RU2750668C2 - Local application of dioxidine in infectious and inflammatory diseases of the oral cavity - Google Patents

Abstract

FIELD: pharmacology; medicine; chemical and pharmaceutical industry.SUBSTANCE: invention relates to pharmacology, medicine and chemical and pharmaceutical industry, namely to a new local application of dioxidine (hydroxymethylquinoxalinedioxide) in the form of 0.001-0.4% wt./vol. of an aqueous solution with a pH of 3 to 7.5, where dioxidine acts as an agent, for the treatment and/or prevention of infectious and inflammatory diseases of the oral cavity and pharynx, such as stomatitis and gingivitis. The above-mentioned dioxidine solution can be used as a spray or liquid for rinsing or cleaning the oral cavity and pharynx, or in the form of drops. The use of such a dioxidine solution in the oral cavity is characterized by the absence of a side effect in the form of nausea and vomiting in case of accidental ingestion, which can be observed with the use of known dioxidine solutions (with a concentration of 0.5% and 1%).EFFECT: use of dioxidine in an aqueous solution with a concentration and pH in the above-mentioned ranges provides an increase in the photostability and resistance to self-oxidation of dioxidine in solution compared to known dioxidine solutions, an increase in the quality of dioxidine solutions and their safety due to the absence of microcrystals in them.24 cl, 5 tbl, 6 ex

Description

The invention relates to pharmacology, medicine and the chemical-pharmaceutical industry, namely to a new local use of dioxidine (hydroxymethylquinoxalindioxide) in the form of a 0.001-0.4% solution for the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx, such as stomatitis, gingivitis, periodontitis, periodontitis, periodontal or periodontal abscesses, as well as for the hygienic treatment of removable dentures, tooth root canals and treatment of wounds after tooth extraction.

Infectious and inflammatory diseases of the oral cavity and pharynx (pharyngitis, glossitis, stomatitis and gingivitis) are among the most common reasons for patients' referral to district therapists, otorhinolaryngologists, pediatricians, which is associated with a high incidence among young people of working age and children. Therapeutic tactics for infectious and inflammatory diseases of the oral mucosa and pharynx include the appointment of drugs with anti-inflammatory, analgesic, immunocorrective action, local antiseptics, decongestants and hyposensitizing drugs [1].

To date, the most widely used drugs for the treatment of acute and chronic infectious and inflammatory diseases of the mouth and throat are antibacterial drugs of both systemic and local action, mainly antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs) [2, 3, 4]. For effective treatment with antibacterial drugs, additional studies are required (identifying the main pathogens of the disease, determining whether they have resistance to antibacterial drugs, choosing the optimal drug in terms of its spectrum of action, effectiveness and safety), which take time, and the use of NSAIDs entails the development of side effects and does not lead to the elimination of pathogens. However, these disadvantages are not the only ones. Thus, in recent years, more and more attention has been paid to the problems of local therapy of this pathology, since it has been proven that most antibiotics penetrate poorly into the tissues of the oral cavity and upper respiratory tract (URT). In addition, microorganisms, both bacteria and fungi, which are the causative agents of various infections, often develop resistance to antibiotics, which also reduces the effectiveness of their use [5, 6]. Therefore, preference is given to the group of antiseptics.

However, another problem with most topical antibacterials, including antiseptics, is that they cause various side effects, including nausea and vomiting. At the same time, the treatment of chronic diseases of the oral cavity and pharynx, which requires the use of long courses of various drugs, further aggravates these side effects [4].

Thus, today the search for new effective and safe drugs for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx of a wide spectrum of action, preferably from the group of antiseptics, remains relevant.

Dioxidine (hydroxymethylquinoxalindioxide, or 2,3-bis- (hydroxymethyl) quinoxaline 1,4-di-N-oxide) is a domestic synthetic broad-spectrum antimicrobial drug. Dioxidine is a derivative of quinoxaline di-N-oxide, has antibacterial and antiprotozoal activity, is characterized by high reactivity, increased ability to polarize and redox reactions. Quinoxaline di-N-oxide derivatives have been intensively developed and studied since the 1960s. both in Russia and in other countries [7]. The drug was approved for medical use in 1976.

hydroxymethylquinoxaline dioxide

Dioxidine is an odorless greenish-yellow crystalline powder; slightly soluble in water, ethanol and chloroform. It has a wide spectrum of antibacterial action of the bactericidal type, is active against both gram-positive and gram-negative bacteria, aerobic and anaerobic, spore-forming and asporogenic bacteria in the form of macrocultures and microbial associations. An antiseptic has a destructive effect on pathogens such as staphylococci, streptococci, gonococci, treponema pallidum, Trichomonas, chlamydia, Proteus vulgaris, dysentery bacillus, Friedlander's stick, Klebsiella, Pseudomonas aeruginosa, salmonella, pathogens, etc. others, as well as herpes viruses, human immunodeficiency viruses, etc. The wide spectrum of action of dioxidine against most pathogens of hospital infections, as well as those bacterial strains that are resistant to other chemotherapy drugs, including antibiotics, determines the importance of dioxidine for therapy.

Dioxidine also has antifungal activity, in particular against Candida albicans. Candida albicans, as you know, is the causative agent of various opportunistic infections in humans, which are transmitted by contact, mainly direct (sexual, fecal-oral, transdermal), but also mediated (through furnishings, personal belongings, dishes, hygiene items, etc.) transmission mechanism. Candida albicans is one of the most common hospital-borne infections.

When used for the treatment of infected wounds, dioxidine promotes faster cleaning of the wound surface, stimulates reparative regeneration, marginal epithelization, and has a beneficial effect on the course of wound healing processes [8].

Dioxidine penetrates well into various organs and tissues, is excreted mainly by renal mechanisms and does not cumulate with repeated administrations. Despite the long period of use of dioxidine (since the 1970s) for the treatment of pyoinflammatory processes in clinical practice, the effectiveness of this drug has remained, which indicates that the resistance of microorganisms to it practically does not develop. This confirms the result of a multicenter study carried out in 2011. Data on good tolerability of the drug when applied topically have been published. During therapy with dioxidine, no nephrotoxic and ototoxic effects, as well as a negative effect on liver function, were noted [7]. The activity of dioxidine is enhanced in an anaerobic environment due to the induction of the formation of reactive oxygen species [9].

Dioxidine is characterized by sensitivity to light (photolability) [10, 11] and at the same time is an oxidizing agent, which makes it difficult to obtain stable solutions with it and the selection of auxiliary substances, especially in connection with the ability of dioxidine to self-oxidize. Based on this, dioxidine must be stored out of the reach of light at a temperature of 15-25 °, however, non-compliance with storage conditions, as noted, makes it difficult to maintain the initial concentration of dioxidine and, accordingly, the proper quality of the drug.

According to the requirements for medicinal products, their quality must be checked both directly at the factory and in pharmacies and other medical institutions after the receipt of the batch. Medicines in liquid forms are checked for authenticity and proper quality in accordance with well-known methods (determination of the color of the solution, transparency, purity of the solution - the presence of crystalline sediment and mechanical impurities, pH of the solution, etc.). One of the existing problems for a number of drugs, including dioxidine, is the rejection of some of the containers with the drug due to the presence of microcrystals in them. Basically, microcrystals are formed in connection with the ingress of impurities into the solution, which, even in small amounts, subsequently become crystallization centers. Over time, the size of the crystals increases. The effect of crystallization of a substance in a preparation can lead to a change in its concentration, the proper efficacy when using it.

