WO2009051510A1 - Ensemble de préparation probiotique sous forme immobilisée et lyophilisée et procédé de fabrication - Google Patents

Ensemble de préparation probiotique sous forme immobilisée et lyophilisée et procédé de fabrication Download PDF

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Publication number
WO2009051510A1
WO2009051510A1 PCT/RU2007/000564 RU2007000564W WO2009051510A1 WO 2009051510 A1 WO2009051510 A1 WO 2009051510A1 RU 2007000564 W RU2007000564 W RU 2007000564W WO 2009051510 A1 WO2009051510 A1 WO 2009051510A1
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Prior art keywords
enterosorbent
bifidobacteria
lactobacilli
consortium
cells
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PCT/RU2007/000564
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English (en)
Russian (ru)
Inventor
Aleksei Vladimirovich Molokeev
Aleksandr Georgievich Kusliy
Vladimir Ivanovich Baybakov
Tatyana Leonidovna Karikh
Leonid Georgievich Nikulin
Vyacheslav Vladimirovich Mironenko
Galina Vladimirovna Yasudis
Irina Aleksandrovna Guseva
Raisa Mikhailovna Yatsentyuk
Roma Miroslavovna Ilyina
Natalya Algimantasovna Zykova
Natalia Valentinovna Molokeeva
Tatyana Vasilevna Sokolova
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Obschestvo S Ogranichennoy Otvetstvennostyu 'sibbiosan'
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Priority to PCT/RU2007/000564 priority Critical patent/WO2009051510A1/fr
Publication of WO2009051510A1 publication Critical patent/WO2009051510A1/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
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • C12N11/14—Enzymes or microbial cells immobilised on or in an inorganic carrier
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • 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

Definitions

  • the technical field The invention relates to drugs for medical and veterinary use and methods for their preparation and can be used in biotechnology, medicine and agriculture.
  • Enterosorbents are widely used for the prevention and treatment of many pathological conditions caused by a violation of endoecology. These are various types of activated carbons, for example, carbactin, carbolong, microsorb, polyphepan, etc. (Senov P.L. Pharmaceutical chemistry. - M .: Medicine, 1978, p. 132-133; RF patent N 2029546, IPC 6 A 61 K 9/16, publ. 02.27.95), natural materials and their analogues (crystalline microcellulose, zeolites, chitosans, pectins, etc.), synthetic mineral sorbents and other materials that are used to cleanse the body of toxins, radionuclides, heavy metals and toxins. Enterosorbents reduce the effects of exo- and endotoxicoses.
  • enterosorbents do not eliminate the causes of exo- and endotoxicosis causing effects, as a rule, they are not selective, work mainly on excess substrate, can have a negative effect due to sorption of the metabolites necessary for the body (vitamins, hormones) and do not actively normalize microbiocenosis.
  • drugs of live bacterial cells were widely used (international application (WO) N 85/03848), MKI A 23 C 9/12, publ. 09/12/85), lactobacilli (application HIS N 0154614, MKI A 23 C 9/123, publ. 09/11/85) and colibacilli, etc.
  • a complex preparation including a porous inorganic carrier and microorganism cells immobilized on it (German application J ⁇ b3410650, MKI C 12 N 11/14, publ. 03.10.85).
  • stalactite substrates with a double pore structure are used.
  • the substrates have through macropores, which make possible the free exchange of liquid and gas from the inside of the carrier into the environment.
  • the size of the macropores lies within the size of the cells of microorganisms.
  • the disadvantage of this drug is that it is not intended for use as a medical or veterinary drug due to the lack of data on the effect of a stalactite carrier with microorganisms deposited on it on the microbiocenosis of the gastrointestinal tract of a human or animal body.
  • a complex pharmaceutical preparation including a pharmaceutically acceptable carrier and microorganisms immobilized on it (international application (WO) JY_> 91/09608, MKI A 61 K 35/74, publ. 11.07.91).
  • the carrier does not violate the viability of microorganisms.
  • microorganisms the strain LIa Stertosossus lactis is used.
