then fed with nutrients to increase production of the final product. The product is then purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
- the second aspect of the invention is production of compound of formula I, its acid form or any salt form, wherein R x is H.
- the compound is obtained by culturing Penicillium species on solid nutrient matrix e.g. wheat bran. The culture is then fed with nutrients to increase production of the final product. The product is then purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
- MgS0 4 .7H 2 0 0.5g/L pH of this medium is adjusted to 6.0 after making up the volume with water.
- the seed flasks were grown at 28 to 30°C for 4 days and used as an inoculum for solid state fermentation.
- the C N ratio of the feed was varied from 5:1 to 28:1.
- the entire substrate was mixed properly with the inoculum and feed and incubated at 28 to 30 deg C for 9 days. Following results were obtained.
- Example 2 The experiment was done as in Example 1. 10 g of wheat bran was packed in petri plates and sterilized. To this 10 ml of seed inoculum was added along with varying volumes of feed having a C : N ratio of 28:1. The entire substrate was mixed properly with the inoculum and feed. These plates were incubated at 28 to 30 deg C for 9 days. Following results were obtained.
- Example 2 The experiment was done as in Example 1. 10 g of wheat bran was packed in petri plates and sterilized. To this 10 ml of seed inoculum was added along with 5 ml feed having a C : N ratio of 28:1. The feeding was done during fermentation to see its effect on yield. 5ml of the feed was added and mixed. The plates were incubated at 28 to 30 deg C for 9 days. The results are given below:
- Seed inoculum of Aspergillus terreus is obtained as explained in Example 1. 3 L of this inoculum was used for inoculating 27 L of the same seed medium taken in a 50 L fermenter. This is grown for 48 hr at 28 to 30°C. This is used as an inoculum for solid state fermentation. 15 kg wheat bran, was loaded into a bioreactor having 22600 cm 2 surface area. The bioreactor was sterilised at 121 deg C for 1 to 2 hours using steam. After the sterilization the temperature of the solid substrate was brought down to 28 deg C. 15 L of the above inoculum and 7.5L feed was added to the solid substrate and mixed. 7.5L of feed was also added on 3rd and 5 th day and mixed. The entire biomass along with the solid substrate was harvested on 9 th day and processed to get pharmaceutically acceptable grade of lovastatin. Totally 425 g of lovastatin was obtained.
- Penicillium sp. was taken and 5ml of distilled water was added. It was shaken thoroughly and 100 micro litre of this inoculum was used for the inoculation of 50 ml seed medium taken in 250 ml conical flask.
- Soy flour 30g/L
- MgS0 4 .7H 2 0 lg/L pH of this medium was adjusted to 5.5 after making up the volume with water.
- the seed flasks were grown at 24 to 26°C for 4 days and used as an inoculum for solid state fermentation.
- Solid state fermentation lOgm wheat bran was taken in a petri plate. Adequate amount of water was added and sterilized at 121 deg C for 30 minutes. 10 ml inoculum from 4 day old seed medium was added along with 5ml feed having a C : N ratio of 28:1. These plates were incubated at 24 to 26 deg C. On 3 rd and 5 th day, 5ml of feed was added and mixed. Following results were obtained.
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Abstract
The present invention provides a novel method for producing compound of formula (I), its acid form or any salt form, where R1 is H or CH3, by solid state fermentation using fed-batch technique by culturing microorganisms capable of producing the compound of formula (I).
Description
TITLE OF INVENTION
FED BATCH SOLID STATE FERMENTATION FOR THE PRODUCTION OF HMG-CoA REDUCTASE INHIBITORS FIELD OF INVENTION
The present invention provides a novel method for producing compound of formula I, its acid form or any salt form, where Rj. is H or CH3, by solid state fermentation using fed-batch technique by culturing microorganisms capable of producing the compound of formula I. BACKGROUND OF THE INVENTION
Several methods for production of the compound of formula I its acid form or any salt form, are disclosed in the prior art. The compound produced by the inventive method is used as hydroxy methyl glutaric acid CoA reductase inhibitor therapeutically.
Formula I
US 6,197,560 disclosed a method for producing lovastatin by a microorganism by a fermentation process involving submerged technique with feeding.
