WO2010058427A2 - Process for production and purification of polymyxin b sulfate - Google Patents

Process for production and purification of polymyxin b sulfate Download PDF

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Publication number
WO2010058427A2
WO2010058427A2 PCT/IN2009/000672 IN2009000672W WO2010058427A2 WO 2010058427 A2 WO2010058427 A2 WO 2010058427A2 IN 2009000672 W IN2009000672 W IN 2009000672W WO 2010058427 A2 WO2010058427 A2 WO 2010058427A2
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polymyxin
fermentation medium
sulphate
sulfate
production
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PCT/IN2009/000672
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English (en)
French (fr)
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WO2010058427A3 (en
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Rangaswamy Vidhya
Baiu Guduri
Hiremath Anand
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Reliance Life Sciences Pvt. Ltd.
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Publication of WO2010058427A2 publication Critical patent/WO2010058427A2/en
Publication of WO2010058427A3 publication Critical patent/WO2010058427A3/en

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    • 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
    • C12N1/20—Bacteria; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid
    • C07K7/62—Polymyxins; Related peptides
    • 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
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to an improved process of production and purification of polymyxin B sulphate.
  • the present invention in particular relates to the fermentative production of polymyxin B sulphate in high yields.
  • polymyxin antibiotics were widely used to treat patients with various gram- negative bacterial infections including meningitis ⁇ Haemophilus influenzae), and urinary tract infections (E. col ⁇ ) during 1960s and 1970s.
  • Polymyxin B is also widely used to treat septic shock caused by endotoxin (Schindler M, Osborn MJ. "Interaction of divalent cations and polymyxin B with lipopolysaccharide" Biochemistry, 1979 Oct 2; 18(20): 4425 ⁇ 430).
  • endotoxin Schotoxin-related bacterium, and others.
  • the polymyxins are a complex mixture of closely related decapeptides obtained from cultures of various strains of Bacillus polymyxa and related species (J. Shoji, H. Hinoo, Y. Wakisaka, K. Koizumi, M. Mayama, S. Mitsuura. J. Antibiotics. 30 (1977) 1029- 1034).
  • Polymyxins contain characteristic constituents such as ⁇ , ⁇ -diaminobutyric acid, L-threonine, and a fatty acid, and differ by the presence or absence of additional amino acid as well as the nature of the fatty acid. See Figure 1.
  • Polymyxin B is a cyclic, branched decapeptide that binds to membrane phospholipids and thereby interferes with membrane function.
  • Polymyxin B is subdivided into at least four types, polymyxin Bl, B2, B3 and B4, which differ from each other only in the fatty acyl moiety: Bl contains 6-methyloctanoic acid, B2 has 6-methylheptanoic cid, B3 has octanoic acid and B4 has heptanoic acid.
  • Pavliuk IuV, Bogatskii MA, Orlova NV Anakhova VA, "Effect of amino acids on the growth of a B. polymyxa 1538 culture and the biosynthesis of polymyxin B," Antibiotiki. 1979 Nov; 24(11):815-20.
  • Pavliuk IuV, Bogatskii MA, Orlova NV Anakhova VA, "Importance of corn extract components for the biosynthesis of polymyxin B by B. polymyxa strain 1538," Antibiotiki. 1979 Aug;24(8):566-70); pH changes during fermentation (PA Stansly, ME Schlosser, NH Ananenko and MH Cook.
  • polymyxin B sulphate is also described in the following patents, for example: US 2,759,868 , US 2,695,261, US 3,413,398, US 2,595,605, US 3,132,994, US 2,599,950 US 2,571,104, US 2,556,376, US 2,602,041, US 1,899,156, US 2,599,950, US 2,565,057, US 2,602,041, US 2,511,104, US 2,595,605, US 2,556,376, US 3,132,994, US 3,413,398, GB 924 652, GB 742 589, GB 315 263, JPl 1140189, and RU2115721.
  • UK patent GB 645 750 provides a process for preparing sulphate or B-naphthalene sulphonate salts of polymyxin B and E, which are precipitated as the free base by treating an aqueous solution of such a salt with an alkali, such as aqueous ammonia, at a temperature between 50 and 100 0 C.
  • the precipitated polymyxin base is then quickly removed from the hot supernatant liquid, washed with hot water, and dried or converted to its hydrochloride or other desired compound.
  • a theoretical yield of about 96.8% of polymyxin E was obtained.
  • UK patent GB991602 describes a purification process for polymyxin which comprises treating an aqueous solution of the polymyxin with a permanganate at pH below 8.0.
  • the examples describe the treatment of solutions of polymyxin B hydrochloride and of the sulphates of polymyxins A, B and E.
