RU2749902C2 - Pharmaceutical composition for treatment of infectious and inflammatory diseases - Google Patents

Abstract

FIELD: medicine; chemical and pharmaceutical industry.

SUBSTANCE: invention relates to the field of medicine and the chemical and pharmaceutical industry, namely, to a new pharmaceutical composition for the treatment of infectious and inflammatory diseases of topical application, including gramicidin C and ambroxol, and to a new combination of gramicidin C and ambroxol or their pharmacologically acceptable salts for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx, in which the active substances are used in the following amounts - ambroxol-7.5-200 mg; gramicidin C-0.2-40 mg and where the active substances are in the mass ratios of gramicidin C: ambroxol from 2:1 to 1:1000, as well as to the method for their application.

EFFECT: invention can be used for treatment of infectious and inflammatory diseases of the oral cavity and pharynx,

72 cl, 5 ex, 5 tbl

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 topical 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 importance are 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 available to modern medicine to combat these diseases, the problem remains relevant. To a large extent, this is due to both the high level of morbidity 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 remained sensitive to penicillin. The growth of resistant forms is due to the fact that antibiotic-resistant mutants constantly appear in bacterial populations, possessing virulence and spreading mainly in cases where sensitive forms are suppressed by an antibiotic. From a population genetic point of view, this process is reversible. Therefore, when the antibiotic is temporarily withdrawn 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 therapists, otorhinolaryngologists, 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 oral mucosa and pharynx include the appointment of drugs with anti-inflammatory, analgesic, immunocorrective action, local antiseptics, antimicrobial, decongestant and hyposensitizing drugs [Morozova S.V. Pain in the throat: causes and possibilities of drug therapy. RMZh, volume 13, no.21, 2005, p. 1447-1452].

For example, a spray for topical application dosed Anti-angina 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, 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 it can stain teeth and tongue, is not compatible with some components of toothpastes, in some cases it can cause irritation of the mucous membranes, allergic reactions, burning sensation, it is recommended for use in children over 12 years old, it can 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 broad-spectrum polypeptide antibiotics, has a bacteriostatic and bactericidal effect on streptococci, staphylococci, pneumococci, pathogens of anaerobic infections and other microorganisms. Produced by the spore bacillus Bacillus brevis or Aneurinibacillus migulanus [RF patent No. 2627182, publ. 03.08.2017].

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 rejoin in the initial viral infection - Streptococcus spp., Staphylococcus spp., Streptococcus pneumoniae, neisseria, etc. The drug also has some fungistatic and antiviral activity. According to modern concepts of rational antibiotic therapy, in order to prevent the emergence and spread of resistant strains of microorganisms in all cases when the causative agent of the infection can be predicted with a high degree of probability, it is recommended to give preference to just such drugs. Resistance to polypeptides is rare. There are very few reports in the literature on 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 [Polin AN, Egorov NS. "Structural and functional features of gramicidin C in connection with its antibiotic activity" // Antibiotics and chemotherapy. - 2003. - No. 48 (12). - from. 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 antibiotic resistance for systemic use.

Gramicidin C

Source [RF patent No. 2532027, publ. 10/27/2014] discloses a liquid composition for topical application containing a pharmaceutical active ingredient, a mixture of solvents containing water, isopropanol in an amount of 5 wt. % up to 20 wt. % and propylene glycol in an amount of 2 wt. % up to 25 wt. %, and a phospholipid blowing agent in an amount of 2 wt. % up to 25 wt. %. An extensive list of substances of different pharmacological groups is listed as active ingredients, including gramicidin C, oxybuprocaine hydrochloride and cetylpyridinium chloride. The composition in the form of a foam is mainly suitable for application to the skin and wounds, and there is no indication of the possibility of oral administration.

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

gramicidin C - 0.2-0.4;

icing 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 its intolerance.

Known pharmaceutical composition for the treatment of infectious and inflammatory diseases in the form of a solution for local use, characterized in that it contains as an active principle a combination of gramicidin C dihydrochloride and cetylpyridinium chloride, as auxiliary substances - 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 other activity besides suppressing the growth of microorganisms, which can reduce the effectiveness of the agent 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 shown below.

