WO2024076257A2

WO2024076257A2 - Composition for treatment of diarrhea of bacterial, viral and bacterial and functional origins

Info

Publication number: WO2024076257A2
Application number: PCT/RU2023/000289
Authority: WO
Inventors: Alexander Vladimirovich DIKOVSKIY; Artemiy Alexandrovich SERGEEV; Vera Gennadevna SHCHANKINA
Original assignee: Dikovskiy Alexander Vladimirovich
Priority date: 2022-10-03
Filing date: 2023-10-02
Publication date: 2024-04-11
Also published as: WO2024076257A3

Abstract

The invention relates to the field of medicine and, in particular, to a composition suitable for the treatment of patients with bacterial and viral and bacterial diarrhea, including unidentified and/or unspecified intestinal infections, containing an intestinal antiseptic in combination with an enterosorbent in effective amounts, where the antiseptic is selected from the group representing nifuroxazide, nifuratel, rifaximin, and the sorbent is selected from the group representing hydrolyzed lignin, activated carbon, silicon dioxide, dismectite. This invention also relates to the field of medicine and, in particular, to a composition used to treat functional diarrhea in diarrhea-predominant irritable bowel syndrome, including concomitant bacterial overgrowth syndrome, containing an intestinal antiseptic in combination with an enterosorbent in effective amounts that provide a therapeutically effective daily dose of the composition. The technical result is the achievement of an unexpected synergistic effect by implementing a mechanism of the simultaneous antibacterial effect of an intestinal antiseptic on pathogenic or opportunistic microorganisms and the sorption and cleansing effects of the enterosorbent on pathogenic or opportunistic microorganisms, as well as their waste products, with simultaneous absorption of excess fluid in the GI lumen in the declared effective amounts capable of normalizing the frequency and the consistency of feces.

Description

COMPOSITION FOR TREATMENT OF DIARRHEA OF BACTERIAL, VIRAL and BACTERIAL AND FUNCTIONAL ORIGINS

Description

The invention relates to the field of medicine and, in particular, to a composition suitable for the treatment of patients with bacterial and viral and bacterial diarrhea, including unidentified and/or unspecified intestinal infections, containing an intestinal antiseptic in combination with an enterosorbent in effective amounts that provide a therapeutically effective daily dose of the composition. This invention also relates to the field of medicine and, in particular, to a composition used to treat functional diarrhea in diarrhea-predominant irritable bowel syndrome, including concomitant bacterial overgrowth syndrome, containing an intestinal antiseptic in combination with an enterosorbent in effective amounts that provide a therapeutically effective daily dose of the composition.

Prevalence of acute intestinal infections (Alls), according to WHO, is known to range from 1 to 1.2 billion cases reported annually. Alls is a polyetiological group of infectious diseases associated with impaired gastrointestinal (GI) motility with diarrhea of various origin.

Bacterial and viral and bacterial diarrhea is a symptom characterized by frequent (more than 2 times a day) watery bowel movements of more than 200 mL in volume which are often accompanied by periumbilical pain, fecal urgency and anorectal incontinence secondary to bacterial or viral and bacterial intestinal infection.

Diarrhea in diarrhea-predominant irritable bowel syndrome is a symptom that occurs secondary to functional intestinal motility disorders, shifts in the intestinal microbiota, changes in the receptor composition of the intestinal mucosa, in which more than 25% of bowel movements present as Bristol stool form types 6 or 7 (loose stools) and less than 25% of bowel movements present as Bristol stool form types 1 or 2 or the patient reports having predominantly a diarrhea (Bristol stool form types 6 or 7). Symptoms occur within the last 3 months with a total follow-up of at least 6 months.

Thus, the object of this invention was to develop a new composition for the treatment of bacterial, viral and bacterial and functional diarrhea, as well as diarrhea in diarrhea- predominant irritable bowel syndrome, including bacterial overgrowth syndrome. The new composition contains an intestinal antiseptic and an enterosorbent. It is highly stable and has no restrictions for use in any age groups and specific groups of patients. The composition can be used as an oral single dosage form, providing a therapeutically effective daily dose.

Intestinal antiseptics are antiseptic substances that have a minimal effect on symbiotic microflora, but eliminate pathogens. Thus, in this invention, intestinal antiseptics belong to the group of “non-absorbable” agents and are nifuroxazide, nifuratel and rifaximin.

