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WO2008059466A1 - Production de compactine au moyen d'une nouvelle souche mutante de penicillium citrinum atcc 38065 - Google Patents

Production de compactine au moyen d'une nouvelle souche mutante de penicillium citrinum atcc 38065 Download PDF

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Publication number
WO2008059466A1
WO2008059466A1 PCT/IB2007/054699 IB2007054699W WO2008059466A1 WO 2008059466 A1 WO2008059466 A1 WO 2008059466A1 IB 2007054699 W IB2007054699 W IB 2007054699W WO 2008059466 A1 WO2008059466 A1 WO 2008059466A1
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Prior art keywords
compactin
mutant strain
process according
mtcc
fermentation medium
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PCT/IB2007/054699
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English (en)
Inventor
Parveen Kumar
Bupinder Kumar Chowdhary
Vivek Kumar Jain
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/80—Penicillium

Definitions

  • the present invention relates to a novel mutant strain of Penia ilium ciirinimi ATCC 38065 and a process for producing compaetin of Formula 1 using the novel mutant strain of Penicillium citriniim ATCC 38065.
  • pravastatin sodium is chemically a sodium salt of (3 R,5R )-3,5-dihydroxy-7- hexahydronaphthalen-l-yl)heptanoate having the structure as represented by Formula 2
  • Pravastatin sodium is an antihyperchol ⁇ sterolemic agent and exhibits a therapeutic advantage in reducing the risk of cardiovascular diseases.
  • Pravastatin and its salts are S obtained by fermentation of compactin using a variety of microorganisms,
  • U.S. Patent Nos. 5,179,013, 4,448,979, 4,346,227, and 4,537,859 and Japanese Patent Publication No. JP 58-010572 A2 provide processes for preparing pravastatin and its salts by microbial hydroxylation of compactin at the 6 / ⁇ -position using strains of species belonging to different genera of fungi including Nocardia, Actinomadura and Streptomyces. 0
  • U.S. Patent No. 3,983,140 provides a process for preparing compactin by cultivation o£ Penicillium citrinum SANK 18767.
  • U.S. Patent No. 5,691 ,173 provides a process for preparing compactin by cultivation of Penicillium adameizoides, which results in compactin titer value of about 800 mg/L during scale up in fcrmentors.
  • U.S. Patent No. 6,323,021 provides a process for preparing compactin by cultivation of a mutant strain of Penicillium citrinum ATCC0 38065, which is deposited at the Federal Industry Research Development Institute (FIRDI). R.O.C., under accession No. CCRC 930024.
  • the titer value of compactin obtained by the method provided in U.S. Patent No. 6,323,021 is 1.5 to 1.8 g/L.
  • 6,204,032 provides a process for preparing compactin by cultivation of a Gliocladumi species.
  • the processes provided in the prior art for the preparation of compactm has a major disadvantage of low compactm productivity. Further, the present inventors have observed that the impurity of Formula 3 is always produced in relatively higher concentrations during the prior ail fermentation processes of preparing compactin.
  • the impurity of Formula 3 is also carried forward and converted into impurity of Formula 4.
  • impurity of Formula 4 necessitates the introduction of additional purification steps in the preparation of pravastatin or its pharmaceutically acceptable salts. Further, the formation of impurities of Formula 3 and Formula 4 15 decreases the overall yield and increases the production cost of campactin, as well as pravastatin or its pharmaceutically acceptable salts.
  • a novel mutant strain of Peniciihum citrinum ATCC 38065 for preparing eompaetiu with productivity of about 6.0 g/L or higher. Further the compaetin produced by cultivating the mutant strain ofPemcilhum cilnnum ATCC 38065 is substantially free of the impurity of Formula 3.
  • the present invention provides a high yielding and economic process for the preparation of compaetin as well as pravastatin or its pharmaceutically acceptable salts,
  • A. first aspect provides a novel mutant strain of Penialhum curinum ATCC 380d5.
