RU2325166C1 - Pharmaceutical formulation of antibiotics and lactulose applied for prevention of enteral disbiosis caused by antibiotic therapy - Google Patents

Abstract

FIELD: medicine; chemical-pharmaceutical industry.

SUBSTANCE: pharmaceutical formulation contains antibiotic or sulphanilamide and lactulose, and antibiotic particles included are from 20 to 160 mcm, sulphanilamide particles are from 40 to 150 mcm, and lactulose particles are up to 0.3 mm and of purity not less than 97%, antibiotic-lactulose proportion is from 1:0.1 to 1:100, and sulphanilamide-lactulose proportion is 1:12; pharmaceutical formulation is injected 2-3 times a day.

EFFECT: provides accelerated epithelisation of defects of mucous coat of stomach, duodenum or uterine neck; stimulates lactobacilli and bifidus bacteria action.

9 cl, 9 ex

Description

The invention relates to medicine, namely to pharmaceuticals and the creation of drugs containing compositions of antibiotics and prebiotics, for correcting the composition of microflora during antibiotic therapy.

The use of broad-spectrum antibiotics for the treatment of infectious and other diseases, as a rule, is accompanied by side effects from the gastrointestinal tract, which are mainly associated with the negative effect of antimicrobials on the intestinal microflora and other cavities.

As a result of oral administration, antibiotics suppress not only pathogenic, but also indigenous microflora of the digestive tract, lead to disturbances in homeostasis and contribute to the development of dysbiosis and allergies.

Imbalance in the intestinal microbiocenosis in some cases leads to disturbances in the immune system, as well as the active reproduction of unicellular fungi that colonize the mucous membrane of the large intestine.

It is known that maintaining normal intestinal microflora in an active state is a necessary condition not only for the digestion and assimilation of nutrients, but also a barrier to the colonization of intestines by pathogenic microorganisms. The intestinal microbiota is also involved in the metabolic detoxification of a number of toxic products, takes part in the absorption of minerals and the biosynthesis of certain vitamins, and limits the reproduction of pathogenic and conditionally pathogenic types of microorganisms parasitizing in the intestine.

The most favorable conditions for the life of microflora arise already in the distal parts of the small intestine, where gastric secrets and pancreatic proteases do not fall, as well as bile components, the bacteriostatic and bactericidal effects of which weaken as they approach the large intestine.

Against the background of dysbiosis, pathogenic pathogens of intestinal infections or opportunistic microorganisms that enter the body quickly colonize the mucous membrane of the small and large intestines, destroying epithelial cells and exhibiting pronounced antagonism towards indigenous microflora. Inflammation develops, which leads to a decrease in the production of short-chain fatty acids that inhibit the growth of pathogenic microorganisms. This occurs in the process of antibiotic therapy with broad-spectrum drugs that are taken orally.

Numerous studies have found that even a partial loss of their own intestinal microflora leads to serious consequences for the body and requires independent treatment.

The restoration of intestinal microflora is often carried out by prescribing a variety of probiotics, which are not always compatible with representatives of individual normoflora and can be eliminated from the intestine within a few days.

As for the development of undesirable effects when using these drugs, they relate to the ability of probiotics to modulate immune inflammation. For example, it is known that 10% of workers in factories producing bacterial (probiotics) and immunobiological preparations after several years of contact with bacteria develop allergic dermatitis.

A more physiological way of maintaining an active state of normal intestinal microflora is to take prebiotics. Prebiotics include indigestible food ingredients that contribute to better health by selectively stimulating the growth and / or metabolic activity of one or more dominant bacteria in the large intestine.

Prebiotics are not absorbed in the stomach, in transit reach the large intestine, in the human body, due to the lack of beta-glycosidases, they are not absorbed, but are used by the microflora of the large intestine as nutrient substrates. Prebiotics are able to selectively stimulate the growth and reproduction of lactobacilli and bifidobacteria i.e. species dominant in the composition of the normoflora of the human intestine.