Nifuroxazide is a 5-nitrofuran derivative that belongs to the group of intestinal antiseptics. Nifuroxazide inhibits the activity of aldolases, dehydrogenases, transketolases and the synthesis of certain macroprotein complexes and as a result impairs the growth and division of the bacterial cell and the repair of the bacterial cell membrane. The effect of nifuroxazide is not due to the pH environment in the intestinal lumen and does not depend on the sensitivity of bacteria to antibiotics. In studies performed, the minimum inhibitory concentration of nifuroxazide for opportunistic microorganisms does not change with repeated use. Thus, nifuroxazide suppresses the growth and activity of bacteria that cause diarrhea in intestinal infections, without a significant effect on the beneficial microflora in the GI tract.

Nifuratel is also a derivative of nitrofuran, whose action is aimed at eliminating infectious and inflammatory diseases and has an effect similar to nifuroxazide, i.e., inhibition of the growth and activity of bacteria that cause diarrhea in intestinal infections, without having a significant effect on the GI microflora.

Rifaximin is a derivative of rifamycin, a broad-spectrum non-absorbable intestinal antiseptic agent. It has a wide spectrum of antimicrobial activity, which includes most gram-negative and gram-positive, aerobic and anaerobic bacteria.

Enterosorbents are substances that have high sorption capacity. Thus, in this invention, activated carbon, silicon oxide, dismectite and hydrolyzed lignin are used as enterosorbents.

Activated carbon is a natural substance that is used in medicine because of its porous texture, which has a negative electrical charge attracting positively charged molecules, such as toxins.

Dismectite is a natural substance that stabilizes the mucous barrier, forms polyvalent bonds with mucus glycoproteins, increases the amount of mucus, and improves its gastroprotective properties (against the negative effect of hydrochloric acid hydrogen ions, bile salts, microorganisms, and their toxins). It has sorption properties, which are explained by its discoid-crystalline structure, and adsorbs microorganisms in the lumen of the gastrointestinal tract.

Silicon dioxide has a high sorption capacity and, in liquid media, it attracts hydroxyl groups and forms a complex spatial structure, the peculiarity of which is the sorption of toxin molecules, excess metabolic products, antigens, and microorganisms on the surface of particles at sites where silicon oxide binds to hydroxyl groups. Silicon dioxide helps reduce metabolic load and has a detoxifying effect.

Hydrolyzed lignin has adsorption and absorption properties due to its chemical and spatial nature, is able to sorb a wide range of molecules of various sizes, ranging from heavy metal ions, water ions to protein molecules, hormones, as well as bacterial cells and viruses, binds and removes pathogenic bacteria and bacterial toxins, drugs, poisons, and heavy metal salts from the body. The properties of hydrolyzed lignin are attributed to its natural porous chemical structure, which can absorb and adsorb substances and microorganisms and cleanse the intestinal mucosa. Hydrolyzed lignin is non-absorbable and not toxic and is completely eliminated unchanged by intestinal excretion within 24 hours. The use of lignin in the complex therapy of diarrhea is effective, including due to its ability to bind free fluid and improve stool consistency.

Due to their natural structure, the enterosorbents used in the claimed combination are a source of insoluble substances that form a bulk of intestinal contents, which, acting on the intestinal mucosa during its movement along the intestines, cleanses the mucosal layer of the intestinal mucosa from some microorganisms, cellular debris and toxins.

Thus, the use of enterosorbents in the claimed combination helps reduce bacterial, antigenic and toxic loads on the intestinal mucosa, decrease the amount of free fluid in the intestine, and increase the antibacterial effectiveness of an intestinal antiseptic agent.

The new developed composition has multidirectional antibacterial, sorption and cleansing properties, which together provide a more effective treatment of diarrhea, increasing the efficacy of therapy with the claimed composition. The components in this composition are well combined when used together and do not cause drug interactions. The composition is highly stable and has no restrictions for use in any age groups and specific groups of patients.

The composition can be used as an oral single dosage form and can also be used to treat bacterial and viral and bacterial diarrhea in unidentified and/or unspecified intestinal infections, and functional diarrhea in diarrhea-predominant irritable bowel syndrome, including bacterial overgrowth syndrome (BOS).

STATE OF THE ART

Patent document RU 2737891 C2 discloses the use of rifaximin in combination with concomitant use of a bifidobacteria strain for the treatment of acute and chronic intestinal infections. The used strain is Bifidobacterium longum W11.

