EA043949B1 - PHARMACEUTICAL COMPOSITION FOR TREATMENT OF INFECTIOUS AND INFLAMMATORY DISEASES - Google Patents

Description

The invention relates to the field of medicine and the chemical-pharmaceutical industry, namely to a new pharmaceutical composition for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx for local use, including gramicidin C and ambroxol or their pharmaceutically acceptable salts, and a method for its preparation and use.

The most common diseases of social significance include infectious diseases of the oral cavity and pharynx (pharyngitis, glossitis, stomatitis and gingivitis), as well as the upper respiratory tract (adenoiditis, tonsillitis, laryngitis). Despite the significant potential of the means that modern medicine has to combat these diseases, the problem still remains relevant. This is largely due to both the high incidence rate and the very nature of microorganisms, which are constantly changing and forming resistant strains. The resistance of microorganisms to antibacterial agents is an important problem that determines the correct choice of a particular drug for treating a patient. In the first years after the discovery of penicillin, about 99% of pathogenic staphylococci were sensitive to this antibiotic; in the 1960s no more than 20-30% of staphylococci remain sensitive to penicillin. The growth of resistant forms is due to the fact that antibiotic-resistant mutants constantly appear in bacterial populations, which are virulent and spread mainly in cases where sensitive forms are suppressed by an antibiotic. From a population genetic point of view, this process is reversible. Therefore, when an antibiotic is temporarily removed from the arsenal of therapeutic agents, resistant forms of microorganisms in populations are again replaced by sensitive forms that multiply faster.

Infectious and inflammatory diseases of the oral cavity and pharynx (tonsillitis, pharyngitis, glossitis, stomatitis and gingivitis) are among the most common reasons for patients to visit local physicians, otolaryngologists, and pediatricians, which is associated with a high incidence rate among young people of working age and children. Therapeutic tactics for infectious and inflammatory diseases of the mucous membrane of the oral cavity and pharynx include the prescription of drugs with anti-inflammatory, analgesic, immunocorrective effects, local antiseptics, antimicrobial, decongestant and hyposensitizing drugs [Morozova S.V. Pain in the throat: causes and possibilities of drug therapy. RMJ, vol. 13, no. 21, 2005, p. 1447-1452].

For example, a dosed Antiangin spray for topical use is known, containing chlorhexidine gluconate in the form of a 20% solution, tetracaine hydrochloride and excipients: glycerin 85% - 60.00 mg/30.00 g, ethanol 96% - 80.00 mg/40, 00 g, aspartame - 0.20 mg/0.10 g, mint flavor - 2.00 mg/1.00 g, propyl parahydroxybenzoate - 0.20 mg/0.10 g, anhydrous citric acid -0.02 mg/0 .01 g, purified water - up to 200 mg/up to 100 g [http://medi.ru/doc/a2901s.htm]. At the same time, chlorhexidine is effective against pathogens of sexually transmitted infections, such as gardnerellosis and genital herpes; gram-positive and gram-negative bacteria - Treponema spp., Neisseria gonorrhoeae, Trichomonas spp., Chlamidia spp., Ureaplasma spp., but does not act on acid-fast forms of bacteria, microbial spores, fungi, has a bitter taste and is not active against most viruses, with prolonged use may stain teeth and tongue, is not compatible with some components of toothpastes, in some cases may cause irritation of the mucous membrane, allergic reactions, burning sensation, recommended for use in children over 12 years of age, may cause vomiting if swallowed.

At the same time, antibiotics remain the main antibacterial drugs used to treat this group of diseases. New generations of antibiotics are being introduced into medical practice. At the same time, there is a tendency, along with the search for new pharmacological agents, to maximize the potential of already known agents.

These drugs include gramicidin C, one of the first domestic antibiotics, first obtained by I.F. Gause and M.G. Brazhnikova in 1942

Gramicidin belongs to the group of polypeptide antibiotics with a broad spectrum of action, has a bacteriostatic and bactericidal effect on streptococci, staphylococci, pneumococci, pathogens of anaerobic infection and other microorganisms. Produced by the spore bacillus Bacillus brevis or Aneurinibacillus migulanus [RF patent No. 2627182, publ. 08/03/2017].

The drug has a pronounced bactericidal effect against pathogenic gram-positive and gram-negative bacteria, which in most cases either directly cause diseases of the oral cavity and pharynx, or are secondary to an initially viral infection - Streptococcus spp., Staphylococcus spp., Streptococcus pneumoniae, Neisseria, etc. The drug also has some fungistatic and antiviral activity. According to modern ideas about rational antibiotic therapy, in order to prevent the emergence and spread of resistant strains of microorganisms, in all cases where the causative agent of infection can be predicted with a high degree of probability, it is recommended to give preference to such drugs. Resistance to polypeptides develops quite rarely. There are very few reports in the literature of the isolation of gramicidin-resistant strains of microorganisms from patients or from natural sources. It is very difficult to obtain strains resistant to this antibiotic in the laboratory.

- 1 043949 tor conditions [Polin A.N., Egorov N.S. Structural and functional features of gramicidin C in connection with its antibiotic activity // Antibiotics and chemotherapy. - 2003. - No. 48(12). - With. 29-32].

Due to the originality of the chemical structure and mechanism of action of gramicidin, resistance to it should not be accompanied by an increase in the level of resistance to antibiotics for systemic use.

Source [RF patent No. 2532027, publ. 10.27.2014] discloses a liquid composition for topical application containing a pharmaceutical active ingredient, a solvent mixture containing water, isopropanol in an amount from 5 to 20 wt.% and propylene glycol in an amount from 2 to 25 wt.%, and a phospholipid foaming agent in an amount from 2 to 25 wt.%. An extensive list of substances from different pharmacological groups is listed as active ingredients, including gramicidin C, oxybuprocaine hydrochloride and cetylpyridinium chloride. The foam formulation is suitable primarily for application to the skin and wounds, and there is no indication of oral administration.

An antibacterial agent is known in the form of a tablet containing gramicidin C and excipients, characterized in that it contains powdered sugar and milk sugar as excipients in a ratio of 1:1, methylcellulose and calcium stearate in the following ratio of components, wt.%:

gramicidin C - 0.2-0.4;

powdered sugar - 48.1-48.4;

milk sugar - 48.1-48.4;

methyl cellulose MC-100 - 0.2-0.4;

calcium stearate - 2.8-3.0 [RF patent No. 2213558, publ. 10.10.2003]. The disadvantage of the disclosed technical solution is the increased sugar content, which can have a harmful effect on tooth enamel, and lactose is unacceptable for patients with lactose intolerance.

A pharmaceutical composition for the treatment of infectious and inflammatory diseases is known in the form of a solution for topical use, characterized in that it contains as an active principle a combination of gramicidin C dihydrochloride and cetylpyridinium chloride, as excipients - ethanol 96%, sucralose, glycerin, citric acid monohydrate , sodium citrate, polysorbate, methylparaben, propylparaben, natural mint flavor, purified water [RF patent No. 2633635, publ. 10/16/2017]. The disadvantage of the proposed solution is the absence of substances with activity other than inhibiting the growth of microorganisms, which can reduce the effectiveness of the drug used due to the fact that the pathogenesis of inflammatory diseases of the oral cavity, pharynx and upper respiratory tract is quite multifactorial and is associated with a comorbid relationship with symptoms of the lower respiratory tract, such as cough as below.

