WO2012055066A1 - Composition d'acarbose ayant un effet de diminution de la glycémie et son procédé de préparation - Google Patents

Composition d'acarbose ayant un effet de diminution de la glycémie et son procédé de préparation Download PDF

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WO2012055066A1
WO2012055066A1 PCT/CN2010/001693 CN2010001693W WO2012055066A1 WO 2012055066 A1 WO2012055066 A1 WO 2012055066A1 CN 2010001693 W CN2010001693 W CN 2010001693W WO 2012055066 A1 WO2012055066 A1 WO 2012055066A1
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acarbose
aspergillus
liquid
cicc2435
extract
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PCT/CN2010/001693
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English (en)
Chinese (zh)
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段震文
郭树仁
巩金妹
薛岚
刘春丽
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北京北大维信生物科技有限公司
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Priority to CN201080069047.3A priority Critical patent/CN103189497B/zh
Priority to PCT/CN2010/001693 priority patent/WO2012055066A1/fr
Publication of WO2012055066A1 publication Critical patent/WO2012055066A1/fr

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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
    • C12N1/14—Fungi; Culture media therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • 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
    • C12R2001/66—Aspergillus

Definitions

  • the present invention relates to the field of microbiology, fermentation, and pharmacy. Specifically, the present invention relates to Aspergillus CICC 2435, a ferment thereof, or a fermented product extract thereof, and the aforementioned Aspergillus CICC 2435, a ferment thereof, or a fermentation product thereof.
  • Diabetes mellitus is a common and endocrine metabolic disease characterized by hyperglycemia and multiple complications due to absolute or relative deficiency of insulin. It is one of the three major diseases that threaten human health.
  • the World Health Organization estimates that 246 million people worldwide have diabetes. This number is likely to reach 335 million by 2025. In 2005, an estimated 1.1 million people worldwide died of diabetes.
  • type 2 diabetes ie non-insulin-dependent diabetes
  • NIDDM ie non-insulin-dependent diabetes
  • inhibition of blood sugar, especially postprandial blood glucose is an important means of treatment of NIDDM.
  • Acarbose is the drug of choice for postprandial blood glucose.
  • acarbose reduces the risk of cardiovascular events and hypertension in patients with impaired glucose tolerance (IGT), significantly reducing the risk of myocardial infarction and any cardiovascular event.
  • ITT impaired glucose tolerance
  • Acarbose is a biosynthesis of pseudotetraose, which is Bayer AG of Germany.
  • the first alpha-glucosidase inhibitor developed was also the first alpha-glucosidase inhibitor approved by the US FDA.
  • Acarbose is a metabolite produced by actinoplanes sp., which has the activity of inhibiting ⁇ -glucosidase, which can reduce the decomposition of polysaccharides and «I in the human intestinal tract, thereby lowering the concentration of blood sugar. It is clinically used as a therapeutic drug for diabetes.
  • Acarbose and ⁇ -glucosidase reversibly bind to inhibit the activity of the enzyme, thereby delaying the degradation of carbohydrates, causing slow absorption of intestinal glucose and lowering blood glucose after meals.
  • acarbose has a weak hypoglycemic effect, although it can be used alone, but it is often used in combination with other related drugs. If you can improve the hypoglycemic effect of acarbose, it will help to further develop the advantages of acarbose. They play an increasingly important role in the synthesis and transformation of rapidly evolving compounds, and microbial enzymatic conversion technologies are generally environmentally friendly and have mild conditions of action; in addition, biocatalysts are highly selective, including chemistry. Selectivity, regioselectivity, enantioselectivity and diastereoselectivity; microbial transformation has the following advantages over chemical conversion: mild conditions, simple equipment, less pollution, faster reaction rate, and more environmentally friendly.
  • the development of new drugs using microbial transformation technology has become a hot spot in the field of drug research and development.
  • the present invention is directed to the use of microbial transformation techniques to further enhance the hypoglycemic effect of acarbose. Summary of the invention
  • One aspect of the invention relates to a novel Aspergillus CICC2435, the preservation date of which is On May 27, 2010, the deposit number was CGMCC No3874, which was deposited at No. 1 Beichen West Road, Chaoyang District, Beijing. No. 3 Institute of Microbiology, Chinese Academy of Sciences, General Microbiology Center of China Microbial Culture Collection Management Committee.
  • the present invention also relates to an enzyme composition comprising the ferment, extracellular ferment or ferment extract of Aspergillus CICC2435 described above.