Known pharmaceutical composition for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx for local use, which contains as an active principle a combination of gramicidin C dihydrochloride, oxybuprocaine hydrochloride and cetylpyridinium chloride, as auxiliary substances - 96% ethanol, sucralose, glycerin, lemon acid monohydrate, sodium citrate, polysorbate, methylparaben, propylparaben, natural mint flavor, purified water [RF patent No. 2604576, publ. 10.12.2016]. The implementation of the invention makes it possible to reduce the side effects from the use of the composition with gramicidin and to increase the uniformity of dosage. The disadvantage of this technical solution is that the presence of an analgesic can mask the symptoms of mucosal inflammation.

Known pharmaceutical composition for the treatment of infectious and inflammatory diseases in the form of a solution for local use, characterized in that it contains as an active principle a combination of gramicidin C dihydrochloride, oxybuprocaine hydrochloride and cetylpyridinium chloride, as auxiliary substances - 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 the above, the disadvantage of this solution is the presence of an analgesic, the action of which can mask the symptoms of inflammation of the mucous membrane.

Currently, a combined preparation in the form of tablets for resorption is being produced for the treatment of infectious and inflammatory diseases of the pharynx and oral cavity "Grammidin with anesthetic neo", which includes gramicidin C, oxybuprocaine hydrochloride and cetylpyridinium chloride [Instructions for medical use of the drug "Grammidin with anesthetic neo ", 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 tract. 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 frequent complaints with which patients go to the doctor. The reason for treatment, as a rule, is a painful cough that disrupts the patient's quality of life, or the appearance of other symptoms that bother the patient with the cough.

Therefore, the creation of new pharmaceutical compositions for the treatment of infectious and 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 a cough with difficult sputum discharge, stimulants of the 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), is a white crystalline powder, odorless, slightly bitter taste, just like bromhexine is an alkaloid derivative vizicin, however, has a more pronounced effect, because 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 in ARVI and has established itself as an effective and safe drug.

High efficiency and good tolerance of Ambroxol allow some foreign authors to recommend it as the 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 experts who have studied the effectiveness of Ambroxol in outpatients with COPD have come to the conclusion that the mucolytic properties of the drug are maximally realized in case of 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 respiratory diseases has been proven not only in adults, but also in children [Baldini G., Gucci M., Taro D., Memmini C. “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 resulted in faster cough and other clinical symptoms elimination compared to placebo, as well as normalization of radiological changes [Spatola J., Poderoso JJ, Wiemeyer JC, 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 was noted by children. 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].

Known solid, intended for resorption or slowly dissolving dosage form of a pharmaceutical composition containing ambroxol or one of its pharmacologically acceptable salts and one or more active substances selected from the group including antiseptics, vitamins, corticosteroids, anti-inflammatory agents, antibiotics, antifungal agents and proteolytic 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 substances selected from the group consisting of antiseptics, vitamins, corticosteroids, anti-inflammatory agents, antibiotics, antifungal agents and proteolytic enzymes, in the form of a gel [RF patent No. 2311176, publ. 27.11.2007]. This technical solution can be taken as the closest analogue (prototype). At the same time, the patent of the Russian Federation 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 also no indication of the possibility of synergy between them.

Known containing ambroxol lozenge based on sugar alcohols as a matrix material, characterized in that it contains a pharmaceutically acceptable layered silicate (for example, talc) and polyethylene glycol and optionally other pharmaceutical auxiliaries, flavoring additives, respectively flavors [Eurasian patent EA004044, publ. 12/25/2003].

A known method for the treatment of acute pharyngitis, which consists in the local application of ambroxol hydrochloride at a dose of 10 mg in a composition suitable for spraying containing ambroxol hydrochloride in an amount of 1 to 30 mg / ml [Eurasian patent EA027291, 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.

We have surprisingly found that the combination has increased anti-inflammatory and antibacterial properties that were not expected from 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 [Instruction for medical use of the drug "Mucoangin, 20 mg lozenge tablets No. 10", website "Mini Doctor", URL: https://mini-doctor.com/pilul/mukoangin_tabletki_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_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500184106.pdf , MW “About some possible anti-inflammatory properties of various membr ane permeant agents "// Agents and Actions, 1975, vol. 5 (2), pp. 133-136).