A pharmaceutical composition for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx for local use is known, which contains as an active principle a combination of gramicidin C dihydrochloride, oxybuprocaine hydrochloride and cetylpyridinium chloride, as excipients - 96% ethanol, sucralose, glycerin, citric acid monohydrate, sodium citrate, polysorbate, methylparaben, propylparaben, natural mint flavor, purified water [RF patent No. 2604576, publ. 12/10/2016]. The implementation of the invention makes it possible to reduce side effects from the use of a composition with gramicidin and increase the uniformity of dosing. The disadvantage of this technical solution is that the presence of an analgesic may mask the symptoms of inflammation of the mucous membrane.

A pharmaceutical composition for the treatment of infectious and inflammatory diseases is known in the form of a solution for topical use, characterized in that it contains as an active principle a combination of gramicidin C dihydrochloride, oxybuprocaine hydrochloride and cetylpyridinium chloride, as excipients - ethanol 96%, sucralose, glycerin, citric acid monohydrate, sodium citrate, polysorbate, methylparaben, propylparaben, natural mint flavor, purified water [RF patent No. 2627423, publ. 08.08.2017]. Similar to what was described above, the disadvantage of this solution is also the presence of an analgesic, the action of which can mask the symptoms of inflammation of the mucous membrane.

Currently, a combined drug is being produced in the form of lozenges for the treatment of infectious and inflammatory diseases of the pharynx and oral cavity Grammidin with the anesthetic neo, which includes gramicidin C, oxybuprocaine hydrochloride and cetylpyridinium chloride [Instructions for the medical use of the drug Grammidin with the anesthetic neo, Internet - website of the Ministry of Health of the Russian Federation, URL: http://grls.rosminzdrav.ru/InstrImg.aspx?idReg=11177].

At the same time, infectious and inflammatory diseases of the oral cavity and pharynx are often accompanied by a cough, which is caused by respiratory viral infections localized in both the upper and lower respiratory tracts. In these cases, coughing contributes to the spread of infection, transferring pathogens from the lower respiratory tract to the pharyngeal cavity and irritating the mucous membrane of the upper respiratory tract.

Cough is one of the common complaints with which patients consult a doctor. The reason for contacting, as a rule, is a painful cough that interferes with the patient’s quality of life, or the appearance of other symptoms that bother the patient along with the cough.

Therefore, the creation of new pharmaceutical compositions for the treatment of infectious inflammatory diseases of the oral cavity and pharynx, accompanied by cough, is an urgent task of modern pharmacology.

In the treatment of diseases accompanied by cough with sputum difficult to separate, stimulants of motor function of the respiratory tract are most often used, one of which is ambroxol.

Ambroxol, 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol (and in the form of hydrochloride), white crystalline powder, odorless, slightly bitter taste, like bromhexine, belongs to derivatives of the alkaloid vizicine , however, has a more pronounced effect, since it is its active metabolite.

Ambroxol

A drug based on ambroxol stimulates mucociliary activity and has an expectorant effect. Ambroxol is widely used in the treatment of cough due to acute respiratory viral infections and has proven itself to be an effective and safe medicine.

The high efficacy and good tolerability of ambroxol allow some foreign authors to recommend it as a drug of choice for the prevention of chronic bronchitis [Michnar M., Milanowski J. Clinical evaluation of efficacy and tolerance of oral treatment with ambroxol in patients with chronic bronchitis//Pneumonol. Alergol. Pol., 1996; 64 (suppl.1): 90-96]. Russian specialists who studied the effectiveness of ambroxol in outpatients with COPD came to the conclusion that the mucolytic properties of the drug are maximally realized in dys- and hypercrinia, i.e. in patients with chronic bronchitis [Novikov Yu.K., Belevsky A.S. Mucolytics in the complex treatment of COPD//Attending physician. 2001. - No. 2 - P.62-64].

The effectiveness of ambroxol in diseases of the respiratory tract has been proven not only in adults, but also in children [Baldini G., Gucci M., Taro D., Memmini S. A controlled study on the action of a new formulation of ambroxol in asthmatiform bronchitis in children/ /Minerva Pediatr. 1989; vol. 41, pp. 91-95].

The addition of ambroxol to antibacterial drugs in children with lower respiratory tract infections led to more rapid elimination of cough and other clinical symptoms compared to placebo, as well as normalization of radiological changes [Spatola J., Poderoso J.J., Wiemeyer J.C., et al. Influence of ambroxol on lung tissue penetration of amoxicillin//Arzneimittelforschung, 1987, vol.37, pp. 965-66]. At the same time, excellent tolerability of the drug by children was noted. The safety of ambroxol is confirmed by its widespread use in neonatology and in pregnant women (II and III trimesters) [Kimya Y., Kucukkomurcu S., Ozan H., Uncu G. Antenatal ambroxol usage in the prevention of infant respiratory distress syndrome. Beneficial and adverse effects//Clin. Exp. Obstet. Gynecol., 1995, vol. 22, pp. 204-11].

A solid, absorbable or slowly dissolving dosage form of a pharmaceutical composition is known, containing ambroxol or one of its pharmacologically acceptable salts and one or more active ingredients selected from the group including antiseptics, vitamins, corticosteroids, anti-inflammatory drugs, antibiotics, antifungals and proteolytic agents. enzymes, as well as a semi-solid dosage form of a pharmaceutical composition containing ambroxol, or one of its pharmacologically acceptable salts and one or more active ingredients selected from the group including antiseptics, vitamins, corticosteroids, anti-inflammatory drugs, antibiotics, antifungals and proteols. tic enzymes, in the form of a gel [RF patent No. 2311176, publ. November 27, 2007]. The specified technical solution can be taken as the closest analogue (prototype). At the same time, RF patent No. 2311176 does not disclose the use of gramicidin together with ambroxol in dosage forms for topical use in the oral cavity and pharynx, and there is no indication of the possibility of synergy between them.

A lozenge containing ambroxol based on sugar alcohols as a matrix material is known, characterized in that it contains a pharmaceutically acceptable layered silicate (for example, talc) and polyethylene glycol and optionally other pharmaceutical excipients, flavoring agents, or flavoring agents [Eurasian patent EA 004044, publ. 12/25/2003].

There is a known method for the treatment of acute pharyngitis, which consists in the local application of ambroxol hydrochloride in a dose of 10 mg as part of a composition suitable for spraying containing ambroxol hydrochloride in an amount of 1 to 30 mg/ml [Eurasian patent EA 027291, publ. 07/31/2017].

However, to date there are no known combinations of gramicidin C and ambroxol or their pharmaceutically acceptable salts for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx.

The authors unexpectedly discovered that the combination has increased anti-inflammatory and antibacterial properties, the presence of which could not be predicted based on the prior art. Without wishing to be bound by any theory, the authors suggest that these properties of the combination may be due to the presence of antibacterial [Instructions for medical use of the drug Mucoangin, lozenges 20 mg No. 10, Mini Doctor website, URL: https:// minr-doctor.com/pilul/mukoangin_tabletkr_dlya_rassasivaniya_po__mg_-13804.pdf) and anti-inflammatory (Product monograph. Revised assessment report Procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data Ambroxol and bromhexine containing medicinal products, available at http: //www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/ Ambroxol_and_bromhexine_31/Recommendation_rovided_by_Pharmacovigilance_Risk_Assessment_ Committee/WC500184106.pdf) properties of ambroxol and anti-inflammatory properties of biomembrane permeabilizing agents such as gramicidins (Famaey, J.P., Whitehouse, M.W. About some possible anti-inflammatory properties of various membrane permeant agents II Agents and Actions, 1975, vol. 5 (2), pp. 133-136).

