WO2024210881A1 - Composite antidiarrheal agent - Google Patents

Abstract

The invention relates to biotechnology and to the food and pharmaceutical industries, and more particularly relates to functional food products for normalizing the condition of an organism and to dietary supplements and medicinal preparations intended for normalizing the condition of the gastrointestinal tract in the case of diarrheal syndrome and intoxication syndrome. A composite antidiarrheal agent that is based on colloids contains at least one proteinaceous colloid selected from the group consisting of: albumin or gelatin in the form of a tannate or a gallate, wherein for each part by weight of the proteinaceous colloid, the antidiarrheal agent additionally contains from 1 to 10 parts by weight of a non-proteinaceous colloid of polyvinylpyrrolidone having a molecular mass of at least 6000 Da but no more than 25000 Da, and from 0.1 to 10 parts by weight of an intestinal absorbent. The invention makes it possible to effectively eliminate the symptoms of diarrhea and to remove toxins, irrespective of their type, from all parts of the gastrointestinal tract, while also reducing undesirable side effects.

Description

COMPOSITE ANTIDIARRHEAL AGENT

The invention relates to biotechnology, food and pharmaceutical industries, namely, to functional food products for normalizing the body's condition and biologically active food supplements (BAS) and medicinal products intended to normalize the condition of the gastrointestinal tract in the presence of diarrheal and intoxication syndromes.

Diarrhea syndrome or simply diarrhea occurs as a result of a disruption of the bowel movement process, which is accompanied by an increase in daily bowel movements over 4 times, with liquid fecal discharge. Every person, regardless of age, has encountered this problem at least once in their life. Among the causes of diarrhea syndrome, the most common are:

- occurrence of infections directly in the gastrointestinal tract (salmonellosis, E. coli, dysentery, viral diseases);

- dysbacteriosis;

- allergic reactions to food;

- diseases of the digestive system (pancreatitis, ulcers, colitis, hepatitis, gastritis);

- poisoning by various chemical substances;

- metabolic disorders; dysfunction of the nervous system (neuroses, depression);

- development of traveler's syndrome (often found in people who travel a lot to other countries, and is caused by the consumption of food and water that is unusual for the body in terms of the qualitative microbial composition;

- inflammatory diseases of the gastrointestinal tract (Crohn's disease, ulcerative colitis, irritable bowel syndrome).

The main danger of diarrhea is dehydration, which is especially unfavorable for children and the elderly. Severe cases of diarrhea syndrome can lead to death. According to statistics, prolonged diarrhea It is very dangerous for children under 5 years of age; mortality from this disease at this age ranks third in the world, amounting to millions of children.

Traditionally, diarrhea is treated with drugs that target the cause that caused it. In case of an infectious process, antibacterial drugs and intestinal antiseptics are used; in case of allergic or inflammatory processes, antiallergic (antihistamines) and anti-inflammatory (aminosalicylic acid derivatives) drugs are used; in severe cases, hormonal drugs are used; in case of poisoning, enteral sorbents are used; in case of nervous causes of diarrhea, drugs that usually have a calming effect are used. At the same time, there are drugs that can reduce the manifestations of diarrhea regardless of the cause that caused it. They act on specific intestinal receptors, which leads to a slowdown and sometimes cessation of intestinal peristalsis and, as a result, the cessation of the external manifestation of diarrhea. However, in most cases of diarrhea, such drugs are dangerous because the contents of the intestine, undergoing processes of decomposition and metabolism by bacteria, which are in the intestines of each person in quantities of about 2 kg, begin to be absorbed into the bloodstream and have a toxic, and sometimes fatal effect on the body, aggravating the already existing state of intoxication.

The use of agents that only weaken intestinal peristalsis in this situation will be dangerous. Enterosorbents are used in such situations, but they are also unable to resolve the situation, since, remaining in the intestine for a long time, silicon-based or activated carbon-based sorbents, obeying Langmuir's law, begin the process of desorption - that is, after the sorbent has absorbed the substance to the maximum level, it begins to release this substance back, again increasing intoxication.

Intoxication of the human and animal organism is a syndrome that always accompanies various pathological processes and conditions that cause diarrhea.

Therefore, in all these cases of diarrhea and severe (acute) intoxications, a differentiated approach is provided for when choosing means for detoxifying the body, which differ depending on the nature of the toxic substances that caused the poisoning. In particular, well-known enterosorbents based on hydrolytic lignin or activated carbon are used.

Various forms of lignin-based enterosorbents for oral use are known. Thus, a composite enterosorbent based on lignin is known, containing hydrolytic lignin, microcrystalline cellulose, pectin and highly dispersed silicon dioxide in the following ratio of components, wt.%: hydrolytic lignin 25.0-35.0, microcrystalline cellulose 25.0-35.0, pectin 4.0-6.0. The enterosorbent can be made in the form of tablets with additives: starch 2.0-4.0% and calcium or magnesium stearate 0.5-1.0% or powder [RU 2234931 C2, IPC: A61K 35/78, 33/00, 47/38; A61P 1/00, published on 27.08.2004].

