EA045641B1 - COMPOSITION FOR RELIEF OF DIARRHEA OF BACTERIAL, VIRAL-BACTERIAL AND FUNCTIONAL GENESIS - Google Patents

Description

Description

The invention relates to the field of medicine and concerns a composition suitable for the treatment of patients with diarrhea of bacterial and viral-bacterial origin, including unidentified and/or unspecified intestinal infections, containing an intestinal antiseptic in combination with an enterosorbent in effective quantities, providing a therapeutically effective daily dose compositions. The invention also relates to the field of medicine and concerns a composition used for the treatment of diarrhea of functional origin in diarrheal-type irritable bowel syndrome, including concomitant bacterial overgrowth syndrome, containing an intestinal antiseptic in combination with an enterosorbent in effective quantities, providing a therapeutically effective daily dose compositions.

It is known that the incidence of acute intestinal infections (AEI), according to WHO, ranges from 1 to 1.2 billion registered annually. OKI is a polyetiological group of infectious diseases, accompanied by impaired motility of the gastrointestinal tract (GIT) with the development of diarrhea of various origins.

Diarrhea of bacterial and viral-bacterial origin is a symptom that manifests itself in the patient as frequent (more than 2 times a day) bowel movements, with watery stools that have a volume of more than 200 ml and are often accompanied by pain in the navel area, urgent urges and anal incontinence against the background of a bacterial or viral-bacterial intestinal infection.

Diarrhea in irritable bowel syndrome of the diarrheal type is a symptom that develops against the background of functional disorders of intestinal motility, changes in the balance of intestinal microflora, changes in the receptor composition of the intestinal mucosa, manifested in the fact that in patients in more than 25% of bowel movements, the shape of stool corresponds to types 6- 7 on the Bristol scale (loose stools) and less than 25% - types 1-2 or the patient reports that he has predominantly diarrhea (types 6-7 on the Bristol scale). Symptoms occur within the last 3 months with a total follow-up of at least 6 months.

Thus, the objective of the present invention was to create a new composition for the treatment of patients with diarrhea of bacterial, viral-bacterial and functional origin, as well as diarrhea characteristic of diarrheal-type irritable bowel syndrome, including bacterial overgrowth syndrome.

The new composition contains an intestinal antiseptic and enterosorbent, is highly stable, without restriction of use in relation to all age and specific groups of patients. The composition can be administered in an oral dosage unit dosage form, providing a therapeutically effective daily dose.

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

Nifuroxazide is a 5-nitrofuran derivative belonging to the group of intestinal antiseptics. Nifuroxazide inhibits the activity of aldolases, dehydrogenases, transketolases and the synthesis of certain macroprotein complexes. As a result of the action of nifuroxazide, the processes of growth and division of the bacterial cell, and repair of the bacterial cell membrane are disrupted. The effectiveness of nifuroxazide is not determined by the pH environment in the intestinal lumen and does not depend on the sensitivity of bacteria to antibiotics. In the framework of the studies, the minimum inhibitory concentration of nifuroxazide against opportunistic microorganisms does not change with repeated use. Thus, the use of nifuroxazide makes it possible to suppress the growth and activity of bacteria that cause diarrhea during intestinal infection, without significantly affecting the beneficial microflora of the gastrointestinal tract.

Nifuratel is also a derivative of nitrofuran, the action of which is aimed at eliminating infectious and inflammatory diseases and has a similar effect to nifuroxazide in suppressing the growth and activity of bacteria that cause diarrhea during intestinal infection, without having a significant effect on the microflora of the gastrointestinal tract.

Rifaximin is a derivative of rifamycin, a non-absorbable intestinal antiseptic with a broad spectrum of action. 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 properties. Thus, in this invention, activated carbon, silicon oxide, dismectite and hydrolytic lignin are used as enterosorbents.

Activated carbon is a naturally occurring substance that is used in medicine due to its porous structure, which has a negative electrical charge and helps attract positively charged molecules such as toxins.

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

Silicon dioxide - has a high sorption capacity and, when released into liquid media, attaches hydroxyl groups to itself and forms a complex spatial structure, the peculiarity of which is that the sorption of toxin molecules, excess metabolic products, antigens, microorganisms occurs on the surface of particles, at points of connection silicon oxide with hydroxyl groups. Silicon dioxide helps reduce metabolic load and detoxify.

Hydrolytic lignin has adsorption and absorptive properties, due to its chemical and spatial nature, it is capable of sorbing a wide range of molecules of various sizes, ranging from heavy metal ions, water to protein molecules, hormones, as well as bacterial cells and viruses, binds and removes pathogenic bacteria from the body and bacterial toxins, drugs, poisons, heavy metal salts. The properties of hydrolytic lignin are associated with its natural porous chemical structure, capable of absorbing and adsorbing substances and microorganisms, and cleansing the intestinal mucosa. Hydrolytic lignin is not absorbed, non-toxic, and is completely excreted unchanged through the intestines 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 strengthen the consistency of stool.