Thus, the objective of the present invention is to create a new combination of gramicidin C and ambroxol for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx.

Technical results:

increasing the effectiveness of products containing gramicidin due to the synergistic effect of gramicidin with ambroxol and, as a result, increasing its anti-inflammatory and antibacterial properties;

increased safety, reduced side effects;

accelerating the onset of the therapeutic effect, expanding the arsenal of drugs for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx.

The problem is solved, and the technical result is achieved by creating a combination of gramicidin C and ambroxol or their pharmaceutically acceptable salts for the treatment of infectious inflammatory diseases of the oral cavity and pharynx.

According to preferred embodiments, this technical result is also achieved by the fact that infectious and inflammatory diseases of the oral cavity and pharynx are selected from the group including pharyngitis, glossitis, stomatitis, gingivitis, adenoiditis, tonsillitis and laryngitis;

active ingredients are in mass ratios of gramicidin C: ambroxol from 2:1 to 1:1000;

active ingredients are in mass ratios of gramicidin C: ambroxol from 1:1 to 1:100;

active ingredients are in mass ratios of gramicidin C: ambroxol from 1:2 to 1:10;

active ingredients are in mass ratios of gramicidin C: ambroxol from 1:5 to 1:10;

active ingredients are in mass ratios of gramicidin C: ambroxol 1:5 or 1:10, or 3:25;

active ingredients are used in daily dosages ambroxol - 7.5-200 mg/day; gramicidin - 0.2-40 mg/day;

active ingredients are used in daily dosages ambroxol - 15-120 mg/day; gramicidin - 1.5-12 mg/day;

active ingredients are used in daily dosages ambroxol - 20-100 mg/day; gramicidin - 1.5-12 mg/day;

active ingredients are used in daily dosages

- 4 043949 ambroxol - 30-45 mg/day; gramicidin - 1.5-4.5 mg/day;

active ingredients are used in daily dosages ambroxol - 7.5-22.5 mg/day; gramicidin - 1.5-4.5 mg/day, the mentioned combination is intended for topical use in the oral cavity and pharynx;

ambroxol and gramicidin C are used simultaneously in the form of a joint dosage form or two different dosage forms;

ambroxol and gramicidin C are used sequentially in the form of two different dosage forms in any order;

the mentioned combination is administered from 1 to 6 times a day;

the mentioned combination is administered 1 to 4 times a day;

the mentioned combination 1 to 3 times a day;

the pharmaceutically acceptable salt of gramicidin C is gramicidin C dihydrochloride, and the pharmaceutically acceptable salt of ambroxol is ambroxol hydrochloride;

said combination contains at least one additional active substance selected from an antiseptic, anesthetic, antibiotic, proteolytic enzyme, vitamin, mucolytic, expectorant, anti-inflammatory, immunomodulatory, antiviral, antifungal and biofilm-disrupting agent;

the anesthetic is selected from the group consisting of lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anesthesin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene, dyclonine, hexylresorcinol and pharmaceutically acceptable salts thereof;

the antibiotic is selected from the group consisting of tyrothricin, bacitracin, amoxicillin, fusafungin, ambazone, polymyxin, neomycin, tobramycin and framycytin;

the proteolytic enzyme is lysozyme or papain;

the vitamin is selected from dexpanthenol, pyridoxine or ascorbic acid;

the antifungal agent is selected from fluconazole or nystatin;

the mucolytic agent is selected from bromhexine, acetylcysteine, carbocysteine or pharmaceutically acceptable salts thereof;

the expectorant is selected from extracts of thermopsis, marshmallow, licorice or salts of glycyrrhizic acid;

the anti-inflammatory agent is selected from non-steroidal anti-inflammatory drugs, zinc salts, benzydamine, allantoin, corticosteroids or choline salicylate;

the immunomodulatory agent is selected from azoximer bromide, alpha-glutamyl tryptophan, pidotimod or glucosaminylmuramyl dipeptide;

the antiviral agent is selected from acyclovir, vitaglutam or inosine pranobex;

The biofilm-disrupting agent is selected from silver nanoparticles, arylrhodanines, enzymes, bacteriophages or auspicic acid.

The stated task is also carried out, and the technical result is achieved by creating a pharmaceutical composition for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx, including gramicidin C and ambroxol or their pharmaceutically acceptable salts, as well as at least one pharmaceutically acceptable excipient.

According to preferred embodiments, this technical result is also achieved by the fact that infectious diseases of the oral cavity and pharynx are selected from the group including pharyngitis, glossitis, stomatitis, gingivitis, adenoiditis, tonsillitis and laryngitis;

the pharmaceutically acceptable salt of gramicidin C is gramicidin C dihydrochloride, and the pharmaceutically acceptable salt of ambroxol is ambroxol hydrochloride;

the active ingredients are in the preferred mass ratios of gramicidin C: ambroxol from 2:1 to 1:1000;

the active ingredients are in the preferred mass ratios of gramicidin C: ambroxol from 1:1 to 1:100;

the active ingredients are in the preferred mass ratios of gramicidin C: ambroxol from 1:2 to 1:10;

the active ingredients are in the preferred mass ratios of gramicidin C: ambroxol from 1:5 to 1:10;

the active ingredients are in the preferred mass ratios of gramicidin C: ambroxol 1:5, 1:10 or 3:25;

the mentioned composition is intended for use in daily dosages of ambroxol - 7.5-200 mg/day; gramicidin - 1.5-12 mg/day;

the mentioned composition is intended for use in daily dosages of ambroxol - 15-120 mg/day; gramicidin - 1.5-12 mg/day;

the mentioned composition is intended for use in daily dosages of ambroxol - 30-45 mg/day; gramicidin - 1.5-4.5 mg/day;

- 5 043949 the mentioned composition is intended for use in daily dosages of ambroxol - 7.5-22.5 mg/day; gramicidin - 1.5-4.5 mg/day;

the mentioned composition is used from 1 to 6 times a day;

the mentioned composition is used from 1 to 4 times a day;

the mentioned composition is used 1 to 3 times a day;

said composition contains at least one additional active substance selected from an antiseptic, anesthetic, antibiotic, proteolytic enzyme, vitamin, mucolytic, expectorant, anti-inflammatory, immunomodulatory, antiviral, antifungal and biofilm-destroying agent;

the anesthetic is selected from the group consisting of lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anesthesin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene, dyclonine, hexylresorcinol and pharmaceutically acceptable salts thereof;

the antibiotic is selected from the group consisting of tyrothricin, bacitracin, amoxicillin, fusafungin, ambazone, polymyxin, neomycin, tobramycin and framycytin;

the proteolytic enzyme is lysozyme or papain;

the vitamin is selected from dexpanthenol, pyridoxine or ascorbic acid;

the antifungal agent is selected from fluconazole or nystatin;

the mucolytic agent is selected from bromhexine, acetylcysteine, carbocysteine or pharmaceutically acceptable salts thereof;

the expectorant is selected from extracts of thermopsis, marshmallow, licorice or salts of glycyrrhizic acid;

the anti-inflammatory agent is selected from non-steroidal anti-inflammatory drugs, zinc salts, benzydamine, allantoin, corticosteroids or choline salicylate;

the immunomodulatory agent is selected from azoximer bromide, alpha-glutamyl tryptophan, pidotimod or glucosaminylmuramyl dipeptide;

the antiviral agent is selected from acyclovir, vitaglutam or inosine pranobex;

the biofilm-destroying agent is selected from silver nanoparticles, arylrhodanines, enzymes, bacteriophages or auspic acid; as excipients, the said composition additionally contains a sweetener and/or flavoring agent;

the sweetener is selected from the group consisting of maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and pharmaceutically acceptable salts thereof;

the flavor is raspberry, strawberry, apricot, mint, pear, melon, mango, lemonade or plum flavor;

said composition is intended for topical use;

said composition is presented in the form of a solution for topical use;

as excipients, said composition contains a pH regulator, a surfactant, a preservative and water;

said composition further contains a thickener;

pH regulators are selected from the group consisting of organic acids and their salts;

the organic acid is selected from the group consisting of malic acid, ascorbic acid, citric acid, acetic acid, succinic acid, tartaric acid, fumaric acid, lactic acid, aspartic acid, glutaric acid, glutamic acid, sorbic acid;