  • a viable sample of the mutant strain is currently deposited at the Microbial Type Culture Collection and Gene Bank (MTCC) under accession number MTCC 5317.
  • the novel mutant strain provided herein is hereinafter referred to as Peniciihum citrinum MTCC 5317.
  • the mutant strain Pemallium atrinum MTCC 5317 exhibits typical colony characteristics when grown on potato-glycerol-agar medium Colony characteristics of the mutant strain Peni ⁇ llium citrinum MTCC 5317 include one or more of a colony diameter of about 8 mm to about 10 rnrn, substantially round shape, positive sporulation, dark green spore color, bright yellow pigmentation, and a flat elevation having a slight elevation in the center.
  • the mutant strain Penicillium citrinum MlCC 5317 is capable of producing compaetin of about 6.0 g/L or higher during cultivation,
  • the mutant strain Peniciihum atrinum MTCC 531 7 is capable of producing compaetin substantially free of the impurity of Formula 3.
  • the mutant strain Pens allium citrmum MTCC 5317 is capable of producing compaetin having the impurity of Formula 3 in a quantity of about 0.10 % w'w or less, preferably in a quantity of about 0,08 % wSv or less.
  • a second aspect provides a process for the preparation of mutant strain Peniciihum citrinum MTCC 5317, wherein the process comprises a step of subjecting Penicillium citrinum ATCC 38065 to irradiation or treating Penu ⁇ hum citrinum ATCC 38065 with a mutagen.
  • the irradiation can be carried out preferably by using ultraviolet rays or gamma rays, more preferably by using ultraviolet rays.
  • the irradiation is carried out for about 10 seconds to about 500 seconds, preferably for about 300 seconds.
  • Peniciihum citrinum M TCC 5317 can also be obtained by treating Penicillium citrinum ATCC 38065 with a mutagen.
  • the mutagen can be selected from N-methyl-N ' -nitro-N- nitrosoguanidine, ethylmethane sulfonate or hydroxy] amine.
  • the mutation process can be carried out in a spore suspension medium comprising Penicilliu ⁇ i citrinum ATCC 38065.
  • the mutant strain PeniciUium citrinum MTCC 5317 can be isolated as colonies from the suspension medium after the mutation process.
  • a third aspect provides a process of the preparation of compaetra comprising the steps of: a) cultivating the mutant strain PeniciUium ciirinum MTCC 5317 in a fermentation medium, and b) isolating compactin from the fermentation medium thereof. Cultivation of the mutant strain PeniciUium citrinum MTCC 5317 is carried out in a fermentation medium. Prior to cultivating in a fermentation medium, the mutant strain Penicillium citrinum MTCC 5317 can optionally be germinated in a potato-glycerol-agar medium and subsequently cultivated in a seed medium, which comprises dextrose, glycerol, soya peptone, soybean meal and inorganic salts in optimal combinations.
  • the mutant strain PeniciUium citrinum MTCC 5317 or a seed culture comprising the mutant strain Pemallium ciirinum MTCC 5317 is inoculated in a fermentation medium. Cultivation of the mutant strain Penicillium ciirinum MTCC 5317 is carried out in the fermentation medium under aerobic conditions.
  • the aerobic cultivation methods such as solid culture or culture under aeration and agitation or shaking, are employed.
  • the culture under aeration and agitation or shaking is employed.
  • the fermentation medium comprises carbon and nitrogen sources in optimal combinations.
  • the fermentation medium further comprises heavy metals, trace elements and inorganic salts.
  • the fermentation medium comprises dextrose, maltose, glycerol, soya peptone, soybean meal, sodium nitrate and magnesium sulfate or its hydrates in optimal combinations. More preferably the fermentation medium comprises about 10 to about 18 g/ ⁇ .
  • an anti-foaming agent can optionally be used to reduce foaming during fermentation.
  • the anti-foaming agent can be silicon oil vegetable oils or surfactants.
  • the pH of the fermentation medium can be in the range of about 3 to about 9
  • the cultivation temperature can be in the range of about 20 °C to about 30 0 C.