Currently, an increasing number of dietary supplements and functional food products are appearing on the pharmaceutical market, containing saccharides and oligosaccharides, in particular lactulose, as effective prebiotics, which reflects the potential of this direction for correcting disorders of intestinal microbiocenosis in humans.

Lactulose is able to perform this function due to the fact that it is practically not split by enzymes of the upper gastrointestinal tract and reaches unchanged in the large intestine. There, it undergoes a fermentation process with bifidobacteria and serves as a growth factor for them. Fermentation occurs due to anaerobic processes. Lactulose is hydrolyzed by bacterial enzymes to form organic acids, mainly lactic, acetic, butyric and propionic. As a result, the contents of the intestine are acidified and the osmotic pressure in the colon increases.

The purpose of complex therapy with the inclusion of lactulose is aimed at eliminating dysbiosis, atrophic processes in the mucous membrane of the colon, and dystrophic changes in the epithelial cover with the restoration of its functional ability.

However, the time-divided administration of antibiotics and lactulose in at least half the cases cannot exclude damage to the intestinal microflora by antibiotics. Most often, they resort to prebiotics after identifying the symptoms of dysbiosis in the form of diarrhea and flatulence. As a result, by the time lactulose is taken after antibiotic therapy, the beneficial microflora is substantially undermined or practically non-viable.

In this regard, it is important to ensure the selective advantages of beneficial microflora over pathogenic or conditionally pathogenic types of bacteria during antibiotic treatment. Therefore, attempts are being made to protect the indigenous intestinal microflora due to the simultaneous administration of an antibiotic and lactulose in the form of a single pharmaceutical composition.

A known pharmaceutical composition, a method for its preparation and a method of use comprising a medicine and saccharides (lactulose). The active ingredient and saccharides are prepared in a special dosage form coated with a polymeric material soluble in organic acids. In this composition, saccharides are fermented by enterobacteria with the formation of organic acids that activate the drug.

The composition is characterized by high specificity of drug delivery to the distal colon (RU 2155605 from 09/10/2000).

The disadvantages of this composition are the narrow range of applications, a limited range of drugs effective only in the large intestine, the absence of antibiotic activity and, therefore, the inability to use in the treatment of diseases caused or complicated by infectious agents, low specificity of the stimulating effect on the main types of indigenous microflora, non-optimal mass the ratio (imbalance) of the drug and lactulose, the non-optimal dispersion of saccharides, which decreases I have the level of fermentation and the therapeutic effect of taking the composition, as well as insufficient absorption of calcium and bone mineralization, the presence of side effects on the blood coagulation system (mainly, prolongation of partial prothrombin time and a decrease in fibrinogen level), a significant frequency of allergic reactions, the complexity of the preparation process and application.

A known pharmaceutical composition, method of its preparation and method of use, containing a prebiotic lactulose and an antibiotic from the group of penicillins, cephalosporins, tetracyclines, lincosamides, macrolides (RU 2284832 from 10.10.2006, prototype).

The disadvantages of this composition are the narrow range of applications, the preparation of compositions with an unsatisfactory composition in terms of antibiotic and not optimal (in the indefinitely wide range specified in this publication) mass ratio of antibiotic and lactulose (i.e., their imbalance), which reduces the antibacterial effect of the product and increases the frequency of allergic reactions, the complexity of the preparation and use.

Negative is the uncertainty of the degree of purity, i.e. the presence in lactulose of most domestic producers of impurities (up to 40%) of lactose, fructose and galactose, stimulating the growth of pathogenic and conditionally pathogenic bacteria of the intestinal group.

In addition, the excessive laxative effect of the composition due to the unbalanced content of lactulose with these antibiotics reduces the transit time of the intestinal contents and, accordingly, reduces the absorption and absorption of nutrients, and therefore, some external signs of dysbiosis, such as diarrhea, may appear.