The pH of the composition is in the range of 3.0-8.0;

The pH of the composition is in the range of 5.0-7.0;

The pH of the composition is in the range of 6.0-7.0;

the surfactants are selected from the group consisting of ethoxylated sorbitan esters, polyethylene glycol hydroxy fatty acid esters, fatty acid monoglycerides, fatty acid esters of sucrose or sorbitan;

preservatives are selected from the group including benzyl alcohol, methenamine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens, alkylpyridinium, benzethonium, and their pharmaceutically acceptable salts;

said composition further contains a co-solvent selected from low molecular weight aliphatic alcohols;

the co-solvent is ethanol;

the thickener is selected from the group consisting of glycerin, gums, pectin, alginic acid, gum arabic, agar-agar, methylcellulose, carboxymethylcellulose and pharmaceutically acceptable salts thereof;

Sucralose, glycerin, citric acid, sodium citrate, polysorbate, methylparaben, propylparaben, ethanol and water were selected as excipients;

said composition is presented in solid form for dispersion in the mouth or in solid form for resorption;

- 6 043949 solid form is a tablet;

said composition further comprises a filler and one or more lubricants;

the filler is sorbitol, mannitol, povidone, copovidone or mixtures thereof;

the lubricant is silicon dioxide, a pharmaceutically acceptable salt of stearic acid, talc, or mixtures thereof.

The stated task is also carried out, and the technical result is achieved by creating a topical medicinal product for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx, including the mentioned combination or the mentioned pharmaceutical composition.

According to preferred embodiments, the specified technical result is also achieved by the fact that the said product is in the form of a spray, rinse solution or syrup;

said agent is in the form of orally dispersible tablets, orally dispersible lozenges, lozenges or lozenges.

The stated task is also carried out, and the technical result is achieved by using the mentioned combination or the mentioned pharmaceutical composition, or the mentioned medicinal product for the treatment or improvement of the condition of an infectious-inflammatory disease of the oral cavity, pharynx and upper respiratory tract locally by irrigation or by spraying onto the oral mucosa and throat, or resorption, or dispersion in the oral cavity.

According to preferred embodiments, this technical result is also achieved by the fact that infectious and inflammatory diseases of the oral cavity, pharynx and upper respiratory tract are selected from the group including pharyngitis, tonsillitis, periodontitis, gingivitis, stomatitis, glossitis, adenoiditis and laryngitis, active ingredients in the mentioned combination , composition or product is used in daily dosages ambroxol - 7.5-200 mg/day; gramicidin - 0.2-40 mg/day;

active ingredients are used in daily dosages ambroxol - 15-120 mg/day; gramicidin - 1.5-12 mg/day;

the active ingredients in the mentioned combination, composition or agent are used in daily dosages ambroxol - 20-100 mg/day; gramicidin - 1.5-12 mg/day;

active ingredients are used in daily dosages ambroxol - 30-45 mg/day; gramicidin - 1.5-4.5 mg/day;

active ingredients are used in daily dosages ambroxol - 7.5-22.5 mg/day; gramicidin - 1.5-4.5 mg/day;

said combination, composition or agent is intended for topical use in the mouth and pharynx;

the mentioned combination is used from 1 to 6 times a day;

the mentioned combination is used 1 to 4 times a day;

the mentioned combination is used 1 to 3 times a day.

In the context of the present invention, antiseptics are used as auxiliary agents, which preferably means quaternary ammonium salts, as well as other compounds: cetylpyridinium, benzalkonium, benzethonium, cetalkonium chloride, cetrimonium chloride, cetrimide, chlorhexidine, didecyldimethylammonium chloride, domiphene bromide, dophanium chloride, tetraethylammonium bromide , but not limited to them;

anesthetics, which preferably means, but is not limited to, lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anesthesin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene and pharmaceutically acceptable salts thereof;

antibiotics, which preferably means, but is not limited to, tyrothricin, bacitracin, amoxicillin, fusafungin, ambazone, polymyxin, neomycin, tobramycin and framycytin;

a proteolytic enzyme, which preferably means, but is not limited to, lysozyme or papain;

vitamin, which preferably means dexpanthenol, pyridoxine or ascorbic acid, but is not limited to them;

an antifungal agent, which preferably means, but is not limited to, fluconazole or nystatin;

a mucolytic agent, which preferably means, but is not limited to, bromhexine, acetylcysteine, carbocysteine, or pharmaceutically acceptable salts thereof;

an expectorant, which preferably means, but is not limited to, an extract of thermopsis, marshmallow, licorice or glycyrrhizic acid salts;

an anti-inflammatory agent, which preferably means, but is not limited to, non-steroidal anti-inflammatory drugs, zinc salts, benzydamine, allantoin, corticosteroids or choline salicylate;

an immunomodulatory agent, which preferably means, but is not limited to, azoximer bromide, alpha-glutamyl-tryptophan, pidotimod or glucosaminylmuramyl dipeptide;

an antiviral agent, which preferably means, but is not limited to, acyclovir, vitaglutam or inosine pranobex;

a biofilm disruptor, which preferably means, but is not limited to, silver nanoparticles, arylrhodanines, enzymes, bacteriophages or auric acid;

sweetener, which preferably means, but is not limited to, maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and pharmaceutically acceptable salts thereof;

flavoring, which preferably means, but is not limited to, raspberry, strawberry, apricot, mint, pear, melon, mango, lemonade or plum flavoring.

Also set forth below are definitions of terms that are used in the description of the present invention.

A medicinal principle (medicinal substance, medicinal 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 manufacture of a medicinal product (drug).

Medicine (drug) - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injection forms, ointments and other finished forms, intended to restore, correct or change physiological functions in humans and animals, as well as for the treatment and disease prevention, diagnostics, anesthesia, contraception, cosmetology and other things.