Patent document RU 2519649 C2 discloses the use of rifaximin for the treatment of bowel diseases, in particular irritable bowel syndrome (IBS), at a dose of 1650 mg/day for 14 days.

Patent document RU 2325166 Cl discloses a pharmaceutical composition of antibiotics and lactulose for the prevention of enteral dysbioses in patients on antibiotic therapy. The composition contains antibiotics, including nitrofuran antibiotics.

Patent document RU 2427389 C2 discloses the use of hydrolyzed lignin in an amount of 1 gram in combination with live yeast cells for the prevention and treatment of infectious and non-infectious diarrheas. This combination has sorbent and pronounced antimicrobial and antiviral effects, or at least a normalizing effect on motor function (in diarrhea of non- infectious origin).

Patent document US 20090163427 discloses pharmaceutical compositions of enterosorbent and prebiotics, dosage forms and methods for the prevention and treatment of gastrointestinal diseases. The pharmaceutical composition is a combination of hydrolysed lignin with a moisture content of 55% to 65%, consisting of particles ranging in size from 0.15 mm to 0.55 mm, an aqueous solution of lactulose from 45% to 55% and an aqueous solution of oligosaccharide from 50% to 55%, with the following ratio of ingredients (mass percentages): aqueous lactulose solution: 10^60; oligosaccharides: 10^50; hydrolysed lignin: q.s. Hydrolysed lignin, lactulose and fructose oligosaccharides are successively added and mixed using a rotary mixer. The composition is administered orally for at least 14 days and not more than 30 days, two to four times a day, depending on the patient's weight and age. The composition is used to treat gastrointestinal diseases, including bacterial, viral, protozoal intestinal infections, food poisoning, antibiotic therapy, chemotherapy and radiation therapy.

Patent RU 2651752 C2 discloses a method for the treatment of subclinical dysentery with nifuroxazide 200 mg 4 times a day for 7 days, polyoxidonium 6 mg i.m. for 5 days and bifiform 2 capsules 3 times a day for 10 days. This method helps to increase the effectiveness of the treatment of subclinical dysentery by suppressing the growth of microorganisms, regulating immunity, as well as the processes of inflammation and regeneration of affected tissues.

The use of antibacterial agents in the treatment of diarrheas leads to destruction or dysfunction of pathogenic or opportunistic bacteria, however, the products of the destruction of such cells or their waste products (endo- and exotoxins) can have an independent toxic, inflammatory effect on the intestinal mucosa, which contributes to the diarrheal symptom.

In addition, antibacterial agents do not have an antiviral activity and therefore cannot treat the diarrhea caused by viruses.

The use of enterosorbents, despite their ability to reduce the toxic load in the intestines caused by bacterial toxins or destroyed bacterial fragments, partial sorption of bacteria, viruses and excess fluid, cannot suppress the viability of pathogenic and opportunistic microorganisms, which also makes the fight against the diarrheal symptom less effective.

The compositions known in the art did not solve the issues of development of a combination in a single oral dosage form with antibacterial, sorption and cleansing properties, which cumulatively provide more effective treatment of symptoms of diarrhea of various origins, thereby increasing the effectiveness of therapy.

THE ESSENCE OF THE INVENTION

The invention relates to a composition based on an intestinal antiseptic and an enterosorbent for combined use in an oral single dosage form due to multidirectional action.

Each component in the combination of an intestinal antiseptic and an enterosorbent used in the treatment of diarrhea was unexpectedly found to have a synergistic effect.

Thus, an intestinal antiseptic suppresses the viability and activity of pathogenic and opportunistic bacteria, and an entrosorbent sorbs toxins, antigens and fragments of destroyed bacteria and cells; a sorbent-containing bulk acting on the surface of the intestinal mucosa, ensures the cleansing of the intestinal mucosal layer, which leads to a decrease in mucosal inflammation and restoration of intestinal functional characteristics, and the cessation of diarrhea. An assessment of the activity of each component in this combination showed no decrease in their activity as the result of interplay. Thus, this invention relates to a composition for the treatment of bacterial, viral and bacterial and functional diarrheas, containing an intestinal antiseptic and an enterosorbent in ratios of 1:1 to 1 :10, respectively.