The lack of effectiveness of the composition is also due to the composition of antibiotics recommended in the composition, since they (penicillins and cephalosporins) are more often used in injectable form, while acting systemically and do not cause significant damage to the intestinal microflora.

At the same time, these antibiotics (tetracyclines and penicillins) have been known for over fifty years and have already largely lost their clinical significance due to the widespread bacterial resistance to penicillins (production of the beta-lactamase enzyme) and tetracyclines (R plasmids with the Tc gene ), however, more often cause allergic reactions.

The technical task of the group of inventions related by a single inventive concept is to create an effective pharmaceutical composition and method for preventing enteric dysbiosis while expanding the arsenal of pharmaceutical compositions and methods for preventing literal dysbiosis.

The technical result that provides the solution of the problem lies in the fact that the range of application of the composition of lactulose and antibiotic is significantly expanded due to the inclusion in the composition of the composition as an antibiotic more effective antibacterial drugs intended for oral administration, for example fluoroquinolones and ansamycins, and elimination of side effects .

At the same time, efficient utilization of the prebiotic component of the composition in the intestine is ensured due to the high degree of homogeneity (purification) of lactulose, which excludes the growth of pathogenic and conditionally pathogenic bacteria, as well as the use of the optimal ratio of antibiotic and lactulose with optimal dispersion of the particles of the composition.

The use of this composition not only creates the conditions for the conservation and growth of indigenous microflora during antibiotic therapy, but also effectively improves the blood composition, the state of the cardiovascular system, creates selective advantages for the growth of beneficial microorganisms and inhibition of the growth of opportunistic and pathogenic bacteria in the intestine .

The essence of the invention, in terms of the pharmaceutical composition for oral administration, is that the pharmaceutical composition contains an antibiotic and lactulose, while it contains an antibiotic selected from the group of beta-lactams with inhibitors of bacterial beta-lactamases, fluoroquinolones, azalides, amphenicols, glycopeptides , ansamycins, nitrofurans, derivatives of phosphonic acid, cycloserine, trimethaprim and sulfonamide preparations, and lactulose is contained in the form of a powder with a particle size of up to 0.3 mm.

The claimed composition contains dry lactulose with a purity of at least 97%, with a mass ratio of antibiotic and lactulose in the composition from 1: 0.1 to 1: 100, respectively, as well as pharmaceutically acceptable amounts of excipients that improve organoleptic properties, from the group of excipients , flavor correctors, flavors, fragrances.

The claimed pharmaceutical composition can be made in a dosage form suitable for oral and topical use, selected from the group: capsules, tablets, powders, pills, dragees, granules, suppositories, sachets, gels, pastes, syrups, emulsions, suspensions, solutions.

A method for the prevention of enteric dysbiosis is that, to preserve microbiocenosis during antibiotic therapy, antibiotics when taken orally or topically are used as part of a fixed pharmaceutical composition with lactulose, with a mass ratio of antibiotic and prebiotic from 1: 0.1 to 1: 100, respectively.

The claimed composition uses dry lactulose in the form of a powder with a degree of purity of not less than 97%, as well as pharmaceutically acceptable amounts of excipients that improve organoleptic properties, from the group of excipients, taste correctors, flavors, fragrances.

This takes into account that the human body is a multi-organ system, the elements of which are specialized to perform various functions. Interaction within the body is carried out by complex neurohumoral regulation and correlating mechanisms involving, in particular, metabolic factors.

Many separate mechanisms that regulate intracellular and intercellular interactions have opposite effects, balancing each other. This maintains the constancy of the internal environment in the body and allows the system as a whole to maintain relative dynamic equilibrium, responding to changes in the environment and shifts that arise in the process of life. Violation of the physiological balance, including those associated with imbalance in microecology, can manifest itself in the form of diseases of various organs.