  • UK patent GB658766 describes purification by recrystallisation of the precipitated polymyxin base with an alcohol containing 2-5 carbon atoms, and further recrystallization after charcoal treatment.
  • UK Patent GB 647925 describes the recovery of polymyxin at pH 4.5 with one or more sulphated fatty alcohols or esters, or their mixtures with salts. The resulting precipitate is separated by filtration and is dried, acid precipitated, and then converted to the base again. The base is then treated with activated charcoal or fractional precipitation.
  • UK patent GB 65897 describes Bacillus polymyxa fermentation culture in a substantially neutral nutrient medium under aerobic conditions for 2-5 days at 20-30 0 C while aerating with 4-64 litres of air per hour per 8 litres of medium. Bacteria and suspended material are removed, and polymyxin is adsorbed from the medium using, e.g., activated carbon or charcoal.
  • the application describes additional examples of the preparation of derivatives of polymyxin, by treating the free base or hydrochloride of polymyxin with formaldehyde, acetaldehyde or 4-nitrobenzaldehyde.
  • Chinese patent CN 1800201 provides a method for preparing polymyxin E, which employs a foam separation method to extract and separate the polymyxin E from the fermentation liquor.
  • the present invention has focused on production of polymyxin by fermentation By doing so the inventors have been successful in producing a high yield of polymyxin, such as 3g polymyxin B sulfate per litre of fermentation medium.
  • the present invention provides an efficient method of producing polymyxin for large scale production, and in particular provides optimal culture conditions for a high yield of polymyxin B.
  • the present invention in particular aims at providing optimal culture conditions that would result in high yield of polymyxin.
  • the present invention provides an improved process for the production of a high yield of polymyxin B sulphate by fermentation, using glucose and oatmeal to maintain the carbon and nitrogen.
  • the present invention provides an efficient method of producing polymyxin for large scale production.
  • the present invention in particular provides optimal culture conditions for a high yield of polymyxin B.
  • the present invention provides a purification method for polymyxin.
  • the invention is an aqueous composition (i.e., fermentation media) for the production of polymyxin B, including polymyxin B sulfate, by fermentation from Bacillus polymyxa.
  • the fermentation medium comprises about 2% ammonium sulphate, about 0.2% dipotassium hydrogen phosphate, about 0.05% magnesium sulphate, about 0.05% sodium chloride, about 0.001% ferrous sulphate, about 0.5% bakers yeast autolysate, about 1-2% glucose, and about 2-3% oatmeal.
  • the composition comprises 2% oatmeal and/or, in others, 2% glucose.
  • the pH is adjusted to about pH 6 to 7. The pH may be adjusted with 25%liquid ammonia or 5N HCl.
  • the invention is a method of producting polymyxin B sulfate.
  • the method comprises:
  • the agitation is about 250 rpm agitation, and the aeration is about 1.2 wm aeration for 72 h.
  • the Bacillus polymxya is Bacillus polymxya ATCC 10401.
  • a yield of at least 3.0g of polymyxin B sulfate per liter of fermentation medium is obtained.
  • the invention comprises a method of purification of polymyxin B sulfate from fermentation medium.
  • the method of purification comprises:
  • the purification further involves the steps of precipitation in acetone and/or lyophilization.
  • the purity of polymyxin B sulfate is greater than 90%. In other embodiments the purity is greater than 92%.
  • the invention also encompasses uses.
  • the invention is the use of the fermentation medium or methods of the invention for the production of polymyxin B sulfate.
  • the polymyxin is further used for the production of a medicament.
  • the invention is the medicament made by growing Bacillus polymyxa in the composition of the invention, or obtained by the method of the invention.
  • the medicament is for the treatment of infection by Gram-negative bacteria, and/or for the treatment of septic shock caused by the lipopolysaccharide of Gram-negative bacteria.
  • Fig.l Structure and composition of various polymyxins.
  • polymyxin B includes polymyxin B sulphate, and is not limited to any specific variant, i.e., sulphate of polymyxin Bl, B2, B3, or B4, or any specific form.
  • Gram-negative bacteria refers to the group of prokaryotes having an outer membrane.
  • Lipopolysaccharide refers to the material of that name that is a major constituent of the outer membrane of gram-negative bacteria.
  • Optmeal refers to grounded oats used in media preparation.
  • Boker's yeast autolysate refers to Bakers' yeast pastes which has been autoclaved and used in media preparation.
  • Bacillus polymyxa is used herein without being limited to specific variants of that bacterial species. In one embodiment, Bacillus polymyxa ATCC 10401 is used.