  • the fermentation product is selected from a solid culture or a liquid culture
  • the extracellular fermentation product is selected from the extracellular components of the aforementioned solid culture or liquid culture
  • the fermentation extract is selected from the foregoing solid culture or liquid culture.
  • Ammonium sulfate precipitate is selected from a solid culture or a liquid culture
  • the Aspergillus CICC2435 When the solid ferment is prepared, the Aspergillus CICC2435 is inoculated into a solid medium consisting of sterilized bran and malt, and cultured at 20-40 ° C to obtain a solid culture; when preparing the liquid fermented product, The Aspergillus CICC2435 of claim 1 is inoculated into a sterilized liquid medium and cultured at 20-40 "C to obtain a liquid culture;
  • a buffer solution is added to the solid medium, and the liquid is separated to obtain a liquid leachate of the extract of the solid fermented product. If the liquid culture is used as a raw material, the solid liquid is separated to obtain a liquid. section,
  • the protein precipitant is added to the liquid extract or the liquid obtained after the solid-liquid separation, and the precipitate is collected under suitable conditions to obtain a crude preparation; if necessary, the crude preparation may be purified by conventional protein purification techniques such as dialysis and filtration. .
  • the invention further relates to the use of Aspergillus CICC2435 and the above enzyme composition for increasing the hypoglycemic effect of acarbose and for the use in the preparation of acarbose reactants.
  • Still another aspect of the present invention relates to a composition
  • a composition comprising Aspergillus CICC2435, a ferment thereof or a fermentate extract thereof and acarbose, and an Aspergillus CICC2435, a ferment thereof or a fermentate extract thereof and acarbose
  • the invention also provides a preparation method of an acarbose composition having hypoglycemic effect.
  • the principle of transformation reaction of Aspergillus CICC2435, its fermented product or its fermented extract with acarbose is that the acarbose is hydrolyzed by Aspergillus CICC 2435, and the structure of some acarbose changes, ie, Acarbose derivatives.
  • the original acarbose forms a composition containing acarbose and an acarbose derivative under the action of an enzyme, and the composition has an obvious hypoglycemic effect, and the effect is superior to the same concentration of acarbose.
  • Aspergillus CICC 2435 in the present invention was identified by activity screening.
  • the fermented product of the strain to be screened or the extract thereof is reacted with acarbose, and a strain which can produce a new substance by acarbose is selected to further identify the action of the strain and acarbose. Whether the composition has hypoglycemic effects and compares it to the hypoglycemic effect of acarbose alone.
  • Aspergillus CICC 2435 or its fermented product extract can interact with the acarbose phase, and the composition of the composition has a hypoglycemic effect, and its hypoglycemic effect is superior to the use of acarbose alone.
  • Aspergillus CICC 2435 was cultured by different culture methods, such as solid fermentation and liquid fermentation, and different culture conditions, and the culture was extracted to further confirm the combination with acarbose. The hypoglycemic effect of the substance.
  • the action condition is that the weight/volume ratio of the fermented product to the acarbose is 1:2 to 1:5, and the transformation temperature is The conversion reaction time is 5 to 48 hours at 20-40 °C.
  • the action condition is that the weight/volume ratio of the fermented product to the acarbose is 1:2 to 1:5, and the conversion temperature is 20-40 e C. , the conversion reaction time is 12-48 hours.
  • the action condition is that the weight/volume ratio of the fermented product to the acarbose is 1:2 to 1:5, and the transformation temperature is 20
  • the conversion reaction time is -4 ° C at -40 ° C.
  • the acarbose composition of the present invention is prepared by the following solid fermentation method: Incubation of the slanted species: Aspergillus strain CICC 2435 is used for strain culture, and the agar is added to the 4 degree wort to obtain a pH of 6-8.
  • the medium is such that each part of the medium contains 0.02-0.1 parts by weight of agar; at 100-120. Sterilize under C conditions, cool after sterilization, and prepare the slope by inoculation and inoculate at 20. C 40.
  • the acarbose composition solid fermentation process is: Incubation of the slanted species: Aspergillus strain CICC 2435 was used for strain culture, and the agar was added to the 4 degree wort to prepare a medium having a pH of 7, so that 0.05 parts by weight of agar per volume of the medium was obtained; at 110 ° C Sterilize, sterilize and cool, obtain a bevel and inoculate at 30. C culture for 5 days, as a slant strain; solid fermentation culture: mix the bran and wort in a ratio of 1:1 by weight to volume, and sterilize for 30 minutes at 110 e C after mixing.