The inventive composition is aimed at eliminating or effectively reducing possible deviations from the physiological balance in the state of intestinal microflora under the influence of destructive factors in the form of antibiotics.

The saccharolytic intestinal microflora (lactobacilli and bifidobacteria) ferment lactulose with glycosidases, which leads to an increase in enzyme production and an increase in the level of saccharolytic activity, while lactulose has a dose-dependent bifidogenic effect.

Since the prebiotic - lactulose enters the claimed composition simultaneously with the antibiotic in a certain mass ratio, when the antibiotic suppresses pathogenic microorganisms, the colon microflora does not die, and simultaneously with the intake of lactulose hydrolyzes (ferments) it with the formation of an effective amount of organic acids: lactic, butyric , acetic and propionic, which acidify the contents of the large intestine.

At the same time, the osmotic pressure in the colon rises to 6.6-8.0 atm and the acidity value decreases below pH 5.0, which leads to reliable maintenance of normal selective permeability of the biological membranes of the intestinal mucosa, retention of ammonium ions, and removal of ammonia from the blood the intestine and, thus, creates completely unfavorable conditions for the development of pathogenic bacteria, for example, salmonella, in the lumen of the large intestine.

The resulting acidic products and other metabolites inhibit the development of proteolytic microflora. As a result, the number of pathogenic bacteria and toxic metabolites in the intestinal lumen decreases, in particular: ammonia, skatol, and indole.

Against the background of the effective maintenance of homeostasis, sufficient reproduction and stimulation of the growth of the preserved natural beneficial intestinal microflora are unhindered. When the acidity of the medium increases, the acid reacts with the amino groups of the protein and, by capturing OH ions, contributes to the emergence of an electropositive protein that suppresses inflammatory processes that could occur in the intestine due to external causes or as a complication of the underlying disease.

The process of preparing the claimed composition involves the preparation of predetermined amounts of powdered antibiotic and lactulose (with a purity of at least 97% guaranteed by the supplier), drying to 2-3% moisture and mixing in the ratio provided by the present invention. Then additives are added to the mixture: anti-caking, flavorings, flavoring corrections, and static electric charges are removed.

Next, packaging is carried out in accordance with the dosage and dosage form.

Compositions were prepared with the following combinations of ingredients:

1. Lactulose with one of the amphenicol, the oligosaccharide (hereinafter - lactulose) in the form of a powder with a particle size of 0.1-0.3 mm, and the antibiotic in the form of a powder with a particle size of 50-150 microns, while the antibiotic and lactulose taken in a mass ratio of 1: 0.2;

2. Lactulose with one of the fluoroquinolones, the oligosaccharide in the form of a powder with a particle size of 0.1-0.3 mm, and the antibiotic in the form of a powder with a particle size of 20-90 microns, while the antibiotic and lactulose are taken in a mass ratio of 1: 3;

3. Lactulose with one of the glycopeptides, the oligosaccharide in the form of a powder with a particle size of 0.1-0.3 mm, and the antibiotic in the form of a powder with a particle size of 30-100 microns, while the antibiotic and lactulose are taken in a mass ratio of 1: 40;

4. Lactulose with one of the ansamycins, the oligosaccharide in the form of a powder with a particle size of 0.1-0.3 mm, and the antibiotic in the form of a powder with a particle size of 20-110 microns, while the antibiotic and lactulose are taken in a mass ratio of 1: 60;

5. Lactulose with one of the derivatives of phosphonic acid (phosphomycin), the oligosaccharide in the form of a powder with a particle size of 0.1-0.3 mm, and the antibiotic in the form of a powder with a particle size of 20-90 microns, while the antibiotic and lactulose are taken in a mass ratio of 1:95;

6. Lactulose with one of nitrofurans, and lactulose in the form of a powder with a particle size of 0.1-0.3 mm, and the antibiotic in the form of a powder with a particle size of 60-160 μm, while the antibiotic and lactulose are taken in a mass ratio of 1: 5.5;

7. Lactulose with one of the sulfanilamide preparations (sulfadimesin), moreover, lactulose in the form of a powder with a particle size of 0.2-0.3 mm, and the sulfonamide preparation in the form of a powder with a particle size of 40-150 microns, while sulfonamide and lactulose are taken in a mass ratio of 1:12.