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 through 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 makes it possible to reduce the bacterial, antigenic and toxic load on the intestinal mucosa, reduce the content of free fluid in the intestine, and increase the effectiveness of the antibacterial action of the intestinal antiseptic.

The created new composition has multidirectional antibacterial, sorption-purifying properties, which together provide more effective elimination of the symptom of diarrhea, increasing the effectiveness of therapy with the claimed composition. The components included in the composition combine well when used together and do not cause drug-drug interactions. The composition is highly stable without restriction of use in relation to all age and specific groups of patients.

The composition can be used in the form of an oral dosage unit dosage form, and can also be used for the treatment of diarrhea of bacterial, viral-bacterial origin in unidentified and/or unspecified intestinal infections, functional origin in diarrhea associated with diarrheal-type irritable bowel syndrome, including excess bacterial syndrome growth (SIBO).

State of the art

From patent document RU 2737891 C2 it is known to use rifaximin in combination with the simultaneous use of a strain of bifidobacteria for the treatment of acute and chronic intestinal infections. The bifidobacterium strain used is Bifidobacterium longum W11.

From patent document RU 2519649 C2 it is known to use rifaximin for the treatment of intestinal diseases, in particular irritable bowel syndrome (IBS) at a dose of 1650 mg/day for 14 days.

From patent document RU 2325166 C1 a pharmaceutical composition of antibiotics and lactulose is known for the prevention of enteral dysbiosis during antibiotic therapy. The composition contains antibiotics, including those of the nitrofuran series.

From patent document RU 2427389 C2, it is known to use hydrolytic lignin in an amount of 1 gram in combination with live cells of a yeast strain for the prevention and treatment of infectious and non-infectious diarrhea. This combination has a sorbent and pronounced antimicrobial and antiviral effect, or at least a normalizing effect on motor function (for diarrhea of non-infectious origin).

From patent document US 20090163427, pharmaceutical compositions of enterosorbent and prebiotics, dosage forms and a method for the prevention and treatment of diseases of the gastrointestinal tract are known. The pharmaceutical composition is a combination of hydrolytic 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 percentage): aqueous solution of lactulose: 10+60; oligosaccharides: 10+50; hydrolytic lignin: sufficient quantity. Hydrolytic lignin, lactulose and fructose oligosaccharides are added sequentially and mixed using a rotary mixer. The composition is administered orally for at least 14 days and no more than 30 days, two to four times a day, depending on the weight and age of the patient. The composition is used as a medicine for the treatment of gastrointestinal diseases, including bacterial, viral, protozoal intestinal infections, food poisoning, antibiotic therapy, chemotherapy and radiation therapy.

Patent RU 2651752 C2 discloses a method for treating erased forms of dysentery. To do this, administer nifuroxazide 200 mg 4 times a day for 7 days, polyoxidonium 6 mg intramuscularly for 5 days and bifiform 2 capsules 3 times a day for 10 days. This method makes it possible to increase the effectiveness of treatment of erased forms of dysentery by suppressing the growth of microorganisms, regulating immunity, as well as the processes of inflammation and regeneration of damaged tissues.

The use of antibacterial agents in the treatment of diarrhea leads to the destruction or disruption of the function of pathogenic or conditionally pathogenic bacteria, however, the products of destruction of such cells or their metabolic 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 effect and, accordingly, cannot affect diarrhea caused by them.

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

The compositions known from the prior art did not solve the problems associated with creating a combination in a single oral dosage form with antibacterial, sorption and cleansing properties, which together provide more effective elimination of symptoms of diarrhea of various origins, thereby increasing the effectiveness of therapy.

The essence of the invention

The invention relates to a composition created on the basis of an intestinal antiseptic and an enterosorbent for joint use in an oral dosage single dosage form due to multidirectional action.

It was unexpectedly discovered that when a combination of an intestinal antiseptic and an enterosorbent is used together in the treatment of diarrhea, a synergistic effect of each component occurs.

Thus, an intestinal antiseptic suppresses the viability and activity of pathogenic and conditionally pathogenic bacteria, and the entrosorbent sorbs the toxins, antigens and fragments of destroyed bacteria and cells formed by bacteria; by the action of the sorbent-containing beam on the surface of the intestinal mucosa, its mucosal layer is cleansed, which leads to a decrease in inflammation of the mucosa and restoration of functional characteristics of the intestines, cessation of diarrhea. At the same time, an assessment of the activity of each of the components in this combination showed that there was no decrease in their activity due to their influence on each other.

Thus, the present invention relates to a composition for the relief of diarrhea of bacterial, viral-bacterial and functional origin, containing an intestinal antiseptic and enterosorbent in ratios from 1:1 to 1:10, respectively.

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

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

According to the present invention, the proposed composition is an orally dosable form made in the form of powder, tablets, capsules, granules, micropellets.

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

In addition, the proposed composition is used to relieve bacterial, viral-bacterial diarrhea, as well as functional diarrhea-type irritable bowel syndrome, including bacterial overgrowth syndrome.

The present invention also relates to a method for relieving diarrhea of bacterial and viral-bacterial origin, which consists of taking the claimed composition in one daily dose for 3-7 days.

