BG1141U1 - Polybacterial complex for immunoprophylaxis and immunotherapy in mammal animals, and drug form containing it - Google Patents

Abstract

The biologically active polybacterial complex for immunoprophylaxis and immunotherapy in mammal animals contains a polybacterial substance of killed bacterial bodies and lysates of: two Escherichia coli strains - Escherichia coli 29 express type 1 and P pili, and Escherichia coli Rc mutant, and one Staphylococcus aureus strain û for the three strains regardless of the depositary number, as well as a stabilizer comprised in the polybacterial substance. Dextran-40 is used as a stabilizer. Each of the two Escherichia coli strains, as part of the polybacterial substance, is in the range of 20 to 40 percent, while the Staphylococcus aureus strain is in the range of 20 to 60 percent. The bacterial substance is in a quantity of 10 x 109 bacterial bodies in mg active substance from each of the three strains and mass with density of 7.5 x 109/ml before the freeze-drying with the use of the stabilizer. The polybacterial substance and the stabilizer are in weight percent as follows: polybacterial substance from 30 to 50, and dextran stabilizer 40 from 50 to 70. The drug form based on the polybacterial complex represents a tablet and contains: polybacterial complex, macrogol 6000 (PEG), crospovidone (colidone), and silicified microcrystalline cellulose (SMCC) in the following weight percent: polybacterial complex from 35 to 41, macrogol 6000 (PEG) from 2.88 to 3.12, crospovidone (colidone) from 10.66 to 11.34, and silicified microcrystalline cellulose (SMCC) from 45.46 to 50.54. The polybacterial complex and the tablet drug form containing it are intended for animals of all age groups, including newborns û either suckers or weaned, as well as pregnant and lactating animals û mothers. They are used for prevention and treatment of acute and chronic infections, particularly in cases of colienteritis and bronchopneumonia, as well as for the full utilization of food and increasing the growth of the animals.

Description

(54) POLYBACTERIAL COMPLEX FOR IMMUNOPROPHYLAX AND IMMUNOTHERAPY IN Mammals and Pharmaceutical Forms Contained

Technical field

The utility model relates to an active biological polybacterial complex for immunoprophylaxis and immunotherapy in mammals and a dosage form tablet containing it, especially intended for the prevention and treatment of acute and chronic infections, especially in the case of collienteritis and bronchopneumonia, which and for the complete absorption of food (including feed, nutrients, nutritional supplements) and increased animal growth.

BACKGROUND OF THE INVENTION

In veterinary practice there is no known active-biological polybacterial complex for immunoprophylaxis and immunotherapy in mammals and a dosage form containing it intended for the prevention and treatment of acute and chronic infections, especially in the case of colienteritis and bronchopneumonia, which contribute to their full value. digestion of food (incl. feed, nutritional mixtures, nutritional supplements) and increase in animal growth applicable incl. in newborn mammals and weaners as well as adults, incl. pregnant and lactating animals - mothers.

The objective of the utility model is to create an active biological polybacterial complex for immunoprophylaxis and immunotherapy in mammals and a dosage form containing it intended for the prevention and treatment of acute and chronic infections, especially in the case of collienteritis and bronchopneumonia, and for the complete absorption of food and the increase in animal growth.

The technical nature of the utility model

The utility model relates to a polybacterial complex for immunoprophylaxis and immunotherapy in mammals and a dosage form containing it.

The active-biological polybacterial complex contains a polybacterial substance of killed bacterial bodies and lysates from: two strains of Escherichia coli - Escherichia coli 29, expressing type 1 and P pills and Escherichia coli Rc mutant and one strain of Staphylococcus aureocus - aureus for the three strains irrespective of the deposit number, as well as a stabilizer included in the polybacterial substance. Dextran 40 is used as a stabilizer. Each of the two Escherichia coli strains as a part of the polybacterial substance ranges from 20 to 45% and the Staphylococcus aureus strain from 20 to 60%. The bacterial substance is in the amount of 10 x 10 ⁹ bacterial bodies in mg of active substance from each of the three strains and weighing 7.5 x 10 ⁹ / ml before lyophilization using the stabilizer. The polybacterial substance and the stabilizer are in wt. as follows: polybacterial substance 30 to 50 and stabilizer 50 to 70.