  • the cultivation may be conducted for about 20 hours to about 360 hours.
  • the compactin obtained by the cultivation of mutant strain Penicillium citriiium MTCC 5317 has a titer value of about of 6.0 g/L or higher
  • the compactin obtained by the cultivation of mutant strain Penicillium clt ⁇ num MTCC 5317 preferably has a titer value of about of 6.4 g/L to about 7.5 g/L.
  • the compactin obtained by the cultivation of mutant strain Penicillium ciirinum MTCC 5317 is substantially free of the impurity of Formula 3.
  • the compactin obtained by the cultivation of mutant strain Penicillium ciirinum MTCC 5317 contains the impurity of Formula 3 in a quantity of about 0.10 % w/w or less, preferably in a quantity of about 0.08 % w/w or less.
  • the productivity of compactin, which is substantially free of the impurity of Formula 3 can be further improved by enriching the carbon and nitrogen sources in the fermentation medium.
  • the compactin so obtained can be isolated from the fermentation medium/broth by extraction with one or more organic solvents.
  • Suitable organic solvents can be selected from one or more esters, halogenated hydrocarbons and aliphatic or aromatic hydrocarbons, or mixtures thereof.
  • Suitable organic solvents are preferably selected from one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropan ⁇ , dichloropropane, chloroform, carbon tetrachloride, n-hexane, toluene and xylene, or a mixture thereof.
  • Compactin may be isolated in the form of acid or lactone.
  • the isolated compactin may be further purified by the recrystallization.
  • An alkanol can be used as a solvent for recrystallization. Suitable alkanols may be selected from one or more of methanol, ethanol, n-propanol, 2- ⁇ ropanol, n-butanol. 2-butanol or a mixture thereof.
  • the compactin so obtained by cultivating the mutant strain Penicillium citrinum MTCC 5317 can be further converted into pravastatin or its pharmaceutically acceptable salts.
  • the conversion of campactin into pravastatin or its pharmaceutically acceptable salts can be carried out by any method, including those provided in U.S. Patent Nos.
  • NTG N-methyl-N'-nitro-n-a.trosoguaiJidiiie
  • EMS Ethyl Methane Sulphonate
  • the weli-sporulated culture slants of the mutant strains obtained from the above methods were selected and harvested under sterile conditions with soy peptone glycerol solution (SPGS) 5 which were further vortexed to obtain homogenous mixtures.
  • SPGS soy peptone glycerol solution
  • the spore suspensions so obtained were serially diluted and incubated for 8 days at 24°C. Most typical colonies were selected and transferred under sterile conditions into test tubes containing 2.0 ml of sterile SPGS and vortexed for 1.0 minute. Each colony suspension was inoculated on corresponding PGA slants.
  • the slants were incubated in an inclined position at 15°C.
  • the sporu ⁇ ation started towards the 2nd day.
  • the surfaces of the slants were covered with a uniform layer of spores.
  • the mature slants were selected and used for productivity testing as provided below.
  • the single spore isolates obtained from the previous step were screened by productivity testing at shake flask level by employing the following media compositions:
  • composition of the Seed Media Dextrose 18 to 22 g/L Sodium nitrate 10 to 12 g/L
  • the pH of the seed media were adjusted to 6.5 prior to sterilization. Sterilization was carried out for 25 mmutcs at 121 0 C, The seed media were inoculated with aliquots of spore suspensions with spore number of the order of 10 s spores/ml and were cultured at 2S°C and at 240 rpm with 50 mm throw for 42 h.
  • the high quality inocula having the following features were selected for production stage:
  • Soyabean meal 25 to 30 g/L lhe pH of the production media were adjusted to 6,5 prior to sterilization.
  • Sterilization was carried out for 25 minutes at 121 0 C. Each production flask was inoculated with 10% of inocula of seed stage and the fermentation was carried out at 24 ⁇ C and at 240 rpm for 264 h. 50% sucrose was fed at 72, 120 and at 16S log hours and coropactin production was determined by HPLC. Broth appearance was observed to be greenish yellow in color with uniform pellets of si/e ranging from 500 to O ⁇ 0 microns.