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According to another embodiment, the present invention relates to a method for relieving diarrhea of functional origin in diarrheal-type irritable bowel syndrome, including bacterial overgrowth syndrome, which consists of taking the claimed composition in one daily dose for 7-14 days.

It should be noted that the created new composition has multidirectional antibacterial, sorption and cleansing properties, which together provide more effective elimination of the symptom of diarrhea, increasing the effectiveness of therapy with the compositions. The active components included in the composition combine well when used together, without causing drug-drug interactions; the compositions are highly stable, without restriction of use in relation to all age and specific groups of patients.

It was found that the claimed composition has an unexpected synergistic effect aimed at treating patients with diarrhea of various origins.

The technical result of the claimed invention is to achieve an unexpected synergistic effect of the claimed composition due to the implementation of the mechanism of simultaneous antibacterial effects of intestinal antiseptics on pathogenic or conditionally pathogenic microorganisms and the sorption-purifying effect of the enterosorbent in relation to pathogenic or conditionally pathogenic microorganisms, as well as their metabolic products, with the simultaneous absorption of excess liquids in the lumen of the gastrointestinal tract in declared effective quantities capable of normalizing the frequency and consistency of stool.

The composition can be used in the form of an oral dosage unit dosage form, and can also be used for the treatment of diarrhea of bacterial, viral-bacterial origin in unidentified and/or unspecified intestinal infections, functional origin in diarrhea associated with diarrheal-type irritable bowel syndrome, including excess bacterial syndrome growth (SIBO).

Carrying out the invention

Example 1.

Choosing the composition of the composition.

To select the composition of the composition, the following main criteria were used: 1) the absence of a negative effect of each component on the activity and/or stability of the other component;

2) providing the required daily dosage of the components in combination. It is known that enterosorbents included in the composition have nonspecific sorption activity. In this regard, it was necessary to confirm the absence of undesirable sorption in relation to intestinal antiseptics, which could negatively affect the specific activity of the claimed intestinal antiseptics.

For this purpose, an in vitro study of the sorption activity of enterosorbents in relation to the intestinal antiseptics used was carried out. To do this, weighed portions of enterosorbents and intestinal antiseptics were mixed in a 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, 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 tested in 6 replicates. The mixtures were incubated for 3 hours at a mixing frequency of 100 rpm in a thermostatic shaker at 37°C. After 3 hours, the samples were filtered through a nylon membrane filter with a pore size of 0.45 μm, after which the residual content of the antiseptic in the filtrate was determined by HPLC.

The sorption capacity was calculated according to the formula:

(Xn2 _k - Xn2 _I0 ) 0.01 1000 (Xn2 _k - Xn2 _I0 ) 10 v K HU/ ' K K HU/

4 leagues 4 leagues

where: _Chn2k is the residual content of intestinal antiseptic in the control solution in mg/ml; _Xn2io residual content of intestinal antiseptic in the test solution in mg/ml; and _lig . - weighed amount of enterosorbent, in milligrams.

The results of the experiment are presented in table. 1.

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Table 1

Sorption capacity of enterosorbent for intestinal antiseptic depending on the concentration ratio in the medium

Name antiseptic Name of enterosorbent Antiseptic: enterosorbent ratio Sorption capacity of enterosorbent, g/g nifuroxazide hydrolytic lignin 1:10 0.0010 + 0.0008 1:4 0.0050 + 0.0013 1:1 0.0480 ± 0.0054 10:1 0.1820 + 0.0113* nifuroxazide Activated carbon 1:10 0.0049 + 0.0010 1:4 0.0099 ± 0.0022 1:1 0.0851 + 0.0124 nifuroxazide silica 1:10 0.0005 ± 0.0001 1:4 0.0015 + 0.0001 1:1 0.0073 ± 0.0004 nifuroxazide dysmectite 1:10 0.0007 + 0.0001 1:4 0.0032 ± 0.0002 1:1 0.0099 ± 0.0003 nifuratel hydrolytic lignin 1:10 0.0008 ± 0.0002 1:4 0.0033 ± 0.0007 1:1 0.0244 + 0.0014 nifuratel Activated carbon 1:10 0.0026 ± 0.0003 1:4 0.0073 ± 0.0009 1:1 0.0688 ± 0.0021 nifuratel silica 1:10 0.0002 ± 0.0000 1:4 0.0012 + 0.0003 1:1 0.0089 ± 0.0007 nifuratel dysmectite 1:10 0.0008 ± 0.0008 1:4 0.0046 + 0.0013 1:1 0.0281 + 0.0023 rifaximin hydrolytic lignin 1:10 0.0014 + 0.0002 1:4 0.0062 ± 0.0006 1:1 0.0523 + 0.0015 rifaximin Activated carbon 1:10 0.0021 ± 0.0004 1:4 0.0083 ± 0.0008 1:1 0.0668 ± 0.0034 rifaximin silica 1:10 0.0003 ± 0.0000 1:4 0.0011 + 0.0003 1:1 0.0137 + 0.0013 rifaximin dysmectite 1:10 0.0006 + 0.0001 1:4 0.0010 + 0.0004 1:1 0.0096 ± 0.0022

- 5 045641 ^Significant difference for the ratio value 1:1 (determined by two-sided t-test

Student's t test p<0.05).

