JPH02503922A - Agents for the transport of radionuclides in living organisms - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Agents for the transport of radionuclides in living organisms field of invention TECHNICAL FIELD The present invention relates to medicine, and more particularly to novel drugs for transporting C radionuclides in living organisms. Regarding drugs.

Conventional technology Radionuclides are widely used in medical practice for the diagnosis and treatment of pathological processes. Used (“)C1inicheskayaRe+ttgeno”adi "logiya", 1985. Moscow, Miflil, 5y na t’ublishin■ House, νo1.4. PI', 3-21.255-261). 7? However, this means that they can only be used in precisely defined areas or tissue sites. accumulation is associated with a number of issues. What is known in the art is the limited A large number of tissue-tropic radionuclides.

For this reason, pharmaceutical formulations that are carriers for radionuclides are widely used. this eye Commonly used are red blood cells, plasma, amino acids and other preparations. However, at present, research on inflammatory processes, lymph nodes, pancreas, and intestinal lymph nodes is limited. There are no sufficiently effective radiopharmaceutical formulations available for this purpose.

Furthermore, due to the small amount of radiation load and undesirable side effects (toxicity 1. allergy, etc.) Therefore, known radiopharmaceutical preparations are not used for therapeutic purposes.

Disclosure of invention The drug for recycling radionuclides in a living body according to the present invention is novel and currently available. Until now ζ′ is not known in the literature.

The present invention provides diagnostic and therapeutic purposes for treating inflammatory lesions, liver, and lymph nodes. directed to novel agents that ensure the transport of radionuclides to the intestinal lymph nodes. child The drug is non-toxic and will have no side effects.

This problem is solved by the fact that the drug for transporting the radionuclide according to the present invention in the living body is can penetrate into tissues and foci of inflammation in the liver, lymph nodes, intestinal lymph nodules. and at least one non-pathogenic bacterial microorganism that can be concentrated therein. - Solved by including J&. It is 10-2X per 1111g of drug. The drug according to the present invention, which contains I09 viable microbial cells, has a preferable interaction with bacteria. [7] Contains the following microbial strains: 534 strains of Bacillus subtilis USS 2811 on March 1988 under registration number B-16661', l. R Science Academy - Institute of Microbial Biochemistry and Physiology's Federal Microbial Depositary (the A11-Llnion Co11ection of microorgani sms of the Institute of Bioche+n1stry and physiology of microorganisms.

Deposited at thejlssRAcademy of 5cien (, O8), And the strain registered under B-16660; - 538 strains of Bacillus sp., January 1988 January 2019 Federal Research Institute's Federal Microbial Deposit of Genetic and Industrial Microbial Selection The A11-Union Re5arch In5titud ofger+etics and 5 selection of 1 industry ial rnicroorganisll+s) and BKPM B - Strains registered under 4401; - Bacillus °barbifaciens (Bacillus Illus pulvifaciens) 535 strains, released on April 1, 1988. Federal Microbial Depositary of the Federal Research Institute for Genetic and Industrial Microbial Selection on the 4th Strain deposited with and registered under BKPM B-4348: 8-P A-3 stock: The novel drug according to the present invention can be delivered by the optimal route, namely through the gastrointestinal tract and into the tissues of the internal medium. It is possible to transport the active ingredients to. Depends on the strain used and the dose. , inflammatory disease, 11ψ viscera, lymph node tissue, and, to a lesser extent, intestinal lymph node tissue. It is concentrated in the nodules and liver within 2-24 hours. 4""i,, i; , the radiation dose of the active ingredient introduced into the living body is lowered by (1-, /): is i J',] and therefore other healthy organs and tissues ＼, 3. Limiting the undesirable effects of Within 24 to 72 hours , 50...80% of the preparation contains main and Schiff 7: liver 1al i; and gastrointestinal ii. It is then discharged. Present invention 1. The drugs involved are effective during the period between 1411 and 1411 (in the tissues between +L, r,',,, 1-μ・ of 17, 2, which can stay is treated as *Applicable to 5j agents for transport of preparations) -,, (: Possible to apply 4.Additional 11. Bacterial strains related to the Ming Dynasty were used as drugs (:L itself had therapeutic efficacy in the Song 4th Dynasty. Ras. In the tissue of the internal medium of the living body (this drug is effective against Graj, positive bacteria 4, Durham negative bacteria, and It inhibits the growth of bacteria and fungi, causes necrosis, contributes to the cleansing of the tissues, and is effective against allergies. ・Prevent one response.