The composition is made in dosage forms suitable for oral administration, in particular in the form of: capsules, tablets, powders, pills, dragees, granules, sachets, gel, paste, syrup, emulsion, suspension, solution.

The composition of the compositions includes pharmaceutically acceptable amounts of excipients that improve organoleptic properties, in particular: fillers, flavor correctors, flavors, fragrances.

Examples of the implementation of the claimed designation

Example 1

Gelatin Capsules (contents):

Moxifloxacin - 400.0 mg Lactulose - 800.0 mg.

Example 2

Tablets (weight 650 mg):

Azithromycin - 250.0 mg Lactulose - 300.0 mg Excipients: Microcrystalline cellulose - 50.0 mg Crospovidone - 20.0 mg Croscarmellose sodium - 20.0 mg Talc - 5.0 mg Magnesium stearate - 5.0 mg.

Example 3

Powder (for preparing a suspension of 5.0 ml):

Amoxicillin - 125.0 mg Clavulanic acid - 31.25 mg Lactulose - 200.0 mg.

The powder is dissolved in 5.0 ml of boiled water cooled to room temperature immediately before use.

Example 4

Syrup:

Nifuroxazide - 200.0 mg Lactulose - 300.0 mg Excipients: Sucrose - 30.0 mg Citric Acid Monohydrate - 1000.0 mg Glycine (flavor enhancer) - 14.5 mg Quinoline yellow (dye) - 5.0 mg Sodium tetraborate (preservative) - 5.0 mg Orange 526 (flavoring) - 4.56 mg Distilled water - 100.0 ml.

Example 5

Gel:

Moxifloxacin - 400.0 mg Lactulose - 800.0 mg The basis: Polyvinylpyrrolidone - 12000.0 mg.

Example 6

Granules (in bags):

Nifuratel - 500.0 mg Lactulose - 400.0 mg.

Example 7. Pasta:

Amoxicillin - 125.0 mg Clavulanic acid - 31.25 mg Lactulose - 200.0 mg The basis: Vaseline oil - 712.5 mg.

Example 8

Ointment:

Azithromycin - 500.0 mg Lactulose - 600.0 mg The basis: Vaseline oil - 11000.0 mg.

Example 9

To study the therapeutic effect of the resulting compositions and confirm their suitability as therapeutic and therapeutic agents, studies were conducted of their effect on the condition of patients with various infectious diseases. The effect of the drugs on the general condition of patients, physical activity, the state of the cardiovascular system, neurological status, and the gastrointestinal tract were evaluated.

In the experimental group under observation were 87 patients aged 18 to 65 years; of them: men - 32, women - 52.

The diagnosis was established during an outpatient examination on the basis of a general medical examination, as well as, in particular, colposcopy, data from an additional examination, including, in particular: laboratory, biochemical, cytological studies, data from instrumental research methods (ECG, echocardiography, fluoroscopy, esophagogastroduodenoscopy (EGDS) )

All patients were divided by nosology into three groups: I (28 people) - with diseases of the gastrointestinal tract: gastritis, duodenitis, gastric ulcer; II (34 people) - with diseases of the upper and lower respiratory tract: acute respiratory infections, tonsillitis, bronchitis, exacerbation of chronic pneumonia; III (25 people) - with diseases of the reproductive system: cervical erosion, vaginal dysbiosis.

Almost all patients (as follows from the anamnesis) for a long time had symptoms of disorders of the gastrointestinal tract: colitis, enterocolitis, dysbiosis, irritable bowel syndrome (IBS), due to the use (in the previous treatment) of antibiotics from the group: penicillins, cephalosporins , tetracyclines, lincosamides, macrolides, which practically did not have the expected effect and, as a rule, caused various allergic reactions.