Pharmaceutical composition means a composition comprising gramicidin C and ambroxol or their pharmaceutically acceptable salts and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliaries, dispensing agents, agents delivery agents, such as preservatives, stabilizers, fillers, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavors, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on their nature, the method of administration of the composition and dosages. Examples of suspending agents include 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. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents, for example, benzyl alcohol, methenamine, ethylenediaminetetraacetic acid, benzoic acid, chlorobutanol, sorbic acid, parabens, alkylpyridinium, benzethonium and their pharmaceutically acceptable salts and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged action of the composition can be achieved using agents that retard the absorption of the active principle, for example, such as hydrophilic polymeric release retardants, for example, cellulose derivatives, polyethylene oxide, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, alginates, carbomers, hydrophobic release retardants, such as glyceryl behenate, aluminum monostearate. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohols, buffer solutions, as well as 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 regulate pH, various organic and inorganic acids can be used, such as malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, and sorbic acids. Examples of dispersing agents and distributing agents are starch, alginic acid and its salts, and silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical or rectal administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard form of administration, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

Pharmaceutically acceptable salt means the relatively non-toxic organic and inorganic salts of the acids and bases claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or specially prepared. In particular, base salts can be prepared specifically starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (A detailed description of the properties of such salts is given in Berge S.M. et al., Pharmaceutical Salts//J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metallic salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be prepared include sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. The organic bases from which salts of the claimed acids can be obtained are amines and amino acids that are sufficiently basic to form a stable salt and suitable for use for medical purposes (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane and the like. In addition, tetraalkylammonium hydroxides, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. The basic amino acids that can be used as amino acids are lysine, ornithine and arginine. Preferred gramicidin salts are gramicidin hydrochloride, preferably gramicidin dihydrochloride. The preferred salt of ambroxol is the hydrochloride.

The examples of implementation of the inventions presented below illustrate, but do not limit, the present invention.

Example 1. Study of anti-inflammatory activity.

The study of anti-inflammatory activity is carried out on a model of ultraviolet erythema in guinea pigs, since this model is the most adequate for assessing the anti-inflammatory effect of dosage forms for external use [Swingle K., Hamilton R., Harrington J., Kvam D. 3-Benzoyldifluoromethanesulfonanilide, sodium salt ( diflumidone sodium, MBR 4164-8): a new antiinflammatory agent//Arch. Int. Pharmacodyn, 1971, vol. 189, pp. 129-144].

Acute inflammatory erythema in albino guinea pigs of both sexes weighing 250-500 g is caused by irradiation of an area of abdominal skin (3x4 cm, hairless 1 day before the experiment) with ultraviolet (UV) rays. A quartz lamp (wavelength 280 nm) is used as a source of UV irradiation; irradiation is carried out from a distance of 10 cm for 60 s (radiation intensity 25.8 W/m ² ). The severity of erythema and swelling of the skin is assessed after 4 hours on an 8-point scale (for an integral assessment of the reaction to irradiation, where 0 points is the absence of erythema or swelling, 8 is clearly defined erythema or swelling). 4 hours after irradiation, erythema develops in 100% of animals, the total intensity is 8 points.

animals were randomly distributed into 11 groups: placebo (group No. 1), gramicidin C in daily dosages of 0.2, 12 and 40 mg (groups No. 2-4), ambroxol in daily dosages of 20, 100 and 200 mg (groups No. 5 -7), combination of gramicidin C + ambroxol in daily dosages of 0.2 + 200 mg, 12 + 100 mg and 40 + 20 mg (groups No. 8-10), and the reference drug tyrothricin (12 mg/day, group No. 11) .

Tyrothricin is a natural polypeptide antibiotic for topical use. Tyrothricin exhibits antibacterial activity due to the presence of cyclic and linear polypeptides. Tyrothricin is represented by a compound of tyrocidins (up to 70-80%) and gramicidins (up to 20-30%). The drug causes bactericidal effects against gram (+) and some gram (-) bacteria (S.aureus (methicillin-sensitive strains), S.haemolyticus, S.pyogenes, S.viridans, Diplococcus pneumoniae, Corynebact. spp., meningococcus, Enterococcus faecalis, some pathogens of gonorrhea, Trichomonas, as well as some types of fungi, including Candida. Tyrothricin, depending on the dose used, can have a bacteriostatic or bactericidal effect on clostridia. The drug destroys the bacterial wall by changing the permeability of the cytoplasmic membrane, inhibits cell growth and division. The drug also relieves pain when used topically [Lang S., Staiger S. Tyrothricin An underrated agent for the treatment of bacterial skin infections and superficial wounds?//Pharmazie, 2016, vol. 71(6), pp. 299-305].

All drugs were applied with a spatula to the affected surface 4 hours after irradiation and then four times a day throughout the study within the specified daily dosages. All doses are given per person. The data is given in table. 1. The results of the study showed that in irradiated animals, erythema, the severity of which was maximum on days 1-2, was observed for 7 days.

In groups receiving a combination of gramicidin C and ambroxol, the severity of erythema and swelling of the skin was significantly reduced, which indicates the effectiveness of their use in reducing local inflammatory reactions. In addition, a synergistic effect of these combinations was also found at all dose levels tested.

Example 2. In vitro study of antibacterial activity.

The antibacterial activity of the combinations (Table 2) was determined by known in vitro methods [Sahm D.F.S., Washington II J.A. Antibacterial Susceptibility Test: Dilution Methods//Manual of Clinical Microbiology. Albert Balows. - Washington, D.C. -1991. - 1363P]. Activity was determined by the agar diffusion method. A suspension of 109 colony-forming units (CFU) of a daily culture of strains Staphylococcus aureus, Streptococcus pyogenes, Str. faecalis, Vas. subtilis, Escherichia coli, Str. pneumoniae, Str. pyogenes, Str. faecalis. The test drug in a volume of 20 μl was added to the wells and after a daily incubation the zones of growth inhibition were measured.

For drugs, the minimum inhibitory concentration (MIC) or working dilution of the sample is determined by serial microdilution. For combinations, the MIC for each of the components is determined. Double dilutions of the drug were prepared in meat-peptone broth in a volume of 0.1 ml in a sterile plate (one control well without the drug). 10 ³ CFU of the studied microorganism culture were added to each dilution well. The count was carried out photometrically at a wavelength of 620 nm, where the MIC is determined as the last dilution in which there was no culture growth.

The study used gramicidin C, ambroxol, combinations of gramicidin C and ambroxol in ratios of 2:1, 1:8.33 and 1:1000 and the reference drug tyrothricin. The research results are given in table. 2.

It has been shown that the antibacterial activity of combinations of gramicidin C and ambroxol when used together is significantly higher than that of these drugs used separately, as well as the reference drug.

Example 3. In vivo study of antibacterial activity.

Outbred white male rats were used for the experiments. 66 animals were randomly distributed into 11 groups according to example 1: placebo (group No. 1), gramicidin C in daily dosages of 0.2, 12 and 40 mg (groups No. 2-4), ambroxol in daily dosages of 20, 100 and 200 mg (group No. 57), the combination of gramicidin C + ambroxol in daily dosages of 0.2 + 200 mg, 12 + 100 mg and 40 + 20 mg (groups No. 8-10), and the reference drug tyrothricin (12 mg/day, group No. eleven).

To model a localized staphylococcal infection in a musculocutaneous wound, the Staphylococcus aureus strain was used. The culture was grown for 24 hours on meat-peptone agar at 37°C, then an infecting suspension of bacteria was prepared in a 0.9% sodium chloride solution. Based on the results of control seeding, the actual content of live pathogen bacteria in the suspension was determined.

On the left side of male white rats, closer to the spine, hair was plucked over an area of 1.5 x 1.5 cm, and 0.4 ml of the prepared suspension was injected intradermally and 0.3 ml subcutaneously using an insulin syringe. After 3 days, a wound covered with a scab formed at the injection site. In all animals, the scab was removed with tweezers and the wound was examined. In all cases, necrotic changes with purulent contents were observed. Treatment was carried out by applying the combinations of the present invention in the indicated dosages superficially.