  • the drug is intended to combat pathogenic microflora of the intestines of humans and animals, causing diarrhea and other gastrointestinal disorders.
  • the disadvantage of the drug is that the strain LIa Stertosossus lactis used in it mainly affects the pathogenic intestinal microflora humans and animals, i.e., exhibits antagonistic properties, but is weakly involved in the restoration of the microflora of the gastrointestinal tract.
  • the antacid properties of the carrier which indicates a weak carrier protection of immobilized Stertosossus lactis cells under the action of the body's internal environment with low pH values.
  • a complex bacterial preparation including a carrier and microbial cells immobilized on it at a concentration of 1 mm 2 2, IxIO 3 - 1, OxIO 5 (RF patent JV ⁇ O 17486, IPC 6 A 61 K 31/00, publ. 08/15/94. )
  • Activated carbon in the form of a powder with a particle size of less than 30 microns is used as a carrier, and lactobacilli and Escherichia coli are used as microorganisms.
  • activated carbon used as a carrier is a finely porous sorbent with a predominance of micropores and a high specific surface area.
  • microbial cells are located on the surface of the sorbent particles and are not adequately protected under adverse environmental influences.
  • Activated carbons actively absorb low molecular weight biologically active substances, vitamins and intestinal gases, which impairs peristalsis. They quickly become clogged and work mainly in the upper parts of the gastrointestinal tract.
  • coals do not have antacid properties, which does not contribute to the survival of cells deposited on them under the action of media with low pH values.
  • the drug does not provide for the simultaneous use of several strains of microorganisms of different types, for example, a mixture of bifidobacteria and lactobacilli, which significantly reduces the effectiveness of the drug, especially when restoring the microflora of the gastrointestinal tract.
  • a known probiotic preparation in immobilized form comprising a carrier, which is a sorbent, and eubiotics cells immobilized on the specified carrier, and the cells are eubiotics used in conjunction with a nutrient medium, and as a sorbent use material with antacid properties, a developed meso- and macroporous structure and a macropore volume of at least 0.01 cm 3 / g in the form of a powder with a particle size of not more than OD mm, or in the form of granules (0.1-5.0) mm, or in the form of tablets in the following quantitative ratio of the components of the drug, May. %: cells of eubiotics with a nutrient medium and a titer of 10 8 - 10 8 CFU / ml - 1.0-50.0; carrier sorbent - the rest is up to 100%.
  • a porous alumina-based material with hydrophilic-hydrophobic topochemistry is used, for example, carbon-modified enterosorbent type CUMC-1, or SIAL type modified organosorbent modified with an organosilicon polymer.
  • eubiotics bifidobacteria or lactobacilli or a mixture thereof are used (RF patent JYg 2118535, IPC 6 A 61 K 35/74, publ. 10.09.98).
  • the sorbents used in this preparation have insufficient efficiency of sorption and desorption of eubiotics bacteria, and also have low colonization activity of the eubiotics bacteria that are part of the preparation.
  • a known method for producing a complex preparation of eubiotics bacteria includes cultivation of deep strains of bifidobacteria and streptococcus, mixing biomass with a protective medium of the following composition (wt.%): sucrose 25-30; gelatin 2 -3; milk powder 3-5; monosodium glutamate 0.5 -1 and contact-sorption dehydration of the target product, which is carried out chilled to minus 8-1O 0 C sorbent, for example aluminum oxide, with a residual moisture content of less than 1% at a mass ratio of 1: 10-12, respectively, and drying carried out for 18-20 hours at a temperature of 0-5 0 C in a closed volume.
  • the sorbent used in this method has insufficient efficiency of sorption and desorption of eubiotics, and also has low colonization activity of eubiotics.
  • the closest technical solution is a probiotic preparation in immobilized and lyophilized form (RF patent JVs 216480I 5 IPC A 61 K 35/74, publ. 10.04.01).