The useful model also relates to a tablet formulation containing the polybacterial complex and excipients macrogol 6000 (PEG) lubricating, crospovidone (colidone) disintegrating and silicified microcrystalline cellulose (SMCC) diluting in the following weights. %: polybacterial complex 35 to 41, macrogol 6000 (PEG) 2.88 to 3.12, crospovidone (colidone) 10.66 to 11.34, silicified microcrystalline cellulose (SMCC) 45.46 to 50.54 .

The bacterial substance preparation method is a standard method for the preparation of lyophilized bacterial strains obtained by standard methods and until a mass of 7.5 x 10 ⁹ / ml is obtained prior to lyophilization using a dextran 40 stabilizer. The bacterial substance is killed. with a chemical agent.

The polybacterial complex was prepared by the standard method.

The preparation of the tablet involves the phases of saturation and sieving of the active complex, to which the previously sieved excipients are successively added. The resulting mixture was homogenized and tableted by conventional methods. The tablet is used as a simple tablet, obtained by standard methods for its formation.

The polybacterial complex and the tablet thereof are administered orally in the fasted morning at a dose of 0.1 to 10 mg / kg live weight. Admission can be discontinued at any time of administration without the risk of adverse reactions.

Benefits of utility model

The advantages of the utility model are that for the first time a polybacterial complex was developed for immunoprophylaxis and immunotherapy in mammals and a tablet form thereof, in particular for the prevention and treatment of acute and chronic infections, especially in the case of colienteritis and bronchopneumonia.

The polybacterial complex and the tablet are applicable to all age groups, incl. newborns - suckling and weaned, and adults - pregnant and lactating animals - mothers.

The advantage of the polybacterial complex and the tablet is that they simultaneously help in the complete absorption of food and increase the growth of animals.

The polybacterial complex can also be used as an adjunct in the prevention and treatment of domestic and farm animals.

The selected stabilizer and excipients ensure the stability of the product, improve its taste and determine the safe effect of the product.

Co-infections are a serious problem in animals, especially when raised in commercial use groups. The widespread prevalence of coli infections and the difficulty in treating and preventing these diseases are also associated with increasing drug microbial resistance, and in particular the suppression of immune system functions.

Of particular importance to the polybacterial complex and tablet being created is the fact that they are in line with the implementation of the EU Directive, which prohibits the use of nutritional antibiotics in veterinary practice that lead to serious allergy to the human body in the consumption of meat and milk from animals fed with antibiotic foods.

With the specifically selected bacterial species - killed bacterial bodies and lysates from two strains of Escherichia coli: Escherichia coli 29, expressing type 1 and P piles and Escherichia coli Rc mutant, and Staphylococcus aureus (Staphylococcus aureus) specific non-specific effect immune response at different levels of the immune system with no toxicity and side effects.

In the clinical studies conducted, the polybacterial complex and the tablet showed clear activity in stimulating specific antibodies of IgG, IgM and IgA classes directed against the bacterial strains contained therein. This clearly indicates that they stimulate the systemic humoral immune response, which is most responsible for overcoming bacterial infections of different localization. This is demonstrated by the lower number of diseased or dead animals from the gastrointestinal or pulmonary infections receiving the agent compared to control animals.

The nature of the product and its easy oral administration make it easy to dose and convenient for use by animals, incl. when they are in flocks.

No side effects were observed.

No incompatibility with other medicines has been observed. May be combined with any other treatment, incl. and antibiotic therapy. Allows multiple applications without the risk of getting used to.

No contraindications are known except for autoimmune diseases. The polybacterial complex and the tablet are contraindicated only in cases of autoimmune diseases with increased antibody synthesis, which is a contraindication to the use of immunostimulants in general.