Assessment of microbial contamination of wounds was carried out immediately after removal of the scab for a week in each group. The scab was removed from the animals using tweezers and a sterile filter paper disc with a diameter of 6 mm was pressed to the wound. The disc soaked with the contents of the wound was placed in 1 ml of a sterile 0.9% sodium chloride solution, shaken and left for 1 hour. Then the eluate was diluted 100 and 1000 times and sown 0.1 ml onto Petri dishes with yolk-salt agar, which is a selective medium for staphylococci. The inoculated dishes were incubated for 24 hours at 37°C, after which the number of grown colonies was counted, followed by recalculation of colony-forming units (CFU) per 1 ml (Table 3).

In groups receiving a combination of gramicidin C and ambroxol, bacterial growth rates were significantly reduced, indicating the effectiveness of their use in the treatment of bacterial infections. In addition, a synergistic effect of these combinations was also found at all dose levels tested.

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Table 1

Study of the anti-inflammatory effect on a model of ultraviolet erythema

A drug Dose, mg/day Severity of skin erythema and swelling, scores (mean ± standard error of the mean) Time, days 1 2 3 4 5 6 7 Placebo - 8.0+0.2 8.0+0.2 7.5+0.3 6.5+0.3 5.4+0.2 4.2+0.2 3.0+0.2 Gramicidin S 0.2 8.0+0.2 7.9+0.3 7.4+0.2 6.4+0.2 5.3+0.3 4.0+0.2 2.8+0.2 12 7.8+0.2 7.5+0.1 6.5+0.3 5.6+0.2 4.5+0.3 3.4+0.2 2.6+0.2 40 7.5+0.1 6.9+0.3 5.8+0.2 4.7+0.3 3.6+0.2 2.4+0.2 1.7+0.1 Ambroxol 20 7.4+0.2 6.5+0.3 5.4+0.2 4.3+0.3 3.2+0.2 2.1+0.1 1.3+0.1 100 7.0+0.2 6.0+0.2 4.9+0.3 3.5+0.3 2.4+0.2 1.1+0.1 0.5+0.1 200 6.5+0.3 5.4+0.2 4.4+0.2 3.1+0.3 2.0+0.2 0.9+0.1 0.3+0.1 Gramicidin C + ambroxol 0.2 + 200 5.0+0.2 * 4.2+0.2 * 3.1+0.3 * 2.0+0.2 * 1.0+0.2 * 0.3+0.1 oh oh 12 + 100 4.5+0.1 ^# 3.3+0.3 ^# 2.3+0.3 ^# 1.2+0.2 ^# 0.2+0.1 ^# 0.0 oh oh 40 + 20 4.8+0.2 ^{$ $} 3.7+0.3 ^$ 2.6+0.2 ^$ 1.6+0.2 ^$ 0.7+0.1 0.4+0.2 oh oh Tyrothricin 12 7.7+0.3 7.4+0.2 6.4+0.2 5.5+0.3 4.4+0.2 3.3+0.3 2.5+0.1

*, #, $ - significant difference from the expected (calculated) 'additive effect' of the combination of gramicidin C and ambroxol (significance level p<0.05) for each dose level at the corresponding time point.

Study of antibacterial activity in vitro, MIC, µM

table 2

A drug Staphylococcus us aureus Str. pyogenes Str. Faecalis You. subtilis Escherichia coli Str. pneumoniae Str. Pyogenes Str. faecal Gramicidin S 2.0+0.1 5.5+0.1 6.5+0.1 8.9+0.1 7.5+0.1 6.0+0.1 6.5+0.1 5.1+0.1 Ambroxol 2000.0 ±5.0 5300.0 ±5.0 6400.0 ±5.0 8500.0 ±5.0 7000.0 ±5.0 6200 ±5.0 6400 ±5.0 5200.0 ±5.0 Gramicidin C + ambroxol, 2:1 For ambroxol 0.4+0.1 1.2+0.1 1.3+0.1 1.4+0.1 1.3+0.1 1.5+0.1 1.3+0.1 ι,ι+ο,ι For gramicidin 0.7+0.1 2.3+0.1 2.5+0.1 3.7+0.1 2.6+0.1 3.0+0.1 2.5+0.1 2.1+0.1 Gramicidin C + ambroxol, 1:8.33 For ambroxol 7.5+0.1 21.6+0.1 21.7+0.1 34.1+0.1 25.0+0.1 27.5+0.1 24.2+0.1 20.8+0.1 For gramicidin 0.9+0.1 2.6+0.1 2.9+0.1 4.1+0.1 3.0+0.1 3.3+0.1 2.9+0.1 2.5+0.1 Gramicidin C + ambroxol, 1:1000 For ambroxol 1600.0+2.0 4300.0+2.0 4400.0+2.0 5500.0+2.0 5000.0+2.0 4200+2.0 4400+2.0 4200.0+2.0 For gramicidin 1.6+0.1 4.3+0.1 4.4+0.1 5.5+0.1 5.0+0.1 4.2+0.1 4.4+0.1 4.2+0.1 Tyrothricin 1.9+0.1 5.4+0.1 6.3+0.1 8.7+0.1 7.4+0.1 5.9+0.1 6.4+0.1 5.0+0.1

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Table 3

Study of antibacterial activity on a model of staphylococcal localized infection

A drug Dose, mg/day CFU/ml (mean ± SEM) Time after scab removal, days 1 2 3 4 5 6 7 Placebo - 2500+50 6400+50 8900+50 10500+50 11600+50 12500+50 12900+50 Gramicidin S 0.2 2400+50 2300+50 2000+50 1500+50 950+50 400+50 100+50 12 2300+50 2000+50 1500+50 900+50 500+50 300+50 0 40 2200+50 1900+50 1200+50 650+50 300+50 0 0 Ambroxol 20 2450+50 2300+50 2200+50 2000+50 1700+50 1500+50 1350+50 100 2400+50 2200+50 1900+50 1500+50 1250+50 800+50 400+50 200 2350+50 2100+50 1800+50 1400+50 1100+50 750+50 300+50 Gramicidin C + ambroxol 0.2 + 200 2400+50 1850+50 * 1550+50* 1150+50* 700+50* 250+50* 0 12+100 2300+50 1700+50 ^# 1200±50 ^# 600±50 ^# 300±50 ^# 0 0 40 + 20 2200+50 1700+50 ^$ 1000±50 ^{$ $} 350±50 0 0 0 Tyrothricin 12 2300+50 2000+50 1500+50 900+50 500+50 300+50 0

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of gramicidin C and ambroxol (significance level p<0.05) for each dose level at the corresponding time point.

Example 4. Method for obtaining a finished pharmaceutical composition in the form of a spray.

Purified water is added to the production tank.

Ambroxol and cetylpyridinium chloride are added to the production tank and mixed until completely dissolved; visual inspection is carried out until complete dissolution.

Glycerin is added to the production tank and mixed.

Citric acid monohydrate, sodium citrate and sucralose are added to the production tank and mixed until completely dissolved.

Purified water, ethanol 96% and polysorbate 80 are added to the pre-mixing tank and mixed.

Add gramicidin C hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate to the pre-mixing tank and mix until completely dissolved.

Add flavoring to the pre-mixing tank and mix, visually inspect until completely dissolved.

Transfer the resulting solution to the production tank.

The final bulk product is mixed in a production tank until completely homogenized.

At this stage, pH and density are controlled and transferred to a temporary storage tank. Filter, fill into vials and package. Examples of the resulting compositions are given in table. 4.