In a preferred embodiment of the invention, an intestinal antiseptic is selected from nifuroxazide, nifuratel, and rifaximin. An enterosorbent is selected from hydrolyzed lignin, activated carbon, silicon dioxide, and dismectite.

In the most preferred embodiment, the composition according to this invention contains nifuroxazide and hydrolyzed lignin in a ratio of 1 :4 in one daily dose. Moreover, in a preferred embodiment of this invention, the daily dose of nifuroxazide ranges from 100 mg to 800 mg per day, the daily dose of nifuratel ranges from 100 mg to 1200 mg per day, and the daily dose of rifaximin ranges from 100 mg to 1100 mg per day. The daily dose of enterosorbent is 1000 to 5000 mg.

According to this invention, the proposed composition is an oral dosage form in the form of a powder, tablet, capsule, granule, micropellet.

According to another embodiment of the invention, the proposed composition may additionally contain pharmaceutically acceptable excipients.

In addition, the proposed composition is used to treat bacterial, viral and bacterial, and functional diarrheas in diarrhea-predominant irritable bowel syndrome, including bacterial overgrowth syndrome.

This invention also relates to a method for treating bacterial, viral and bacterial diarrhea using a single daily dose of the claimed composition for 3 7 days.

According to another embodiment, this invention relates to a method for treating functional diarrhea in diarrhea-predominant irritable bowel syndrome, including bacterial overgrowth syndrome, using a single daily dose of the claimed composition for 7-14 days. the new developed composition has multidirectional antibacterial, sorption and cleansing properties, which cumulatively provide a more effective treatment of the diarrheal symptom, increasing the effectiveness of therapy with compositions. The active ingredients of the composition are well compatible with each other causing no drug interactions; the compositions are highly stable and have no restrictions for use in any age groups and specific groups of patients. The claimed composition was found to have an unexpected synergistic therapeutic effect in patients with diarrhea of various origins.

The technical result of the claimed invention is the achievement of an unexpected synergistic effect of the claimed composition by implementing a mechanism of the simultaneous antibacterial effect of an intestinal antiseptic on pathogenic or opportunistic microorganisms and the sorption and cleansing effects of the enterosorbent on pathogenic or opportunistic microorganisms, as well as their waste products, with simultaneous absorption of excess fluid in the GI lumen in the declared effective amounts capable of normalizing the frequency and the consistency of feces.

IMPLEMENTATION OF THE INVENTION

Example 1.

Choosing the components of the composition

The components of the composition were selected using the following main criteria:

1) the absence of a negative effect of each component on the activity and/or stability of the other component;

2) ensuring the required daily dosage of the components in the combination.

The enterosorbents that make up the composition are known to have non-specific sorption activity. In this regard, it was necessary to confirm the absence of undesirable sorption for intestinal antiseptics, which could adversely affect the specific activity of the claimed intestinal antiseptics.

For this purpose, an in vitro study of the sorption activity of enterosorbents with respect to the intestinal antiseptics used was carried out. In this study, samples of enterosorbents and intestinal antiseptics were mixed in sodium-phosphate buffer with pH = 7.4-7.6 to obtain certain final concentrations. The final concentration of enterosorbents in the suspension was 4.8 mg/mL and the final concentrations of intestinal antiseptics were 0.48 mg/mL, 0.8 mg/mL, 1.2 mg/mL, 2.4 mg/mL, 4.8 mg/mL and 48.0 mg/mL to ensure intestinal antiseptic/enterosorbent ratios of 1:10, 1:6, 1:4, 1 :2, 1:1, and 10:1, respectively. Each mixture was analyzed in 6 replicates. The mixtures were incubated for 3 hours in a thermostatic shaker at a stirring speed of 100 rpm and a temperature of 37°C. After 3 hours, the samples were filtered through a membrane nylon filter with a pore size of 0.45 microns and the residual antiseptic content in the filtrate determined by HPLC.

The sorption capacity was calculated using the following formula: (Aw2_c - Xw2_ts) ■ 0.01 • 1000 (Xw2_c - Xw2_ts) ■ 10

where:

Xw2_c is the residual content of intestinal antiseptic in the control solution in mg/mL;

Xw2_ts is the residual content of intestinal antiseptic in the test solution in mg/mL; aiig is the weight of enterosorbent, in milligrams.

The results of the experiment are presented in Table 1.

Table 1.