BEST MODE FOR CARRYING OUT THE INVENTION Drugs that are associated with misfires are transmitted from the gastrointestinal tract to the liver, lymph nodes, intestinal lymph nodes, and inflammatory diseases. prepared from non-pathogenic bacterial microorganisms that can penetrate into nests and concentrate therein .

First, microorganisms are isolated from sub-healing wounds from human and animal living bodies. experiment Among them, inflammatory disease, liver, lymph nodes, intestinal lymph nodule tissues. 3. Select the one that can penetrate. erence, acute and chronic toxicity, and gamma allergy effects. desirable 2. If the strain has no side effects, the strain 4 can be used as a new transport agent.

For this, the nuclei are cultured on a nutrient medium and -,40--1. , -40℃ Freeze-dry for 24 hours under a pressure of 5-70 Pa at a temperature drop of 1. Store the powdered preparation in a sealed container at room temperature. Radionuclides when needed is incorporated into the base of the medicament according to the invention. 1-, lyophilized, - culture medium Add nutrients and radionuclides to 8G''-J medium and inoculate 12-2. Grow for 00 hours. Suspension of living bacteria in an aqueous solution of radionuclide, 5, salt or sugar Liquid, '-3f...: 3゛/at: 1: [True], 1 to 12 hours of contact 13 In C62, the radionuclide is incorporated into the drug according to the present invention. J. is possible. The bacteria are then separated from the medium 7 and dried or 11. :Ta A suspension of salt or sugar in an aqueous solution is prepared. The number of viable bacteria can vary from 10 to 2 x 10' cells in one drug of the invention. Can be done. The specific activity of the radionuclide is 0.01 to 50 MBq per drug of the present invention. , or within the range of 0.01 to 50 MBq (megabenzyl) in 1 eaf of suspension. Can be different. The drug according to the invention is administered orally.

For the preparation of the medicament according to the invention, preferably the following new strains are used: A novel Bacillus subtilis strain 534 was isolated from a non-purulent wound of a patient; It has the following morphological characteristics and physiological properties.

They are bacilli. The size of cells cultured on agar for 1 day is (2-4) x (0, 6-0,8) m. virulent bacteria. Forms spores and does not form capsules. da Lamb positive. Flesh - Colonies on peptone agar have fan-shaped edges, slightly pink, 2 It is of rough shape with a diameter of ~12 ornaments. This strain can be used at temperatures within the range of 15-50℃. The optimal growth temperature is 36-37°C. Gluco does not generate gas. decomposes saccharose, mannitol, sucrose, and mannitol into acids. Does not ferment lactose.

Does not produce hydrogen sulfide or indole. benzylpenicillin, ampicillin, Susceptible to erythromycin, monomycin, lincomycin, and tetracycline and is insensitive to polymyxins.

This strain inhibits the growth of Staphylococcus, Streptococcus, Proteus bacteria, Pseudomonas aeruginosa, fungal yeast, etc. produce antibiotics with a broad spectrum of action that cause harm. Furthermore, protein Release proteolytic enzymes and immunomodulatory substances that degrade.

A novel Bacillus sp. 538 strain is isolated from a human organism.

They are bacilli. The size of cells cultured on agar for 1 day is (5-10) x (0 , 7-1, 2p@). They grow as chains of 3-5 cells. style It is active and Durham positive. Spores are located near the ends and do not form capsules. Meat- Colonies on peptone agar are slightly prominent, yellowish, and have a diameter of 2-4. +++a+. Meat - on peptone broth, they form a membrane on the surface and below as flakes. They are in 7% NaCl , grows under aerobic and anaerobic conditions at temperatures of 25-40°C. The optimum temperature is 36-37℃. Lactose, glucose, sucrose, mannitol, arabic North, does not ferment xylose. They produce hydrogen sulfide, but indole does not form. It does not clot plasma and does not give a positive reaction in the skin necrosis test.

The strain contains erythromycin, oleandomycin, methicillin, carbenicillin, Sensitive to restomycin, lepomycetin; polymyxin, lincomycin , resistant to monomycin.

The strain produces antimicrobial substances with a broad spectrum of action.

The strain produces proteolytic enzymes that degrade albumin, fibrin, and hemoglobin. into the surrounding medium. Produces immunomodulating substances that reduce allergic reactions .