However, such an enterosorbent in the form of tablets does not contain a sufficient amount of sorbent, therefore, to achieve the effect, they must be used several at a time, and in the form of powder, it has unpleasant organoleptic properties.

Derivatives of softwood native lignin having an aliphatic hydroxyl content of about 2.5 mmol/g to about 7 mmol/g are known. It was unexpectedly found that consistent and predictable antioxidant activity can be achieved by selecting native lignin derivatives with a specific aliphatic hydroxyl content and can be used as a nutraceutical, dietary supplement, etc. [EP 2435455 A1, IPC: A23K 10/32, published 15.02.2010].

However, such derivatives, although they have antioxidant properties, which is important in the treatment of diarrheal or intoxication syndrome, have weak sorption properties, which is unlikely to help solve the problem of treating diarrheal syndrome.

A method for producing an enterosorbent based on lignin is known, which includes hydrolysis of crushed lignin-containing plant material with an aqueous acid solution, followed by washing the resulting lignin with water, activating the lignin with an aqueous alkali solution, separating the alkali solution from the lignin, washing it with water, neutralizing the remaining alkali in it with an aqueous solution, drying and grinding it, wherein nut shells and/or grape and/or fruit seeds, and/or buckwheat and/or sunflower husks are used as raw materials [RU 2084236 C1, IPC: A61K 35/78, published 20.07.1997].

However, it is more appropriate to use sorbents based on activated carbon as adsorbents.

Activated carbon-based sorbents are used for many gastrointestinal diseases, including diarrheal syndrome [DO Cooney, Activated Charcoal Antidotal and other Medical Uses. Marcel Dekker, New York, and Basel, 1983].

However, coal has significant drawbacks and limitations, so to achieve the effect it must be used in a dose of 5 to 15 grams, which corresponds to 25-75 tablets, which is almost impossible to swallow. Use in powder form has such a disadvantage as poor organoleptic properties, and sharp particles can cause injury to the oral mucosa. Therefore, attempts are being made to improve the organoleptic characteristics and compliance for patients.

It is known to use carbon microspheres of an adsorbent having a particle size of about 0.01 to about 2 mm for the preparation of a medicinal product for the treatment of one or more symptoms of irritable bowel syndrome, wherein irritable bowel syndrome is characterized by abdominal discomfort or pain and one or both constipation and diarrhea [EP 1957090 A1, IPC: A61 K 33/44, published 12.05.2006].

The disadvantages of such solid tablet forms of lignin and carbon enterosorbents are low affinity to the surface of the mucous membrane in the intestinal lumen, which sharply reduces the contact of the enterosorbent with toxins, and the sorbent itself can irritate the intestinal mucosa. In addition, such sorbents have a low ability to bind and remove microbial and uremic toxins.

Compositions for detoxification in the form of gels are known - methylsilicic acid hydrogels and a method for their production according to a patent [RU 2111979 C1, published 05/27/1998 C08G 77/02, GB1079265, published 08/16/2007 SOSh 33/158].

However, such sorbents have unpleasant organoleptic properties, which can cause dyspeptic symptoms already present in the intoxication syndrome, before vomiting develops, which makes their use impossible. In addition, methylsilicic acid gel has a relatively low ability to sorb protein fractions of microbial toxins, which causes insufficient efficiency in many cases of infectious diarrhea.

The use of polymer-crosslinked chitosan and its composition as components in intestinal disorder syndrome is known [US8703924 B2, C08B 37/08, A61K 31/722, A61K 47/36, A61K 47/38, A61K 8/73, A61K 9/14, A61K 9/52, A61P 37/04, A61P 13/09, A61P 43/00, published 20.09.2010]. However, chitosan by itself, or in combination with other sorbents, is not able to solve the problem of diarrheal syndrome.

Also known is a composition for cleansing the body of toxins and normalizing the composition of the microflora of the digestive tract, disrupted as a result of various diseases, bacterial or chemical intoxication, including during antibiotic therapy, where one of the main active components is cocoa butter [RU 2433751 C2, A23L 1/30, published 11/10/2011].

However, this remedy alone is not able to help with diarrhea, much less intoxication syndrome.

In this regard, there is a need to develop therapeutic and prophylactic compositions for the comprehensive elimination of symptoms of diarrhea and intoxication of any cause.