The sorption capacity of the enterosorbent with respect to intestinal antiseptic, by concentration ratio in the medium

*A significant difference for the 1 :1 ratio (using the 2-sided t-test p < 0.05)

As shown in Table 1, with the intestinal antiseptic: enterosorbent ratios of 1:10 to 1 :4 the sorption of the intestinal antiseptic is less than 1.0%, i.e. following a single daily dose of intestinal antiseptic of 100 mg, no more than 1 mg of the antibiotic is absorbed, which minimizes the risk of reducing the specific antibacterial activity of the antiseptic.

The experiments demonstrated that the observed synergistic effect of the claimed composition is achieved over the entire claimed range of active substances constituting this composition.

Example 2.

The effect of the intestinal antiseptic on the sorption activity of the enterosorbent

The effect of the antiseptic on the sorption activity of the enterosorbent was assessed in vitro by measuring the adsorption capacity of the enterosorbent for methylene blue in the presence of different concentrations of intestinal antiseptic in the medium.

In this study, samples of enterosorbent and antiseptic were placed into the flasks to the specified final concentrations, then a methylene blue solution (0.75 mg/mL) was added. The enterosorbent concentration was 5 mg/mL, the antiseptic concentration was 0.5 mg/mL, 1.25 mg/mL, and 50.0 mg/mL. As control samples, a mixture containing only enterosorbent (with no antiseptic added) was used, as well as mixtures with each of the tested antiseptic concentrations added with no enterosorbent added. Each mixture was analyzed in 5 replicates. The mixtures were incubated for 1 hour on a magnetic stirrer at a stirring speed of at least 120 rpm. Then 1 mL of supernatant obtained after centrifugation at 6000 rpm, 15 min, was diluted to 100 mL with water (= test solution). The residual concentration of methylene blue was determined spectrophotometrically by measuring the optical density of the test solution in comparison with the standard methylene blue solution and water at a wavelength of 665 nm with a cuvette thickness of 10 mL.

The adsorption activity of the enterosorbent was calculated using the following formula: ((C - CJ - G) — ~ ” a where X is adsorption activity, mg,

C is the content of methylene blue in the stock solution, mg,

C/ is the content of methylene blue in the solution after incubation, mg, a is the weight of the enterosorbent sample, mg.

The methyl blue content was calculated using the optical densities of the test solutions and reference solutions, taking into account the dilutions performed. The data were described using descriptive statistics, namely, the average adsorption activity of the enterosorbent for methylene blue, as well as the standard deviation of 10 independent measurements, were determined.

Statistical processing was performed using the Shapiro-Fork method to assess the normality of the distribution; the variances were compared using the F-test and the mean values using the two-sided t-test. No significant differences in adsorption activity were found with any antiseptic and enterosorbent ratios tested (p > 0.05). The data obtained are presented in Table 2.

Table 2.

The adsorption activity of the enterosorbent for methylene blue depending on the concentration of the antiseptic in the medium

In the tested range of 10.0 to 1000.0 mg, the antiseptic in the combination does not have a significant effect on the adsorption activity of the enterosorbent taken in an amount of 100.0 mg. Thus, the observed synergistic effect of the claimed composition is achieved over the entire claimed range of active substances constituting this composition.

Example 3.

The effect of enterosorbent on the antibacterial activity of intestinal antiseptic

The effect of enterosorbent on the antibacterial activity of the antiseptic was assessed in vitro using bacterial strains that are the most common pathogens of acute intestinal infections.

Campylobacter jejuni ATCC 11168 was chosen as the test strains. After determining the minimum inhibitory concentration of an antiseptic that inhibits the growth of 90% of the bacterial strain (MIC90), the bacteria were incubated (the final concentration of bacteria in the medium is 10⁴ - 10⁵ CFU/mL) in a liquid minimal nutrient medium in the presence of the antiseptic at a concentration equivalent to MIC90, with or without enterosorbent at certain concentrations.

For Campylobacter jejuni ATCC 11168, enterosorbent concentrations were 32 pg/mL, 128 pg/mL, 320 pg/mL.

Each combination was analyzed in 6 replicates. After incubation for 8 hours at 37°C, the suspensions were thoroughly mixed, sequentially diluted and inoculated in appropriate dense diagnostic media with further cultivation for 72 hours. After that, colonies were counted and bacterial survival was assessed.

The results of the experiment are presented in Table 3.

Table 3.