Cough strains are non-virulent and non-pathogenic.

The novel Bacillus bulbifaciens strain 535 was isolated from a non-purulent wound in a patient. be separated. This is a bacillus, and the cell size when cultured on agar for 1 day is (2-4) 0,6-0,8)4.

It is a virulent bacterium and when grown on meat-peptone agar, it develops a wrinkled membrane. Form. Forms spores and does not form capsules. Durham positive. Meat - on peptone agar Colonies are rough-shaped, with fan-shaped edges, slightly pink in color, and 2-9 m in diameter. o+ and they grow under aerobic and anaerobic conditions. They are 15-5 It breeds at a temperature of 0°C. The optimum temperature is 36-37℃. without producing gas, Decomposes glucose, sucrose, maltose, dalgit, and galactose into acids do. Lactose, mannitol, xylose, rhamnose, lysine, arginine Do not ferment ornithine. Does not produce hydrogen sulfide or indole. milk to peptonize. Does not produce lecithinase. Acetyl methyl carbinol and catalase, but does not hydrolyze starch.

The strain contains erythromycin, ampicillin, methicillin, benzylpenicillin, Oxacillin, Lincomycin, Neomycin, Lepomycetin, Monomycin, Sensitive to ristomycin, kanamycin, tetracycline, and oleandomycin and insensitive to polymyxins.

Bacillus pulvifacien S) strain is a proteolytic enzyme that produces albumin, hemoglobin, and fibrin. The company produces broad-spectrum antibiotics and immunomodulators. the antibiotic Pathogenic microorganisms that are susceptible to are Staphylococcus, Streptococcus, Escherichia coli, Pseudomonas aeruginosa, Proteus bacteria, Salmonella enterica, Shigella bacteria, Talebsiella bacteria, and fungal yeasts. that does not inhibit the proliferation of microfilariae that are parasitic on spoilage. Furthermore, the antibiotic It is completely destroyed very quickly (within a few hours) and leaves no room for the development of food allergies. stomach.

Proteolytic enzymes contribute to the digestion of food.

The main difference between this strain and Bacillus subtilis strain 534 is the ability to hydrolyze starch. and inability to cleave mannitol.

The strain is non-virulent and non-pathogenic.

The harmless nature of the drug according to the invention, from the gastrointestinal tract to foci of inflammation, pancreas, lymph nodes, intestines Penetrates into lymph nodes and liver tissue, concentrates, and lasts from 2 hours to 14 days The ability to persist for a long time has been established in animal studies and has been successfully demonstrated in humans in hospitals. It was justified.

Survival of Bacillus subtilis strain 534 in acute toxicity of the drug according to the present invention Three series of preparations obtained from the cultures were used. One dose of each series is 0. 9% sodium chloride solution IC! 1! to a dose of 10 and 20 bln, cell number in Injected intraperitoneally into three white mice and three Vistar white rats, respectively. Administered intravenously. All animals survived. They had a voracious appetite.

Animals were sacrificed on days 3, 7 and 14 of the experiment. Histological studies show that the brain , no inflammatory or dystrophic changes in the lungs, kidneys, liver, or heart. Indicated. In the pancreas, the size of the vesicles and the number of units of lymphoid tissue in the blood vessels An increase was observed.

Balacis subtilis white mice and 6 V. doses of 10 and 20 bln, cell number, respectively, to rats of the istar series. It was administered once with a meal. All animals survived. sacrifice them the next day Ta. Histological studies of the brain, myocardium, lungs, kidneys, stomach, small intestine and large intestine were performed in the control group showed no change compared to animals (10 mice and 10 rats). It was. In the liver, some increase in the number of lymphoid tissues occurs along the course of the portal vein. It was confirmed that there was an intrusion. In the pancreas, an increase in the size of vesicles, in blood vessels The appearance of numerous lymphoid tissue units and giant multinucleated cells was observed.

Balasis parvifaci 2 bln, which had been killed in advance by formalin vapor, and the number of cells The dose was administered intraperitoneally to 20 white mice. Another 3 viable cultures of the same strain 1 in each of 0 white mice and 30 Vista-series white rats. Administered at doses of 0 and 20 bln, cell number. All animals survived.