The following dosage forms of dioxidine are known and introduced into clinical practice: 0.5% and 1% solutions for injections and 5% ointment. It is known to use these dosage forms of dioxidine as a topical agent for the treatment of a number of infectious and inflammatory processes in the throat [7], as well as in surgery.

A clear drawback of existing dosage forms is the lack of stability of dioxidine as a result of its photolability and the effect of self-oxidation, and the presence of microcrystals in dioxidine solutions, as well as a possible side effect in the form of nausea and vomiting if the dioxidine solution is accidentally swallowed while gargling.

Thus, the object of the present invention is to develop an effective, stable during storage, economically feasible, industrially sold preparative composition of dioxidine for topical use in the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx, which has high efficiency, increased photostability, increased resistance to self-oxidation, increased safety due to the absence of microcrystals, and no side effect of nausea and vomiting if accidentally swallowed.

The authors of the present invention unexpectedly found that aqueous 0.001-0.4% solutions of dioxidine have high antimicrobial and anti-inflammatory activity, similar to the activity of the known 0.5 and 1% solutions, in the treatment and / or prevention of infectious-inflammatory diseases of the oral cavity and pharynx in significantly increased stability and safety, and do not cause side effects in the form of nausea and vomiting if accidentally swallowed, which made it possible to create an effective, safe and stable finished dosage form for the treatment of such diseases.

The dioxidine solutions according to the present invention do not contain microcrystals due to the fact that the microcrystallization processes in them are more complicated and longer than in 1% and 0.5% dioxidine solutions, and the filtration process of dioxidine solutions according to the invention by means of membrane and tangential filtration systems is faster and more efficient than for 1% and 0.5% dioxidine solutions. The increased stability and safety of dioxidine solutions according to the present invention compared to 0.5 and 1% solutions is due to their increased resistance to self-oxidation, reduced photolability and the absence of microcrystals. Thus, the present inventors have been able to improve the quality and safety of dioxidine solutions while maintaining their effectiveness.

The technical results of the claimed invention are:

- preservation of the antimicrobial and anti-inflammatory activity of dioxidine in solutions according to the present invention in comparison with known solutions of dioxidine (0.5% and 1% solutions);

- increasing the photostability of dioxidine in solutions according to the present invention;

- increasing the resistance of dioxidine to self-oxidation in solutions according to the present invention;

- improving the quality of dioxidine solutions according to the present invention and their safety due to the absence of microcrystals in them;

- no side effect in the form of nausea and vomiting in case of accidental ingestion of dioxidine solutions according to the present invention for topical use in the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx in comparison with known dioxidine solutions (0.5% and 1% solutions) ;

- expanding the arsenal of anti-infectious and anti-inflammatory drugs for local use for the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx.

The following are definitions of terms that are used in the description of the present invention.

"Medicinal principle" or "active principle" (drug substance, drug substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, which has pharmacological activity and is the active principle of a pharmaceutical composition used for the production and manufacturing of a medicinal product (product).

"Medicinal product (preparation)" - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of a spray, liquid for rinsing or washing, capsules, injections, ointments and other ready-made forms, intended for local treatment and prevention of diseases, as well as restoration of damage epithelium and mucous membranes.

"Finished dosage form" - the state of a drug in a convenient state for use, corresponding to the methods of its administration and use, and ensuring the achievement of the required therapeutic effect.

"Pharmaceutical composition" means a composition comprising 0.001-0.4% dioxidine solution and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distribution agents such as preservatives, stabilizers, fillers, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavoring agents, flavor neutralizers, fragrances, flavors, antibacterial agents, fungicides, lubricants, the choice and ratio of which depends on their nature, method administration of the composition and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as other pharmaceutically acceptable surfactants, and mixtures of these substances. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Examples of suitable carriers, solvents, diluents, and delivery vehicles are water (purified, distilled, bidistilled, injectable), ethanol, polyalcohols, buffers and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, microcrystalline cellulose, sodium citrate, calcium carbonate, calcium phosphate, and the like. To adjust the pH, various organic and inorganic acids can be used, such as malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids, and their pharmaceutically acceptable salts, as well as pharmaceutically acceptable bases such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, ethylenediamine, monoethanolamine, diethanolamine, triethanolamine, guanidine, morpholine, piperidine, pyrrolipine, 1-buperazyl-1 , N-methylpiperazine, 1,4-dimethylpiperazine, N-benzylphenylethylamine, tris- (hydroxymethyl) aminomethane, N-methylglucosamine, arginine, lysine, ammonia, sodium hydroxide, calcium hydroxide, potassium hydroxide, aluminum hydroxide, iron hydroxide, magnesium hydroxide and zinc hydroxide, as well as other amino acids and pharmaceutically acceptable compounds. Examples of dispersing agents and distributing agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, colloidal silicon dioxide, and high molecular weight polyethylene glycol. A pharmaceutical composition for topical administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, as a mixture with conventional pharmaceutical carriers. Suitable unit forms of administration include rinses or rinses, or suspensions, sprays, aerosols, gels, ointments, and other topical forms of administration.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, auxiliary agents and / or carriers used in the pharmaceutical field. The pharmaceutical composition, along with 0.001-0.4% dioxidine solution according to the present invention, may include other active substances, including those with activity, provided that they do not cause undesirable effects.

If it is necessary to use the pharmaceutical composition of the present invention in clinical practice, it can be mixed with conventional pharmaceutical carriers.

The carriers used in the pharmaceutical compositions of the present invention are those used in the pharmaceutical field for the preparation of common forms, in particular binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, flavors, bases, diluents, additional antiseptic agents.

The dioxidine solutions according to the present invention can be aqueous solutions, aqueous alcoholic and alcoholic solutions. The dioxidine solutions according to the present invention can be isotonic solutions, hypotonic or hypertonic solutions. The most preferred are isotonic solutions of dioxidine, since they provide the most favorable conditions for epithelial cells and cells of the mucous membranes of the body. However, local application of dioxidine does not exclude the possibility of using hypertonic and hypotonic solutions, which, when applied topically, do not have pronounced adverse effects on the cells of the body.

An isotonic agent is a compound that is physiologically tolerable and imparts a suitable tonicity to the composition to prevent free passage of water through cell membranes in contact with the composition. Agents for adjusting tonicity can be any pharmaceutically acceptable compounds and non-ionic agents, including pharmaceutically acceptable salts (in particular sodium chloride), polyols (including sugar alcohols such as C3-6 sugar alcohol, glycerin, erythritol, traitol, arabitol, xylitol, ribitol, sorbitol, mannitol, dulcitol and idit), sugars or amino acids (in particular glycine). As a solvent. The solvent in aqueous solutions of dioxidine according to the present invention can be purified water, distilled water, water for injection, bidistilled water (which can be brought to isotonic solution by adding suitable pharmaceutically acceptable agents, for example, a weighed portion of sodium chloride), sodium chloride solution, solution glucose, preferably isotonic, alcohol, water-alcohol solution.