Thus, the object of the present invention is to provide 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 agents 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;

- acceleration of 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 and inflammatory diseases of the oral cavity and pharynx.

According to preferred embodiments, the specified technical result is also achieved in 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 substances are in mass ratios gramicidin C: ambroxol from 2: 1 to 1: 1000;

- active substances are in mass ratios gramicidin C: ambroxol from 1: 1 to 1: 100;

- the active substances are in mass ratios gramicidin C: ambroxol from 1: 2 to 1: 10;

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

- the active substances are in mass ratios 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

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 is intended for topical application 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 above combination is administered from 1 to 6 times a day;

- said combination is administered 1 to 4 times a day;

- the mentioned combination from 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-destroying agent;

- the anesthetic is selected from the group consisting of lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anestezin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene, diclonin, hexylresorcinol and their pharmaceutically acceptable salts;

- the antibiotic is selected from the group consisting of tyrothricin, bacitracin, amoxicillin, fusafungin, ambazon, polymyxin, neomycin, tobramycin and framicitin;

- 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 their pharmaceutically acceptable salts;

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

- 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 azoxymer bromide, alpha-glutamyl-tryptophan, pidotimod or glucosaminylmuramyl dipeptide;

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

- a biofilm-destroying agent selected from silver nanoparticles, arylrodanins, enzymes, bacteriophages or usic acid.

The task is also achieved, 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, the specified technical result is also achieved in 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 substances are in preferred mass ratios of gramicidin C: ambroxol from 2: 1 to 1: 1000;

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

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

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

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

- said composition is intended for use in daily dosages:

ambroxol - 7.5-200 mg / day;

gramicidin - 1.5-12 mg / day;

- said composition is intended for use in daily dosages:

ambroxol - 15-120 mg / day;

gramicidin - 1.5-12 mg / day;

- said composition is intended for use in daily dosages:

ambroxol - 30-45 mg / day;

gramicidin - 1.5-4.5 mg / day;

- said composition is intended for use in daily dosages:

ambroxol - 7.5-22.5 mg / day;

gramicidin - 1.5-4.5 mg / day;

- said composition is used from 1 to 6 times a day;

- said composition is used from 1 to 4 times a day;

- said composition is used from 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 destructive agent;

- the anesthetic is selected from the group consisting of lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anestezin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene, diclonin, hexylresorcinol and their pharmaceutically acceptable salts;

- the antibiotic is selected from the group consisting of tyrothricin, bacitracin, amoxicillin, fusafungin, ambazon, polymyxin, neomycin, tobramycin and framicitin;

- 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 their pharmaceutically acceptable salts;

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

- 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 azoxymer bromide, alpha-glutamyl-tryptophan, pidotimod or glucosaminylmuramyl dipeptide;

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

- a biofilm-destroying agent selected from silver nanoparticles, arylrodanins, enzymes, bacteriophages or usic acid.

- as auxiliary substances, said composition additionally contains a sweetener and / or flavor;

- 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 their pharmaceutically acceptable salts;

- the flavor is a 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 application;

- as auxiliary substances, said composition contains a pH regulator, a surfactant, a preservative and water;

- said composition additionally 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;

- surfactants selected from the group consisting of oxyethylated sorbitan esters, polyethylene glycol esters with fatty hydroxy acids, monoglycerides of fatty acids, esters of fatty acids and sucrose or sorbitan;

- preservatives are selected from the group consisting of benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens, alkylpyridinium, benzethonium, and their pharmaceutically acceptable salts;

- said composition additionally 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 their pharmaceutically acceptable salts;

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

- said composition is presented in a solid form for dispersion in the oral cavity or in a solid form for resorption;

- the solid form is a tablet;

- said composition additionally contains 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 stearic acid salt, talc, or mixtures thereof.

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

According to preferred embodiments, the specified technical result is also achieved in that:

- said agent is made in the form of a spray, rinse solution or syrup;

- said agent is made in the form of oral dispersible tablets, oral dispersible lozenges, lozenges or lozenges.

The task is also achieved, and the technical result is achieved by using the said combination or the said pharmaceutical composition, or the said drug for the treatment or improvement of the condition with an infectious-inflammatory disease of the oral cavity, pharynx and upper respiratory tract locally by irrigation or by spraying on the oral mucosa and throat, or resorption, or dispersion in the oral cavity.