Table 4

Ready-made formulations in spray form

Ingredient Weight, mg Gramicidin S 1.0 0.319 0.02 Ambroxol 0.5 2.65 20.0 Cetylpyridinium chloride 0.50 0.50 0.50 Methylparaben 0.92 0.92 0.92 Propylparaben 0.10 0.10 0.10 Ethanol 95.0 95.0 91.0 Sucralose 1.0 1.0 1.0 Glycerol 169.5 166.85 143.0 Flavoring 4.1 4.1 4.1 Citric acid monohydrate 0.29 0.29 0.29 Sodium citrate 0.11 0.11 0.11 Polysorbate 2.0 2.0 2.0 Purified water the rest, up to 1 ml

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Claims (77)

Example 5. Method for obtaining a finished pharmaceutical composition in the form of lozenges. The method of obtaining the specified pharmaceutical composition in the form of a tablet includes weighing and sifting the starting substances, mixing them and tableting them. Preferably, tabletting is carried out by direct compression. Ready-made tablets can be packaged in blisters, and blisters in cardboard packs. Examples of the resulting compositions are given in table. 5. Table 5 Ready-made formulations in the form of lozenges Ingredient Weight, mg Gramicidin S 0.7 0.35 0.024 Ambroxol 0.35 2.92 24.0 Mannitol 150.9 150.0 140.0 Copovidon 0.4 0.4 0.4 Crospovidone 33.15 31.83 23,076 Sorbitol 3.3 3.3 h,o Maltitol 2.4 2.4 2.0 Sodium saccharinate 2.0 2.0 2.0 Colloidal silicon dioxide 1.8 1.8 1.5 Flavoring 5.0 5.0 4.0 Tablet weight 200 200 200 The invention can be used in medicine, chemistry, pharmacology and the chemical-pharmaceutical industry. CLAIM 1. A combination of gramicidin C and ambroxol or their pharmaceutically acceptable salts for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx, characterized in that gramicidin C and ambroxol are in mass ratios from 2:1 to 1:1000 (gramicidin C: ambroxol). 2. The combination according to claim 1, where infectious and inflammatory diseases of the oral cavity and pharynx are selected from the group including pharyngitis, glossitis, stomatitis, gingivitis, adenoiditis, tonsillitis and laryngitis. 3. The combination according to claim 1, characterized in that the active ingredients are in mass ratios of gramicidin C: ambroxol from 1:1 to 1:100. 4. The combination according to claim 3, characterized in that the active ingredients are in mass ratios of gramicidin C: ambroxol from 1:2 to 1:10. 5. The combination according to claim 4, characterized in that the active ingredients are in mass ratios of gramicidin C: ambroxol from 1:5 to 1:10. 6. The combination according to claim 5, characterized in that the active ingredients are in a mass ratio of gramicidin C: ambroxol 1:5, or 1:10, or 3:25. 7. The combination according to claim 1, characterized in that said combination is intended for topical use in the oral cavity and pharynx. 8. The combination of claim 1, wherein the pharmaceutically acceptable salt of gramicidin C is gramicidin C dihydrochloride and the pharmaceutically acceptable salt of ambroxol is ambroxol hydrochloride. 9. The combination according to claim 1, characterized in that said combination contains at least one additional active substance selected from an antiseptic, anesthetic, antibiotic, proteolytic enzyme, vitamin, mucolytic, expectorant, anti-inflammatory, immunomodulatory, antiviral, antifungal and biofilm destroyer facilities. 10. The combination according to claim 9, characterized in that the anesthetic is selected from the group including lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anesthesin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene, dyclonine, hexylresorcinol and their pharmaceutically acceptable salts. 11. The combination according to claim 9, characterized in that the antibiotic is selected from the group including tyrothricin, bacitracin, amoxicillin, fusafungin, ambazone, polymyxin, neomycin, tobramycin and framycytin. 12. The combination according to claim 9, characterized in that the proteolytic enzyme is lysozyme or papain. 13. The combination according to claim 9, characterized in that the vitamin is selected from dexpanthenol, pyridoxine or - 13 043949 ascorbic acid. 14. The combination according to claim 9, characterized in that the antifungal agent is selected from fluconazole or nystatin. 15. The combination according to claim 9, characterized in that the mucolytic agent is selected from bromhexine, acetylcysteine, carbocysteine or their pharmaceutically acceptable salts. 16. The combination according to claim 9, characterized in that the expectorant is selected from extracts of thermopsis, marshmallow, licorice or salts of glycyrrhizic acid. 17. The combination according to claim 9, characterized in that the anti-inflammatory agent is selected from non-steroidal anti-inflammatory drugs, zinc salts, benzydamine, allantoin, corticosteroids or choline salicylate. 18. The combination according to claim 9, characterized in that the immunomodulatory agent is selected from azoximer bromide, alpha-glutamyl tryptophan, pidotimod or glucosaminylmuramyl dipeptide. 19. The combination according to claim 9, characterized in that the antiviral agent is selected from acyclovir, vitaglutam or inosine pranobex. 20. The combination according to claim 9, characterized in that the biofilm-destroying agent is selected from silver nanoparticles, arylrhodanines, enzymes, bacteriophages or auspicic acid. 21. Pharmaceutical composition for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx, including gramicidin C and ambroxol or their pharmaceutically acceptable salts, as well as at least one pharmaceutically acceptable excipient, characterized in that the active substances are in the preferred mass ratios of gramicidin C :ambroxol from 2:1 to 1:1000. 22. The pharmaceutical composition according to claim 21, where infectious diseases of the oral cavity and pharynx are selected from the group including pharyngitis, glossitis, stomatitis, gingivitis, adenoiditis, tonsillitis and laryngitis. 23. The pharmaceutical composition according to claim 21, characterized in that the pharmaceutically acceptable salt of gramicidin C is gramicidin C dihydrochloride, and the pharmaceutically acceptable salt of ambroxol is ambroxol hydrochloride. 24. Pharmaceutical composition according to claim 21, in which the active ingredients are present in the preferred mass ratios of gramicidin C: ambroxol from 1:1 to 1:100. 25. Pharmaceutical composition according to claim 24, in which the active ingredients are present in the preferred mass ratios of gramicidin C: ambroxol from 1:2 to 1:10. 26. Pharmaceutical composition according to claim 25, in which the active ingredients are present in the preferred mass ratios of gramicidin C: ambroxol from 1:5 to 1:10. 27. Pharmaceutical composition according to claim 26, in which the active ingredients are present in the preferred mass ratios of gramicidin C: ambroxol 1:5, 1:10 or 3:25. 28. The pharmaceutical composition according to claim 21, characterized in that said composition contains at least one additional active substance selected from an antiseptic, anesthetic, antibiotic, proteolytic enzyme, vitamin, mucolytic, expectorant, anti-inflammatory, immunomodulatory, antiviral, antifungal and destructive biofilm agents. 29. The pharmaceutical composition according to claim 28, characterized in that the anesthetic is selected from the group including lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anesthesin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene, dyclonine, hexylresorcinol and their pharmaceutically acceptable salts. 30. The pharmaceutical composition according to claim 28, characterized in that the antibiotic is selected from the group including tyrothricin, bacitracin, amoxicillin, fusafungin, ambazone, polymyxin, neomycin, tobramycin and framycytin. 31. Pharmaceutical composition according to claim 28, characterized in that the proteolytic enzyme is lysozyme or papain. 32. Pharmaceutical composition according to claim 28, characterized in that the vitamin is selected from dexpanthenol, pyridoxine or ascorbic acid. 33. The pharmaceutical composition according to claim 28, characterized in that the antifungal agent is selected from fluconazole or nystatin. 34. The pharmaceutical composition according to claim 28, characterized in that the mucolytic agent is selected from bromhexine, acetylcysteine, carbocysteine or their pharmaceutically acceptable salts. 