The dioxidine solutions according to the present invention have a pH (pH, acidity) of 3.0 to 7.5. However, the authors of the present invention found that the greatest activity of dioxidine solutions, including the ability to accelerate wound healing, restore damaged epithelium, reduce complications during treatment, provide conditions for rapid epithelialization of epithelial lesions of the mucous membranes, as well as the greatest stability of dioxidine solutions (photostability, resistance to self-oxidation, absence of microcrystals) is achieved at a pH value of 5.0 to 7.5, while the optimum activity of dioxidine solutions appears at a pH value of 5.2 to 7.2. Thus, more preferably, the dioxidine solutions of the present invention have a pH of 5.0 to 7.5, even more preferably, the dioxidine solutions of the present invention have a pH of 5.2 to 7.2. The pH of the dioxidine solutions according to the present invention can be adjusted by the addition of organic or inorganic pharmaceutically acceptable acids and bases.

The subject of the present invention is the use of dioxidine in the form of a 0.001-0.4% solution for the treatment and / or prevention of infectious-inflammatory diseases of the oral cavity and pharynx, more preferably in the form of a 0.01-0.4% solution, more preferably in the form of 0 05-0.40% solution, more preferably 0.095-0.40% solution, more preferably 0.10-0.40% solution, more preferably 0.10-0.35% solution more preferably in the form of a 0.10-0.30% solution, more preferably in the form of a 0.10-0.25% solution, more preferably in the form of a 0.10-0.20% solution, more preferably in the form of 0.10-0.15% solution, for example, 0.01% solution, 0.05% solution, 0.10% solution, 0.15% solution, 0.20% solution, 0.25% solution, 0 , 30% solution, 0.35% solution or 0.40% solution.

More preferred is the application where at least one infectious-inflammatory disease of the oral cavity and pharynx is selected from the group consisting of stomatitis, gingivitis, periodontitis, periodontitis, periodontal and periodontal abscess.

More preferred is the use where the infectious-inflammatory disease of the oral cavity and pharynx is an exacerbation of chronic gingivitis.

More preferred is the application where the infectious-inflammatory disease of the oral cavity and pharynx is chronic stomatitis.

More preferred is the application where the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferred is the use where the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferable is the application where the infectious-inflammatory disease of the oral cavity and pharynx is in an exacerbation stage.

More preferred is the use where the infectious-inflammatory disease of the oral cavity and pharynx is an abscess.

More preferred is an application that includes hygienic treatment of removable dentures, treatment of root canals of a tooth, and / or treatment of wounds after tooth extraction.

More preferred is the use where the dioxidine solution is a 0.1% solution.

More preferred is the application where the dioxidine solution is a 0.25% solution.

More preferred is the use where the dioxidine solution is used as a spray or liquid to rinse or rinse the mouth and throat.

More preferred is the application where the dioxidine solution is used 1 to 6 times a day.

More preferred is the application where the dioxidine solution is applied 2 to 4 times a day.

More preferred is the application where the dioxidine solution is applied 3 times a day.

More preferred is the application where the dioxidine solution is applied for 1-7 days.

More preferred is the application where the dioxidine solution is applied for 14 days.

More preferred is the application where the dioxidine solution is applied for 21 days.

More preferred is the application where the dioxidine solution is applied for 30 days.

More preferred is the application where the dioxidine solution is administered in the form of drops.

More preferred is the application where the dioxidine solution is injected into the root canals of the tooth.

More preferred is the application where the dioxidine solution is used 1 to 6 times a day.

More preferred is the application where the dioxidine solution is applied 2 to 4 times a day.

More preferred is the application where the dioxidine solution is administered to the patient 3 times a day.

More preferred is an application where the duration of the course of treatment is 1-7 days.

More preferred is an application where the duration of the course of treatment is 10 days.

More preferred is an application where the duration of the course of treatment is 14 days.

More preferred is an application where the duration of the course of treatment is 21 days.

More preferred is an application where the duration of the course of treatment is 30 days.

More preferred is the use where the dioxidine solution has a pH of 3.0 to 7.5.

More preferred is the application where the dioxidine solution has a pH of 5.0 to 7.5.

More preferred is the use where the dioxidine solution has a pH of 5.2 to 7.2.

More preferred is the use where the dioxidine solution is an isotonic solution.

More preferred is an application where sodium chloride solution is used as the isotonic solvent.

More preferred is the use where the dioxidine solution is a hypotonic solution.

More preferred is the use where the dioxidine solution is a hypertonic solution.

More preferable is the application where the solvent is a solvent selected from the group consisting of purified water, distilled water, bidistilled water, water for injection, sodium chloride solution, glucose solution.

More preferred is the use where the tonicity of the dioxidine solution is adjusted with a tonicity agent selected from the group consisting of pharmaceutically acceptable compounds, acids and bases, and nonionic agents, including pharmaceutically acceptable salts such as sodium chloride, polyols, sugar alcohols such as SZ-6 sugar alcohol, glycerin, erythritol, traitol, arabitol, xylitol, ribitol, sorbitol, mannitol, dulcite and idit, sugars or amino acids.

More preferred is the use where the dioxidine solution is an alcoholic solution.

More preferred is the use where the dioxidine solution is an aqueous alcoholic solution.

More preferred is the use where the dioxidine solution is an aqueous solution.

More preferred is the use where the dioxidine solution contains an adjuvant selected from the group consisting of a sweetener, a flavoring agent, and a flavor neutralizer.

Also, the subject of the present invention is a method for the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx, comprising local treatment of the oral cavity and throat with a 0.001-0.4% dioxidine solution, more preferably 0.01-0.4% solution, more preferably 0.05-0.40% solution, more preferably 0.095-0.40% solution, more preferably 0.10-0.40% solution, more preferably 0.10-0.35% solution, more preferably , 0.10-0.30% solution, more preferably 0.10-0.25% solution, more preferably 0.10-0.20% solution, more preferably 0.10-0.15% solution, e.g. 0.01% solution, 0.05% solution, 0.10% solution, 0.15% solution, 0.20% solution, 0.25% solution, 0.30% solution, 0.35% solution, or 0.40% solution.

More preferred is a method where at least one infectious-inflammatory disease of the oral cavity and pharynx is selected from the group consisting of stomatitis, gingivitis, periodontitis, periodontitis, periodontal and periodontal abscess.

More preferred is a method where the infectious-inflammatory disease of the oral cavity and pharynx is an exacerbation of chronic gingivitis.

More preferred is a method wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic stomatitis.

More preferred is a method wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferred is a method wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferable is the method, where the infectious-inflammatory disease of the oral cavity and pharynx is in the stage of exacerbation.

More preferred is a method where the infectious-inflammatory disease of the oral cavity and pharynx is an abscess.

More preferred is a method that includes hygienic treatment of removable dentures, treatment of root canals of a tooth, and / or treatment of wounds after tooth extraction.

More preferred is a method wherein the dioxidine solution is a 0.1% solution.

More preferred is a method wherein the dioxidine solution is a 0.25% solution.

More preferred is a method where the dioxidine solution is used as a spray or liquid to rinse or rinse the mouth and throat.

More preferred is a method where the dioxidine solution is applied 1 to 6 times a day.

More preferred is a method where the dioxidine solution is applied 2 to 4 times a day.

More preferred is the method where the dioxidine solution is applied 3 times a day.

More preferred is a method where the dioxidine solution is applied for 1-7 days.

More preferred is a method where the dioxidine solution is applied for 14 days.