  • the present invention provides a process for the preparation of polymyxin, which results in high yields and can be produced on a large scale.
  • the present invention provides optimized conditions for fermentation.
  • the present invention provides the effect of various physiological and nutrient requirements on fermentation.
  • the present invention has focused on the nutritional parameters such as the amount of glucose and oatmeal in the production medium. These parameters showed a significant effect on the production of polymyxin B. Maximum yields were obtained with a medium having glucose at 1-2 % (w/v), and oatmeal at 1-3 % (w/v).
  • EXAMPLE 1 Bacteria and growth conditions:
  • Bacillus polymxya ATCC 10401 was maintained on nutrient agar.
  • a seed culture was grown in nutrient broth incubated at 3O 0 C, agitated at 200 rpm for 24 h.
  • the cells were grown in the production medium sterile production media containing (w/v) 2% ammonium sulphate, 0.2% dipotassium hydrogen phosphate anhydrous, 0.05% magnesium sulphate heptahydrate, 0.05% sodium chloride, 0.001% ferrous Sulphate heptahydrate, 0.5% bakers yeast autolysate, 1% glucose and 2% oatmeal.
  • the fermentation was carried out in 1.5 L bioreactor (B.Braun) at 3O 0 C, 250 rpm agitation, 1.2 wm aeration for 72 h.
  • the pH of the medium was maintained at 6.5 by addition of either 25% liquid ammonia or 5 N HCl.
  • Polymyxin B sulphate produced during fermentation was monitored by an agar diffusion bioassay, using Escherichia coli as an indicator strain.
  • the zone size obtained by Standard Polymyxin B sulphate ( lmg/ml) was compared with that of the sample ( lmg/ml) and the purity was determined.
  • Physiological and nutritional parameters for maximum production of polymyxin B sulphate were optimized at shake-flask level in production medium.
  • Nutritional parameters were optimized by varying the glucose and oatmeal concentrations. pH control for optimal production of polymyxin B sulphate was revealed by the bioassay. There was no production if pH was left uncontrolled. The maintenance of pH for production of polymyxin B sulphate was found to be very stringent and the bioassay was positive only if the pH was controlled at pH 6.to 7.
  • Nutritional parameters such as the amount of glucose and oatmeal in the production medium also had a significant effect on the production of polymyxin B sulphate.
  • a medium having glucose at 2 % (w/v) and oatmeal at 2-3 % (w/v) concentration gave the maximum yield of polymyxin B sulphate.
  • Yeast extract also had a significant effect on PMB production, as replacement of yeast extract with bakers yeast autolysate increased the PMB yield by two-fold.
  • Bacillus polymxya ATCC 10401 was maintained on nutrient agar.
  • the seed culture was grown in nutrient broth.
  • the culture was incubated at 3O 0 C at 200 rpm for 24 h.
  • the production medium consisted of (w/v) 2% ammonium Sulphate, 0.2% dipotassium hydrogen phosphate anhydrous, 0.05% magnesium sulphate heptahydrate, 0.05% sodium carbonate anhydrous, 0.001% ferrous sulphate heptahydrate, 0.25% bakers yeast autolysate, 2% glucose and 2% oatmeal.
  • the production medium (1350 ml) was inoculated with 10% (WV) seed culture.
  • the fermentation was carried out in 1.5 L bioreactor (B.Braun) at 3O 0 C, 250 rpm agitation, and 1.2 vvm aeration for 72 h.
  • the pH of the medium was maintained at 6.5 by addition of either 25% liquid ammonia or 5 N HCl. A yield of 3 g/L was obtained in 72 h.
  • the concentrate was dialyzed using a membrane having a molecular weight cutoff of 1.2 kD (benzoylated dialysis tubing, Sigma - Aldrich, D7884-10FT) against distilled water, overnight, at room temperature.
  • the dialyzed solution was lyophilized.
  • the lyophilized powder was tested against E. coli in the bioassay.
  • the bioassay is carried out at different stages during the purification process.
  • the lyophilized polymyxin B sulphate powder was 92 % pure according to the bioassay, with a final yield of 35 %.
  • Fermentation broth 100 ml having a polymyxin B titre of 3.0 g/L was treated as per Example 5.
  • the final yield was 99 mg of lyophilized polymyxin B sulphate powder with purity of 93.3% according to the bioassay, with a yield of 33%.
  • a typical purification chart is shown below.
  • Fermentation broth 1000 ml having a polymyxin B titre of 2.15 g/L was treated as per Example 5, up to the dialysis step. After dialysis, the solution was concentrated in a rota vapor to one fifth its volume, and was added drop wise to a beaker containing 10 volumes of acetone to precipitate the polymyxin B sulphate. The sticky precipitate was collected, dissolved in distilled water and lyophilized. The lyophilized powder was tested against E. coli in the bioassay. The final recovery was 450 mg of lyophilized polymyxin B sulphate powder with purity of 93.3 % according to the bioassay, and a yield of 21 %.