According to preferred embodiments, the specified technical result is also achieved 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.

- the active substances in said combination, composition or agent 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;

- the active substances in said 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 application in the oral cavity and pharynx;

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

- the above combination is used from 1 to 4 times a day;

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

In the context of the present invention, the following are used as auxiliary means:

"Antiseptics", 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 imidylammonium chloride, not limited to

"Anesthetics", which preferably means lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anestezin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene and their pharmaceutically acceptable salts, but are not limited to them;

"Antibiotics", which preferably means, but not limited to, tyrothricin, bacitracin, amoxicillin, fusafungin, ambazone, polymyxin, neomycin, tobramycin, and framicitin;

"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;

"Antifungal agent", which preferably means, but is not limited to, fluconazole or nystatin;

"Mucolytic agent", which preferably means, but is not limited to, bromhexine, acetylcysteine, carbocysteine, or their pharmaceutically acceptable salts;

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

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

"Immunomodulatory agent", which preferably means, but is not limited to, azoxymer bromide, alpha-glutamyl-tryptophan, pidotimod or glucosaminylmuramyl dipeptide;

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

"Biofilm destructive agent", which preferably means silver nanoparticles, arylrodanins, enzymes, bacteriophages or usic acid, but is not limited to them;

"Sweetener", which preferably means maltitol, isomalt, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol, and their pharmaceutically acceptable salts, but are not limited to them;

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

Below are also definitions of terms that are used in the description of the present invention.

"Medicinal 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 manufacture of a drug (means ).

"Drug (preparation)" - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injectable forms, ointments and other ready-made forms, intended for the restoration, correction or change of physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"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, auxiliary, distribution agents, delivery vehicles such as preservatives, stabilizers, fillers, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavorings, antibacterial agents, fungicides, lubricants, sustained delivery regulators, the choice and ratio of which depends on their nature , method of 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. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents, such as benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acids, chlorobutanol, sorbic acid, parabens, alkylpyridinium, benzethonium and their pharmaceutically acceptable salts and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided by agents slowing down the absorption of the active principle, for example, such as hydrophilic polymer release agents, for example, cellulose derivatives, polyethylene oxide, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, alginates, carbomers, hydrophobic release retardants such as glycerolate, aluminum monostearate. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, buffers, 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 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. 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, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local 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 administration form, as a mixture with traditional pharmaceutical carriers. Suitable unit forms of administration 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 administration forms and rectal administration forms.

"Pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of acids and bases disclosed in the present invention. These salts can be obtained in situ during the synthesis, isolation, or purification of compounds, or they can be specially prepared. In particular, base salts can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of the salts obtained in this way 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 (For a detailed description of the properties of such salts, see Berge SM, et al., “Pharmaceutical Salts” // J. Pharm. Sci. 1977, 66: 1-19 ). Salts of the claimed acids can also be specially prepared by reacting a 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 derived are sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which the salts of the claimed acids can be obtained, amines and amino acids are selected that are basic enough to form a stable salt and are suitable for medical use (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. Basic amino acids - lysine, ornithine and arginine - can be used as amino acids. Preferred gramicidin salts are gramicidin hydrochloride, preferably gramicidin dihydrochloride. The preferred salt of ambroxol is the hydrochloride salt.

The following examples of implementation of the inventions 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 anti-inflammatory agent ”// Arch. Int. Pharmacodyn, 1971, vol. l89, pp. 129-144].

Acute inflammatory erythema in albino guinea pigs of both sexes weighing 250-500 g is caused by irradiation with ultraviolet (UV) rays of the abdominal skin area (3 × 4 cm, devoid of hair 1 day before the experiment). A quartz lamp (wavelength 280 nm) is used as a source of UV radiation; irradiation is carried out from a distance of 10 cm for 60 seconds (radiation intensity 25.8 W / m ² ). The severity of erythema and skin edema is assessed after 4 hours on an 8-point scale (for an integral assessment of the response to radiation, where 0 points - no erythema or edema, 8 - pronounced erythema or edema). 4 hours after irradiation, erythema develops in 100% of animals, the total intensity is 8 points.