More preferred is a method where the dioxidine solution is used for 21 days.

More preferred is a method where the dioxidine solution is applied for 30 days.

More preferred is the method where the dioxidine solution is applied in the form of drops.

More preferred is a method where the dioxidine solution is injected into the root canals of the tooth.

More preferred is a method where the dioxidine solution is applied 1 to 6 times a day.

More preferred is a method where the dioxidine solution is applied 2 to 4 times a day.

More preferred is a method wherein the dioxidine solution is administered to the patient 3 times a day.

More preferred is a method where the duration of the course of treatment is 1-7 days.

More preferred is a method where the duration of the course of treatment is 10 days.

More preferred is a method where the duration of the course of treatment is 14 days.

More preferred is a method where the duration of the course of treatment is 21 days.

More preferred is a method where the duration of the course of treatment is 30 days.

More preferred is a process wherein the dioxidine solution has a pH of 3.0 to 7.5.

More preferred is a process wherein the dioxidine solution has a pH of 5.0 to 7.5.

More preferred is a process wherein the dioxidine solution has a pH of 5.2 to 7.2.

More preferred is a method wherein the dioxidine solution is an isotonic solution.

More preferred is a method where sodium chloride solution is used as the isotonic solvent.

More preferred is a method wherein the dioxidine solution is a hypotonic solution.

More preferred is a method wherein the dioxidine solution is a hypertonic solution.

More preferable is a method where a solvent selected from the group consisting of purified water, distilled water, bidistilled water, water for injection, sodium chloride solution, glucose solution is used as a solvent.

More preferred is a method where the regulation of the tonicity of the dioxidine solution is carried out with a tonicity agent selected from the group consisting of pharmaceutically acceptable compounds, acids and bases, and non-ionic agents, including pharmaceutically acceptable salts such as sodium chloride, polyols, sugar alcohols such as SZ-6 sugar alcohol, glycerin, erythritol, traitol, arabitol, xylitol, ribitol, sorbitol, mannitol, dulcitol and iditol, sugars or amino acids.

More preferred is a method wherein the dioxidine solution is an alcoholic solution.

More preferred is a method wherein the dioxidine solution is a water-alcohol solution.

More preferred is a method wherein the dioxidine solution is an aqueous solution.

More preferred is a method wherein the dioxidine solution contains an adjuvant selected from the group consisting of a sweetener, a flavoring agent, and a flavor neutralizer.

The subject of the present invention is also a medicament for the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx, which is a 0.001-0.40% solution of dioxidine, more preferably 0.01-0.40% solution, more preferably 0 05-0.40% solution, more preferably 0.10-0.40% solution, more preferably 0.10-0.35% solution, more preferably 0.10-0.30% solution, more preferably 0.10-0.25% solution, more preferably 0.10-0.20% solution, more preferably 0.10-0.15% solution, for example 0.01% solution, 0.05% solution, 0.10% solution, 0.15% solution, 0.20% solution, 0.25% solution, 0.30% solution, 0.35% solution, 0.40% solution.

More preferred is a drug wherein the dioxidine solution has a pH of 3.0 to 7.5.

More preferred is a drug wherein the dioxidine solution has a pH of 5.0 to 7.5.

More preferred is a drug wherein the dioxidine solution has a pH of 5.2 to 7.2.

More preferred is a drug wherein the dioxidine solution is an isotonic solution.

More preferable is a drug in which sodium chloride solution is used as an isotonic solvent.

More preferred is a drug wherein the dioxidine solution is a hypotonic solution.

More preferred is a drug wherein the dioxidine solution is a hypertonic solution.

More preferable is a drug, where a solvent selected from the group consisting of purified water, distilled water, bidistilled water, water for injection, sodium chloride solution, glucose solution is used as a solvent.

More preferred is a medicament where the regulation of the tonicity of the dioxidine solution is carried out using an agent for adjusting the tonicity selected from the group consisting of pharmaceutically acceptable compounds, acids and bases, and non-ionic agents, including pharmaceutically acceptable salts such as sodium chloride, polyols , sugar alcohols such as SZ-6 sugar alcohol, glycerin, erythritol, traitol, arabitol, xylitol, ribitol, sorbitol, mannitol, dulcitol and idit, sugars or amino acids.

More preferred is a drug wherein the dioxidine solution is an alcoholic solution.

More preferred is a drug wherein the dioxidine solution is an aqueous alcoholic solution.

More preferred is a drug wherein the dioxidine solution is an aqueous solution.

More preferred is a medicament wherein the dioxidine solution contains an adjuvant selected from the group consisting of a sweetening agent, a flavoring agent, and a flavor neutralizer.

More preferred is a drug wherein at least one infectious-inflammatory disease of the oral cavity and pharynx is selected from the group consisting of stomatitis, gingivitis, periodontitis, periodontitis, periodontal and periodontal abscess.

More preferred is a drug wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic gingivitis.

More preferred is a drug wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic stomatitis.

More preferred is a drug wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferred is a drug wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferable is a drug, where the infectious-inflammatory disease of the oral cavity and pharynx is in an exacerbation stage.

More preferable is a drug where the infectious-inflammatory disease of the oral cavity and pharynx is an abscess.

More preferred is a medicament, where treatment and / or prophylaxis includes hygienic treatment of removable dentures, treatment of root canals of a tooth, and / or treatment of wounds after tooth extraction.

More preferred is a drug that is an aqueous 0.1% dioxidine solution.

More preferred is a drug that is an aqueous 0.25% dioxidine solution.

More preferred is a medicament, wherein said agent is a spray or liquid for rinsing or rinsing the mouth and throat.

More preferred is a medicament wherein said agent is intended to be administered 1 to 6 times a day.

More preferred is a medicament wherein said agent is intended to be administered 2 to 4 times a day.

More preferred is a medicament wherein said agent is intended to be administered 3 times a day.

More preferred is a medicament, wherein said agent is intended to be administered for 1-7 days.

More preferred is a medicament wherein said agent is intended to be used for 14 days.

More preferred is a medicament wherein said agent is intended to be used for 21 days.

More preferred is a medicament wherein said agent is intended to be administered within 30 days.

More preferred is a medicament, wherein said agent is intended to be administered in the form of drops.

More preferred is a medicament wherein said agent is introduced into the root canals of a tooth.

More preferred is a medicament wherein said agent is intended to be administered 1 to 6 times a day.

More preferred is a medicament wherein said agent is intended to be administered 2 to 4 times a day.

More preferred is a medicament wherein said agent is intended to be administered 3 times a day.

More preferable is a drug where the duration of the course of treatment is 1-7 days.

More preferred is a medicament where the duration of the course of treatment is 10 days.

More preferable is a drug where the duration of the course of treatment is 14 days.

More preferred is a drug in which the duration of the course of treatment is 21 days.

More preferred is a medicament where the duration of the course of treatment is 30 days.

The subject of the present invention is also a pharmaceutical composition for the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx, which is a 0.001-0.40% solution of dioxidine, more preferably 0.01-0.40% solution, more preferably 0 05-0.40% solution, more preferably 0.10-0.40% solution, more preferably 0.10-0.35% solution, more preferably 0.10-0.30% solution, more preferably 0.10-0.25% solution, more preferably 0.10-0.20% solution, more preferably 0.10-0.15% solution, for example 0.01% solution, 0.05% solution, 0.10% solution, 0.15% solution, 0.20% solution, 0.25% solution, 0.30% solution, 0.35% solution, 0.40% solution.

