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WO2004003214A1 - Fermentation a l'etat solide et production a ecoulement discontinu d'un immunosuppresseur - Google Patents

Fermentation a l'etat solide et production a ecoulement discontinu d'un immunosuppresseur Download PDF

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Publication number
WO2004003214A1
WO2004003214A1 PCT/IN2002/000141 IN0200141W WO2004003214A1 WO 2004003214 A1 WO2004003214 A1 WO 2004003214A1 IN 0200141 W IN0200141 W IN 0200141W WO 2004003214 A1 WO2004003214 A1 WO 2004003214A1
Authority
WO
WIPO (PCT)
Prior art keywords
fermentation
solid substrate
rice
wheat
bran
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.)
Ceased
Application number
PCT/IN2002/000141
Other languages
English (en)
Inventor
Anand Prakash Khedkar
Nitin Sopanrao Patil
Nazhath Ul-Ainn
Bhasker Neelakantan
Ramavana Gururaja
Ramakrishnan Melarkode
Shrikumar Suryanarayan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biocon Ltd
Original Assignee
Biocon Ltd
Biocon India Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Biocon Ltd, Biocon India Ltd filed Critical Biocon Ltd
Priority to AU2002321821A priority Critical patent/AU2002321821A1/en
Priority to PCT/IN2002/000141 priority patent/WO2004003214A1/fr
Publication of WO2004003214A1 publication Critical patent/WO2004003214A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • the present invention provides a novel method for producing compound of Formula I or its any salt form by solid state fermentation, optionally with fed-batch technique by culturing microorganisrns capable of producing the compound of Formula I.
  • the compound of Formula I or its any salt form produced by the inventive method is used as an immunosuppressant therapeutically.
  • This agent inhibits the proliferative response of lymphocytes to alloantigen stimulation, and a variety of T cell associated immune reaction.
  • the compound suppresses immune responses in vivo as well as in vitro and is more highly potent than cyclosporin.
  • the immunosuppressive action of FK506 is applicable in organ transplantation.
  • EP 0 184 162 disclosed production of FK-506 by submerged fermentation from Streptomyces tsukubaensis.
  • Hirokazu et al. discussed isolation of the compound of Formula I, known as FK506 or Tacrolimus hydrate from Streptomyces tsukubaensis by submerged fermentation (Yakugaku Zasshi (1997), 17(8), 542-554).
  • EP 0 497 515 disclosed manufacture of irnrnunosuppressant FK- 506 with cultures of Streptomyces sp. ATCC 55098. Yoon, Yeo Joon et al. discussed nutrient effect on FK-506 production by Streptomyces sp. in a defined medium for submerged fermentation Q. Ferment Bioeng. (1997), 83(6), 599-603).
  • the present invention provides a novel method for production of compound of Formula I or its salts.
  • the invention provides a fermentation process in which the compound of Formula I or it's any salt form, is produced on solid nutritious matrix.
  • the fermentation is also carried out in fed-batch mode to increase the productivity/yields of the final product in a contained bio-reactor.
  • the present invention provides a process for the manufacture of compound of Formula I and its salts by solid substrate fermentation comprising the steps of
  • Streptomyces inoculating a solid substrate matrix with the inoculum prepared, incubating the inoculated solid substrate matrix for 4-7 days at 25-30 deg.C and extracting the incubated solid substrate matrix to obtain the said product.
  • the extract if desired is subjected to further purification step by conventional techniques, such as filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
  • the micro-organism is Streptomyces tsukubaensis.
  • the solid substrate for fermentation is selected from wheat bran, wheat rava, oat meal, broken wheat, boiled rice, rice bran, rice rava, beaten rice, maize bran, maize grits, oat bran, bagasse, tapioca residue, soy grits, soy flakes, rice flakes, ceramic beads, glass beads, sponge or a mixture of two or more of these.
  • the solid substrate fermentation is a fed-batch fermentation. The feeding for fed-batch fermentation is done at the beginning of the fermentation or at intervals throughout the fermentation.
  • the carbon source for feeding is selected from glucose, sucrose, starch (maize, wheat, tapioca, potato), modified starch, maltose, malto- dextrin, soybean oil, acetate or a mixture of two or more of these.
  • the nitrogen source for feeding is selected from ammonium sulphate, dried yeast, arnmoniurn nitrate, sodium nitrate, bacteriological peptone, yeast extract, casein hydrolyzate, soy peptone, soy flour, cotton seed flour, corn steep liquor or a mixture of two or more of these.
  • 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.
  • 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.
  • 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.
  • the present invention discloses a process for production of compound of Formula I or its any salt form, by culturing a microorganism capable of producing such compound on solid nutrient matrix wherein, optionally the nutrients are fed in adequate quantities during the growth of the culture so that the production of the product increases significantly.
  • Another aspect of invention is production of compound of Formula I or its any salt form.
  • the compound is afforded by culturing Streptomyces sp. on solid nutrient matrix e.g. wheat bran, oatmeal, soybean meal, wheat flour, soybean flakes, maize bran etc.
  • the culture is then fed with nutrients to increase production of the final product
  • the product is purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
  • Cottonseed meal 5g/L
  • Calcium carbonate 2g/L pH of this medium is adjusted to 6.5 after making up the volume with water.
  • the seed flasks were grown at 28°C for 4 days and used as an inoculum for solid state fermentation.
  • Solid state fermentation lOgm each of wheat bran, maize flakes, wheat rawa, rice rawa, oat meal, maize grits, maize bran, soy grits, rice flake, were taken in separate petri plates. 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. The entire substrate was mixed properly with the inoculum and incubated at 28 deg C for 7 days. Following results were obtained.
  • Example 2 Solid state fermentation was conducted as in Example 1 using 75 g ceramic beads as the solid support in a petri-plate, 15 mL of Streptomyces tsukubaensis inoculum grown in seed medium was added. The result obtained is given in the table below.
  • Example 2 Solid state fermentation was conducted as in Example 1 using different solid supports in combination. lOgm of this substrate is taken in petri plate and 10ml of Streptomyces tsukubaensis inoculum grown in seed medium was added. The results obtained are given in the table below.
  • Solid state fermentation was conducted as in Example 3 using a mixture of wheat bran, wheat rawa and rice flakes. lOgm of this substrate is taken in petri plate and 10ml of Streptomyces tsukubaensis inoculum grown in seed medium was added along with a liquid nutrient feed consisting of glucose and dried yeast. The feed was added every alternate day up to 4 th day.
  • Seed inoculum of Streptomyces tsukubaensis is obtained as explained in Example 1. 3.5L of this inoculum was used for inoculating 35 L of the same seed medium taken in a 50L fermenter. This is grown for 48 hr at 28°C. This is used as an inoculum for solid state fermentation. 15 kg of substrate mixture consisting of wheat bran, oatmeal and rice flake 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 was added to the solid substrate along with 2 L of glucose and dried yeast feed and mixed.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de production d'un composé représenté par la formule (I) ou d'un de ses sels formé par fermentation à l'état solide, éventuellement à l'aide d'une technique à écoulement discontinu par culture de micro-organismes capables de produire ledit composé.
PCT/IN2002/000141 2002-06-28 2002-06-28 Fermentation a l'etat solide et production a ecoulement discontinu d'un immunosuppresseur Ceased WO2004003214A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002321821A AU2002321821A1 (en) 2002-06-28 2002-06-28 Solid state fermentation and fed batch for the production of an immunosuppressant
PCT/IN2002/000141 WO2004003214A1 (fr) 2002-06-28 2002-06-28 Fermentation a l'etat solide et production a ecoulement discontinu d'un immunosuppresseur