The effect of the enterosorbent on the antibacterial properties of the intestinal antiseptic against the Campylobacter jejuni NCTC 11168 test strain

The studies with the Campylobacter jejuni strain demonstrated that the combination of antiseptic and enterosorbent in a ratio of 1 :4 had not reduced the antibacterial effectiveness of the antiseptic. There was a dose-dependent significant (p<0.05) increase in the antibacterial activity of the antiseptic and enterosorbent combination observed starting with an enterosorbent dose of 32 pg in multiple comparisons with PC groups.

Example 4.

Results of a clinical study with the claimed combination of intestinal antiseptic and enterosorbent using a combination of nifuroxazide and hydrolyzed lignin as an example for the treatment of bacterial and viral and bacterial diarrhea (unidentified/unspecified intestinal infections)

This was a randomized open-label study of the efficacy and safety of combinations of nifuroxazide and lignin in comparison with only nifuroxazide in patients with acute bacterial and mixed diarrheas.

The clinical study enrolled 79 male and female subjects aged 22 to 59 years (median 41 years) diagnosed with mild to moderate acute intestinal infection (All) (ICD-10 code: A02-A04, A08).

At enrollment, patients had had symptoms of acute diarrhea for not more than 72 hours.

All patients were randomized into 2 groups: 1) a study group (patients received a combination of nifuroxazide and hydrolyzed lignin) and 2) a control group (patients were treated with nifuroxazide only).

Study Results The analysis of the efficacy of the combination of nifuroxazide and hydrolyzed lignin in comparison with nifuroxazide only in patients with acute bacterial and mixed intestinal infections showed that the time (hours) to clinical remission (stool frequency not more than 3 times a day, formed stool pattern) differed significantly between two groups with an error probability of less than 5% (p = 0.041). In the group of the claimed combination, the mean time to recovery was 78.7 hours with the standard deviation of 17.1 hours. The mean time to stool normalization in the control group treated with nifuroxazide only was 91.0 hours with the standard deviation of 28.6 hours.

A comparative analysis between groups was conducted using the Student's t-test (the data in groups followed the Gaussian distribution), see Fig. 1 for graphic presentation. Thus, the difference in the onset time of clinical remission between group 1 and group 2 was 12.3 hours, which is clinically significant.

Brief description of the drawings:

Fig. 1 shows the onset time of clinical remission in patients in two groups: group 1 - study group - therapy with a combination of nifuroxazide and hydrolyzed lignin, group 2 - control group - only nifuroxazide

Fig. 2 shows the cumulative percentage of patients with clinical remission in the treatment of acute intestinal infections. To plot this graph, the primary efficacy outcome was assessed using a survival analysis and the Kaplan-Meier method. To confirm the statistical significance of the results, the two groups were compared using the Cox-Mentel test and the differences between the groups were found to be statistically significant (p = 0, 042).

The designations in Figure 2 are survival curves using the “onset time of clinical remission” in two groups: group 1 - study group - a combination of nifuroxazide and hydrolyzed lignin, group 2 - control group - only nifuroxazide.

For the secondary efficacy outcome, changes in stool consistency over time in patients on therapy, the combination of nifuroxazide and hydrolyzed lignin was found to be superior to nifuroxazide only. On Day 5 of treatment, stool had a normal consistency in 22 (64.7%) patients in the study group vs. 11 (30.6%) subjects in the control group (p = 0.009).

Example 5.

The outcomes of diarrhea treatment using a combination of intestinal antiseptic and enterosorbent in a model of diarrhea-predominant irritable bowel syndrome. One of the causes of diarrhea-predominant irritable bowel syndrome is intestinal microflora imbalance due to various factors, including the use of drugs, primarily systemic antibiotics. There was created a model of diarrhea-predominant irritable bowel syndrome in golden Syrian hamsters aged 6-8 weeks and weighing 60 to 80 g, which were orally administered a solution of amoxicillin and clavulanic acid in a dose of 5.33 + 0.76 mg/kg/day for 10 days. This dose of antibiotic causes changes in stool characteristics and diarrhea in 80-100% of animals after 5-10 days of daily administration.

In these experiments, animals in study and control groups (n = 10) were administered a solution of amoxicillin with clavulanic acid (ACA) at a dose of 5.33+0.76 mg/kg/day for 10 days with study groups receiving various combinations of antiseptic and enterosorbent for 14 days starting 5 days after the initiation of ACA treatment. The rate of diarrhea following the use of the combined drug was assessed immediately after the end of treatment. The results are summarized in Table 4.