US 6,165,757 disclosed a submerged fermentation process for producing an HMG-CoA reductase inhibitor such as lovastatin or compactin, in particular, relating to a process wherein at least part of the assimilable nitrogen source and, optionally, the carbon source is provided continuously or intermittently to the culture medium.
WO 99/19458 disclosed a submerged fermentation of Aspergilfus terreus for production of lovastatin. US 5,691,173 disclosed a novel microorganism, Penicillium adametzioides and a process of using the microorganism to produce compactin, the process consisting of fermentation in a nutrient medium.
The continuous production of compactin by Penicillium cyclopiυm in fermentor using a sponge as a novel solid support and MGPB-citrate as a feedstock has been disclosed (Bazaraa-W-A et. al., Abstr.Gen.Meet.Am.SocMicrobioL; 1993 93 Meet., 319).
WO 00/37665 disclosed synthesizing a natural product from fungi by immobilizing spores onto a support which are exposed to nutrient media in a submerged or bioreactor system producing natural products such as antibiotics or growth regulators from fungi, especially, mevastatin.
Szakacs-G et al. dislcosed production of lovastatin by a wild strain of Aspergillus terreus by Solid-state fermentation on extracted sweet sorghum pulp supplemented with cheese whey
(Biotechnol.Lett; 1998, 411, 15). US 6,197,573 also discloses a
bioreactor for the production pharmaceutically active ingredients like lovastatin using solid state fermentation.
The prior art literature does not disclose production of compound of formula I, its acid form or any salt form, wherein Ri is H or CH3 by solid substrate fermentation with fed-batch technique. Solid state fed - batch methods used till now for cellulase and gibberalic acid production involved atomizing ammonium sulphate for feeding Q.Chem.Technol.Biotechnol.; (1997) 69, 4, 429-32), shot addition of solid corn starch in a 50 L continuously rotating reactor (Process- Biochem.; (1997) 32, 2, 141-45), shot addition of only carbon source at very small scale (Biotechnol.Lett; (1987) 9, 3, 179-82)
Producing biological compounds by fermentation, especially fed batch fermentation, in submerged fermentation process is an expensive procedure, as the demand for purified water and clean steam (for sterilization) can be high, the process is generally labor intensive, requiring skilled workers at all levels of production. The cost of high grade nutrients and other ingredients necessary for culture media can be high.
A need to provide a simple fed batch fermentation system that minimizes the cost for production of the compound of interest by providing required nutrients in proper feed rate, with the right component constitution required during the process and in a cost effective manner. To Maximize yield of the compound of interest and avoiding problems that may occur in media preparation such as precipitation of certain ingredients or the formation of chemical intermediates during sterilization was felt.
Accordingly, it is an objective of the present invention to provide a fermentation system/process that reduces the cost of production by an innovative process of fed-batch fermentation in solid state matrix. SUMMARY OF THE INVENTION
The present invention provides a novel method for increasing the fermentation yields of compound of formula I, its free acid form or any salt form, wherein Ri is either H or CH3.
Formula I
In preferred embodiments, the invention provides a fermentation process in which the compound of formula I, its acid form or any salt form, is produced on solid nutritious matrix. The fermentation is carried out in fed-batch mode to increase the productivity/yields of the final product. The fermentation is also carried out in a contained bio- reactor.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Definitions
"Solid state fermentation" or "solid state cultivation":
The term "solid state fermentation" or "solid state cultivation", sometimes referred to as "semi-solid state fermentation" as used herein, means the process of fermenting microorganisms on a solid medium that provides anchorage points for the microorganisms in the absence of any freely flowing substance. The amount of water in the solid medium can be any amount of water. For example, the solid medium could be almost dry, or it could be slushy. A person skilled in the art knows that the terms "solid state fermentation" and "semi-solid state fermentation" are interchangeable.
"Fed-batch fermentation" or "fed-batch technique": The term fed-batch fermentation as used herein, means a fermentation process carried out where substrate or nutrients are added in small increments as the fermentation progresses. The substrate or nutrient is added in small increment that would encourage the production of secondary metabolites because some secondary metabolite production is inhibited by high concentrations of substrate or substrates, so this method would encourage the production of such metabolites. Supplement of nutrients at a time when the initially fed nutrient are consumed by the microorganisms or culture also help in providing more energy to the microorganism which in turn increases the overall production of the secondary metabolites.