More preferred is a pharmaceutical composition wherein the dioxidine solution has a pH of 3.0 to 7.5.

More preferred is a pharmaceutical composition wherein the dioxidine solution has a pH of 5.0 to 7.5.

More preferred is a pharmaceutical composition wherein the dioxidine solution has a pH between 5.2 and 7.2.

More preferred is a pharmaceutical composition wherein the dioxidine solution is an isotonic solution.

More preferred is a pharmaceutical composition where sodium chloride solution is used as an isotonic solvent.

More preferred is a pharmaceutical composition wherein the dioxidine solution is a hypotonic solution.

More preferred is a pharmaceutical composition wherein the dioxidine solution is a hypertonic solution.

More preferable is a pharmaceutical composition, where a solvent selected from the group consisting of purified water, distilled water, bidistilled water, water for injection, sodium chloride solution, glucose solution is used as a solvent.

More preferred is a pharmaceutical composition wherein the tonicity of the dioxidine solution is adjusted with a tonicity agent selected from the group consisting of pharmaceutically acceptable compounds, acids and bases, and nonionic agents, including pharmaceutically acceptable salts such as sodium chloride, polyols , sugar alcohols such as SZ-6 sugar alcohol, glycerin, erythritol, traitol, arabitol, xylitol, ribitol, sorbitol, mannitol, dulcitol and idit, sugars or amino acids.

More preferred is a pharmaceutical composition wherein the dioxidine solution is an alcoholic solution.

More preferred is a pharmaceutical composition wherein the dioxidine solution is an aqueous alcoholic solution.

More preferred is a pharmaceutical composition wherein the dioxidine solution is an aqueous solution.

More preferred is a pharmaceutical composition wherein the dioxidine solution contains an adjuvant selected from the group consisting of a sweetening agent, a flavoring agent, and a flavor neutralizer.

More preferred is a pharmaceutical composition, where at least one infectious-inflammatory disease of the oral cavity and pharynx is selected from the group consisting of stomatitis, gingivitis, periodontitis, periodontitis, periodontal and periodontal abscess.

More preferred is a pharmaceutical composition, where the infectious-inflammatory disease of the oral cavity and pharynx is an exacerbation of chronic gingivitis.

More preferred is a pharmaceutical composition wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic stomatitis.

More preferred is a pharmaceutical composition wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferred is a pharmaceutical composition wherein the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferable is a pharmaceutical composition, where the infectious-inflammatory disease of the oral cavity and pharynx is in an exacerbation stage.

More preferred is a pharmaceutical composition wherein the infectious-inflammatory disease of the oral cavity and pharynx is an abscess.

More preferred is a pharmaceutical composition, where treatment and / or prophylaxis comprises hygienic treatment of removable dentures, treatment of root canals of a tooth, and / or treatment of wounds after tooth extraction.

More preferred is a pharmaceutical composition wherein the dioxidine solution is a 0.1% solution.

More preferred is a pharmaceutical composition wherein the dioxidine solution is a 0.25% solution.

More preferred is a pharmaceutical composition wherein the dioxidine solution is administered as a spray or liquid to rinse or rinse the mouth and throat.

More preferred is a pharmaceutical composition wherein the dioxidine solution is administered in the form of drops.

More preferred is a pharmaceutical composition wherein the dioxidine solution is injected into the root canals of the tooth.

The subject of the present invention is also a finished dosage form for the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx, which is 0.001-0.40% dioxidine solution, more preferably 0.01-0.40% solution, more preferably 0.05-0.40% solution, more preferably 0.10-0.40% solution, more preferably 0.10-0.35% solution, more preferably 0.10-0.30% solution, more preferably , 0.10-0.25% solution, more preferably 0.10-0.20% solution, more preferably 0.10-0.15% solution, e.g. 0.01% solution, 0.05% solution , 0.10% solution, 0.15% solution, 0.20% solution, 0.25% solution, 0.30% solution, 0.35% solution, 0.40% solution.

More preferred is a finished dosage form where the dioxidine solution has a pH of 3.0 to 7.5.

More preferred is a finished dosage form where the dioxidine solution has a pH of 5.0 to 7.5.

More preferred is a finished dosage form where the dioxidine solution has a pH value of 5.2 to 7.2.

More preferred is a finished dosage form where the dioxidine solution is an isotonic solution.

More preferable is the finished dosage form, where sodium chloride solution is used as an isotonic solvent.

More preferred is a finished dosage form, where the dioxidine solution is a hypotonic solution.

More preferred is the finished dosage form, where the dioxidine solution is a hypertonic solution.

More preferable is the finished dosage form, where a solvent selected from the group consisting of purified water, distilled water, bidistilled water, water for injection, sodium chloride solution, glucose solution is used as a solvent.

More preferred is a finished dosage form, where the regulation of the tonicity of the dioxidine solution is carried out using an agent for adjusting the tonicity selected from the group consisting of pharmaceutically acceptable compounds, acids and bases, and non-ionic agents, including pharmaceutically acceptable salts such as sodium chloride, polyols, sugar alcohols such as C3-6 sugar alcohol, glycerin, erythritol, traitol, arabitol, xylitol, ribitol, sorbitol, mannitol, dulcitol and iditol, sugars or amino acids.

More preferred is a finished dosage form where the dioxidine solution is an alcoholic solution.

More preferable is the finished dosage form, where the dioxidine solution is a water-alcohol solution.

More preferred is a finished dosage form where the dioxidine solution is an aqueous solution.

More preferred is a finished dosage form where the dioxidine solution contains an excipient selected from the group consisting of a sweetening agent, a flavoring agent and a flavor neutralizer.

More preferred is a finished dosage form, where at least one infectious-inflammatory disease of the oral cavity and pharynx is selected from the group consisting of stomatitis, gingivitis, periodontitis, periodontitis, periodontal and periodontal abscess.

More preferable is the finished dosage form, where the infectious-inflammatory disease of the oral cavity and pharynx is an exacerbation of chronic gingivitis.

More preferable is the finished dosage form, where the infectious-inflammatory disease of the oral cavity and pharynx is chronic stomatitis.

More preferable is the finished dosage form, where the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferable is the finished dosage form, where the infectious-inflammatory disease of the oral cavity and pharynx is chronic periodontitis.

More preferable is the finished dosage form, where the infectious-inflammatory disease of the oral cavity and pharynx is in an exacerbation stage.

More preferable is the finished dosage form, where the infectious-inflammatory disease of the oral cavity and pharynx is an abscess.

More preferable is the finished dosage form, which includes hygienic treatment of removable dentures, treatment of root canals of the tooth and / or treatment of wounds after tooth extraction.

More preferred is a finished dosage form where the dioxidine solution is a 0.1% solution.

More preferred is a finished dosage form where the dioxidine solution is a 0.25% solution.

More preferred is a finished dosage form where the dioxidine solution is used as a spray or liquid to rinse or rinse the mouth and throat.

More preferred is a finished dosage form where the dioxidine solution is used 1 to 6 times a day.

More preferred is a finished dosage form where the dioxidine solution is used 2 to 4 times a day.

More preferred is a finished dosage form where the dioxidine solution is administered to the patient 3 times a day.