  • the mutant strain Penicilhum citrinum MTCC 5317 was inoculated on to PGA (Potato-Glycerol-Agar) medium and incubated for 11 days at 24°C. The spores were harvested with peptone-glyccroi solution.
  • the medium was sterilized for 25 minutes at 121 ' C.
  • the sterilized seed medium was inoculated with the spore suspension of the mutant strain of Penicilhum citrinum MTCC 5317.
  • the seed fermentation was carried out for 42 h to obtain a pli of about 4.5 and Packed Mycelial Volume (PMV) of 16% with small flowery (ginger shaped) microscopic growth structures.
  • the growth centers were discrete and of 125 to 150 ⁇ m size.
  • Fermentation medium (15 L) containing dextrose (12 g/L), sodium nitrate (0.5 g/L), magnesium sulphate (0.75 g-'L), maltose (10 g/L), glycerol (45 g/L), soya peptone (5 g/L) and soybean meal (20 g/L) in a stirred tank bior ⁇ actor (20 L) was prepared.
  • the medium was sterilized at 121°C and at 15 psi for 25 minutes,
  • the mature seed culture of mutant strain Pe n i cillium citrinum MTCC 5317 obtained from Example 2 was used to inoculate the sterilized medium.
  • the dissolved oxygen concentration was maintained during fermentation above 15% by controlling following process parameters:
  • Air flow 0.5 VVM (Volume of air per volume of media)
  • Back pressure 0.5 kg/cm 2 RJ 31 M (Revolutions per minute): 350
  • the fermentation profile is provided in Figure 1.
  • the fermentation batch exhibited a typical pll trend, Two distinct peaks of pH were observed till log 76 h, first being at iog 25 h and the second at log 55 h.
  • the formation of typical pH peaks indicated the consumption of carbon sources available in the production medium.
  • the pH reached its lowest point at 16 h (5.0) and later at 76 h (5 J) and finally started to rise fast. At this time, dosing with 50 % sucrose was initiated to maintain the pH at about 5.6 — 6.0.
  • the seed development was carried out according to the method provided in Example 2.
  • glycerol (55 g/L), soya peptone (S g/L) and soybean meal «32 g/L) in a stirred tank bioreactor (20 L) was prepared, The medium was sterilized at 121 0 C for 25 minutes.
  • the mature seed culture of mutant strain Penicillimu citnnum MTCC 5317 obtained from Example 2 was used to inoculate the sterilized medium.
  • the dissolved oxygen concentration was maintained daring fermentation above 15% by controlling following process parameters:
  • the fermentation profile is provided in Figure 2.
  • the pH trend of the fermentation batch was different (Figure 2) m comparison to that obtained in Example 3, Two distinct peaks of pH were observed till log 52 h, first being at log 30 h and the second at iog 43 h.
  • the formation of second peak of pH was early in comparison to Example 3 indicating that the consumption of carbon sources has occurred faster in the improved production medium of present example.
  • the pH reached it lowest point at log 14 h (value 4.5) and at log 52 h (value 5.5) and immediately started to rise fast. At this time (about 55 hours), dosing with 50 % sucrose was initiated to maintain the pH around 5.6.
  • the pH of the fermentation broth was subsequently maintained in the range 5.8 to 6.0 till end of the fermentation.
  • the broth (12 L) obtained from Example 4 was extracted with ethyl acetate (12 L), The organic phase was concentrated under reduced pressure. The concentrated solution was cooled to 28°C and washed two times with 5% sodium bicarbonate solution, The washed organic layer was further concentrated under reduced pressure, followed by the addition of n-hexane and stirred at 28 0 C for 60 minutes to obtain a slurry. The slurry so obtained was cooled to S 0 C, stirred for 60 minutes and filtered. The wet cake was washed with a mixture of ethyl acetate and n-hexane (1 : 1 ) at 5 0 C and dried at 15 0 C to afford crude compactin,
  • Impurity of Formula 3 0.08 % w/w