They had a voracious appetite. Animals were sacrificed on days 3, 7 and 14 of the experiment. I made it. Histological studies detect inflammatory or dystrophic changes in the brain, lungs, kidneys, liver, and heart. It was shown that no change was observed at all. In the pancreas, vesicle size and blood vessel An increase in the number of lymphoid tissue units was observed.

10 mice were administered to 15 white mice and 15 Vistar white rats. Bacillus barbifaciens (Bacil A suspension of a viable frozen culture of 535 strains of S. pulvifaciens was administered orally. administered. The animal survived. The next day they were sacrificed. Brain, heart muscle, lungs, kidneys, stomach , histological study of the small and large intestines showed no changes compared to control group animals. Didn't show it. In the liver, an increase in the size of the vesicles, a large number of lymphoid cells in the blood vessels A 1-day viable culture with 0.9% chloride was observed to show the appearance of fibrous units and giant multinucleated cells. 100.000 in sodium solution 17; 10 mIn, 1 bin, and 5 It was administered subcutaneously at a dose of .bin and number of cells.

The general condition of the animals remained unchanged and all survived. Totally local at the location of administration No changes were observed, but the infected area was inoculated with spore-producing bacteria for two weeks. .

0.9% salt in each of the white mice and three white rats of the Vista series. 200 ml in sodium solution ld, and 1. bln, 30 at the dose of cell number It was administered intraperitoneally for 1 day. Additionally, each of the three series of preparations was administered to six animals at the same dose. It was orally administered to white mice and six Vistar type white rats, respectively. all of animals survived. The mass of the animals in the test group was that of the control (10 mice). (p<0.05) compared to 10 rats). trial Mice and rats in the experimental group had shiny white and fluffy fur. there was. Histological studies of the brain, myocardium, kidneys, lungs, stomach, small intestine and large intestine show no changes. Didn't show it. In the liver, there was a large amount of portal vein compared to animals in the control group. Invasion of lymphoid tissue located along the tract was noted. Pancreas of test group animals In this study, lymphoidization of blood vessels and an increase in the size of vesicles were observed, but large No multinucleated cells were detected.

In the process of studying chronic toxicity, six white mice were exposed to odd days between days 11 and 21. She gave birth to 23 children. Later, she gave birth to seven more non-deformed children.

In testing for chronic toxicity, Bacillus pulvifaciens) strain 535 and Bacillus sp. ,) A 1-day viable culture of strain 538 was diluted with 1 cJl of 0.9% IJum solution. to 40 white mice at a dose of 200-500 mIn, cell number, and 2 bln, cell number dose in 30 Vista series rats for 30 days It was administered intraperitoneally every day. In addition, 48 white mice and 30 Vistar mice Rats in rows were each given 200 mIn of live lyophilized cultures of the above strains, and It was orally administered with water every day for 30 days at a dose of 1 bin per cell count. all the animals Survived.

The mass of animals in the test group was 11-19% compared to that of animals in the control group. it was high. Mice and rats in the test group were shiny white and fluffy It had body hair. Histological studies of the brain, heart muscle, lungs, kidneys, stomach, small and large intestines are , showed no change at all. In the liver, compared to control group animals, A large amount of lymphoid tissue located along the portal vein and outside it was observed. . # In the organs, lymphoid formation of blood vessels and an increase in the size of vesicles were observed. , no giant multinucleated cells were detected.

In the process of studying chronic toxicity, nine white mice were exposed to odd days between days 11 and 21. She gave birth to 54 children. After that, she gave birth to nine more children who were not malformed. Therefore , viable cultures of the strain do not affect fetal development even when administered intraperitoneally, and did not cause genetic disorders.

Bacillus subtilis (Bacillus 5ubtilis) 534 strains were vectored. 3 series of preparations in 0.9% sodium chloride solution LCR&M2B in, administered subcutaneously to four guinea pigs at a dose of cell number. on the 31st day 1 cIl of 0.9% sodium chloride! 2 bins, total at the dose of cell number I gave a sarcastic injection to a guinea pig.

No local or systemic signs of allergic response were observed.

(0.9% chloride) 2 bln in 1 eaf of IJum solution, at a dose of cell number. Twenty-four guinea pigs (one strain per 12 animals) were administered subcutaneously six times a day. 311 days 2bln in 0.9% sodium chloride solution 1eaf.

All guinea pigs were subcutaneously injected with cells of the same strain of microorganism at a dose of the number of cells. That's it There were no local or systemic signs of a Lugi response.