More preferable is the finished dosage form, where the dioxidine solution is used for 1-7 days.

More preferable is the finished dosage form, where the dioxidine solution is used for 14 days.

More preferable is the finished dosage form, where the dioxidine solution is used for 21 days.

More preferable is the finished dosage form, where the dioxidine solution is used for 30 days.

More preferable is the finished dosage form, where the dioxidine solution is used in the form of drops.

More preferable is the finished dosage form, where the dioxidine solution is injected into the root canals of the tooth in 5 drops of the solution.

More preferred is a finished dosage form where the dioxidine solution is used 1 to 6 times a day.

More preferred is a finished dosage form where the dioxidine solution is used 2 to 4 times a day.

More preferred is a finished dosage form where the dioxidine solution is administered to the patient 3 times a day.

More preferable is the finished dosage form, where the duration of the course of treatment is 1-7 days.

More preferable is the finished dosage form, where the duration of the course of treatment is 10 days.

More preferred is a pharmaceutical composition wherein the duration of the course of treatment is 14 days.

More preferred is a pharmaceutical composition wherein the duration of the course of treatment is 21 days.

More preferred is a pharmaceutical composition wherein the duration of the course of treatment is 30 days.

Also, the subject of this invention is a kit for the treatment and / or prevention of infectious-inflammatory diseases of the oral cavity and pharynx, comprising a vial with a drug according to the present invention, a pharmaceutical composition according to the present invention or a finished dosage form according to the present invention, at least one nozzle selected from the group consisting of a spray nozzle and a dropper nozzle, and instructions for use.

The examples below illustrate, but do not cover all possible embodiments of the invention and do not limit the invention.

Example 1. Obtaining solutions of dioxidine.

Method for preparing dioxidine solutions 1.

10 g of dioxidine was mixed with 1000 ml of water for injection. The resulting solution was filtered, diluted with water for injection, and the corresponding weighed portions of NaCl were added to obtain isotonic solutions with dioxidine concentrations of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5, and 1%. The resulting solutions were filtered and placed in 10 ml ampoules, which were sealed. The pH of the solutions was in the range from 5.2 to 7.2.

Method for preparing dioxidine solutions 2.

10 g of dioxidine was mixed with 1000 ml of isotonic isotonic 0.9% NaCl solution. The resulting solution was filtered and diluted with isotonic 0.9% NaCl solution to dioxidine concentrations of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5 and 1%. The obtained isotonic solutions of dioxidine were filtered and placed in 10 ml ampoules, which were sealed. The pH of the solutions was in the range from 5.2 to 7.2.

Method for preparing dioxidine solutions 3.

We purchased a ready-made solution of dioxidine 10 mg / ml (1%), manufactured by Valenta Pharm JSC, ampoules of 10 ml, and diluted with water for injection and added the corresponding weighed amounts of NaCl until isotonic solutions were obtained with dioxidine concentrations of 0.001, 0.01, 0.1 , 0.25, 0.3, 0.4, 0.5 and 1%. The pH of the solutions was in the range from 5.2 to 7.2.

Dioxidine solutions prepared according to Production Method 1, Production Method 2 and Production Method 3 did not show statistically significant (p <0.05) differences in activity and stability. The following examples provide data on dioxidine solutions prepared according to Production Method 2.

Example 2. Study of the photostability of dioxidine solutions.

Photostability was studied on a series of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5 and 1.0% dioxidine solutions obtained in example 1, which were placed in chemically inert transparent containers with a volume 10 ml.

The light source used was an artificial daylight fluorescent lamp emitting in the visible and ultraviolet (UV) ranges, equivalent to the emission standard D65 / ID65. The samples were exposed to light providing illumination of at least 1.2 Mill. Lux / hr and the total energy of the ultraviolet spectrum near at least 200 W × h / m ² during the day [12].

The dioxidine concentration was determined by HPLC (Table 1). The initial concentration of dioxidine in the corresponding solutions of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5 and 1.0% was taken as 100%.

Sequentially chromatographed 0.02 ml of the test solution, obtaining at least five chromatograms for each of the solutions. Chromatogram registration time - not less than 6-fold retention time of the main peak of hydroxymethylquinoxylindoxide. The retention time of hydroxymethylquinoxylindoxide was about 4.4 min [13].

Table 1. The amount of dioxidine in% of the initial content according to HPLC.

Irradiation time, h Dioxidine solution concentration,% 0.001 0.01 0.1 0.25 0.3 0,4 0.5 1.0 0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 four 88.0 ± 0.2 90.1 ± 0.1 95.0 ± 0.1 93.2 ± 0.1 89.6 ± 0.1 86.0 ± 0.2 87.6 ± 0.2 81.2 ± 0.2 eight 86.5 ± 0.2 87.1 ± 0.1 91.6 ± 0.1 88.0 ± 0.2 85.0 ± 0.2 82.4 ± 0.3 77.8 ± 0.2 73.6 ± 0.3 12 80.2 ± 0.3 84.2 ± 0.2 87.4 ± 0.2 86.2 ± 0.2 82.8 ± 0.2 79.2 ± 0.2 74.8 ± 0.2 68.4 ± 0.6 eighteen 77.8 ± 0.3 81.9 ± 0.3 85.6 ± 0.2 83.4 ± 0.2 81.4 ± 0.2 77.2 ± 0.3 71.2 ± 0.2 66.0 ± 0.5 24 75.1 ± 0.5 80.6 ± 0.3 85.0 ± 0.3 82.0 ± 0.3 80.2 ± 0.2 75.0 ± 0.3 70.4 ± 0.4 65.0 ± 0.9

It was found that after a day of irradiation, solutions of dioxidine 0.01, 0.1, 0.25, 0.3, 0.4% according to the present invention had better indicators of chemical purity in comparison with solutions with concentrations of 0.5 and 1.0% ...

Example 3. Study of the resistance of dioxidine to self-oxidation.

An experiment was carried out on the resistance of dioxidine to self-oxidation in aqueous solutions.

The resistance to self-oxidation of dioxidine in aqueous solutions was studied on a series of solutions of dioxidine 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5 and 1.0%, prepared according to example 1, and placed in ampoules of 10 ml, which were sealed. For better visualization of self-oxidation processes, ampoules with dioxidine solutions were placed in a thermostat at 70 ° (normal storage conditions for dioxidine solutions suggest storage in a place inaccessible to light at 15-25 °) [12]. The results of the study are presented in Table 2.

The dioxidine concentration was determined by HPLC (Table 2). The initial concentration of dioxidine in the corresponding solutions of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5 and 1.0% was taken as 100%.

Sequentially chromatographed 0.02 ml of the test solution, obtaining at least five chromatograms for each of the solutions. The chromatogram registration time is at least 6 times the retention time of the main peak of hydroxymethylquinoxylindoxide [13].

Table 2. The amount of dioxidine in% of the initial content according to HPLC data in an aqueous solution when heated to 70 °.