  • Preparation of the substrate Dissolve the acarbose in an aqueous solution, and prepare a solution containing 0.1 part by weight of acarbose per part by volume. After being aseptically filtered through a microporous membrane as a substrate; enzymatic conversion reaction: mixing the crude enzyme solution with the substrate in a volume ratio of 1:4 at a conversion temperature of 30 e C, and the conversion reaction time is 24 hours, that is, Get the composition.
  • the acarbose composition of the present invention can also be prepared by the following liquid fermentation method: Incubation of the slanted species: Aspergillus strain CICC 2435 is used for strain culture, and the agar is added to the 4 degree wort to prepare a medium having a pH of 6-8. , so that each part of the medium contains 0.02-0.1 parts by weight of agar; at 100-120.
  • the conversion time is 5-48 hours, that is, the composition is obtained.
  • the acarbose composition liquid fermentation process is:
  • Incubation of the slanted species Aspergillus strain CICC 2435 was used to culture the strain, and the agar was added to the 4 degree wort to prepare a medium having a pH of 7, so that 0.05 parts by weight of agar per volume of the medium was obtained; Sterilize under C conditions, cool after sterilization, obtain bevel and inoculate, and incubate for 5 days at 30 e C as a slant strain; liquid fermentation: add glucose, beef extract, peptone, ammonium nitrate, magnesium sulfate to water A medium having a pH of 7 was prepared so that 0.05 parts by weight of glucose, 0.05 part by weight of beef extract, 0.04 parts by weight of peptone, 0.03 parts by weight of ammonium nitrate, and 0.04 parts by weight of magnesium sulfate per part by volume of the medium; 50 parts by volume of the medium At 110.
  • preparation of substrate acarbose is dissolved in aqueous solution, and the prepared solution contains 0.1 part by weight of acarbose per volume, and is aseptically filtered through a microporous membrane as a substrate; : using liquid fermentation broth as an enzyme source, adding the substrate to the liquid fermentation broth to 0.00008 parts by weight of acarbose per volume of fermentation broth, at a conversion temperature of 30 C, and a conversion time of 28 hours , that is, the composition.
  • the invention has screened a strain of Aspergillus CICC 2435 through a large number of experiments, and the fermented product or the extract thereof can react with the acarbose phase, and the acarbose composition formed by the conversion reaction has obvious hypoglycemic effect. , its effect is better than acarbose.
  • the microbial transformation method utilized has mild conditions, high selectivity and environmental friendliness. The invention lays a foundation for the development of new drugs for diabetes and provides a new way.
  • Experimental Example 1 Screening of strains which have a transforming effect on acarbose (solid fermentation method)
  • the key to the present invention is to screen for strains which have a transforming effect on acarbose.
  • the screening strains are CICC 3093, CICC 2203, CICC3005, CICC 2435, which are derived from the China Industrial Microbial Culture Collection Management Center.
  • Incubation of the slanted species Agar was added to the 4 degree wort to prepare a medium having a pH of 7, so that each liter of the medium contained 0.05 g of agar; Sterilize under C conditions, cool after sterilization, obtain a slope and inoculate the selected strain, and culture at 30 ° C for 5 days as a slant strain;
  • Solid fermentation culture Mix bran and wort in a ratio of 1:1 by weight to volume, mix and sterilize at 110 ° C for 30 minutes, sterilize and cool, and connect to the slant strain to make the slope
  • Preparation of substrate Acarbose is dissolved in aqueous solution, and the prepared solution contains 0.1 g of acarbose per ml, and is aseptically filtered through a microporous membrane as a substrate; Enzymatic conversion reaction: The crude enzyme solution and the substrate were mixed at a volume ratio of 1:4, the conversion temperature was 30 ° C, and the conversion reaction time was 24 hours, that is, the composition was obtained.
  • reference substance 1 Dissolve acarbose in aqueous solution, and prepare a solution containing 0.1 g of acarbose per ml. After sterile filtration through a microporous membrane, take 0.5 ml of filtrate, add 0.25 ml of 7j, 20 -40. C reaction for 24h, that is, the reference product one.
  • Figure 1 shows the acarbose standard, that is, the reference substance 1;
  • Figure 2 shows the reference substance II prepared by CICC 3093, and the liquid phase diagram shows that the liquid phase profiles of the crude enzyme liquids prepared by the four bacteria are substantially the same.
  • Figure 3 shows a liquid phase diagram of the enzymatic reaction composition of CICC 2435 with acarbose, i.e., a composition of the present invention, with new products appearing (arrows), and Figure 4 showing other species such as CICC 3093 and Akapo. No new substances appeared after the carbohydrase conversion reaction.