From the data presented in table. 1, it follows that when the ratio of intestinal antiseptic: enterosorbent is from 1:10 to 1:4, the sorption of intestinal antiseptic is less than 1.0%, i.e. When a single daily dosage of 100 mg of intestinal antiseptic is ingested, no more than 1 mg of antibiotic is absorbed, which minimizes the risk of reducing the specific antibacterial activity of the antiseptic.

As a result of the tests, it was found that the observed synergistic effect of the claimed composition is achieved over the entire declared range of active substances included in its composition.

Example 2.

The influence of intestinal antiseptic on the sorption activity of enterosorbent.

The influence 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 various concentrations of intestinal antiseptic in the medium.

To do this, weighed amounts of enterosorbent and antiseptic were added to the flasks to the specified final concentrations, then a solution of methylene blue (0.75 mg/ml) was added. The enterosorbent concentration was 5 mg/ml, the antiseptic concentrations were 0.5 mg/ml, 1.25 mg/ml and 50.0 mg/ml. As control samples, we used a mixture containing only enterosorbent without the addition of an antiseptic, as well as a mixture with the addition of each of the tested concentrations of an antiseptic without the addition of an enterosorbent. Each mixture was tested in 5 replicates. The mixtures were incubated for 1 hour on a magnetic stirrer at a stirring frequency of at least 120 rpm. Next, 1 ml of the supernatant obtained after centrifugation at 6000 rpm for 15 minutes was brought to 100 ml with water to obtain the test solution. The residual concentration of methylene blue was determined spectrophotometrically by measuring the optical density of the test solution in comparison with a standard solution of methylene blue and water at a wavelength of 665 nm, the thickness of the cuvette was 10 ml. Calculation of the adsorption activity of the enterosorbent was carried out according to the formula:

((C - C _g ) G)

L ----------a where X is adsorption activity, mg,

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

Cl is the content of methylene blue in the solution after incubation, mg, and is the mass of the enterosorbent sample, mg.

The content of methyl blue was calculated based on the data on the optical density of the test solutions and reference solutions, taking into account the dilutions performed.

To describe the data, the method of descriptive statistics was used, namely, the average value of the adsorption activity of the enterosorbent in relation to methylene blue was determined, as well as the standard deviation for 10 independent changes. Statistical processing of data was carried out using the assessment of normality of distribution by the Shapiro-Wilk method, comparison of variances was carried out using the F-test, comparison of mean values was carried out using a two-sided Student's t test. As a result, no significant differences in adsorption activity were found in all used ratios of antiseptic and enterosorbent (p>0.05). The obtained data are presented in table. 2.

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table 2

Adsorption activity of enterosorbent towards methylene blue depending on the concentration of antiseptic in the medium

Name antiseptic Name of enterosorbent Antiseptic: enterosorbent ratio Adsorption activity of enterosorbent towards methylene blue, mg nifuroxazide hydrolytic lignin 1:10 81.9 ± 1.1 1:4 84.8 ± 1.0 10:1 82.2 ± 2.6 1:1 84.8 ± 1.0 nifuroxazide Activated carbon 1:10 93.6 ±2.3 1:4 90.3 ±2.1 10:1 92.2 ± 1.8 1:1 90.2 ±2.1 nifuroxazide silica 1:10 76.2 ± 1.3 1:4 77.0 ± 0.8 10:1 75.2 ± 2.2 1:1 77.0 ± 0.8 nifuroxazide dysmectite 1:10 79.3 ± 2.6 1:4 76.8 ± 1.7 10:1 78.1 ± 1.9 1:1 76.5 ± 1.7 nifuratel hydrolytic lignin 1:10 82.3 ± 0.5 1:4 83.1 ± 1.4 10:1 85.3 ±2.7 1:1 83.0 ± 1.4 nifuratel Activated carbon 1:10 89.8 ± 1.0 1:4 94.2 ± 1.8 10:1 91.3 ±2.1 1:1 94.1 ± 1.7 nifuratel silica 1:10 80.2 ± 1.3

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1:4 78.8 ± 1.1 10:1 80.1 ±2.6 1:1 78.6 ± 1.0 nifuratel dysmectite 1:10 81.7 ± 1.5 1:4 80.8± 1.8 10:1 79.9± 1.3 1:1 80.6 ± 1.8 rifaximin hydrolytic lignin 1:10 77.8 ± 0.9 1:4 80.1 ± 1.8 10:1 79.5 ± 2.8 1:1 80.0 ± 1.8 rifaximin Activated carbon 1:10 82.4 ± 1.2 1:4 83.9 ± 1.1 10:1 80.9 ± 0.9 1:1 83.8 ± 1.1 rifaximin silica 1:10 80.0 ±2.1 1:4 78.9 ±2.8 10:1 81.1 ± 1.6 1:1 78.7 ±2.8 rifaximin dysmectite 1:10 77.5 ± 2.2 1:4 79.8 ± 1.7 10:1 78.3 ± 0.6 1:1 79.7 ± 1.7

In the tested range from 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 combination is achieved over the entire declared range of active substances included in its composition.