Storage time, h Dioxidine concentration in solution,% 0.1 0.25 0.3 0,4 0.5 1.0 0 100.0 100.0 100.0 100.0 100.0 100.0 five 99.9 ± 0.01 99.8 ± 0.01 99.7 ± 0.01 99.7 ± 0.02 99.6 ± 0.2 99.1 ± 0.3 10 99.8 ± 0.1 99.7 ± 0.2 99.7 ± 0.2 99.5 ± 0.2 99.2 ± 0.2 98.3 ± 0.2 fifteen 99.8 ± 0.1 99.6 ± 0.2 99.5 ± 0.2 99.3 ± 0.3 98.9 ± 0.3 97.6 ± 0.4 twenty 99.7 ± 0.2 99.6 ± 0.2 99.4 ± 0.5 99.1 ± 0.2 98.5 ± 0.3 97.1 ± 0.4 thirty 99.6 ± 0.2 99.4 ± 0.3 99.3 ± 0.2 98.8 ± 0.3 97.9 ± 0.4 96.7 ± 0.5 45 99.5 ± 0.3 99.4 ± 0.3 99.1 ± 0.2 98.3 ± 0.4 96.8 ± 0.5 95.2 ± 0.6

It was found that by the end of the second day of heating, dioxidine solutions according to the present invention had better stability indicators (resistance to self-oxidation) compared to solutions with concentrations of 0.5 and 1.0% with a statistical significance level of p <0.05.

Example 4. Study of the antimicrobial activity of dioxidine solutions against potential causative agents of various infections in the field of surgery and diseases of the oral cavity and pharynx.

The study is carried out on a panel of 39 strains of bacteria and fungi (Table 3) on a series of solutions of dioxidine 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5 and 1.0%, prepared according to example 1.

Table 3. Tested strains of microorganisms

Types of bacteria (gram - + / -) Strain code Types of bacteria (gram - + / -) Strain code Facultative anaerobes Serratia marcescens (-) ATCC 29021 Staphylococcus aureus (+) ATCC 29213 Citrobacter werkmanii (-) ATCC 51114 Staphylococcus aureus (+) NRS384 * Aerobic bacteria Staphylococcus aureus (+) NRS123 * Haemophilus influenzae (-) ATCC 49247 Staphylococcus aureus (+) NRS100 * Pseudomonas aeruginosa (-) ATCC 27853 Staphylococcus aureus (+) NRS70 * Stenotrophomonas maltophilia (-) ATCC 700267 Staphylococcus aureus (+) NRS382 * Acinetobacter baumannii (-) ATCC 17978 Staphylococcus aureus (+) NRS483 * Moraxella catarrhalis (-) ATCC 43617 Staphylococcus aureus (+) NRS71 * Neisseria meningitidis (-) ATCC 13077 Staphylococcus aureus (+) NRS112 * Anaerobic bacteria Staphylococcus aureus (+) NRS1 * Peptostreptococcus anaerobius (+) ATCC 27337 Staphylococcus epidermidis (+) ATCC 35983 Bacterioides fragilis (-) ATCC 25285 Streptococcus pneumoniae (+) ATCC 49619 Treponema denticola (-) ATCC 35405 Streptococcus pyogenes (+) ATCC BAA-572 Porphyromonas gingivalis (-) ATCC 33277 Streptococcus oralis (+) ATCC 55229 Fusobacterium nucleatum (-) ATCC 25586 Enterococcus faecalis (+) ATCC 29212 Prevotella intermedia (-) ATCC 25611 Enterococcus faeclum (+) ATCC 700221 Aggregatibacter actinomycetemcomitans (-) ATCC 33384 Escherichia coli (-) ATCC 25922 Actinomyces israelii (+) ATCC 23860 Klebsiella pneumoniae (-) ATCC 43816 Mushrooms Enterobacter cloacae (-) ATCC 222 Candida albicans ATCC 10231 Enterobacter aerogenes (-) ATCC 13048 Aspergillus niger ATCC 16404 Proteus mirabilis (-) ATCC 29906 Candida glabrata ATCC 60406

Notes: * MRSA (methicillin-resistant Staphylococcus aureus)

Used 39 96-well plates to test the antimicrobial activity of dioxidine, each plate was used to determine the antimicrobial activity of dioxidine solutions in relation to one of the strains of bacteria or fungi (see Table 3). All operations were performed in compliance with sterility requirements. In 55 wells of the plate, 100 μl of a suitable medium for the cultivation of the strain were sequentially introduced, then 100 μl of the cell suspension of the corresponding strain were added and thoroughly mixed. Then, 100 μL of 0.001% dioxidine solution was sequentially introduced into five wells of the plate and the resulting mixture was thoroughly mixed again. A similar procedure was performed for all subsequent concentrations of dioxidine solutions up to 1% solution. Wells 51 to 55 of the plate did not add dioxidine solution, they only contained culture medium and cell suspension, and served as a control. The plate was further incubated under conditions optimal for the given strain [14]. After 24 hours, the results were checked by viewing the plates in transmitted light and determining the optical density (OD) of the cell culture in the wells using a microplate reader [15]. The growth of the culture in the presence of dioxidine was compared with the growth of the culture in five control wells.

All series of dioxidine solutions were highly active against all tested bacterial strains and Candida albicans fungi, inhibiting cell growth. The Aspergillus niger fungal strain showed resistance to dioxidine.

Thus, dioxidine solutions with concentrations of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4% exhibited high antibacterial activity, comparable to currently used solutions with concentrations of 0.5 and 1.0 %.

Example 5. Study of dioxidine solutions for the presence of the effect of vomiting when swallowed.

The study used 90 Wistar rats of both sexes, which were randomly divided into 9 groups, in each experimental group, 10 animals: dioxidine 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0, 5 and 1.0%, as well as the control group. Dioxidine solutions were prepared according to example 1. The rats were housed in five rats in temperature-controlled boxes (with an average temperature of 21 ° C) under a 12-hour day and night cycle and with sufficient water and food.

Each experimental group was orally administered using a probe a solution of dioxidine with an appropriate concentration in an amount of 20 ml / kg, and the control group - isotonic NaCl solution at a rate of 20 ml / kg. Within 10 minutes after administration of the solution, the rats were placed in air conditioning chambers made of black opaque plexiglass (22.5 x 26 x 20 cm), which were located on a table with a transparent glass top in a dark room with two 25 W lamps next to the chambers. ... A mirror under the camera at an angle of 45 ° facilitated the view of the ventral surface of the rat to observe orofascial reactions. The rats were left in the chamber for 5 minutes, during which their behavior was recorded on video. Videos from the test trial were later assessed by an observer for the gaping response (mouth wide open with lower incisors open). Immediately after the 5 minute test, the rats were given a 15 minute locomotion test to assess their condition. The practice chamber was built of white plexiglass measuring 60 cm x 25 cm x 25 cm and was located in another room, illuminated by red light. A video camera installed on an extension cord recorded the activity of the rat and sent the data to a computer for analysis of the distance traveled (cm) using the Ethovision program (Noldus, Inc, NL) [16, 17]. After analyzing the data obtained, the reactions of gaping to dioxidine solutions were classified according to their severity (weak, moderate, medium, strong).

Table 4. Reaction of rats to dioxidine solutions when swallowed.

Dioxidine concentration in solution,% Gaping reaction The severity of the gaping reaction control Absent* Absent 0.1 Absent* Absent 0.25 Absent* Absent 0.3 Absent* Absent 0.5 Present at 3 out of 10 ** Moderate in 1, weak in 2 1.0 Present at 9 out of 10 *** Moderate in 3, strong in 1, moderate in 3, weak in 2

* Animals from the group did not show a gaping response; no statistically significant differences in their motor activity were found compared to animals from the control group.