Table 4.

Efficacy of the combination of antiseptic and enterosorbent in treatment of diarrhea caused by 10-day administration of amoxicillin and clavulanic acid in golden hamsters

All tested combinations of enterosorbent and antiseptic were found to have a pronounced reliable ability to treat systemic antibiotic-induced diarrhea in the hamster model of irritable bowel syndrome. However, combinations of rifaximin with dismectite and silicon dioxide in a ratio of 10:1 showed a significant difference in the rate of diarrhea following a 14-day combined therapy in the analysis using a paired one-sided Fisher’s exact test only (p=0.03).

Example 6.

The results of the clinical study of the combination of intestinal antiseptic using as an example nifuroxazide and hydrolyzed lignin for the treatment of diarrhea in diarrhea- predominant irritable bowel syndrome

This was a randomized open-label study of the efficacy and safety of a combination of nifuroxazide and hydrolyzed lignin compared with nifuroxazide only in adult patients with intestinal dysbiosis in diarrhea-predominant irritable bowel syndrome.

The clinical study enrolled 90 (64 female and 26 male) aged 21 to 55 years (mean age 38.5 years, median age 39.4 years). According to the protocol, patients diagnosed with irritable bowel syndrome with diarrhea (ICD-10 code: K58.0) were enrolled in the study. All subjects had one or more clinical symptoms of dysbiosis, such as abdominal pain, distention, nausea, flatulence, increased stool frequency, and changes in stool consistency.

All patients were randomized into 3 groups: group 1 (30 patients) received a combination of nifuroxazide, 800 mg and hydrolyzed lignin, 3200 mg in a daily dosage for 7 days.

Group 2 (30 patients) received a monotherapy with hydrolyzed lignin in a daily dose of 3200 mg for 7 days.

Group 3 (30 patients) received a monotherapy with nifuroxazide at a daily dose of 800 mg for

7 days. The results are shown in Table 5.

Table 5.

Comparative analysis of the “stool consistency” during 7 days of therapy with hydrolyzed lignin and nifuroxazide in combination or alone.

A comparative analysis of the above parameter showed that, starting from Day 5, there were statistically significant differences between groups 1 and 2, as well as 1 and 3, i.e. stool recovered more effectively in patients receiving a combination of nifuroxazide and hydrolyzed lignin compared to monotherapy with hydrolyzed lignin or monotherapy with nifuroxazide. After 7 days of therapy, no differences were observed between the groups treated with the claimed combination and the nifuroxazide only group; however, the lignin only was significantly less effective in restoring stool consistency.

Thus, the claimed combination has an advantage over monotherapy with hydrolyzed lignin being more effective in restoring the stool consistency and ensures a significantly faster restoration of the consistency of feces compared with monotherapy with nifuroxazide.

Example 7.

Preparation of a composition containing an intestinal antiseptic and an enterosorbent

To obtain the intestinal antiseptic and enterosorbent composition, the following procedures were performed:

1) crushing enterosorbents using a mill with a mesh size of 0.4 mm.

2) sieving substances to remove foreign matter and lumps using a vibrating screen with a mesh size of 0.32 mm. Each component was sieved separately. The sieved raw materials were re-weighed. The screenings should not exceed 6% wt.

3) preparing compositions - calculating the amount of active ingredients to ensure a daily dosage of an intestinal antiseptic: the daily dose of nifuroxazide ranges 100 mg to 800 mg per day; the daily dose of nifuratel ranges 100 mg to 1200 mg per day; the daily dose of rifaximin ranges 100 mg to 1100 mg per day. The daily dose of enterosorbent is 1000 to 5000 mg. The raw materials were weighed. The raw materials were loaded into the mixer batchwise. The resulting mass was mixed for 20 minutes at a mixer speed of 15-20 rpm until the components were evenly distributed. The resulting composition was packed in an airtight container made of opaque glass or plastic, labeled with information identifying the ratio of active ingredients, the manufacturing date and storage conditions.

Example 8.