  • the preparation includes a carrier, which is a sorbent, and probiotic cells immobilized on the indicated carrier, the probiotic cells being used in conjunction with a nutrient medium, and a material with antacid properties, a developed meso- and macroporous structure and a macropore volume of at least 0.01, is used as a sorbent cm 3 / g in the form of a powder with a particle size of not more than 0.1 mm, or in the form of granules with a size of (0.1-5.0) mm, or in the form of tablets, according to the invention, the preparation additionally contains a protective environment, and the cells of probiotics with feeder second medium are dry concentrate of bifidobacteria based on milk with a titer of 10 8 to 10 10 CFU
  • Gelatin, sucrose, ascorbic acid and sodium chloride are used as a protective medium in the following components, wt.%: gelatin - 8.5-11.5; ascorbic acid - 0.8-1.2; sodium chloride - 1.7-3.0; sucrose - the rest is up to 100%.
  • a porous material based on alumina with hydrophilic-hydrophobic topochemistry is used, for example, carbon-modified enterosorbent type CUMC-1.
  • the preparation as probiotic bacteria additionally contains dry sourdough of viscous strains of acidophilic bacteria Lactobacillus acidorhilus type AB, the ratio of which to dry bifidobacterium concentrate is 1: (8-9), respectively.
  • Bifidum bifidum Na I 5 or Ns 791, or JIB A-3, or Bifidobacterm lopgum 379, or Bifidobacterium adolesceptis MC-42, or a mixture of bacterial cells of the indicated strains, taken in equal weight, are used as bifidobacteria in a dry concentrate.
  • the closest method is the method of obtaining a complex preparation of probiotic in immobilized and lyophilized form, described in the description of the patent of the Russian Federation Ns 2164801, IPC A 61 K 35/74, publ. 04/10/2011, including washing and sterilization of the porous enterosorbent CUMC-1, carbon-modified, and cooling it to room temperature, mixing enterosorbent and eubiotics with nutrient and protective media in a ratio of not more than 1: 1 and keeping the mixture for at least 1 hours with stirring and a temperature of +4 0 C until the bacterial cells are completely immobilized on enterosorbent, washing the resulting complex preparation in isotonic saline solution, followed by freezing and freeze drying
  • the sorbents used in the indicated preparation and the method for its preparation also have insufficient efficiency of sorption and desorption of eubiotics bacteria.
  • the specified technical result is achieved by the fact that in a complex probiotic preparation in an immobilized and lyophilized form, including a carrier, which is a porous enterosorbent CUMC-1 based on aluminum oxide, modified with carbon with hydrophilic-hydrophobic topochemistry of the surface, and cells of eubiotics bacteria with a nutritious and protective media immobilized on the specified carrier-enterosorbent, according to the invention, the cells of bacteria-eubiotics with a nutrient medium are lyophilized ontsentrat consortium bifidobacteria or lactobacilli, or a mixture thereof with a titer of 10 - 10 cfu / g, and as modified porous carbon enterosorbent CUMC-1 it comprises enterosorbent CUMC-1 further treated with a solution of a metal salt in accordance with the method according to claims 5 and 6 of the claims in the following ratio of the components of the drug in lyophilized form, wt.%: Cells with a
  • a preparation with a microbial biomass content of less than O 5 I wt.% Has a low biotiter with a predominance of cells firmly bound to the sorbent, i.e. acts primarily as an enterosorbent.
  • the number of microbial cells introduced into the preparation does not exceed 15 wt.% As a result of which the entire biomass of the bacteria of the preparation is in a protected state.
  • the CUMC-1 enterosorbent in the preparation retains its main properties, which ensure the binding and elimination of toxins, products of incomplete metabolism and pathogenic microorganisms from the intestine.
  • lactobacilli As a consortium of lactobacilli, it contains strains of lactobacilli Lactobacusus acidorhilus 57S, Lactobacillus plaptrum P-75, Lactobacillus casi Sb in a ratio of 4: 1.0: 1.0.
  • a mixture of consortia of bifidobacteria and lactobacilli has a ratio of 1: 1 to W: l.