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

Tyrothricin is a natural polypeptide antibiotic for topical use. Tyrothricin exhibits antibacterial activity due to the presence of cyclic and linear polypeptides in it. 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-susceptible strains), S. haemolyticus, S. pyogenes, S. viridans, Diplococcus pneumoniae, Corynebact.spp., Meningococci, Enterococcus faecalis, some pathogens of gonorrhea, Trichomonas, as well as some types of fungi, including Candida.Tyrothricin, depending on the dose used, is capable of bacteriostatic or bactericidal effect on Clostridia.The drug destroys the bacterial wall by changing the permeability of the cytoplasmic membrane, inhibits the growth and division of cells. relieves pain when applied topically. [Lang C., Staiger C. Tyrothricin “An underrated agent for the treatment of bacterial skin infections and superficial wounds?” // Pharmazie, 2016, vol. 71 (6), pp. 299-305 ].

All preparations were applied with a spatula to the affected surface 4 hours after irradiation and then four times a day during the entire study period within the indicated daily dosages. All doses are per person. The data are shown in Table 1. The results of the study showed that in the irradiated animals, erythema, the severity of which was maximal on days 1-2, was observed within 7 days.

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

Example 2. Investigation of antibacterial activity in vitro.

The antibacterial activity of the combinations (Table 2) was determined by known in vitro methods [Sahm DFS, Washington II JA Antibacterial Susceptibility Test: Dilution Methods // Manual of Clinical Microbiology. Albert Balows. - Washington, DC - 1991. - 1363P]. The activity was determined by the agar diffusion method. A suspension of 10 ⁹ colony-forming units (CFU) of a daily culture of Staphylococcus aureus, Streptococcus pyogenes, Str. faecalis, Bac. subtilis, Escherichia coli, Str. pneumoniae, Str. pyogenes, Str. faecalis. The test drug in a volume of 20 μL was introduced into the wells, and after a 24-hour incubation, the growth inhibition zones were measured.

For preparations, the minimum inhibitory concentration (MIC) or working dilution of the sample is determined by the serial microdilution method. For the combinations, the MIC is determined for each of the components. Prepared two-fold dilutions of the drug in mesopatamia broth in a volume of 0.1 ml in a sterile plate (one control well without the drug). In each well of the dilution was introduced 10 ³ CFU of the studied culture of microorganisms. Accounting was carried out photometrically at a wavelength of 620 nm, where MIC is defined as the last dilution in which there was no culture growth.

The study used gramicidin C, ambroxol, a combination of gramicidin C and ambroxol in the ratios of 2: 1, 1: 8.33 and 1: 1000, and the reference drug tyrothricin. The research results are shown in Table 2.

It has been shown that the antibacterial activity of the 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. Investigation of antibacterial activity in vivo.

Outbred white male rats were used for the experiments. 66 animals were randomly assigned to 11 groups according to Example 1: placebo (group 1), gramicidin C at daily dosages of 0.2, 12 and 40 mg (groups 2-4), ambroxol at daily dosages of 20, 100 and 200 mg (groups No. 5-7), a 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 a comparison drug tyrothricin (12 mg / day, group No. 11).

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

On the left side of male white rats, closer to the spine, hair was plucked on an area of 1.5x1.5 cm, 0.4 ml of the prepared suspension was injected intradermally with an insulin syringe and 0.3 ml subcutaneously. After 3 days, a scab wound 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. The treatment was carried out by superficially applying the combinations of the present invention at the indicated dosages.

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

In the groups receiving the combination of gramicidin C and ambroxol, the rates of bacterial reproduction are significantly reduced, which indicates the effectiveness of their use for the treatment of bacterial infections. In addition, a synergistic effect of these combinations was also found at all tested dose levels.

Table 1. Study of anti-inflammatory action on the model of ultraviolet erythema

A drug Dose,
mg / day The severity of erythema and skin edema, points
(mean ± standard error of the mean) Time, days one 2 3 four five 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 C 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 twenty 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 0.0 12 + 100 4.5 ± 0.1 ^# 3.3 ± 0.3 ^# 2.3 ± 0.3 ^# 1.2 ± 0.2 ^# 0.2 ± 0.1 ^# 0.0 0.0 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 0.0 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.