  • the method for cultivating the slant strain is the same as that described in Experimental Example 1; Liquid fermentation: Add glucose, beef extract, peptone, ammonium nitrate, magnesium sulfate to water to prepare pH 7 medium, so that 0.05 ml of glucose per ml of medium, 0.05 g of beef extract, 0.04 g of peptone, 0.03 g of ammonium nitrate. , magnesium sulfate 0.04 g; 50 ml of medium was placed in a 250 ml tripod flask at 110. Under C conditions, sterilize for 30 minutes, cool after sterilization, and access the slant strain, so that the volume of the slant strain accounts for 8% of the medium, at 30. C, shake flask fermentation at a shaker speed of 150 r / min, cultured for 3 days, as a liquid fermentation broth;
  • the preparation method of the substrate is the same as that described in Experimental Example 1;
  • Enzyme reaction The liquid fermentation broth is used as an enzyme source, and the substrate is added to the liquid fermentation broth to a 0.00008 g of acarbose per ml of the fermentation broth, the transformation temperature is 30 ° C, and the conversion time is 28 hours. That is, the composition is obtained.
  • Preparation of reference substance 2 Prepare the crude enzyme solution by using the four screening strains according to the method in the preparation of the test sample, and add 0.25 ml of each crude enzyme solution to 0.5 ml of water, and react at 20-40 ° C for 24 h.
  • Figure 5 shows the acarbose standard
  • Figure 6 shows the enzyme solution prepared by CICC 3093
  • the liquid phase map shows that the liquid phases of the enzymes prepared by the four bacteria are substantially the same
  • Figure 7 shows The enzymatic reaction composition of CICC 2435 with acarbose, i.e., the liquid phase spectrum of the composition of the present invention, has new products (arrows)
  • Figure 8 shows other strains such as CICC 3093 and acarbozyme conversion reaction. No new substances appeared afterwards.
  • Group A mixture of acarbose substrate and enzyme solution for 12-48 hours (Example 1 composition)
  • Group B a mixture of Akapoose substrate with the same concentration of A and hydrolysed with the same volume of crude enzyme solution for 12-48h
  • FBG fasting blood glucose
  • FBG fasting blood glucose
  • Example 1 Solid fermentation preparation method of acarbose composition
  • Seed culture slant Aspergillus strain selected from the group cultured for CICC 2435, the agar was added 4 degrees wort prepared culture medium pH 7, such that per ml agar medium containing 0.05 g; sterilization conditions at 110 ° C for After sterilization, it is cooled, and the slope is prepared and inoculated, and cultured at 30 ° C for 5 ⁇ as a slant species;
  • Acarbose is dissolved in aqueous solution, and the prepared solution contains 0.1 g of acarbose per ml, and is aseptically filtered through a microporous membrane as a substrate;
  • Enzymatic conversion reaction The crude enzyme solution and the substrate were mixed at a volume ratio of 1:4, the conversion temperature was 30 ° C, and the conversion reaction time was 24 hours, that is, the composition was obtained.
  • the solid fermentation preparation method of the above acarbose composition can achieve the effects of the experimental examples of the present invention after changing various culture conditions. See Table 3 for specific experimental conditions. Table 3 Other solid fermentation preparation methods
  • Example 2 Liquid fermentation preparation method of acarbose composition
  • Liquid fermentation Add glucose, beef extract, peptone, ammonium nitrate, magnesium sulfate to water to prepare pH 7 medium, so that 0.05 ml of glucose per ml of medium, 0.05 g of beef extract, 0.04 g of peptone, 0.03 g of ammonium nitrate.
  • Enzyme reaction Using liquid fermentation broth as enzyme source, the substrate is added to the liquid fermentation broth to 0.00008g of acarbose per ml of fermentation broth at a transformation temperature of 30 ° C and a conversion time of 28 In the hour, the composition is obtained.
  • liquid fermentation preparation method of the above acarbose composition can achieve the effects of the experimental examples of the present invention after changing various culture conditions. See Table 4 for specific experimental conditions.

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Abstract

L'invention concerne une souche CICC 2435 d'Aspergillus et un bouillon de fermentation ou un extrait de bouillon de fermentation produit par la souche CICC 2435 d'Aspergillus. Le bouillon de fermentation ou l'extrait de bouillon de fermentation peut partiellement hydrolyser l'acarbose pour produire une composition qui est plus efficace que l'acarbose dans la diminution de la glycémie. L'invention concerne également les utilisations du bouillon de fermentation, de l'extrait de bouillon de fermentation et de la composition dans la préparation de médicaments pour diminuer la glycémie.
PCT/CN2010/001693 2010-10-25 2010-10-25 Composition d'acarbose ayant un effet de diminution de la glycémie et son procédé de préparation WO2012055066A1 (fr)

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CN201080069047.3A CN103189497B (zh) 2010-10-25 2010-10-25 一种具有降血糖作用的阿卡波糖组合物及其制备方法
PCT/CN2010/001693 WO2012055066A1 (fr) 2010-10-25 2010-10-25 Composition d'acarbose ayant un effet de diminution de la glycémie et son procédé de préparation

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