Components of the composition containing intestinal antiseptic and enterosorbent One embodiment of the invention based on the disclosed antiseptic and enterosorbent compositions is a combined drug in the form of tablets containing excipients from the following categories: stabilizers, filling agents, anti-caking and binding agents: hemicellulose, guar gum, acacia gum, gum arabic, locust bean gum, starches, including starch esters and modified starches, dextrins, pectins, lecithins, polydextroses, cellulose, including modified celluloses, polyvinyl pyrrolidone, silicon dioxide, magnesium silicates, magnesium aluminosilicates, calcium carbonate, lactose monohydrate; disintegrants: povidone and its modifications, starches, including modified, cellulose, including modified, croscarmellose; lubricants: talc, silicon dioxide, macrogol, stearic acid and its salts; dyes: curcumin, titanium dioxide, azorubin, iron salts, etc.; flavoring agents: aspartame, acesulfame potassium, polyols, sucralose; antioxidants: ascorbic acid and its salts, citric acid and its salts, tocopherols, tartaric acid and its salts; film coatings and excipients for film coatings: adhesives (sugar syrup, polyvinyl pyrrolidone, cellulose, including modified cellulose, polyethylene glycol, etc.); filling agents (sugar, magnesium oxide, calcium oxide, talc, magnesium carbonate, etc.); plasticizers (vegetable oils, cellulose, including modified cellulose, Tweens, etc.); filmforming agents for the formation of waterproof coatings (shellac, polyacrylic resins, zein); dyes (tropeolin 00, tartrazine, acid red 2C, indigo carmine, etc.); flavoring agents (sugar, citric acid, cocoa, vanillin, etc.).

The selected excipients were used in quantities that ensure their technological properties and characteristics required for the finished dosage form.

Another embodiment of the invention based on the disclosed compositions of antiseptics and enterosorbents is combined drugs in the form of powder containing the following excipients: stabilizers, filling agents, anti-caking agents: hemicellulose, starches, including starch esters and modified starches, dextrins, pectins, lecithins, polydextroses, cellulose, including modified cellulose, polyvinyl pyrrolidone, silicon dioxide, magnesium silicates, calcium carbonate, lactose monohydrate; acidity regulators: acetic acid and its salts, ascorbic acid and its salts, citric acid and its salts, lactic acid and its salts, malic acid and its salts, tartaric acid and its salts, hydrochloric acid, hydrogen peroxide; dyes: curcumin, anthocyanins, carmine, betanin, tannins, capsorubin, titanium dioxide, azorubin, iron salts, etc.; flavoring agents: aspartame, acesulfame potassium, polyols, sugar, sucrose, sucralose; lubricants: talc, silicon dioxide, macrogol, stearic acid and its salts; antioxidants: ascorbic acid and its salts, citric acid and its salts, tocopherols, tartaric acid and its salts; preservatives: sorbic acid and its salts, benzoic acid and its salts, acetic acid and its salts, propionic acid and its salts; commercially available flavors.

The selected excipients were used in quantities that ensure their technological properties and characteristics required for the finished dosage forms.

Claims

INVENTION FORMULA

1. The composition for the treatment of bacterial, viral and bacterial and functional diarrheas, containing an intestinal antiseptic and an enterosorbent in ratios of 1 : 1 to 1:10, respectively.

2. The composition according to claim 1, characterized in that nifuroxazide, nifuratel, rifaximin are chosen as an intestinal antiseptic.

3. The composition according to claim 1, characterized in that hydrolyzed lignin, activated carbon, silicon dioxide, and dismectite are selected as an enterosorbent.

4. The composition according to claim 1, characterized in that it contains nifuroxazide and hydrolyzed lignin in a ratio of 1 :4 in one daily dose.

5. A composition according to any of claims 1-4, characterized in that it is an oral dosage form in the form of a powder, tablet, capsule, granule, micropellet.

6. A composition according to any of claims 1-5, characterized in that it additionally contains pharmaceutically acceptable excipients.

7. Use of a composition according to any of claims 1-6 for treatment of bacterial, viral and bacterial, and functional diarrheas in diarrhea-predominant irritable bowel syndrome, including bacterial overgrowth syndrome.

8. A method for treatment of bacterial, viral and bacterial diarrhea, characterized in that the composition is taken according to one of claims 1-6 in one daily dose for 3-7 days.

9. A method for treatment of functional diarrhea in diarrhea-predominant irritable bowel syndrome, including bacterial overgrowth syndrome, characterized in that the composition is taken according to one of claims 1-6 in one daily dose for 7-14 days.