Table 2. Investigation of antibacterial activity in vitro, MIC, µM

A drug Staphylococcus aureus Str. pyogenes Str. Faecalis Bac. subtilis Escherichia coli Str. pneumoniae Str. Pyogenes Str. faecal Gramicidin C 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 By 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 1.1 ± 0.1 By 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 By 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 By 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 By 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 By 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

Table 3. Study of antibacterial activity on the model of staphylococcal localized infection

A drug Dose, mg / day CFU / ml
(mean ± standard error of the mean) Time after removal of the scab, days one 2 3 four five 6 7 Placebo - 2500 ± 50 6400 ± 50 8900 ± 50 10500 ± 50 11600 ± 50 12500 ± 50 12900 ± 50 Gramicidin C 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 twenty 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. A method of obtaining a finished pharmaceutical composition in the form of a spray.

Purified water is introduced into the production tank.

Ambroxol and cetylpyridinium chloride are added to the production tank and stirred until complete dissolution, visual control is carried out until complete dissolution.

Add glycerin to the production tank and mix.

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 preliminary mixing tank and mixed.

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

The flavoring agent is added to the pre-mixing tank and mixed, visual inspection is carried out until complete dissolution.

Transfer the resulting solution to the production tank.

The final bulk product is mixed in the production tank until complete homogenization.

At this stage, the pH and density are monitored and transferred to a temporary storage tank. Filtered, poured into vials and packaged. Examples of the formulations obtained are shown in Table 4.

Table 4. Ready formulations in the form of a spray

Ingredient Weight, mg Gramicidin C 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

Example 5. A method of obtaining a finished pharmaceutical composition in the form of tablets for resorption.

The method of obtaining the specified pharmaceutical composition in the form of a tablet includes weighing and sieving the starting materials, mixing and tableting. Preferably, tableting is carried out by direct compression. Finished tablets can be packed in blisters, and blisters in cardboard boxes. Examples of the formulations obtained are shown in Table 5.

Table 5. Ready formulations in the form of tablets for resorption

Ingredient Weight, mg Gramicidin C 0.7 0.35 0.024 Ambroxol 0.35 2.92 24.0 Mannit 150.9 150.0 140.0 Copovidone 0,4 0,4 0,4 Crospovidone 33.15 31.83 23,076 Sorbitol 3.3 3.3 3.0 Maltit 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 chemical-pharmaceutical industry.

Claims (80)