"Bioreactor": The term "bioreactor" as used herein, means a device capable of holding fermentation media inoculated with microorganism and carrying out the process of solid state fermentation
in a contained manner. A bioreactor can be used to grow any microorganism capable of growing under specified conditions in a contained environment. Some examples of microorganisms capable of growing in a bioreactor are fungi, yeast and bacteria. Particularly preferred microorganisms are fungi.
The present invention discloses a process for production of compound of formula I, its acid form or any salt form, by culturing a microorganism capable of producing such compound on solid nutrient matrix wherein, the nutrients are fed in adequate quantities so that the production of the product increases significantly.
The instant invention discloses a process for the manufacture of compound of formula I, its acid form or any salt form, wherein Ri is either CH3 or H, by fed batch solid substrate fermentation to enhance productivity comprising: - mixing solid substrate medium with a microbial strain capable of producing compound of formula I, feeding nutrient in the course of fermentation and incubating the mixture to obtain compound of formula I.
The microbial strain used for solid substrate fermentation is Aspergillus terreus for the production of compound of formula I, its free acid or any salt form, when Ri is CH3.
The microbial strain used for solid substrate fermentation is Penicillium sp for the production of compound of formula I, its free acid or any salt form, when Ri is H. The solid substrate for fermentation is selected from wheat bran, wheat rawa, broken wheat, boiled rice, rice bran, rice rawa, beaten
rice, maize bran, maize grits, oat bran, bagasse, tapioca residue, soya grits, soya flakes, rice flakes, ceramic beads, glass beads or a mixture of two or more of these.
The nutrient feeding for fed-batch fermentation is done at the beginning of the fermentation or throughout the fermentation. The nutrient feeding for fed-batch fermentation is done with the carbon : nitrogen ratio in the feed maintained between 15 :1 to 100
:1.
The nutrient feeding for fed-batch fermentation is done with the carbon : nitrogen ratio in the feed maintained between 15 : 1 to 50 : 1.
The carbon feed for fed-batch fermentation is selected from glucose, sucrose, starch (maize, wheat, tapioca, potato), modified starch, maltose, malto-dextrin, soyabean oil, acetate or a mixture of one or more of these. The nitrogen feed for fed-batch fermentation is selected from ammonium sulphate, ammonium nitrate, sodium nitrate, bacteriological peptone, yeast extract, casein hydrolyzate, soy peptone, soy flour, cotton seed flour, corn steep liquor or a mixture of one or more of these. The nutrient for feeding is selected from a carbon source, nitrogen source or any other source capable of enhancing the production of Formula I.
The fist aspect of invention is production of compound of formula I, its acid form or any salt form, wherein Rx is CH3. The compound is obtained by culturing Aspergillus terreus on solid nutrient matrix e.g. wheat bran. The culture is then fed with nutrients to
increase production of the final product. The product is then purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
The second aspect of the invention is production of compound of formula I, its acid form or any salt form, wherein Rx is H. The compound is obtained by culturing Penicillium species on solid nutrient matrix e.g. wheat bran. The culture is then fed with nutrients to increase production of the final product. The product is then purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
The advantages of the instant invention over the other reported methods are: (i) Feeding method is easily scalable since the liquid feed is added directly (no need of spraying) to the solid substrate followed by mixing for uniform distribution (ii) Liquid feed can be easily steam sterilized and sent through the bioreactor (iii) The feed is given intermittently which minimizes mixing and hence is ideal for shear sensitive cultures (iv) Overall dosing of nutrients per unit volume gets increased resulting in higher productivity (v) Economical at large scale of operations.