Examples of implementation of the utility model

Example 1. Composition of the polybacterial complex

A / Composition of the polybacterial substance The polybacterial substance contains the following components: a polybacterial substance of killed bacterial bodies and lysates of two strains of Escherichia coli 29, Escherichia coli expressing type 1 and P and Escherichia coli mutantucus mutant Staphylococcus aureus) - for the three strains irrespective of the depositary number, in% by weight, as follows:

Components / Example 1.A.1. 1.A.2. 1.A.Z. 1.A.4. 1.A.5. 1.A.6. 1.A.7. 1.A.8. 1.A.9. Escherichia coli 29 25 20 35 33,3 45 35 30 40 37 Escherichia coli Rc 25 20 35 33,3 35 40 30 35 38 Staff. aureus 50 60 30 33,3 20 25 40 25 25

The polybacterial substance is in an amount of 10 x 10 ⁹ bacterial bodies in mg of active substance and a mass of 7.5 x 10 ⁹ / ml density before lyophilization using a dextran 40 stabilizer.

B / Composition of the polybacterial complex The active biological polybacterial complex contains, as a stabilizer, dextran 40, incorporated into the polybacterial substance, by weight. %, as in the following embodiments:

Ingredients / Example 1.B.1 1.B.2 1.B.Z. 1.B.4. 1.B.5 1.B.6. 1.B.7. 1.B.8.

Polybact. 30 33 37 40 42 44 46 50 substance Dextran 40 70 67 63 60 58 56 54 50

Example 2. Composition of a tablet with a polybacterial complex.

A / The tablet contains the following components: polybacterial complex and excipients as follows in wt. %:

Ingredients / Example 2.A.1. 2.A.2. 2.A.Z. 2.A.4. 2.A.5 2.A.6, 2.A.7. 2.A.8.

Polybacterial 3435 complex

Excipients 6665

37 38 39 4041

63 62 61 6059

B / In an exemplary composition, the following components are used as excipients to form the tablet: macrogol 6000 (PEG) lubricant, crospovidone (colidone) disintegrating, and silicified microcrystalline cellulose (SMCC) diluting as follows in wt. %:

Components / Example 2.B.1. 2.B.2. 2.B.Z. 2.B.4. 2.B.5. 2.B.6. 2.B.7. Polybacterial complex 35 36 37 38 39 40 41 Macrogol 6000 (PEG) 3.12 3.08 3.04 3 2.96 2.90 2.88 Crospovidone (colidone) 11,34 11,22 11.13 11 10.89 10.70 10.66 Silicified microcr. 50.54 49.70 48.83 48 47.20 46.40 45.46

cellulose (SMCC)

Example 3. Method for Preparation of Bacterial Substance and Polybacterial Complex.

The bacterial substance preparation method is a standard method for the preparation of lyophilized bacterial strains prepared by standard methods. The bacterial suspensions were mixed in ratios ensuring 10 x 10 ⁹ of both strains of Escherichia coli and 10 x 10 ⁹ Staphylococcus aureus to obtain a mass of 7.5 x 10 ⁹ / ml before lyophilization using a dextran stabilizer. The killing of the bacterial substance is carried out with a chemical agent. Dextrin is added to the bacterial substance and the resulting bacterial complex is stored in sealed polyethylene bags at a temperature of 2 to 8 ° C for no more than 36 months from the date of lyophilization. For tablet manufacturing, the bacterial complex of the envelopes is homogenized in a mixer.

Example 4. Method of Preparing the Tablet.

The process for preparing the tablet involves the phasing and sieving phases of the polybacterial complex to which the pre-screened excipients are sequentially added. The resulting mixture was homogenized and tableted by conventional methods.

Example 5. Product administration and storage.

The product is administered orally.

Usually, the polybacterial complex and the tablet are administered in the morning in the fasting state. The dose is calculated based on the amount of polybacterial complex. It is included in a small portion of the food or with a limited amount of drinking water. After dosing, the pause is paused for about 30 minutes, after which the animal is given the remaining food and water.

5.A / In pigs, pregnant pigs and sows

The mother-pig is given 30 mg of the polybacterial complex per kg / weight per day for 30 days prior to term.

Admission is discontinued 10 days after birth.

In another embodiment, administration is continued throughout the lactation period.