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, in which the active ingredients are used in an amount: ambroxol - 7.5-200 mg; gramicidin C - 0.2-40 mg and where the active substances are in mass ratios gramicidin C: ambroxol from 2: 1 to 1: 1000. 2. The combination according to claim 1, where the infectious and inflammatory diseases of the oral cavity and pharynx are selected from the group consisting of pharyngitis, glossitis, stomatitis, gingivitis, adenoiditis, tonsillitis and laryngitis. 3. A 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. A 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. A 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 substances are in the mass ratios of gramicidin C: ambroxol 1: 5 or 1:10, or 3:25. 7. A combination according to claim 1, wherein the pharmaceutically acceptable gramicidin C salt is gramicidin C dihydrochloride and the pharmaceutically acceptable ambroxol salt is ambroxol hydrochloride. 8. A 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 destructive funds. 9. A combination according to claim 8, characterized in that the anesthetic is selected from the group consisting of lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anestezin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene, diclonin, and their hexylresorcinol salts. 10. A combination according to claim 8, wherein the antibiotic is selected from the group consisting of tyrothricin, bacitracin, amoxicillin, fusafungin, ambazon, polymyxin, neomycin, tobramycin and framycin. 11. A combination according to claim 8, wherein the proteolytic enzyme is lysozyme or papain. 12. A combination according to claim 8, wherein the vitamin is selected from dexpanthenol, pyridoxine or ascorbic acid. 13. A combination according to claim 8, wherein the antifungal agent is selected from fluconazole or nystatin. 14. A combination according to claim 8, wherein the mucolytic agent is selected from bromhexine, acetylcysteine, carbocysteine, or pharmaceutically acceptable salts thereof. 15. A combination according to claim 8, characterized in that the expectorant is selected from extracts of thermopsis, marshmallow, licorice or glycyrrhizic acid salts. 16. A combination according to claim 8, wherein the anti-inflammatory agent is selected from non-steroidal anti-inflammatory drugs, zinc salts, benzydamine, allantoin, corticosteroids or choline salicylate. 17. A combination according to claim 8, wherein the immunomodulatory agent is selected from azoxymer bromide, alpha-glutamyl-tryptophan, pidotimod or glucosaminylmuramyldipeptide. 18. A combination according to claim 8, wherein the antiviral agent is selected from acyclovir, vitaglutam or inosine pranobex. 19. A combination according to claim 8, characterized in that the biofilm-destroying agent is selected from nanoparticles of silver, arylrodanins, enzymes, bacteriophages or usic acid. 20. Pharmaceutical composition for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx, comprising gramicidin C and ambroxol or their pharmaceutically acceptable salts, as well as at least one pharmaceutically acceptable excipient, in which the active substances are used in an amount: ambroxol - 7.5 -200 mg, gramicidin C - 0.2-40 mg; and where the active substances are in mass ratios of gramicidin C: ambroxol from 2: 1 to 1: 1000. 21. The pharmaceutical composition according to claim 20, wherein the infectious diseases of the oral cavity and pharynx are selected from the group consisting of pharyngitis, glossitis, stomatitis, gingivitis, adenoiditis, tonsillitis and laryngitis. 22. The pharmaceutical composition of claim 20, wherein the pharmaceutically acceptable gramicidin C salt is gramicidin C dihydrochloride and the pharmaceutically acceptable ambroxol salt is ambroxol hydrochloride. 23. A pharmaceutical composition according to claim 20, in which the active substances are in a weight ratio of gramicidin C: ambroxol from 1: 1 to 1: 100. 24. The pharmaceutical composition according to claim 23, in which the active substances are in mass ratios of gramicidin C: ambroxol from 1: 2 to 1:10. 25. The pharmaceutical composition according to claim 24, in which the active substances are in mass ratios of gramicidin C: ambroxol from 1: 5 to 1:10. 26. The pharmaceutical composition according to claim 25, in which the active substances are in the mass ratios of gramicidin C: ambroxol 1: 5, 1:10 or 3:25. 27. The pharmaceutical composition according to claim 20, 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 means. 28. A pharmaceutical composition according to claim 27, wherein the anesthetic is selected from the group consisting of lidocaine, benzocaine, ultracaine, bupivacaine, dicaine, anestezin, promecaine, mepivacaine, trimecaine, oxybuprocaine, acetylaminonitropropoxybenzene, diclonin, and ichylresorcinol salts. 29. A pharmaceutical composition according to claim 27, characterized in that the antibiotic is selected from the group consisting of tyrothricin, bacitracin, amoxicillin, fusafungin, ambazone, polymyxin, neomycin, tobramycin and framycin. 30. A pharmaceutical composition according to claim 27, wherein the proteolytic enzyme is lysozyme or papain. 31. A pharmaceutical composition according to claim 27, wherein the vitamin is selected from dexpanthenol, pyridoxine or ascorbic acid. 32. A pharmaceutical composition according to claim 27, wherein the antifungal agent is selected from fluconazole or nystatin. 33. A pharmaceutical composition according to claim 27, wherein the mucolytic agent is selected from bromhexine, acetylcysteine, carbocysteine, or pharmaceutically acceptable salts thereof. 34. A pharmaceutical composition according to claim 27, characterized in that the expectorant is selected from extracts of thermopsis, marshmallow, licorice or glycyrrhizic acid salts. 