  • the indicated technical result is also achieved by the fact that in the method for producing a complex probiotic preparation in an immobilized and lyophilized form, including washing and sterilizing the porous carbon modified SUMC-1 enterosorbent and cooling it to room temperature, mixing enterosorbent and eubiotics with nutrient and protective media in a ratio of not more than 1: 1 and maintaining the mixture for at least 1 hour with stirring and at a temperature not higher than +4 0 C to complete immobilization of bacterial Cleto for enterosorbent, washing the resulting complex preparation in isotonic saline, followed by freezing and freeze drying, according to the invention, before sterilization, the CUMC-1 enterosorbent is treated with a metal salt solution in a volume ratio of not more than 1: 1 and washed with a 2-3 times distilled volume from the reagent water, and as bacteria
  • eubiotics use a concentrate of a consortium of bifidobacteria or lactobacilli, or a mixture of them with a titer of 10 s - 10 10 CFU / g.
  • a solution of a metal salt a 3% solution of magnesium sulfate is used.
  • strains of bifidobacteria are used as a consortium of bifidobacteria: Bifidobacterium bifidum 8-3, Bifidobacterium lopgum DVA-13,
  • strains of lactobacilli are used as a consortium of lactobacilli Lactobacillus ascidhilus 57S, Lactobacillus plaptagam P-75 and Lactobacillus casi Sb in a ratio of 4: 1.0: I 5 O.
  • the mixture of consortia of bifidobacteria and lactobacilli has a ratio of 1: 1 to 3: 1.
  • Bifidobacter bifidum 8-3 The strain of bifidobacteria: Bifidobacter bifidum 8-3 is deposited at the All-Russian Research Institute of Genetics in VKPM under JYaB 5799.
  • strain of lactobacilli Lactobasillus ascidhilus 57S was deposited at the All-Russian Research Institute of Genetics at VKPM under JMa B 5863.
  • strain Lactobacillus plaptagam P-75 was deposited at the All-Russian Research Institute of Genetics at VKPM at Ns B 3962.
  • the basis of the liquid bacterial suspension for drying is eubiotics cells in a milk culture medium with an increased titer of cells (10 9 - 10 10 CFU / ml) - a liquid concentrate of bifidobacteria.
  • Milk culture medium with eubiotics cells contains an increased amount of protein (at least 12% COM - dry milk residue). This allows you to increase the antibiotic properties of probiotic bacteria in the drug.
  • an increased amount of protein increases the antacid properties of the drug.
  • a high concentration of cells in a liquid bacterial suspension allows their use in the preparation in a dry form at a concentration of 1.0 - 10.0% with a titer of 10 8 -10 10 CFU / ml.
  • the sorbent carrier is a mechanically strong powder particles or granules or tablets made of aluminum oxide, the surface of which is modified with carbon to obtain a black CUMC-1 type sorbent.
  • Sorbents have a specific surface area of up to 300 m 2 / g and a developed structure of meso and macropores.
  • the sizes of the macropores of the sorbent are comparable with the sizes of microbial cells, which allows filling the macropores with the indicated cells.
  • CUMC-1 sorbents, to a lesser extent than other similar materials, extract vitamins and hormones from the body and do not disturb peristalsis, which makes them possible to use for long courses.
  • the presence of alumina in the sorbent gives its surface certain buffered antacid properties, which contributes to better preservation of activity and survival of microbial cells immobilized on it, for example, when the drug passes through the stomach (eliminates the negative effect of gastric juice on microbial cells) or under other adverse conditions (low pH).
  • the macroporous structure of the sorbent carrier also helps to protect these immobilized cells from inactivating environmental factors.
  • microbial cells located in the pores and cells located close to the outer surface of the sorbent carrier differ in their desorption abilities, and such heterogeneity of the cell properties provides a prolonged effect of the drug and promotes the colonization of not only the upper, but also lower intestines.
  • Porous carrier being enterosorbent, removes the effects of local (and through it general) toxicosis, which contributes to the survival of the drug bacteria and intestinal microflora, and also reduces the burden on the detoxification organs of a person or animal.
  • Example 1 The probiotic preparation "Ecoflor” in the form of a powder with a particle size (40-100) microns (wt.%): Cells with a nutrient medium of a consortium of lactobacilli with a titer of 10 10 CFU / g 1,0 protective environment, including: Gelatin 0.085
  • Sucrose 0.89 enterosorbent CUMC-1 additionally treated with a 3% solution of magnesium sulfate, the rest up to 100%.