Example 3.

The influence of enterosorbent on the antibacterial activity of intestinal antiseptic.

The influence of enterosorbent on the antibacterial activity of the antiseptic was assessed in vitro using bacterial strains that are most often the causative agents of acute intestinal infections.

Campylobacter jejuni ATCC 11168 was chosen as test strains of bacteria. 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 was 10 ⁴ -10 ⁵ CFU/ml) in a liquid minimal nutrient environment in the presence of an antiseptic in a concentration equivalent to MIC90, with or without the addition of enterosorbent in certain concentrations.

For Campylobacter jejuni ATCC 11168, enterosorbent concentrations were 32 μg/ml, 128 μg/ml, 320 μg/ml.

Each combination was tested in 6 replicates. After incubation for 8 hours at a temperature of 37°C, the suspensions were thoroughly mixed and serial dilutions were carried out with seeding on appropriate solid nutrient diagnostic media, followed by cultivation for 72 hours. Colony counts and bacterial survival were then assessed. The results of the experiment are presented in table. 3.

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Table 3

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

Group name N Observable parameters assessed for the study groups: Concentration of bacteria in lgKOE/ml (M+SM) Delta s PKO, in 1g P-value With jejuni, 0 h (QOL) 9 6.08+0.08 0.65 <0.01 With jejuni, 6 hours (PKO) 9 8.72+0.15 But. But. With jejuni, 6 hours NF 32 mcg/ml 9 6.57+0.05 2.15 <0.01 With jejuni, 6 hours NPF 32 mcg/ml 9 6.73+0.13 2.15 <0.01 With jejuni, 6 hours RIF 32 mcg/ml 9 7.08+0.08 2.15 <0.01 With jejuni, 6 hours, NF 32 mcg/ml + LH 128 9 4.13+0.06 4.59 <0.01 µg/ml, ratio 1:4 With jejuni, 6 hours, NIF 32 µg/ml + LH 128 µg/ml, ratio 1:4 9 4.08+0.03 4.64 <0.01 With jejuni, 6 hours, RIF 32 µg/ml + LH 128 µg/ml, ratio 1:4 9 4.73+0.16 3.99 <0.01 With jejuni, 6 hours, NF 32 µg/ml + AU 128 µg/ml, ratio 1:4 9 4.56+0.08 4.16 <0.01 With jejuni, 6 hours, NIF 32 µg/ml + AU 128 µg/ml, ratio 1:4 9 4.33+0.13 4.39 <0.01 With jejuni, 6 hours, RIF 32 µg/ml + AU 128 µg/ml, ratio 1:4 9 5.13+0.18 3.59 <0.01 With jejuni, 6 hours, NF 32 µg/ml + DC (silicon dioxide) 128 µg/ml, ratio 1:4 9 5.36+0.24 3.36 <0.01 With jejuni, 6 hours, NIF 32 µg/ml + DC 128 µg/ml, ratio 1:4 9 5.03+0.03 3.69 <0.01 With jejuni, 6 h, RIF 32 μg/ml + DC 128 µg/ml, ratio 1:4 9 5.82+0.15 2.90 <0.01 With jejuni, 6 hours, NF 32 µg/ml + dysmectite 128 µg/ml, ratio 1:4 9 5.03+0.06 3.69 <0.01 With jejuni, 6 hours, NIF 32 µg/ml + dysmectite 128 µg/ml, ratio 1:4 9 4.93+0.18 3.79 <0.01 With jejuni, 6 hours, RIF 32 µg/ml + dysmectite 128 µg/ml, ratio 1:4 9 5.63+0.08 3.09 <0.01 With jejuni, 6 hours LH 320 mcg/ml 9 8.64+0.03 0.08 0.15 LH 320 mcg/ml (MBC) 9 k.o. But. But.

Note: QL - control of the viability of C.jejuni, sowing after 0 hours; PKO positive control for growth of culture C jejuni for 6 hours; MBC - control of microbiological sterility in relation to C jejuni; NF - nifuroxazide; NPF - 9 045641 nifurotel; RIF - rifaximin; DC - silicon dioxide; LH - hydrolytic lignin; AU activated carbon; CFU - colony forming units; 1g - logarithm of the number by

Ibase 10; M - arithmetic mean value; SM - standard deviation of the mean; k.o. - no colonies were found; But. - the value was not determined; P-value - the level of significance of differences between the group mean values and the LOQ, determined by a two-sided Student's t-test for equal variances and samples for multiple comparisons with the Schoffe correction; N is the number of repetitions of bacterial concentration measurements.

Based on the results of studies conducted with the Campylobacter jejuni strain, it was found that the combination of an antiseptic and an enterosorbent in a ratio of 1:4 did not reduce the antibacterial effectiveness of the antiseptic. A dose-dependent significant (p<0.05) increase in the antibacterial activity of the combination of antiseptic and enterosorbent was noted, starting with a dose of enterosorbent of 32 mcg in multiple comparisons with the PCO groups.