The following Examples further illustrate the invention, it being understood that the invention is not intended to be limited by the details disclosed therein. EXAMPLES: EXAMPLE 1 A well grown slant of Aspergillus terreus was taken and 5ml of distilled water was added. It was shaken thoroughly and 100 micro litre of this spore suspension was used for the inoculation of 50 ml seed medium taken in 250 ml conical flask. The composition of seed medium is as follows:
Glucose = 200g/L
Soluble starch = 40g/L
Malt extract = 5g/L
Peptone = lOg/L
NaCl = 2g/L
KH2P04 = 0.5g/L
MgS04.7H20 = 0.5g/L pH of this medium is adjusted to 6.0 after making up the volume with water. The seed flasks were grown at 28 to 30°C for 4 days and used as an inoculum for solid state fermentation. Solid state fermentation: lOgm wheat bran was taken in a petri plate. Adequate amount of water was added and sterilized at 121 deg C for 30 minutes. 10 ml inoculum from 4 day old seed medium was added. 5ml of carbon and nitrogen sources were added to this substrate in liquid form. This nutrient solution is called as feed. The C : N ratio of the feed was varied from 5:1 to 28:1. The entire substrate
was mixed properly with the inoculum and feed and incubated at 28 to 30 deg C for 9 days. Following results were obtained.
EXAMPLE 2
The experiment was done as in Example 1. 10 g of wheat bran was packed in petri plates and sterilized. To this 10 ml of seed inoculum was added along with varying volumes of feed having a C : N ratio of 28:1. The entire substrate was mixed properly with the inoculum and feed. These plates were incubated at 28 to 30 deg C for 9 days. Following results were obtained.
The experiment was done as in Example 1. 10 g of wheat bran was packed in petri plates and sterilized. To this 10 ml of seed inoculum was added along with 5 ml feed having a C : N ratio of 28:1. The feeding was done during fermentation to see its effect on yield. 5ml of the feed was added and mixed. The plates were incubated at 28 to 30 deg C for 9 days. The results are given below:
EXAMPLE 4
Seed inoculum of Aspergillus terreus is obtained as explained in Example 1. 3 L of this inoculum was used for inoculating 27 L of the same seed medium taken in a 50 L fermenter. This is grown for 48 hr at 28 to 30°C. This is used as an inoculum for solid state fermentation. 15 kg wheat bran, was loaded into a bioreactor having 22600 cm2 surface area. The bioreactor was sterilised at 121 deg C for 1 to 2 hours using steam. After the sterilization the temperature of the solid substrate was brought down to 28 deg C. 15 L of the above inoculum and 7.5L feed was added to the solid substrate and mixed. 7.5L of feed was also added on 3rd and 5th day and mixed. The entire biomass along with the solid substrate was harvested on 9th day and
processed to get pharmaceutically acceptable grade of lovastatin. Totally 425 g of lovastatin was obtained.
EXAMPLE 5
75 g of ceramic beads were packed in a petri-plate and sterilized. 10ml of inoculum and 5ml feed were added and mixed. These plates were incubated at 28 to 30 deg C. On 3rd and 5th day, 5ml of feed was added and mixed. Following results were obtained.
EXAMPLE 6 For the production of compactin, a well grown slant of
Penicillium sp. was taken and 5ml of distilled water was added. It was shaken thoroughly and 100 micro litre of this inoculum was used for the inoculation of 50 ml seed medium taken in 250 ml conical flask. The composition of seed medium is as follows: Sucrose = 200g/L
Soy flour = 30g/L
Peptone = lOg/L
NaN03 = 2g/L
MgS04.7H20 = lg/L
pH of this medium was adjusted to 5.5 after making up the volume with water. The seed flasks were grown at 24 to 26°C for 4 days and used as an inoculum for solid state fermentation.
Solid state fermentation: lOgm wheat bran was taken in a petri plate. Adequate amount of water was added and sterilized at 121 deg C for 30 minutes. 10 ml inoculum from 4 day old seed medium was added along with 5ml feed having a C : N ratio of 28:1. These plates were incubated at 24 to 26 deg C. On 3rd and 5th day, 5ml of feed was added and mixed. Following results were obtained.
Claims
1. A process for the manufacture of compound of formula I, its acid form or any salt form, wherein Ri is either CH3 or H, by fed batch solid substrate fermentation to enhance productivity comprising:
Formula I 
mixing solid substrate medium with a microbial strain capable of producing compound of formula I, feeding nutrient in the course of fermentation and incubating the mixture at a temperature between 22 to 30 ° C to obtain compound of formula I.
2. A process in claim 1, wherein the microbial strain used for solid substrate fermentation is Aspergillus terreus x the production of compound of formula I, its free acid or any salt form, when Ri is CH3.
3. A process in claim 1, wherein the microbial strain used for solid substrate fermentation is Penicillium sp for the production of compound of formula I, its free acid or any salt form, when Ri is H.