  • Example 2 The probiotic preparation "Ecoflor” in the form of a powder with a particle size (40-100) microns (wt.%): Cells with a nutrient medium of a consortium of bifidobacteria with a titer of 10 9 CFU / g 7.0 protective environment, including:
  • Example 3 The probiotic preparation "Ecoflor" in the form of granules of size (0.5-5.0) mm (wt.%): Cells with a nutrient medium and a titer of 10 8 CFU / g of a mixture of consortia of bifidobacteria and lactobacilli in a ratio of 1: 1 10.0 protective atmosphere, including:
  • Example 4 The probiotic preparation "Ecoflor" in the form of granules of size (0.5-5.0) mm (wt.%): Cells with a nutrient medium and a titer of 10 9 CFU / g of a mixture of consortia of bifidobacteria and lactobacilli in a ratio of 3: 1 5.0 protective environment, including:
  • Sucrose 8.9 enterosorbent CUMC-1 further processed 3% solution of magnesium sulfate, the rest is up to 100%.
  • Example 5 The technology for the preparation of the finished form of the preparation "Ecoflor" Using a special technology, the initial sorbents of the CUMC-1 type (RF patent Na 2026733) are prepared in which the aluminum oxide is modified with carbon, with the required porous structure, chemical surface nature and particle or granule size. Next, a measured amount of CUMC-1 enterosorbent is poured into a cylindrical container, filled with distilled water in a volume ratio of 1: 1 and mixed thoroughly. Wash at least 3 times with distilled water until the carbon film and suspension disappear completely.
  • the CUMC-1 enterosorbent is treated with a solution of a metal salt, namely a 3% solution of magnesium sulfate in a volume ratio of 1: 1. Wash off sulfate ions with 2-3 times the volume of distilled water. After treatment of the enterosorbent CUMC-1 with a 3% solution of magnesium sulfate, the efficiency of its biosorption increases by 1.4 times, and the biodesorption efficiency, which determines the clinical effect of the drug, is equal to 1.
  • Sterilization of CUMC-1 is carried out by dry heat in an oven in bulk with a layer of not more than 1.5-2.0 cm at a temperature of (160 ⁇ 2) ° C for 2 hours.
  • Sterility control CUMC-1 is determined microbiologically. The control of the sterilization process CUMC-1 is carried out using chemical tests.
  • the immobilization process of CUMC-1 is carried out under aseptic conditions.
  • For immobilization take equal in volume (1: 1) amounts of enterosorbent CUMC-1 and culture of consortia of microorganisms.
  • For immobilization use a consortium of bifidobacteria (with a titer of at least 10 10 CFU / ml) or a consortium of lactobacilli (with a titer of at least 10 8 CFU / ml), or a mixture thereof in a volume ratio of 9: 1, respectively, in accordance with examples 1-3.
  • Bacterial biomass is prepared on dairy a nutrient medium containing an increased amount of protein (at least 12% COM - the dry residue of milk) according to standard technology.
  • the mixture of CUMC-1 enterosorbent with the cells of eubiotics bacteria is thoroughly mixed for 5 minutes and placed on a shaker for 1 hour at an intensity of 100 vibrations per minute at a temperature of 6 ⁇ 2 0 C.
  • the immobilization process can be carried out in a glass dish on a roller installation.
  • the washed product is frozen in a Kelvinator type low-temperature refrigerator at a temperature of minus (40-45) ° C for (24-48) hours.
  • Cassettes with pre-frozen preparation are loaded into the drying chamber when the temperature of the plates reaches minus (20-3O) 0 C and the chamber is evacuated.
  • the finished preparation "Ecoflor" in dry immobilized form is Packed in bottles and hermetically closed with corks. Mass fraction of moisture is not more than 3.0 wt.%.
  • Table 1 shows the adsorption capacities of CUMC-1 after surface modification (measured by adsorption of methylene blue according to FS 42-3283-96). Table 1 Data on the adsorption capacity of enterosorbent CUMC-1 after treatment with metal salts
  • the treated surface of CUMC-1 was evaluated in biological tests by:
  • the JYab option (Table 1) for the treatment of MgSO 4 6H 2 O (3%) is the most optimal.