Example 4.

The results of a clinical study of the use of the proposed combination of intestinal antiseptic and enterosorbent using the example of a combination of nifuroxazide and hydrolytic lignin for the treatment of diarrhea of bacterial and viral-bacterial origin (unidentified/unspecified intestinal infections).

A randomized, open-label study was conducted on the effectiveness and safety of combinations of nifuroxazide and lignin compared with nifuroxazide monotherapy in patients with acute diarrhea of bacterial and mixed origin.

The clinical study involved 79 male and female patients aged from 22 to 59 years (median 41 years) with an established diagnosis of mild to moderate acute intestinal infection (ACI) (ICD-10 code: A02-A04, A08) .

Symptoms of acute diarrhea at the time of inclusion of patients in the study were observed for no more than 72 hours.

All patients were randomized into 2 groups: 1) experimental group - patients received a combination of nifuroxazide and hydrolytic lignin and 2) control group - patients received monotherapy with nifuroxazide.

Research results.

When analyzing the effectiveness of the combination of nifuroxazide and hydrolytic lignin in comparison with nifuroxazide monotherapy in patients with acute bacterial and mixed intestinal infections, it was found that the rate (number of hours) of clinical remission (stool frequency no more than 3 times a day, stool character - formal) was statistically significantly different in the two groups with a probability of error less than 5% (p=0.041). Recovery in the group receiving therapy with the claimed combination occurred on average after 78.7 hours, the standard deviation was 17.1 hours. Normalization of stool in the comparison group receiving monotherapy with nifuroxazide was recorded on average after 91.0 hours, standard deviation - 28.6 hours.

A comparative analysis between groups was carried out using Student's t-test (data in groups correspond to a Gaussian distribution), a visual representation of the data in Fig. 1. Thus, the difference in the onset of clinical remission in group 1 and group 2 was 12.3 hours, which is a clinically significant result.

Brief description of drawings

In fig. Figure 1 shows the time of onset of clinical remission in patients of two groups: group 1 - experimental group - therapy with a combination of nifuroxazide and hydrolytic lignin, group 2 - control group - monotherapy with nifuroxazide.

In fig. Figure 2 shows the cumulative proportion of patients with the onset of clinical remission during the treatment of acute intestinal infections. To obtain this graph, the primary efficacy parameter was assessed using survival analysis and the Kaplan-Meier method. To confirm the statistical significance of the results, a comparison was made between the two groups using the Cox-Mentel test, which showed that the differences between the groups were statistically significant (p = 0.042).

Designations in Fig. 2 represent survival curves in terms of the time of onset of clinical remission of two groups: group 1 - experimental group - combination of nifuroxazide and hydrolytic lignin, group 2 - control group - nifuroxazide monotherapy.

According to the secondary effectiveness parameter, the dynamics of changes in stool consistency in patients during therapy, the superiority of the use of a combination of nifuroxazide and hydrolytic lignin, compared with nifuroxazide monotherapy, has been proven. On the fifth day of treatment, 22 (64.7%) patients in the experimental group had normal stool consistency, versus 11 (30.6%) patients.

- 10 045641 eyelids of the control group (p=0.009).

Example 5.

Results of relief of diarrhea using a combination of intestinal antiseptic and enterosorbent in a model of diarrheal-type irritable bowel syndrome.

One of the reasons for the development of diarrheal-type irritable bowel syndrome is an imbalance of intestinal microflora caused by various reasons, including as a consequence of the action of various medications, including primarily systemic antibiotics. A model of irritable bowel syndrome of the diarrheal type was developed in golden Syrian hamsters aged 6-8 weeks and weighing 60-80 g, which were orally administered a solution of amoxicillin with clavulanic acid at a dose of (5.33 + 0.76 mg/day) for 10 days. kg/day). This dose of antibiotic causes changes in stool characteristics and diarrhea in animals after 5-10 days of daily administration in 80-100% of animals.

During the research, animals of the experimental and control groups (n=10) were administered a solution of amoxicillin with clavulanic acid (AA) at a dose of (5.33 + 0.76 mg/kg/day) for 10 days, while the experimental groups of animals received 5 days after the start of AA administration and for 14 days, therapy with various combinations of an antiseptic and enterosorbent. The frequency of diarrhea after using the combination drug was recorded immediately after the end of therapy. The research data are given in table. 4.