In another embodiment, the em is terminated on the 20th day after birth.

5.B / In newborn piglets

1. From 5 to 20 days of age

A newborn piglet 5 to 20 days postpartum is given 1 mg per kg / weight per day of fasting polybacterial complex in the morning.

1.1. Through drinking water

The daily dose is dissolved in a small amount of water and is given by mouth via a dispenser.

1.2. Through the spray method

The daily dose is dissolved in a small amount of pure water and the solution obtained is sprayed evenly in front of the starter mixture. 30 min is then given to the rest of the presenter and allowed to breastfeed.

2. Newborn piglets from 21 to 45 days of age

Newborn pigs 21 to 45 days after birth are given a 2 mg / kg polybacterial complex for each animal in the fasting morning.

2.1. Through the spray method

The daily dose is dissolved in a small amount of pure water and the pre-mixture is uniformly sprayed with the resulting solution. 30 min is then given to the rest of the presenter and allowed to breastfeed.

2.2. Through feed

The daily dose is mixed with about 70 g of the morning ration feed. After about 30 minutes, the remaining amount of feed is given and allowed to the mother during the mammal period.

2.3. Through drinking water

The piglets are left thirsty in the morning for 1-2 hours, after which the daily dose is dissolved in a small amount of water and the ready solution is given through suitable drinking vessels. After consuming the solution, the feed mixture is placed under free access to drinking water, with mammals being allowed to the mothers.

C / In newborns and adult dogs

The product is given at a dose of 1 mg / kg live weight, in the morning in the fasted state, with water or with the first swallow of food.

Example 6. Testing the preparation in scientific and economic trials.

The trial was conducted between February and August 2006 in two pig farms, with 12 sows in a group of experimental and control pigs and their offspring having an average of 10 piglets per mother.

The annexed table presents the data on the number of animals and the study options (Table 1).

Table 1. Scheme of scientific and economic experiments

EXPERIENCE GROUP CONTROL GROUP THE FARM Pregnant Pigs Lactating Pigs Breastfeeding pigs Weaned adolescents pigs Pregnant Pigs Lactating Pigs i_________________________________________________________________________________________ Breastfeeding pigs Weaned adolescents pigs + - number + number i + number + number + number + number I + number + number “AGROSLAVIAN Ltd. town of Stara Zagora + 6 - 6 + 30 + 30 - 6 - 6 P. 30 P. 30 - 30 - 30 - 30 - 30 Ivey Ltd., Sevlievo + 6 - 6 + 70 + 70 - 6 - 6 - 70 - 70

Note: "+" <=> with NATSTIM => without NATSTIM "P" & PLACEBOO

The sows of the two experiments were aligned in the order of the piglets. The mothers trial also included the last month of pregnancy. The litters were placed under the conditions of the respective ex- perimental variant with respect to the test preparation. Their cultivation generally corresponded to the accepted order in the farms. The duration of the pig trial included the mammalian period and after weaning up to 55 days of age. The animals were further monitored after the end of the experiment, ie. through growing up and fattening. The preparation was administered as described in Example 5.

Table 2 below provides averaged data on the main economic results of the survey.

Table 2. Averaged main results of the Agroslavaine study

Indicator Control group 1 Experienced group (p INSTITUTE) II Experimental group (without NASTIM) 1 Test group to control group,% II Test group to control group,% 1. Duration of the period, days ° Pigs mothers - pregnancy 32,2 32.3 - lactation 28.7 28.5 □ for the offspring 53,7 53,7 2. Number of pigs - average / sow - live births 12,83 12.33 96.1 - repulsed 12.17 11,99 11,68 98.5 96.0 - at the end of the experiment 12,0 11,99 11,48 99,9 95,7 - dropped out 4 + 1 1 ' 2 + 1 20,0 60.0 3. Feed consumption, kg / animal / over the period ° Pigs mothers - pregnant 91.47 93.55 102,3 - lacquering 172.75 177,2 102,6 ^with Piglet - pre-stern feed, total 4,536 th most common 4,126 th most common 90.96 -for the mammal 0.563 0.676 120,1 - after weaning 3,973 th most common 3,450 th most common 86,8 = Starting feed, total 7,534 th most common 7,113 th most common 94,4 L - Feed for the whole experience 12.07 11,239 th most common 93,1 ⁴ Live weight of pigs / cd - at birth 1,497 th most common 1,499 th most common 1,504 th most common 100.13 100.47 - at weaning 7,381 th most common 8,049 th most common 7,383 th most common 109.05 100.03 - at the end of the experiment 14.91 16,500 15,056 th most common 110,66 100,98 5. Increase in average daily, g - bosom period 212 235 212 110,85 100,0 - after weaning 290 325 295 112,0 101,7 - birth - end of experience 250 279 252 111,6 100,8 6. Feed utilization - during the end of I34 feed, 1.53 kg / kg gain 1,25 1.49 81,7 97,4