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Abstract

L'invention concerne une nouvelle souche mutante de Penicillium citrinum ATCC 38065 ainsi qu'un procédé pour produire de la compactine de formule (1) au moyen d'une nouvelle souche mutante de Penicillium citrinum ATCC 38065.
PCT/IB2007/054699 2006-11-17 2007-11-19 Production de compactine au moyen d'une nouvelle souche mutante de penicillium citrinum atcc 38065 Ceased WO2008059466A1 (fr)

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IN2487DE2006 2006-11-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827123A (zh) * 2012-08-02 2012-12-19 丽珠集团新北江制药股份有限公司 美伐他汀的分离提取工艺

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2524355A1 (de) * 1974-06-07 1975-12-18 Sankyo Co Physiologisch aktive verbindungen und verfahren zu ihrer herstellung
US5691173A (en) * 1995-09-21 1997-11-25 Apotex, Inc. Fermentation process for preparation of compactin
WO1998006867A1 (fr) * 1996-08-09 1998-02-19 Yungjin Pharmaceutical Ind. Co., Ltd. Nouveau procede de production du precurseur de la pravastatine, ml-236b
US6323021B1 (en) * 1999-01-15 2001-11-27 Industrial Technology Research Institute Mutant strain of penicillium citrinum and use thereof for preparation of compactin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2524355A1 (de) * 1974-06-07 1975-12-18 Sankyo Co Physiologisch aktive verbindungen und verfahren zu ihrer herstellung
US5691173A (en) * 1995-09-21 1997-11-25 Apotex, Inc. Fermentation process for preparation of compactin
WO1998006867A1 (fr) * 1996-08-09 1998-02-19 Yungjin Pharmaceutical Ind. Co., Ltd. Nouveau procede de production du precurseur de la pravastatine, ml-236b
US6323021B1 (en) * 1999-01-15 2001-11-27 Industrial Technology Research Institute Mutant strain of penicillium citrinum and use thereof for preparation of compactin

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ABE Y ET AL: "Molecular basis of ML-236B production in the high-producing mutant No. 41520 of Penicillium citrinum", JOURNAL OF GENERAL AND APPLIED MICROBIOLOGY, XX, XX, vol. 50, no. 3, 2004, pages 169 - 176, XP002400774 *
CHAKRAVARTI R ET AL: "Compactin - a review", APPLIED MICROBIOLOGY AND BIOTECHNOLOGY, SPRINGER VERLAG, BERLIN, DE, vol. 64, no. 5, 19 March 2004 (2004-03-19), pages 618 - 624, XP002400772, ISSN: 0175-7598 *
HOSOBUCHI M ET AL: "PRODUCTION OF ML-236B, AND INHIBITOR OF 3-HYDROXY-3-METHYLGLUTARYL COA REDUCTASE, BY PENICILLIUM CITRINUM: IMPROVEMENTS OF STRAIN AND CULTURE CONDITIONS", BIOSCIENCE BIOTECHNOLOGY BIOCHEMISTRY, JAPAN SOC. FOR BIOSCIENCE, BIOTECHNOLOGY AND AGROCHEM, TOKYO, JP, vol. 57, no. 9, 1993, pages 1414 - 1419, XP002036624, ISSN: 0916-8451 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827123A (zh) * 2012-08-02 2012-12-19 丽珠集团新北江制药股份有限公司 美伐他汀的分离提取工艺
CN102827123B (zh) * 2012-08-02 2015-04-22 丽珠集团新北江制药股份有限公司 美伐他汀的分离提取工艺

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