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PCT/IN2009/000672 2008-11-24 2009-11-20 Process for production and purification of polymyxin b sulfate WO2010058427A2 (en)

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Cited By (8)

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CN103130876A (zh) * 2011-11-30 2013-06-05 天津市海德安科医药科技发展有限公司 一种高纯度多粘菌素b的制备方法
CN103509839A (zh) * 2013-10-12 2014-01-15 河北圣雪大成制药有限责任公司 一种降低多粘菌素e发酵液中氨氮含量的方法
CN103540633A (zh) * 2013-10-24 2014-01-29 河北圣雪大成制药有限责任公司 一种发酵法生产多粘菌素b的方法
CN108977482A (zh) * 2018-08-21 2018-12-11 浙江日升昌药业有限公司 一种硫酸多粘菌素b的制备方法
CN109206486A (zh) * 2018-09-03 2019-01-15 杭州中美华东制药有限公司 一种硫酸多黏菌素b的杂质及其制备方法
CN112553277A (zh) * 2019-09-10 2021-03-26 华北制药集团新药研究开发有限责任公司 一种提高硫酸多粘菌素b发酵水平的方法
CN112940083A (zh) * 2019-11-26 2021-06-11 重庆乾泰生物医药有限公司 一种高纯度硫酸多粘菌素b1晶型及其制备方法
CN113755548A (zh) * 2021-09-02 2021-12-07 河北圣雪大成制药有限责任公司 一种提高多粘菌素b发酵水平的方法

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