4. A process in claim 1, wherein the solid substrate for fermentation is selected from wheat bran, wheat rawa, broken wheat, boiled rice, rice bran, rice rawa, beaten rice, maize bran, maize grits, oat bran, bagasse, tapioca residue, soya grits, soya flakes, rice flakes, ceramic beads, glass beads or a mixture of two or more of these.
5. A process in claim 1, wherein the nutrient feeding for fed-batch fermentation is done at the beginning of the fermentation or throughout the fermentation.
6. A process in claim 1, wherein the nutrient feeding for fed-batch fermentation is done with the carbon : nitrogen ratio in the feed maintained between 15 :1 to 100 :1.
7. A process in claim 6, wherein the nutrient feeding for fed-batch fermentation is done with the carbon : nitrogen ratio in the feed maintained between 15 : 1 to 50 :1.
8. A process in claim 6 - 7, wherein the carbon feed for fed-batch fermentation is selected from glucose, sucrose, starch (maize, wheat, tapioca, potato), modified starch, maltose, malto-dextrin, soyabean oil, acetate or a mixture of one or more of these.
9. A process in claim 6 - 7, wherein the nitrogen feed for fed-batch fermentation is selected from ammonium sulphate, ammonium nitrate, sodium nitrate, bacteriological peptone, yeast extract, casein hydrolyzate, soy peptone, soy flour, cotton seed flour, corn steep liquor or a mixture of one or more of these.
10. A process in claim 1, wherein the nutrient for feeding is selected from a carbon source, nitrogen source or any other source capable of enhancing the production of Formula I.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002337600A AU2002337600A1 (en) | 2002-07-04 | 2002-07-04 | Fed batch solid state fermentation for the production of hmg-coa reductase inhibitors |
| PCT/IN2002/000145 WO2004005275A1 (en) | 2002-07-04 | 2002-07-04 | Fed batch solid state fermentation for the production of hmg-coa reductase inhibitors |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2002/000145 WO2004005275A1 (en) | 2002-07-04 | 2002-07-04 | Fed batch solid state fermentation for the production of hmg-coa reductase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004005275A1 true WO2004005275A1 (en) | 2004-01-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2002/000145 Ceased WO2004005275A1 (en) | 2002-07-04 | 2002-07-04 | Fed batch solid state fermentation for the production of hmg-coa reductase inhibitors |
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| WO (1) | WO2004005275A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112501226A (en) * | 2020-11-27 | 2021-03-16 | 广州双桥（重庆）有限公司 | Preparation method of syrup for medical lovastatin |
| CN115873727A (en) * | 2022-12-29 | 2023-03-31 | 六盘水师范学院 | A high-efficiency tannin-degrading bacterium SL006 from Rosa roxburghii and its application |
-
2002
- 2002-07-04 AU AU2002337600A patent/AU2002337600A1/en not_active Abandoned
- 2002-07-04 WO PCT/IN2002/000145 patent/WO2004005275A1/en not_active Ceased
Non-Patent Citations (4)
| Title |
|---|
| DATABASE CA [online] WANG LIXIN ET AL.: "Production of lovastatin with solid state fermentation of monascus ruber", accession no. STN Database accession no. 132:206980 * |
| NOVAK N., GERDIN S., BEROVIC M.: "Increased lovastatin formation by aspergillus terreus using repeated fed-batch process", BIOTECHNOLOGY LETTERS, vol. 19, no. 10, 1997, pages 947 - 948 * |
| SZAKACS GYORGY, MOROVJAN GYORGY, TANGERDY ROBERT P.: "Production of lovastatin by a wild strain of aspergillus terreus", BIOTECHNOLOGY LETTERS, vol. 20, no. 4, 1998, pages 411 - 415 * |
| ZHONGGUO KANGSHENGSU ZAZHI, vol. 24, no. 2, 1999, pages 96 - 98, 115 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112501226A (en) * | 2020-11-27 | 2021-03-16 | 广州双桥（重庆）有限公司 | Preparation method of syrup for medical lovastatin |
| CN115873727A (en) * | 2022-12-29 | 2023-03-31 | 六盘水师范学院 | A high-efficiency tannin-degrading bacterium SL006 from Rosa roxburghii and its application |
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