Before the start of taking the claimed composition, all patients were examined for blood: general analysis, biochemical parameters: ACT, ALT, creatinine, glucose, calcium, total bilirubin, protein, serum iron, OZHSS, sodium, potassium, cholesterol, uric acid, urea, albumin, alkaline phosphotase, GGT, triglycerides, p-lipoproteins; urine: general analysis; intestinal contents: microbiological analysis of intestinal contents and coprogram; For patients with diseases of the gastrointestinal tract, additional EGD was performed, and for women, before and after treatment, they performed diagnostic procedures: colposcopy followed by a biopsy of the cervical mucosa for cytological examination and took a smear from the cervical canal and vagina for microbiological examination of the contents .

In each nosological group were identified: one experimental and two control groups.

So, patients of group I were divided as follows:

The 1st group of patients (experimental) - 10 people, took a pharmaceutical composition in the form of granules, including nifuratel and lactulose, 2-3 times a day after meals, for 7-10 days.

The 2nd group of patients (control) - 9 people, took nifuratel at a dose of 500.0 mg and lactulose at a dose of 400.0 mg separately for 7-10 days.

3rd group (control) - took nifuratel at a dose of 500.0 mg and placebo at a dose of 400.0 mg (instead of lactulose) for 7-10 days.

Control studies were carried out for 2 months every 10-14 days.

Summary: an improvement in the general condition was recorded in most patients of the experimental group (9 people) after 5-6 days of taking the claimed composition. Patients with gastric and duodenal ulcer (duodenal ulcer) noted the disappearance of pain in the stomach, duodenum and intestines, and in the analysis of intestinal contents there was an increase in the content of lactobacilli and bifidobacteria; 14 days after the start of treatment (during the control endoscopy), they noted a significant decrease in hyperemia and edema of the gastric mucosa and duodenum and the appearance of the first signs of ulcerative epithelization.

6-9 days after the start of treatment, the condition of the patients in the control groups also improved, however, in the first group (in 5 patients) and in the second group (in 7 patients), the symptoms of the effect of antibiotics on the intestinal microflora clearly appeared: discomfort in the abdomen , mild pain along the colon, flatulence and diarrhea (intestinal dysbiosis).

In 2 patients of these groups, intestinal dysbiosis led to a decrease in appetite and sleep disturbance.

Patients of group II (with diseases of the upper and lower respiratory tract) were also divided into three groups:

The 1st group of patients (experimental) - 12 people, took the claimed composition in tablet form, azithromycin with lactulose, 1 time per day, during or after meals for 8-10 days; the total dose of azithromycin corresponded to the amount determined by the instructions for the use of azithromycip in standard treatment regimens for specific diseases of the upper and lower respiratory tract and, as a rule, did not exceed 1.5 grams;

The 2nd group of patients (control) - 11 people took azithromycin at a dose of 500.0 mg and lactulose at a dose of 600 mg separately, 1 time per day with an interval of 2-2.5 hours;

The 3rd group of patients (control) - 11 people took azithromycin at a dose of 500.0 mg and placebo at a dose of 600.0 mg (instead of lactulose) 1 time per day with an interval of 2-2, 5 hours, for 8- 10 days.

In each group, patients were comparable in age, duration and severity of the disease, as well as in concomitant pathology.

Control studies were performed for 2 months every 8-10 days.

Summary: general condition improvement was registered in 9 patients of the experimental group after 5-8 days of taking the composition. During lung fluoroscopy, a decrease in peribronchial and intrabronchial inflammation, an increase in the transparency of the lungs, an increase in the mobility of the diaphragm, and an improvement in the drainage function of the bronchi were noted.