*) Fallen pigs are crushed by mothers

Experimental animals (sows), incl. controls received from the polybacterial complex 32 days during the last phase of pregnancy. The restriction period was 28.7 for the control and 28.5 days for the experimental group. The experimental period for the offspring is 53.7 days.

The tests showed the positive effect of the product on morbidity and mortality in newborn piglets receiving the polybacterial complex relative to the control group of 5 animals. These results are given in Table 3.

Table 3. Morbidity and mortality of the offspring of control and experimental sows (Agroslavin)

Indicator The bosom period Fri. iodine after weaning Control group Experimental group Control group Experimental group And with Naststim 2 without Naststim Total And with Naststim 2 without Naststim Total Pigs, number 77 36 * 38 * 74 * 73 35 * 36 * 71 * Colibacteriosis sufferers - number -% 6 7.8 - 1 2.6 1 1.35 - - 1 2.78 1 1.41 Duration of illness, Days 2 - 2 2 - - 2 2 Weight of the clinical picture ++ - + - - + + They died - number -% 4 5.19 1 2.78 2 5,26 3 4.05 1 1.37 - 1 2.78 1 1.41 Consumption of medicines, BGN in total for the group 1,20 - 0.20 0.20 29.50 ** - 0.20 0.20

Note:

*) The difference in the number of piglets between the suckling period and the growing up is the result of crushed by the mothers **) The observed lev value is the result of the medicated feed used

Example 7. Impact on immunological reactivity. Studies on the effect of the polybac-4θ territorial complex on the humoral systemic immune response in sows and newborn pigs.

The polybacterial complex was administered orally, according to the regimen and dosage, as in Example 45, for 30 consecutive days prior to the piglets and in the piglets 5 days after birth for 45 days. At 0.30 and 54 days from the start of maternal administration and at 0 and 45 days in piglets, specific (antibacterial) serum IgA, IgM and IgG antibodies determined by ELISA to the bacterial constituents of the preparation were monitored . The results showed a statistically significant increase in antibodies after 45 days of treatment with the infant pigs, compared to their baseline level - day 0 (autocontrol). This increase ranged from 21 to 60% in the animals tested, depending on the type of antibody (from the three immunoglobulin classes against the two bacterial antigens).

1141 Ul

0.400

0.350 < V) -! 0.300 w e p 0.250 0.200 © & S5 0.150 p Yu w 0.100 Fr. K. Fr. 0.050 0.000

□ S. aureus Ig G

Data analysis convincingly proved that the preparation most actively stimulates the production of specific IgM antibodies to both components.

In the clinical studies conducted, the polybacterial complex showed a clear activity in stimulating specific antibodies of IgG, IgM and IgA classes directed against the bacterial strains contained therein. This clearly indicates that this complex stimulates the systemic humoral immune response, which is most responsible for overcoming bacterial infections with different localization. This is demonstrated by the lower number of diseased or dead animals from gastrointestinal or pulmonary infections receiving the polybacterial complex compared to control animals.

Example 8. Pharmacological - immunological features.