35. Pharmaceutical composition according to claim 28, characterized in that the expectorant is selected from extracts of thermopsis, marshmallow, licorice or salts of glycyrrhizic acid. 36. The pharmaceutical composition according to claim 28, characterized in that the anti-inflammatory agent is selected from non-steroidal anti-inflammatory drugs, zinc salts, benzydamine, allantoin, corticosteroids or choline salicylate. 37. The pharmaceutical composition according to claim 28, characterized in that the immunomodulatory agent is selected from azoximer bromide, alpha-glutamyltryptophan, pidotimod or glucosaminylmuramyl di- - 14 043949 peptide. 38. The pharmaceutical composition according to claim 28, characterized in that the antiviral agent is selected from acyclovir, vitaglutam or inosine pranobex. 39. The pharmaceutical composition according to claim 38, characterized in that the biofilm-destroying agent is selected from silver nanoparticles, arylrhodanines, enzymes, bacteriophages or usnic acid. 40. The pharmaceutical composition according to claim 21, characterized in that said composition additionally contains a sweetener and/or flavoring agent as excipients. 41. The pharmaceutical composition according to claim 40, characterized in that the sweetener is selected from the group including maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts. 42. The pharmaceutical composition according to claim 40, characterized in that the flavor is raspberry, strawberry, apricot, mint, pear, melon, mango, lemonade or plum flavor. 43. Pharmaceutical composition according to any one of claims 21-42, characterized in that said composition is intended for topical use. 44. The pharmaceutical composition according to claim 43, characterized in that said composition is presented in the form of a solution for topical use. 45. The pharmaceutical composition according to claim 44, characterized in that said composition contains a pH regulator, a surfactant, a preservative and water as excipients. 46. Pharmaceutical composition according to claim 44, characterized in that said composition additionally contains a thickener. 47. Pharmaceutical composition according to claim 45, characterized in that the pH regulators are selected from the group including organic acids and their salts. 48. The pharmaceutical composition according to claim 47, characterized in that the organic acid is selected from the group consisting of malic acid, ascorbic acid, citric acid, acetic acid, succinic acid, tartaric acid, fumaric acid, lactic acid, aspartic acid, glutaric acid, glutamic acid, sorbic acid. 49. Pharmaceutical composition according to claim 47, characterized in that the pH of the composition is in the range of 3.0-8.0. 50. Pharmaceutical composition according to claim 49, characterized in that the pH of the composition is in the range of 5.0-7.0. 51. Pharmaceutical composition according to claim 50, characterized in that the pH of the composition is in the range of 6.0-7.0. 52. The pharmaceutical composition according to claim 45, characterized in that the surfactants are selected from the group consisting of ethoxylated sorbitan esters, polyethylene glycol esters with hydroxy fatty acids, fatty acid monoglycerides, fatty acid esters of sucrose or sorbitan. 53. The pharmaceutical composition according to claim 45, characterized in that the preservatives are selected from the group including benzyl alcohol, methenamine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens, alkylpyridinium, benzethonium and their pharmaceutically acceptable salts. 54. The pharmaceutical composition according to claim 44, characterized in that said composition additionally contains a co-solvent selected from low molecular weight aliphatic alcohols. 55. The pharmaceutical composition according to claim 54, characterized in that the co-solvent is ethanol. 56. The pharmaceutical composition according to claim 46, characterized in that the thickener is selected from the group consisting of glycerin, gums, pectin, alginic acid, gum arabic, agar-agar, methylcellulose, carboxymethylcellulose and their pharmaceutically acceptable salts. 57. Pharmaceutical composition according to claim 43, characterized in that sucralose, glycerin, citric acid, sodium citrate, polysorbate, methylparaben, propylparaben, ethanol and water are selected as excipients. 58. The pharmaceutical composition according to claim 43, characterized in that said composition is presented in a solid form for dispersion in the oral cavity or in a solid form for resorption. 59. Pharmaceutical composition according to claim 59, characterized in that the solid form is a tablet. 60. The pharmaceutical composition according to claim 59, characterized in that said composition further contains an excipient and one or more lubricants. 61. Pharmaceutical composition according to claim 60, characterized in that the filler is sorbitol, mannitol, povidone, copovidone or mixtures thereof. 62. The pharmaceutical composition according to claim 60, characterized in that the lubricant is - 15 043949 silicon dioxide, pharmaceutically acceptable salt of stearic acid, talc or mixtures thereof. 63. A topical medicinal product for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx, including a combination according to any of claims 1-20 or a pharmaceutical composition according to any of claims 21-62, where the medicinal product is in the form of a spray or lozenges . 64. Use of a combination according to any of claims 1-20, or a pharmaceutical composition according to any of claims 21-62, or a medicinal product according to claim 64 for the treatment or improvement of an infectious-inflammatory disease of the oral cavity, pharynx and upper respiratory tract locally by irrigation or by spraying onto the mucous membrane of the mouth and throat, or resorption, or dispersion in the oral cavity. 65. Use according to claim 64, characterized in that infectious and inflammatory diseases of the oral cavity, pharynx and upper respiratory tract are selected from the group including pharyngitis, tonsillitis, periodontitis, gingivitis, stomatitis, glossitis, adenoiditis and laryngitis. 66. Use according to claim 64, characterized in that ambroxol and gramicidin C are used simultaneously in the form of a joint dosage form or two different dosage forms. 67. Use according to claim 64, characterized in that ambroxol and gramicidin C are used sequentially in the form of two different dosage forms in any order. 68. Application according to claim 64, characterized in that the active ingredients in said combination, composition or agent are used in daily dosages of ambroxol - 7.5-200 mg/day; gramicidin - 0.2-40 mg/day. 69. Application according to claim 64, characterized in that the active ingredients in said combination, composition or agent are used in daily dosages of ambroxol - 7.5-200 mg/day; gramicidin - 1.5-12 mg/day. 70. Application according to claim 68, characterized in that the active ingredients in said combination, composition or agent are used in daily dosages of ambroxol - 15-120 mg/day; gramicidin - 1.5-12 mg/day. 71. Application according to claim 70, characterized in that the active ingredients in said combination, composition or agent are used in daily dosages of ambroxol - 20-100 mg/day; gramicidin - 1.5-12 mg/day. 72. Application according to claim 64, characterized in that the active ingredients in said combination, composition or agent are used in daily dosages of ambroxol - 30-45 mg/day; gramicidin - 1.5-4.5 mg/day. 73. Application according to claim 64, characterized in that the active ingredients in said combination, composition or agent are used in daily dosages of ambroxol - 7.5-22.5 mg/day; gramicidin - 1.5-4.5 mg/day. 74. Use according to claim 64, characterized in that said combination, composition or agent is intended for topical use in the oral cavity and pharynx. 75. Use according to claim 64, characterized in that said combination, composition or agent is administered from 1 to 6 times a day. 76. Use according to claim 75, characterized in that said combination, composition or agent is administered 1 to 4 times a day. 77. Use according to claim 76, characterized in that said combination, composition or agent is administered 1 to 3 times a day. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2