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2002/000141 WO2004003214A1 (fr) 2002-06-28 2002-06-28 Fermentation a l'etat solide et production a ecoulement discontinu d'un immunosuppresseur

Publications (1)

Publication Number Publication Date
WO2004003214A1 true WO2004003214A1 (fr) 2004-01-08

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Family Applications (1)

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PCT/IN2002/000141 Ceased WO2004003214A1 (fr) 2002-06-28 2002-06-28 Fermentation a l'etat solide et production a ecoulement discontinu d'un immunosuppresseur

Country Status (2)

Country Link
AU (1) AU2002321821A1 (fr)
WO (1) WO2004003214A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006011156A1 (fr) * 2004-07-29 2006-02-02 Concord Biotech Limted Procede de production de tacrolimus (fk - 506) au moyen d'huile vegetale comme seule source de carbone
EP1756290A4 (fr) * 2004-04-12 2011-05-11 Biocon Ltd Procede de production de macrolides au moyen d'une nouvelle souche de streptomyces espece bicc 7522
CN108220359A (zh) * 2018-01-29 2018-06-29 天津大学 利用化学触发剂提升fk506产量的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4029547A (en) * 1974-07-01 1977-06-14 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Biologically active substance, bestatin, and production thereof
EP0184162B1 (fr) * 1984-12-03 1994-04-27 Fujisawa Pharmaceutical Co., Ltd. Composés tricycliques, procédé pour leur préparation et composition pharmaceutique les contenant
US6197573B1 (en) * 1998-11-17 2001-03-06 Biocon India Limited Solid state fermentation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4029547A (en) * 1974-07-01 1977-06-14 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Biologically active substance, bestatin, and production thereof
EP0184162B1 (fr) * 1984-12-03 1994-04-27 Fujisawa Pharmaceutical Co., Ltd. Composés tricycliques, procédé pour leur préparation et composition pharmaceutique les contenant
US6197573B1 (en) * 1998-11-17 2001-03-06 Biocon India Limited Solid state fermentation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1756290A4 (fr) * 2004-04-12 2011-05-11 Biocon Ltd Procede de production de macrolides au moyen d'une nouvelle souche de streptomyces espece bicc 7522
WO2006011156A1 (fr) * 2004-07-29 2006-02-02 Concord Biotech Limted Procede de production de tacrolimus (fk - 506) au moyen d'huile vegetale comme seule source de carbone
CN108220359A (zh) * 2018-01-29 2018-06-29 天津大学 利用化学触发剂提升fk506产量的方法
CN108220359B (zh) * 2018-01-29 2021-12-21 天津大学 利用化学触发剂提升fk506产量的方法

Also Published As

Publication number Publication date
AU2002321821A1 (en) 2004-01-19

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