There are approaches to the use of colloidal substances based on albumin or gelatin in the form of a complex with tannins for the treatment of diarrhea and intoxication syndromes. Such agents act regardless of the type of diarrhea, since the tannin component has an antibacterial, anti-inflammatory, anti-allergic effect, and colloidal substances ensure its delivery and neutralization of toxins, since it is well known that albumin is the main detoxification protein of the mammalian body, which can bind most known substances on its surface. It is not for nothing that in various intoxications, especially associated with the mass formation of toxins (endotoxic shock), intravenous use of purified human albumin is indicated.

However, this drug in its pure form is not able to solve the problem of intoxication completely, since it contains an insufficient amount of colloidal substance when taken orally, and it is also digested by enzymes of the gastrointestinal tract.

The closest to the technical solution that is claimed is a pharmaceutical composition based on another colloidal substance, namely, gelatin tannate and a complex of prebiotic bacteria, described in the patent [EP 2526939A1, A61K 38/01, published 28.11.2012].

However, this composition has significant drawbacks and is also not able to solve the problem of intoxication-dehydration syndrome in diarrhea, since in This composition lacks an object that would rehydrate, and the colloidal fraction is clearly insufficient for the absorption of toxins.

The basis of the claimed invention is the task of creating a composite antidiarrheal agent that would effectively eliminate the symptoms of diarrhea syndrome due to the anti-inflammatory, anti-infective, antiviral, antitoxic action of protein colloids and ensure the removal of toxins regardless of their type from all parts of the digestive tract, reduce unwanted side effects, and also expand the arsenal of compositions suitable for eliminating diarrhea.

The stated problem is solved in that the composite antidiarrheal agent, made on the basis of colloids, according to the invention, contains at least one protein colloid selected from the group: albumin, gelatin in the form of tannate or galate, where per 1 mass part thereof there is additionally contained from 1 to 10 mass parts of non-protein colloid polyvinylpyrrolidone with a molecular weight of not less than 6000 Da and not more than 25000 Da and from 0.1 to 10 mass parts of enterosorbent.

The composite antidiarrheal agent may additionally contain from 1 to 10 mass parts of a rehydrating agent in the form of sodium, potassium, magnesium and/or calcium ions in the form of pharmaceutically acceptable salts per 1 mass part of the protein colloid.

The enterosorbent is selected from the group: silica gel, methyl silica gel (monomethylsilanetriol), methyl silica gel polymer (polymonomethylsilanetriol, otherwise known as polymethylsiloxane or methylsilicic acid), aluminosilicate clays (smectites, bentonites).

The composite antidiarrheal agent may additionally contain one or more types of monosaccharides or oligo(poly)saccharides of linear or cyclic types - cyclodextrins.

The composite antidiarrheal agent may additionally contain prebiotics selected from the group: inulin, lactiol, lactulose, chitosan and/or an antibacterial component, for example, taurolidine, nisin, or probiotics, for example, Saccharomyces boulardii, inulin.

The composite antidiarrheal agent, which is claimed to be effective due to its anti-inflammatory, anti-infective, antiviral, antitoxic properties the action of protein colloids eliminates the symptoms of diarrhea syndrome and ensures the removal of toxins, regardless of their type, from all parts of the digestive tract, reducing unwanted side effects.

The technical result of the claimed solution consists in effective binding, growth suppression and retention in the composition of the colloidal matrix of pathogenic agents formed on the surface of the compromised intestinal mucosa of the protective colloidal layer and the elimination or reduction of the phenomena of dehydration of body tissues.

Additionally, the composition has an effective detoxifying effect while using significantly less product, reducing unwanted side effects associated with the need for infusion detoxifying therapy.

The advantages of a composite antidiarrheal agent are the expansion of the possibility of producing accessible and convenient forms of the product for mass consumption, both its medicinal variants and non-medicinal consumer forms (biologically active additives, functional food products, etc.). This achieves a significant expansion of the area of technological implementation of the composition.

In other embodiments, the composite antidiarrheal agent may additionally contain at least one flavor additive, preferably a natural food flavoring agent in an amount of no more than 3 wt.%.

The composite antidiarrheal agent may additionally contain at least one flavor additive sweetener in an amount of no more than 20 wt.%.

The composite antidiarrheal agent may additionally contain a preservative in an amount of no more than 1 wt.%.

The composite antidiarrheal agent can be used in the form of tablets or granules for oral administration directly or for dispersion in water, powder or granules placed in a capsule for oral administration directly or for dispersion in water and subsequent oral administration, in the form of a gel, suspension or paste used directly orally in the required dose or for dissolving the required minimum amount of water.

In its best form, the composite antidiarrheal agent contains: - Gelatin tannate - 250 mg

- Polyvinylpyrrolidone - 2,500 mg

- Silica gel (Silicon dioxide) - 2,000 mg

- Potassium gluconate – 250 mg

- Sodium citrate - 500 mg

- Calcium gluconate - 500 mg

- Sugar - up to 10 g

When using, the contents of a sachet or stick with the described composition are poured into 100 ml of water and mixed or shaken until a homogeneous emulsion is obtained, which is drunk.