In patients of both control groups in the first days of taking the composition, the condition was assessed as unsatisfactory: there was an increase in body temperature, weakness, depression, flatulence, constipation or diarrhea. 6–9 days after the start of treatment, the condition of the patients in the control group also improved, however, in the first group, in 4 in the second group, in 6 patients, the symptoms of the negative effect of antibiotics on the intestinal microflora manifested themselves in the form of discomfort in the abdomen, weak pain along the large intestine, flatulence and diarrhea.

Group III patients were also conditionally divided into 3 groups:

The 1st group of patients (experimental) - 9 people, took the claimed pharmaceutical composition in the form of capsules containing moxifloxacin with lactulose, 2 times a day, during or after meals for 7-10 days.

The 2nd group of patients (control) - 8 people, took moxifloxacin at a dose of 400.0 mg and lactulose at a dose of 800.0 mg separately, twice, with an interval of 2-2.5 hours, for 7-10 days.

The 3rd group of patients (control) - 8 people, took moxifloxacin at a dose of 400.0 mg and placebo at a dose of 800.0 (instead of lactulose) twice, after eating for 7-10 days.

Summary: general condition improvement was registered in 9 patients of the experimental group after 5-8 days of taking the composition. During colposcopy, 21 days after the start of treatment, the appearance of the first signs of regional epithelialization of erosion and the appearance of lactobacilli and bifidobacteria in the vaginal microbiocenoses were noted; discharge significantly decreased and pain completely disappeared. The data of a cytological study after taking the drug indicated almost complete replacement of the cylindrical epithelium with squamous epithelium, and smears indicated a decrease in inflammation.

In patients of all control groups in the first days of taking the composition, the condition was assessed as unsatisfactory: there was an increase in body temperature, weakness, depression, flatulence, constipation or diarrhea. 6–9 days after the start of treatment, the condition of the patients in the control groups improved, however, in the first group, in 5 and in the second group, in 6 patients, the symptoms of the negative effect of antibiotics on the intestinal microflora clearly appeared: in the form of discomfort in the abdomen, weak pain along the large intestine flatulence and diarrhea.

In almost all patients of the experimental groups (taking into account the division according to nosology), the functional state of the gastrointestinal tract returned to normal, the number of muscle fibers, fat, fatty acids, undigested fiber in the coprogram was within normal limits. The analysis of the dynamics of a number of biochemical parameters showed that there is a significant decrease in bilirubin, β-lipoproteins, triglycerides, ALT, ACT. Structural and functional changes in plasma proteins demonstrate an increase in the binding ability of albumin, an increase in the activity of antibodies and proteins of the complement system. The results of biochemical studies and the cellular composition of peripheral blood also indicate a positive process dynamics.

At the same time, the amount of synthesized urea increased, which indicates an improvement in the processes of transamination and transamination of amino acids in the liver, i.e. about the normalization of metabolic detoxification processes in the liver.

Almost all patients of the experimental groups noted an improvement in the quality of life by increasing physical activity, improving mood and sleep, normalizing appetite and bowel function. The negative side effects of taking the compositions with antibiotics did not appear in any way during the treatment, or during subsequent observation.

In the control groups in patients who received the antibiotic and lactulose separately, the indices of the intestinal homeostasis approached the indices of the experimental group in only 53% of cases.

In the control groups, in patients receiving a placebo antibiotic, regardless of the decrease in the severity of the symptoms of the underlying disease under the influence of the antibiotic, the indicators of intraintestinal homeostasis in 87% of cases did not have a clear improvement trend.

Monitoring of the condition of most patients of the experimental groups receiving the claimed drug (taking into account the severity of the underlying disease) continued for the next 18 months, and confirmed a decrease in the incidence of acute respiratory viral diseases, increased efficiency, normalization of sleep, a decrease in the recurrence rate of the underlying disease and a stable improvement in quality life, in particular the evacuation activity of the intestine.