To test the stability of the preparations of the invention, Bacillus sub-sealed flasks were tested. Stored at room temperature for 7 years. Another 9 capsules for 3 months at a temperature of -20 to -22℃ The 9 capsules were stored at a temperature of 110° C. for 2 months. Viable particles in the capsule The number of bacteria was determined by the method of serial dilution inoculation.

The content of bacteria in the capsule before the start of the experiment was 5.4±0.5 bin.

The number of cells stored for 7 years is 5.2 ± 0.5 bins, which is equal to the number of cells. , 5.4 ± 0, 5 bins, number of cells stored at a temperature of -20 to -22°C When stored at a temperature of 110℃, the number of cells was 5.3±0.6. there were. Therefore, the data obtained indicate that the agents according to the invention are It has been proven that it can be stored for up to a year.

1311, 9! A 5-fold re-inoculation was used to grow on media containing ITc. the After that, 0.9% sodium chloride solution 1c [2 bln in Ir, each at a dose of cell number The strain was administered orally to 5 mice. All animals survived and showed no signs of poisoning. It was. Therefore, repeated inoculations showed that the drug according to the invention is stable. Thin Virulence and pathogenicity of the fungus were not demonstrated.

Preparation of the medicament according to the invention and its testing in order to better understand the invention Some specific examples are given below to illustrate.

Example 1 Patients with Bacillus subtilis 534 strain isolated from non-purulent wounds. that it causes undesirable negative effects It has been demonstrated that the gastrointestinal tract can penetrate into the tissues of the internal medium without . The strain was plated on 1.5% peptone agar containing 14C-labeled H3-leucine. , grown for 1 day at a temperature of 37°C. 0.9% chloride of the strain) IJum solution and lyophilize.

The thus obtained drug according to the present invention was added in an amount of 500 mL in 1 inch of dry substance. Contains viable cells of the following strains. The activity of drug 1 according to the present invention is 0.1 MBq. Ru.

The drugs according to the invention are then tested. The drug in 0.9% sodium chloride solution Prepare a suspension of Each of 4 healthy rabbits and 4 rabbits with dorsal wounds. 10 cd of suspension containing 1 bin of viable bacterial cells of the above strain (dry solids) 2) Administer.

Radiological diagnosis after 24 hours revealed the following distribution of radionuclides in healthy rabbits: Shows: in the lungs - 23-36% of the dose, in the lymph nodes of the peritoneal cavity - 7-12%, in the intestines. In the lymph nodes - 3-5%, in the liver - 4-9%. injured (with foci of inflammation) In rabbits, the distribution of radionuclides was as follows: -29 to 4 in the injured area. 1%, in the pancreas - 12-16%, in the lymph nodes of the peritoneal cavity - 2-4%, in the lymph nodes of the intestine -1-2%, in the liver -7-11%. After 72 hours, the release in those organs and tissues Radionuclides were reduced by 50-82% and completely eliminated by the 7th day.

Example 2 Bacillus bulbifaciens in 0.9% sodium chloride solution A suspension containing 10 bln of bacterial cells of strain 535 (S. pulvifaciens) 99Tc with an activity of 800 MBq is introduced into the suspension.

This mixture was incubated in a thermostat at 37°C for 6 hours, then centrifuged. do. Remove supernatant. The obtained drug according to the present invention contains a radionuclide in 1. Approximately 500 mIn with 113Tc.

Contains viable bacterial cells. The activity of the drug 1 is approximately 10 MBq.

5 mg of the drug of the present invention containing the radionuclide "Tc" is orally administered to the patient. After an hour, a scanogram of a healthy pancreas is obtained.

Example 3 Bacillus pulvifaciens ) 535 shares, 13! On 2% peptone broth containing albumin labeled with 7 Grow for 12 hours at a temperature of 37°C. Centrifuge the resulting culture mixture and separate the residue. Separate and dry, approximately 100 mIn with radionuclide +31　■ in drug 1■ A medicament according to the invention is obtained which contains viable bacterial cells of . Drug 1 according to the present invention Activity is 0. It is OIMBq. A dose of 1 g of the drug was administered to experimental limb abscesses, pulmonary Orally administered to rabbits with inflammation and adrenalitis. Inflammatory foci in all rabbits A scanned image of the image was obtained.