The activity of the active polybacterial complex is based on highly immunostimulatory bacterial substances - lipopolysaccharides, teichoic acids, peptidoglycans, etc., obtained from common infectious diseases in mammals. The polybacterial complex stimulates nonspecific factors of the immune system - phagocytosis, complement, interferon, secretory IgA antibodies, T and B lymphocyte clones, as well as building a specific immune response to the bacterial species contained therein. Thus, this complex helps to more easily overcome the infections that occur in animals and reduces the mortality rate in newborns. It is also known that bacterial polysaccharide stimulates the center of appetite in the diencephalon of animals, which explains the improved absorption of feed and weight gain. Activates systemic and local immunity.

Example 9. Pharmacokinetics.

The oral polybacterial complex stimulates the intestinal lymphatic tissue, the so-called. Gut associated lymphoid tissue (Gut associated lymphoid tissue), and based on the integral function of the immune system, exerted by a wide range of cytokines, stimulation of the so-called Gut associated lymphoid tissue is achieved. bronchial associated lymphoid tissue, with the end result - stimulation of all mucus associated lymphoid tissue in the body. This allows this complex, as an immunostimulatory product taken by mouth, to enhance the protective immune mechanisms in both the lung system and the gastrointestinal tract.

Example 10. Pharmacodynamics.

The polybacterial complex, the object of the utility model and the tablet thereof, is intended for non-specific immunoprophylaxis and immunotherapy in mammals, for the prevention and treatment of acute and chronic infections, especially in the case of collienteritis, bronchopneumonia, neonatal diarrheal diarrhea . Its immunological activity is due to a complex of antigens: from gram (-) bacteria (E. coli): lipopolysaccharide (LPZ), endotoxins, lipoproteins and from gram (+) bacteria (S. aureus): muramyl peptide, lipoteichoic acids, peptidoglycans. This diverse antigenic complex enhances the body's natural resistance, activates various elements and mechanisms of the immune system - specific and non-specific, and determines the protective effect of the preparation against various infections. The preparation stimulates the functions of macrophages, granulocytes, complement, natural killer cells (NK) and dendritic cells, T and B lymphocytes, as well as the production of α- and interferons, cytokines (IL-1, IL-2, IL-6, TNF and etc.), lung surfactant, specific / homologous and cross-reacting / heterologous protective antibodies of the IgG, IgA, IgM classes. Oral administration of the complex and its tablet, and the contact of the active components with the nasopharyngeal (NALT) and gastrointestinal mucosa (GALT) induces mucosal immunity, both in the intestine and in distant efferent sites - the bronchi associated with lymphoid leukemia and ALT during lactation as part of the overall mucosal lymphoid tissue-associated (MALT). This results in the production of specific secretory immunoglobulins, mainly S-IgA, providing local protection in the mucous membranes.

Collagen antibodies, which are predominantly IgG, play a primary role in the protection of newborns to various infections during the first few days (passive immunity).

Example 11. Therapeutic indications for individual animal species.

The apolybacterial complex, the object of the utility model and the tablet thereof, have been shown to be a means of preventing and treating acute and chronic infections in mammals, especially in the case of gastrointestinal infections and bronchopneumonia. They also contribute to a more complete absorption of feed and an increase in animal growth.

No side effects were observed.

No contraindications are known except for autoimmune diseases.

No incompatibility with other medicines has been observed. May be combined with any other treatment, incl. and antibiotic therapy. Allows multiple applications without the risk of getting used to. Depending on the condition of the animal, the administration of the tablets may be repeated 2-3 times a year.

Example 12. Toxicity Study.

A / For acute toxicity.

1. White mice

For this purpose, 30 white mice of an ICR strain weighing 18-20 g were used, 10 of which were controls. 20 of the mice were orally probe-fed for 5 days with 50 mg each of the biologically active complex in a volume of 0.5 ml saline. This dose is equivalent to about 5000 human doses. The control group was fed in the same way only with saline. All mice were monitored daily for their general condition, nutrition, and weight, and blood was taken to determine their major hematologic parameters (erythrocytes, leukocytes, hemoglobin, and differential counting).

On the second day after the last feeding, the animals were sectioned under a weak ether anesthesia and were subjected to a macroscopic examination. Material for histological and electron microscopic examination was taken from the main parenchymal organs (lung, liver, spleen and brain).