  • the CUMC-1 enterosorbent is treated with a 3% solution of magnesium sulfate, its biosorption efficiency increases 1.4 times (the ratio of sorbed cells to the total number of bacteria in the initial suspension), and the biodesorption efficiency, which determines the clinical effect of the action of the complex preparation (ratio of bacteria desorbed from the surface of the MC-I SU to the number of bacteria adsorbed on it). equal to 1, which indicates that almost all bacteria can be desorbed in the gastrointestinal tract.
  • Tl (CFU / ml) is the original titer of bacterial biomass
  • T2 (CFU / ml) - titer of the biomass of bacteria remaining after immobilization on enterosorbent is the original titer of bacterial biomass
  • T3 T1 ⁇ T2 ⁇ titer (CFU / ml) of bacterial cells immobilized on a sorbent; T4 - titer (CFU / ml) of bacterial cells after desorption, which determines the clinical effect of the drug
  • Ecoflora helps to reduce subjective clinical (malaise, weakness, loss of appetite) and objective laboratory criteria (normalization of the leukocyte intoxication index and hematological intoxication index, relief of cytolysis syndrome and normalization of total serum protein, as well as a decrease in the severity of urinary syndrome), reflecting endogenous intoxication syndrome;
  • the drug "Eclofloor” helps to restore intestinal microflora: E. coli, bifidoflora; decrease in coccal forms, E. coli with weak enzyme properties, lactose-negative enterobacteria;

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Abstract

L'invention concerne des biotechnologies. Une préparation probiotique comprend un entérosorbant SUMS-1 fabriqué à base d'alumine et cellules de bactéries eubiotiques avec des milieux de culture et de protection immobilisées sur un entérosorbant véhicule. Les cellules de bactéries eubiotiques avec un milieu de culture se présentent comme un concentré liophylisé d'un consortium de bifidobactéries ou de lactobactéries ou leur mélange avec un titre de 10 8 - 10 10 UFC /g. Elle contient en tant que entérosorbant SUMS-1 poreux modifié par carbone un entérosorbant SUMS-1 accessoirement traité avec une solution d'un sel métallique avec un rapport suivant de composants de la préparation sous une forme lyophilisée, en % en masse : des cellules avec un milieu de culture d'un consortium de bifidobactéries ou de lactobactéries eubiotiques ou leur mélange avec un titre de 10 8 - 10 10 UFC /g - 1,0-10,0, un milieu de protection - 0,1 - 10,0, un entérosorbant SUMS-1 accessoirement traité avec une solution d'un sel métallique, le reste jusqu'à 100 %. Le procédé de fabrication de la préparation comprend le traitement de l'entérosorbant poreux SUMS-1 avec une solution de sel métallique dans un rapport volumique inférieur ou égal à 1 : 1 et son rinçage visant à éliminer le réactif avec de l'eau minérale, le mélangeage de l'entérosorbant et des bactéries eubiotiques avec les milieux de culture et de protection dans des proportions inférieures ou égales à 1 : 1 et la retenue du mélange jusqu'à l'immobilisation complète des cellules bactériennes sur l'entérosorbant suivi de sa congélation et le séchage par lyophilisation avant la stérilisation. On utilise en tant que bactéries un concentré d'un consortium de bifidobactéries ou de lactobactéries ou leur mélange avec un titre de 10 8 - 10 10 UFC /g.
PCT/RU2007/000564 2007-10-15 2007-10-15 Ensemble de préparation probiotique sous forme immobilisée et lyophilisée et procédé de fabrication WO2009051510A1 (fr)

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Cited By (2)

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CN113069424A (zh) * 2021-04-06 2021-07-06 北京菲瑞阳林医药技术研发有限公司 益生菌含化糖冻干闪释片及其制备方法
CN114767722A (zh) * 2022-05-05 2022-07-22 郑州大学 一种药碳点修饰益生菌制剂及其制备方法与应用

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