Table 4 Efficacy of a combination of antiseptic and enterosorbent in relieving diarrhea in golden hamsters caused by 10 days of oral administration of amoxicillin with clavulanic acid

Group Name drug (antiseptic and enterosorbent) Antiseptic: enterosorbent ratio Frequency diarrhea, animals with diarrhea/ animals in group(%) Level of significance of differences from control, p-Value* IBS-D control Water But. 9/10 (90) But. NF+LH Nifuroxazide + hydrolytic lignin 1:10 0/10 (0) <0.05 1:4 0/10 (0) <0.05 10:1 1/10 (10) <0.05 1:1 0/10 (0) <0.05 NF+AU Nifuroxazide + activated carbon 1:10 0/10 (0) <0.05 1:4 0/10 (0) <0.05 10:1 1/10 (10) <0.05 1:1 0/10 (0) <0.05 NF+DK Nifuroxazide + silicon dioxide 1:10 0/10 (0) <0.05 1:4 1/10 (10) <0.05 10:1 1/10 (10) <0.05 1:1 1/10 (10) <0.05 NF+DS Nifuroxazide + dysmectite 1:10 0/10 (0) <0.05 1:4 1/10 (10) <0.05 10:1 2/10 (20) <0.05 1:1 2/10 (20) <0.05 NIF+LH Nifuratel + hydrolytic lignin 1:10 0/10 (0) <0.05 1:4 0/10 (0) <0.05 10:1 2/10 (20) <0.05 D.1 1/10 (10) <0.05 NIF+AU Nifuratel 1:10 0/10 (0) <0.05

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+activated carbon 1:4 0/10 (0) <0.05 10:1 1/10 (10) <0.05 1:1 1/10 (10) <0.05 NIF+DK Nifuratel +silicon dioxide 1:10 1/10 (10) <0.05 1:4 1/10 (10) <0.05 10:1 2/10 (20) <0.05 1:1 1/10 (10) <0.05 NIF+DS Nifuratel + dysmectite 1:10 1/10 (10) <0.05 1:4 2/10 (20) <0.05 10:1 2/10 (20) <0.05 1:1 2/10 (20) <0.05 RIF+LG Rifaximin + LIGNIN hydrolytic 1:10 0/10 (0) <0.05 1:4 1/10 (10) <0.05 10:1 3/10 (30) <0.05 1:1 2/10 (20) <0.05 RIF+AU Rifaximin + activated carbon 1:10 0/10 (0) <0.05 1:4 1/10 (10) <0.05 10:1 3/10 (30) <0.05 1:1 1/10 (10) <0.05 RIF+DK Rifaximin + silicon dioxide 1:10 3/10 (30) <0.05 1:4 3/10 (30) <0.05 10:1 4/10 (40) 0.06 1:1 3/10 (30) <0.05 RIF+DS Rifaximin + dysmectite 1:10 2/10 (20) <0.05 1:4 3/10 (30) <0.05 10:1 4/10 (40) 0.06 1:1 3/10 (30) <0.05

Note: NF - nifuroxazide; NIF - nifurotel; RIF - rifaximin; DC - silicon dioxide; LH - hydrolytic lignin; AU - activated carbon. Nifuroxazide, nifuratel and rifaximin were used at a dose of 16 mg/kg/day; enterosorbents were used in doses of 160; 64; 1.6 mg/kg/day. The animals were administered drugs in a volume of 0.2 ml twice a day; * - comparison of the frequency of diarrhea in experimental groups was carried out using paired two-sided Fisher's exact test; n.o. - not determined.

As a result, it was established that all tested combinations of enterosorbent and antiseptic had a significant, reliable ability to relieve systemic antibiotic-induced diarrhea in hamsters, modeling irritable bowel syndrome. However, combinations of rifaximin with dysmectite and silica in a ratio of 10:1 showed a significant difference in the incidence of diarrhea after 14 days of combination therapy only when using a paired one-sided Fisher's exact test (p = 0.03).

Example 6.

Results of a clinical study of the use of a combination of intestinal antiseptic using the example of nifuroxazide and hydrolytic lignin for the relief of diarrhea in diarrheal-type irritable bowel syndrome.

A randomized, open-label study was conducted on the effectiveness and safety of a combination of nifuroxazide and hydrolytic lignin in comparison with nifuroxazide monotherapy in patients with intestinal dysbiosis in adult patients with irritable bowel syndrome, with a predominance of diarrhea in the acute stage.

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The clinical study involved 90 (64 women and 26 men) aged from 21 to 55 years (mean age 38.5 years, median age 39.4 years). According to the protocol, patients with a diagnosis of irritable bowel syndrome and diarrhea (ICD10 code: K58.0) were included in the trial.

All subjects had one or more clinical symptoms of dysbiosis, such as: abdominal pain, bloating, nausea, flatulence, increased stool frequency, change in stool consistency.

All patients were randomized into 3 groups:

group (30 patients) received a combination of nifuroxazide, 800 mg and hydrolytic lignin, 3200 mg in a daily dosage. The duration of taking the combination was 7 days.

group (30 patients) received monotherapy with hydrolytic lignin at a daily dose of 3200 mg. The duration of taking the drug in patients of group 2 is 7 days.

group (30 patients) received nifuroxazide monotherapy at a daily dose of 800 mg. The duration of taking the drug in patients of group 3 is 7 days. The results are shown in table. 5.