Method for manufacturing a composite antidiarrheal agent.

The product is manufactured using methods known to specialists: calculating and weighing the required amounts of powders, mixing them using appropriate equipment to ensure uniform mixing (for example, a “drunk barrel” mixer) and dosing into consumer packaging: sticks, sachets, bottles, etc.

The production of other forms (tablets, dispersible tablets, capsules, gel, etc.) does not present any difficulties for a pharmacist.

To assess antidiarrheal activity, in vivo efficacy was assessed using a standard serotonin-induced model of experimental diarrhea.

Diarrhea in mice weighing 20+/-5 grams was induced by intraperitoneal administration of serotonin hydrochloride (5-hydroxytryptamine - 5-HT) (H9523, Sigma-Aldrich, USA) at a dose of 0.32 mg/kg. Serotonin hydrochloride was used 30 minutes after intragastric administration of the composition and its components separately. Sodium chloride was used as a control drug, and activated carbon at a dose of 200 mg/kg was used as a comparison drug. In the experimental groups, the animals were given a single intragastric administration of aqueous suspensions of enterosorbents: gelatin tannate group 500 mg/kg, polyvinylpyrrolidone group 500 mg/kg, silicon dioxide group 100 mg/kg, polymethyl siloxane group 100 mg/kg, rehydrants group at 100 mg/kg, composition group (500 mg/kg gelatin tannate, 500 mg/kg polyvinylpyrrolidone, 100 mg/kg silicon dioxide, rehydrants 100 mg/kg).

After modeling the pathology, mice were placed one by one on a white sheet of paper to assess the time of onset of diarrhea and to count the number of defecations at hourly intervals for 4 hours. The paper covering was changed every hour. The time of onset of diarrhea and the total number of defecations were taken into account.

In the intact control group, after 15 minutes, 100% of the animals had diarrhea with a large amount of fluid and a total number of defecations of 22+/-3.

In the coal group, after 56+/-8 min., 100% of the animals had diarrhea with a total of 12+/-3 bowel movements. In the gelatin tannate (protein colloid) group, after 66+/-8 min., 100% of the animals had diarrhea with a total of 10+/-4 bowel movements.

In the polyvinylpyrrolidone (non-protein colloid) group, after 48+/-12 min., 100% of the animals had diarrhea with a total of 14+/-4 bowel movements.

In the colloid mixture group, after 78+/-10 min, 67% of the animals had diarrhea, with a total of 9+/-2 bowel movements.

In the group of the mixture of colloids and silicon dioxide, after 74+/- 12 minutes, 50% of the animals had diarrhea with a total of 7+/-2 bowel movements.

In the group of a mixture of colloids, silicon dioxide and rehydrants, after 84+/- 12 minutes, 33% of the animals had diarrhea and a total of 7+/-3 bowel movements. That is, 4 animals out of 7 had no diarrhea at all.

The results obtained indicate that the composition according to the invention has a pronounced additive effect and expands the arsenal of antidiarrheal drugs.

Claims

CLAUSE OF THE INVENTION 1. A composite antidiarrheal agent made on the basis of colloids, which is characterized in that it contains at least one protein colloid selected from the group: albumin, gelatin in the form of tannate or galate, where per 1 mass part thereof there is additionally contained from 1 to 10 mass parts of non-protein colloid polyvinylpyrrolidone with a molecular weight of not less than 6,000 Da and not more than 25,000 Da and from 0.1 to 10 mass parts of enterosorbent. 2. A composite antidiarrheal agent according to claim 1, which is characterized in that it additionally contains from 1 to 10 parts by weight of a rehydrating agent in the form of sodium, potassium, magnesium and/or calcium ions in the form of pharmaceutically acceptable salts per 1 part by weight of protein colloid. 3. A composite antidiarrheal agent according to claim 1, which is characterized in that the enterosorbent is selected from the group: silica gel (silicon dioxide), methyl silica gel (monomethylsilanetriol), methyl silica gel polymer (polymonomethylsilanetriol, otherwise called polymethylsiloxane or methylsilicic acid), aluminosilicate clays (smectites, bentonites). 4. A composite antidiarrheal agent according to claim 1, which is characterized in that it contains one or more types of monosaccharides or oligo(poly)saccharides of linear or cyclic types - cyclodextrins. 5. A composite antidiarrheal agent according to claim 1, which is characterized in that it additionally contains prebiotics selected from the group: inulin, lactiol, lactulose, chitosan and/or an antibacterial component, for example, taurolidine, nisin, or probiotics, for example, Saccharomyces boulardii, inulin.