No changes were observed in the overall condition of the feed-fed animals compared to the control group. Haematological indices in both groups were within the normal range. Histological and electron microscopic examination revealed no abnormal changes in the organs examined.

2. The rabbits

15 chinchilla rabbits weighing 1500 - 1600 g were used. Ten of them were fed for 5 days with a 2 g probe of the biologically active complex in a volume of 2 ml of saline. This dose is equivalent to about 2000 human doses. The control group of 5 rabbits were fed in the same way only with saline. All rabbits were monitored daily for their general condition, diet, and weight, and blood was collected to determine their major hematologic parameters (erythrocytes, leukocytes, hemoglobin, and differential counting).

On the second day after the last feeding, the animals were excised after treatment with 300 mg of hexobarbital sodium and were subjected to a macroscopic examination. Material for histological and electron microscopic examination was taken from the main parenchymal organs (lung, liver, spleen and brain).

No changes were observed in the general condition of the feed-fed animals (weight and behavior) compared to the control group. Haematological indices in both groups were within the normal range. Histological and electron microscopic examination revealed no abnormal changes in the organs examined.

B / Repeated toxicity.

1. The rats

For this purpose, 30 Wistar rats weighing 180-200 g were used. For 4 months, 20 rats were orally fed a 0.5 g probe of the biologically active complex in a volume of 1 ml of saline. This dose is equivalent to about 5000 human doses. The control group of 10 rats was fed in the same way only with saline. All rats were monitored daily for their general condition, diet, weight, morbidity, and mortality. Hematological parameters were examined for each group for 4 months each month.

days after the end of the chronic experiment, the animals were sectioned under weak ether anesthesia and were subjected to macroscopic examination and material for histological and electron microscopic examination from the main parenchymal organs (lung, liver, spleen and brain).

No changes were observed in the general condition of the feed-fed animals (weight, diet, morbidity, and mortality) compared to the control group. Haematological indices in both groups were within the normal range. Histological and electron microscopic examination revealed no abnormal changes in the organs examined.

B / Ecotoxicity.

The product does not contain any living pathogens and does not pose an environmental hazard.

The production of the polybacterial complex and its tablet is accomplished on a closed cycle that complies with GMP requirements. Technology cycles are fully compliant with environmental requirements and do not pose a risk of contamination of soil, air and water. There is also no risk of direct contact of the active substance or the finished product with the environment.

Claims

Claims (4)

1. Polybacterial complex for immunoprophylaxis and immunotherapy in mammals, characterized in that it contains a polybacterial substance of killed bacterial bodies and lysates of two strains Escherichia coli - Escherichia coli 29 expressing colic E and coli Rc mutant, and one strain of Staphylococcus aureus (Staphylococcus aureus) - for the three strains independently of the depositary number, as well as a dextrin 40 stabilizer included in the polybacterial substance in the following weights. %: polybacterial substance 30 to 50 and dextran 40 50 to 70. A dosage form comprising a polybacterial complex according to claim 1, characterized in that it is a tablet and contains in addition to the polybacterial complex also auxiliaries for forming 1141H of the tablet - macrogol 6000 (PEG), crospovidone (colidone) and silicified microcrystalline cellulose (SMCC) in the following wt. %: polybacterial complex from 3 5 to 41, macrogol 6000 (PEG) from 2,88 to 3,12, crospovidone (colidone) from 10,66 to 11,34, silicified microcrystalline cellulose (SMCC) from 45,46 to 50, 54. Polybacterial complex according to claim 1, characterized in that each of the two Escherichia coli strains as a part of the polybacterial substance is in the range of 20 to 45% and the Staphylococcus aureus strain is 20 to 60%. Polybacterial complex according to 5 Claims 1 and 3, characterized in that the polybacterial substance contained therein is in an amount of 10 x 10 ⁹ bacterial bodies in mg of active substance from each of the three strains and a mass of 7.5 x 10 ⁹ / ml before lyophilization using the stabilizer. Publication of the Patent Office of the Republic of Bulgaria 1797 Sofia, 52-B Dr. GM Dimitrov Blvd.