Table 5 Comparative analysis of stool consistency indicator during 7 days of therapy with a combination and single preparations of hydrolytic lignin and nifuroxazide

Therapy day Mean stool consistency score assessed for the three groups, M±SD (n=30) Significance level for Kruskal-Wallis rank ANOVA for three groups Group 1 Group 2 Group 3 1 day 0.60+0.77 0.53+0.68 0.50+0.57 p = 0.968 Day 2 0.70+0.99 0.70+0.84 0.57+0.73 p = 0.854 Day 3 0.83+0.87 0.70+0.79 0.93+0.74 p = 0.417 4 day 1.20+0.89 1.03+0.89 1.11+0.77 p = 0.627 5 day 1.53+0.82 1.07+0.87* 1.13+0.85* p = 0.046 Day 6 1.60+0.60 1.10+0.80* 1.18+0.94* p = 0.042 Day 7 1.77+0.86 0.97+0.81* 1.49+0.85# p < 0.022 Note: group 1 - patients received a combination of nifuroxazide and hydrolytic lignin 800/3200 mg, respectively; group 2 - patients received hydrolytic lignin 3200 mg; group 3 - patients received nifuroxazide 800 mg; * significant difference compared with group 1, Mann Whitney test at p<0.05; # significant difference compared to group 2, Mann Whitney test at p<0.05; M is the arithmetic mean of stool consistency; SD is the standard deviation for stool consistency in groups.

A comparative analysis of the above indicator showed that, starting from the fifth day, there are statistically significant differences between groups 1 and 2, as well as 1 and 3, i.e. stool was restored more effectively in patients receiving a combination of nifuroxazide and hydrolytic lignin when compared with hydrolytic lignin monotherapy or nifuroxazide monotherapy. Moreover, after 7 days of therapy, no differences were observed between the groups with the claimed combination and the nifuroxazide monotherapy group; however, the lignin therapy group had a significantly less effective restoration of stool consistency.

Thus, the claimed combination has an advantage compared to monotherapy with hydrolytic lignin, consisting in a more effective restoration of stool consistency, and also, when compared with nifuroxazide mototherapy, a significantly faster restoration of stool consistency.

Example 7.

Preparation of a composition containing an intestinal antiseptic and enterosorbent.

To obtain the composition of intestinal antiseptic and enterosorbent, the following procedures were carried out:

1) grinding of enterosorbents was carried out using a mill with a mesh size of 0.4 mm;

2) sifting of substances - to remove foreign inclusions and lumps, sifting of substances was carried out using a vibrating sieve with a mesh size of 0.32 mm. Each component was sieved separately. The sifted raw materials were re-weighed. The amount of screenings should not exceed 6 wt.%;

3) obtaining compositions - the amount of active ingredients was calculated, allowing

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Claims (2)

provide a daily dosage of intestinal antiseptic: 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; The daily dose of rifaximin ranges from 100 mg to 1100 mg per day. The daily dose of enterosorbent is from 1000 to 5000 mg. The raw materials were weighed. The raw materials were loaded in portions into the mixer, the resulting mass was stirred for 20 minutes at a mixer rotation speed of 15-20 rpm until the components were evenly distributed. The resulting composition was packaged in sealed containers made of opaque glass or plastic, and labeled indicating the ratio of active components, production date and storage conditions. Example 8. Composition of a composition containing an intestinal antiseptic and enterosorbent. One embodiment of the invention based on the disclosed compositions of an antiseptic and an enterosorbent is a combined medicinal product in the form of tablets, for the creation of which excipients from the following range were used: stabilizers, fillers, 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, polydextrose, cellulose, including modified celluloses, polyvinylpyrrolidone, silicon dioxide, magnesium silicates, magnesium aluminosilicates, calcium carbonate, lactose monohydrate; raising agents: povidone and its modifications, starches, including modified ones, cellulose, including modified ones, croscarmellose; lubricants: talc, silicon dioxide, macrogol, stearic acid and its salts; dyes: curcumin, titanium dioxide, azorubine, 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 shells and auxiliary substances for film shells: adhesives (sugar syrup, polyvinylpyrrolidone, cellulose, including modified cellulose, polyethylene glycol, etc.); fillers (sugar, magnesium oxide, calcium oxide, talc, magnesium carbonate, etc.); plasticizers (vegetable oils, cellulose, including modified cellulose, Tweens, etc.); film formers for the formation of moisture-proof 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 ensured their technological properties and characteristics required for the finished form. Another variant of the invention based on the disclosed compositions of antiseptics and enterosorbents are combined medicinal preparations in powder form, for the creation of which the following excipients were used: stabilizers, fillers, anti-caking agents: hemicellulose, starches, including starch esters and modified starches, dextrins, pectins, lecithins, polydextrose, cellulose, including modified celluloses, polyvinylpyrrolidone, 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, azorubine, 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 ensured their technological properties and characteristics required for the finished forms. CLAIM 1. Composition for the relief of diarrhea of bacterial, viral-bacterial and functional origin, containing an intestinal antiseptic selected from nifuroxazide and rifaximin, and an enterosorbent selected from hydrolytic lignin, activated carbon, silicon dioxide, dismectite, in a ratio of 1:1 to 1, respectively :10. 2. The composition according to claim 1, characterized in that it contains nifuroxazide and hydrolytic lignin in a ratio of 1:4. -