Example 4 Lb, plantarum (Lb, plantarum) 8-PA-3, 14c The cells are grown on milk containing H5-leucine labeled with . The resulting culture mixture About 100 ml of bacterial viable cells were dried together with the radionuclide 14C in 1 mg. A drug according to the present invention containing cells is obtained.

The activity of drug 1 according to the present invention is 0.1 MBq.

The drug is administered twice a week at a dose of 25 μ to 5 hens with avian leukemia. . The average lifespan of the hens was 123 days, compared to 71 days for the control group of diseased hens. It was day.

Example 5 B. bifidum (B. bifidum) N1 strain was grown under anaerobic conditions at 37°C. Grow on Blaurock nutrient medium for 7 days at temperature and then Freeze-dry. The obtained drug of the present invention contains about 10% of the radionuclide "C" in 1. Contains 0.000 viable bacterial cells. The activity of drug 1 of the present invention is 0.　OIMBq It is.

A suspension of the drug thus obtained in 0.9% sodium chloride solution is prepared. 5 A suspension (12d) containing 0 to 500 viable bacterial cells was administered to each of five white mice. give Tissue radiographic studies of radioactive labeling of bacteria in pancreatic tissue were performed for 6 to 48 hours. showed their presence in the pancreas.

Example 6 E. coli M17 on Endo medium at 37°C for 24 hours Proliferate. The resulting culture was washed with 5% glucose solution and incubated at −40°C to + Freeze-dry for 24 hours under a pressure of 5-70 Pa at a temperature drop of 40°C. obtained The drug contains 2 x 1.0' viable cells per volume of bacteria. The drug is described in Example 2. It takes in radionuclides introduced in the same manner as the The resulting preparation 1 The activity is (L2 MBq). 10 mg of the preparation was orally administered to rabbits. Liver scans were obtained 3 hours after administration of the product.

Control studies showed complete exit of the radionuclide from the organ within one day.

Industrial applicability The agent according to the invention can be used in veterinary medicine and medicine for the transport of radionuclides. as well as foci of inflammation in various locations and radiation of the lymph nodes of the liver, lymph nodes, and intestines. It is useful in conducting radiology research. The present invention in which radionuclides are incorporated This drug is useful as a treatment for leukemia and neoplastic diseases of the liver and lymph nodes. It is for use.

The drug of the present invention can be used to remove inflammatory lesions from the gastrointestinal tract. ! internal organs, lymph nodes, liver tissue, For the preparation of new physiological preparations based on the possibility of transporting active ingredients to can also be used.

international search report

Claims (7)

[Claims] 1. A drug for the transport of radionuclides in living organisms, from the gastrointestinal tract to the spleen and lymph nodes. Penetrates and concentrates in the tissues of the lymph nodes of the intestines and foci of inflammation comprising cells of at least one non-pathogenic organism capable of being treated; and the agent It is characterized by containing 10 to 2 x 10 viable cells of the microorganism in 1 mg. drugs. 2. As Bacteria, USSR Academy of Sciences Microbial Biochemistry, March 28, 1988 ・Federal Microbial Depositary of the National Institute for Physiological Sciences (the All-Union Coll. Ection of microorganisms of the Instrument itute of biochemistry and physiology of microorganisms, the USSR Academy of Bacillus deposited with B.Science and registered under B-1666D. Containing 534 strains of Bacillus subtilis The drug according to claim 1, characterized in that: 3. As a bacterium, on January 20, 1988, the linkage of genes and selection of industrial microorganisms was introduced. The Federal Depositary for Industrial Microorganisms of the Japanese Research Institute (the All-Union C collection of industrial microorganis msof the All-Union Research Institute e of genetics and selection of industry iral microorganisms) and BKPM B-4 538 strains of Bacillus sp. registered under 401 Medicament according to claim 1, characterized in that it comprises. 4. As a bacterium, on April 14, 1988, the linkage of genes and selection of industrial microorganisms Deposited in the Federal Depositary of Industrial Microorganisms of the Japanese Research Institute and BKPM B-4 Bacillus vulvifaciens registered under 348 Claim 1, characterized in that it comprises the strain A. pulvifaciens) 535. Drugs listed in. 5. As a bacterium, Escherichia coli M The drug according to claim 1, characterized in that it comprises 17 strains. 6. As a bacterium, Lactobacillus plantarum s plantarum) 8-PA-3 strain. The drug according to item 1. 7. As a bacterium, Bacterium bifidum ifidum bifidum) N1 strain. The drug described in 1.