When compared with the average age-related incidence rates in patients of the experimental groups, a decrease in the incidence of oncological diseases, cardiovascular diseases, diseases of the musculoskeletal system, as well as a reduction in recovery time for minor injuries of ligaments, bones and joints, was also established.

Based on the foregoing, it can be reasonably concluded that the claimed composition is an effective and safe treatment for diseases caused by infectious agents, while the composition has a stimulating effect on lactobacilli and bifidobacteria, inhibiting, at the same time, the growth and reproduction of extraneous microflora, providing , thus, a pronounced preventive effect.

Thus, an effective pharmaceutical composition was created and a method for the prevention of enteric dysbiosis was developed.

At the same time, the range of application of the composition, including the antibiotic and lactulose, has been significantly expanded, due to the inclusion of more effective antibacterial drugs for oral administration (for example, fluoroquinolones, ansamycins) and the side effects of antibiotic therapy have been eliminated.

At the same time, the efficient utilization of the prebiotic component of the composition in the intestine is ensured by using the optimal ratio of antibiotic and lactulose with the optimal particle size dispersion of the composition.

In addition, the pharmaceutical composition has a stimulating effect on the immune system, helps to reduce inflammation, activates the mineral metabolism and synthesis of vitamins, and also normalizes intestinal activity, i.e. provides a preventive effect.

Claims (9)

1. A pharmaceutical composition for the prevention of enteric dysbiosis during antibiotic therapy, characterized in that it includes an antibiotic and lactulose, the antibiotic being included with a particle size of from 20 to 160 microns, and lactulose with a particle size of up to 0.3 mm and a purity of at least 97% while the ratio of antibiotic and lactulose is from 1: 0.1 to 1: 100, the pharmaceutical composition is administered orally 2-3 times a day. 2. The pharmaceutical composition according to claim 1, characterized in that it includes an antibiotic selected from the group: beta-lactams with bacterial beta-lactamase inhibitors, fluoroquinolones, azalides, amphenicols, glycopeptides, ansamycins, nitrofurans, phosphonic acid derivatives. 3. A pharmaceutical composition for the prevention of enteric dysbiosis during antibiotic therapy, characterized in that it includes a sulfanilamide preparation and lactulose, wherein the sulfanilamide preparation is included with a particle size of from 40 to 150 microns, and lactulose with particle sizes up to 0.3 mm and a purity of at least 97%, while the ratio of sulfanilamide preparation and lactulose is 1:12, the pharmaceutical composition is administered orally 2-3 times a day. 4. The pharmaceutical composition according to claim 3, characterized in that it includes sulfadimezin as a sulfonamide preparation. 5. The pharmaceutical composition according to claim 1 or 3, characterized in that it further includes excipients selected from the group: excipients, flavor correctors, flavors and perfumes, taken in a pharmaceutically acceptable amount. 6. The pharmaceutical composition according to claim 1 or 3, characterized in that it is made in a dosage form suitable for oral administration, selected from the group: capsules, tablets, powders, pills, dragees, granules, sachets, gels, pastes, syrups, emulsions , suspensions and solutions. 7. The method of obtaining the pharmaceutical composition according to claim 1 by mixing an antibiotic and lactulose taken in the form of a powder, the antibiotic powder having a particle size of from 20 to 160 microns, and lactulose up to 0.3 mm and a purity of at least 97% with an antibiotic ratio and lactuloses from 1: 0.1 to 1: 100. 8. The method for producing the pharmaceutical composition according to claim 3 by mixing the sulfanilamide preparation and lactulose taken in the form of a powder, the powder of the sulfanilamide preparation has a particle size of from 40 to 150 microns, and lactulose up to 0.3 mm and a purity of at least 97% at the ratio of sulfonamide drug and lactulose is 1:12. 9. The method of obtaining the pharmaceutical composition according to claim 7 or 8, further comprising mixing with excipients selected from the group: fillers, flavor correctors, flavorings and perfumes.