** The remaining animals from the group did not show a yawning response, but there was a statistically significant decrease in their motor activity compared to animals from the control group;

*** The remaining animal from the group did not show a yawning response, but there was a statistically significant decrease in its motor activity compared to animals from the control group.

The presented data indicate that accidental ingestion of small amounts of dioxidine solution with a concentration of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4% does not cause such a side effect as vomiting.

Example 6. Study of the antibacterial activity of dioxidine solutions on the model of acute periodontal disease.

The study used 90 Wistar rats of both sexes, which were randomly divided into 9 groups, in each experimental group, 10 animals: dioxidine 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0, 5 and 1.0%, as well as the control group. Dioxidine solutions were prepared according to example 1. The rats were housed in five rats in temperature-controlled boxes (with an average temperature of 21 ° C) under a 12-hour day and night cycle and with sufficient water and food.

In order to reproduce inflammatory and degenerative lesions of the soft tissues of the periodontal rats anesthetized with ether, 0.15 ml was injected into the outer part of the gums at the level of the lower molars on each side of a 2% aqueous solution of formaldehyde (the total volume of the injected solution was 0.3 ml). The injections were made once [18]. Severe inflammation in the oral cavity in rats occurred two days after the introduction of formaldehyde and was expressed in reddening and bleeding of the gums, and swelling of periodontal tissues. By the end of the second day, rats were injected into the gum area with 5 μl of suspensions of microorganisms Porphyromonas gingivalis and Bacterioides fragilis at a concentration of 1⋅10 ⁷ CFU / ml. On the second or third day after the introduction of microorganisms, the level of inflammatory reactions reached a maximum, with pronounced extensive inflammatory and degenerative changes in the soft tissues of the periodontium, intense hyperemia and edema in the periodontal area, and serous-purulent discharge from the periodontal tissues. Acute abscess formation of the process was observed in some rats (in 20% of rats). The animals refused to eat. In animals, a gradual increase in body temperature to subfebrile (by an average of 0.8 ° C) was recorded, and by the fifth day in the control group, the temperature in some animals reached febrile numbers (an average of 1.9 ° C).

Solutions of the test drug dioxidine at concentrations of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5 and 1.0% washed the oral cavity of animals through a syringe 3 times a day for 5 days in a volume of 5 ml. Control (with no treatment) animals were rinsed with a saline solution in a volume of 5 ml.

To assess the systemic effect of solutions of the test drug dioxidine at concentrations of 0.001, 0.01, 0.1, 0.25, 0.3, 0.4, 0.5 and 1.0% on the body in the blood of experimental animals, the level of TNF- α after 4 hours and INF-γ after 16 hours, the level of C-reactive protein (CRP) after 72 hours from the moment of drug administration [19]. The data obtained are presented in table 5 with a statistical significance level of p <0.05.

Table 5. Activity of dioxidine solutions in the model of acute periodontal disease.

Dioxidine solution concentration,% TNF-α, ng / ml INF-γ, ng / ml C-reactive protein, mg / l Control 257 ± 5 73 ± 4 35.7 ± 0.3 0.001 194 ± 5 * 59 ± 6 * 22.8 ± 0.5 * 0.01 189 ± 5 * 56 ± 6 * 22.4 ± 0.4 * 0.1 183 ± 5 * 54 ± 5 * 22.1 ± 0.3 * 0.25 175 ± 2 * 51 ± 2 * 19.4 ± 0.3 * 0.3 171 ± 3 * 49 ± 2 * 19.1 ± 0.4 * 0,4 166 ± 3 * 48 ± 3 * 18.7 ± 0.2 * 0.5 158 ± 2 * 46 ± 3 * 18.2 ± 0.2 * 1.0 144 ± 5 * 41 ± 3 * 17.4 ± 0.2 *

* - significance level p <0.05 in comparison with the control group according to Student's test.

In addition to assessing the levels of TNF-α, INF-γ and CRP in the blood of animals after the start of treatment with dioxidine solutions, a visual assessment of the state of periodontal tissues was also performed. After the application of dioxidine solutions, already on day 3, the animals showed a noticeable decrease in inflammation in the periodontal tissues, their redness and swelling, and the appearance of appetite.

Thus, in the course of the experiment, it was shown that when using solutions of the studied drug as a therapy, dioxidine at concentrations of 0.001%, 0.01%, 0.1%, 0.25%, 0.3%, 0.4%, 0 , 5% and 1.0%, a statistically significant (p <0.05) pronounced anti-inflammatory effect was revealed, which makes it possible to use them in the treatment of infectious and inflammatory diseases of the oral cavity as an antibacterial and anti-inflammatory agent.

The invention can be used in medicine, chemistry, pharmaceutical industry.

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Claims (24)

1. The use of dioxidine in the form of 0.001-0.4% wt./about. an aqueous solution with a pH of 3 to 7.5, where dioxidine acts as an active principle, for topical use for the treatment and / or prevention of infectious and inflammatory diseases of the oral cavity and pharynx, such as stomatitis and gingivitis. 2. Use according to claim 1, characterized in that the infectious-inflammatory disease of the oral cavity and pharynx is in an exacerbation stage. 3. Use according to claim 2, characterized in that the infectious-inflammatory disease of the oral cavity and pharynx is an abscess. 4. The use according to claim 1, characterized in that the dioxidine solution is 0.1% w / v. solution. 5. The use according to claim 1, characterized in that the dioxidine solution is 0.25% w / v. solution. 6. Use according to claim 1, characterized in that the dioxidine solution is used in the form of a spray or liquid for rinsing or rinsing the mouth and throat. 7. Use according to claim 1, characterized in that the dioxidine solution is used from 1 to 6 times a day. 8. Use according to claim 1, characterized in that the dioxidine solution is used 2 to 4 times a day. 9. Use according to claim 1, characterized in that the dioxidine solution is used 3 times a day. 10. Application according to PP. 1, 7-9, characterized in that the dioxidine solution is used for 1-7 days. 11. Application according to PP. 1, 7-9, characterized in that the dioxidine solution is used for 10 days. 12. Application according to PP. 1, 7-9, characterized in that the dioxidine solution is used for 14 days. 13. Application according to PP. 1, 7-9, characterized in that the dioxidine solution is used for 21 days. 14. Application according to PP. 1, 7-9, characterized in that the dioxidine solution is used within 30 days. 15. Use according to claim 1, characterized in that the dioxidine solution is used in the form of drops. 16. Use according to claim 15, characterized in that the dioxidine solution is used 1 to 6 times a day. 17. Use according to claim 15, characterized in that the dioxidine solution is used 2 to 4 times a day. 18. Use according to claim 15, characterized in that the dioxidine solution is administered to the patient 3 times a day. 19. Application according to PP. 15-18, characterized in that the duration of the course of treatment is 1-7 days. 20. Application according to PP. 15-18, characterized in that the duration of the course of treatment is 10 days. 21. Application according to PP. 15-18, characterized in that the duration of the course of treatment is 14 days. 22. Application according to PP. 15-18, characterized in that the duration of the course of treatment is 21 days. 23. Application according to PP. 15-18, characterized in that the duration of the course of treatment is 30 days. 24. Use according to claim 1, characterized in that the dioxidine solution contains an auxiliary substance selected from the group consisting of a sweetening agent, a flavoring agent and a flavor neutralizer.