35. A pharmaceutical composition according to claim 27, wherein the anti-inflammatory agent is selected from non-steroidal anti-inflammatory drugs, zinc salts, benzydamine, allantoin, corticosteroids or choline salicylate. 36. A pharmaceutical composition according to claim 27, wherein the immunomodulatory agent is selected from azoxymer bromide, alpha-glutamyltryptophan, pidotimod or glucosaminylmuramyl dipeptide. 37. A pharmaceutical composition according to claim 27, wherein the antiviral agent is selected from acyclovir, vitaglutam or inosine pranobex. 38. A pharmaceutical composition according to claim 27, characterized in that the biofilm-destroying agent is selected from nanoparticles of silver, arylrodanins, enzymes, bacteriophages or usnic acid. 39. A pharmaceutical composition according to claim 20, characterized in that said composition additionally contains a sweetener and / or flavoring agent as auxiliary substances. 40. The pharmaceutical composition according to claim 39, characterized in that the sweetener is selected from the group consisting of maltitol, isomalt, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts. 41. A pharmaceutical composition according to claim 39, wherein the flavor is raspberry, strawberry, apricot, mint, pear, melon, mango, lemonade or plum flavor. 42. The pharmaceutical composition according to any one of paragraphs. 20-41, characterized in that said composition is intended for topical use. 43. A pharmaceutical composition according to claim 42, wherein said composition is in the form of a topical solution. 44. A pharmaceutical composition according to claim 20, characterized in that said composition contains a pH regulator, a surfactant, a preservative and water as auxiliary substances. 45. A pharmaceutical composition according to claim 20, wherein said composition further comprises a thickening agent. 46. A pharmaceutical composition according to claim 44, wherein the pH adjusters are selected from the group consisting of organic acids and their salts. 47. A pharmaceutical composition according to claim 46, wherein 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. 48. A pharmaceutical composition according to claim 44, wherein the pH of the composition is in the range of 3.0-8.0. 49. A pharmaceutical composition according to claim 48, wherein the pH of the composition is in the range of 5.0-7.0. 50. A pharmaceutical composition according to claim 49, wherein the pH of the composition is in the range of 6.0-7.0. 51. A pharmaceutical composition according to claim 44, characterized in that the surfactants are selected from the group consisting of oxyethylated sorbitan esters, polyethylene glycol esters with hydroxy fatty acids, monoglycerides of fatty acids, esters of fatty acids and sucrose or sorbitan. 52. A pharmaceutical composition according to claim 44, wherein the preservatives are selected from the group consisting of benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens, alkylpyridinium, benzethonium, and pharmaceutically acceptable salts thereof. 53. A pharmaceutical composition according to claim 27, wherein said composition further comprises a co-solvent selected from low molecular weight aliphatic alcohols. 54. A pharmaceutical composition according to claim 53, wherein the co-solvent is ethanol. 55. A pharmaceutical composition according to claim 45, 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. 56. A pharmaceutical composition according to claim 20, characterized in that the auxiliary substances are sucralose, glycerin, citric acid, sodium citrate, polysorbate, methylparaben, propylparaben, ethanol and water. 57. A pharmaceutical composition according to claim 42, wherein said composition is in a solid form for dispersion in the oral cavity or in a solid form for resorption. 58. A pharmaceutical composition according to claim 57, wherein the solid form is a tablet. 59. A pharmaceutical composition according to claim 58, wherein said composition further comprises a filler and one or more lubricants. 60. A pharmaceutical composition according to claim 59, wherein the filler is sorbitol, mannitol, povidone, copovidone, or mixtures thereof. 61. A pharmaceutical composition according to claim 59, wherein the lubricant is silicon dioxide, a pharmaceutically acceptable stearic acid salt, talc, or mixtures thereof. 62. A topical drug for the treatment of infectious and inflammatory diseases of the oral cavity and pharynx, comprising a combination according to any one of claims. 1-19 or a pharmaceutical composition according to any one of claims. 20-61, where the medicament is in the form of a spray or lozenges. 63. The use of a combination according to any one of paragraphs. 1-19 or a pharmaceutical composition according to any one of claims. 20-61 or a drug according to claim 62 for the treatment or improvement of the condition in case of an infectious-inflammatory disease of the oral cavity, pharynx and upper respiratory tract, topically by irrigation or by spraying on the mucous membrane of the oral cavity and throat, or by absorption or dispersion in the oral cavity ... 64. Use according to claim 63, 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. 65. Use according to claim 63, characterized in that the active substances in said combination, composition or agent are used in daily dosages: ambroxol - 15-120 mg / day; gramicidin - 1.5-12 mg / day. 66. Use according to claim 63, characterized in that the active substances in said combination, composition or agent are used in daily dosages: ambroxol - 20-100 mg / day; gramicidin - 1.5-12 mg / day. 67. Use according to claim 63, characterized in that the active substances in said combination, composition or agent are used in daily dosages: ambroxol - 30-45 mg / day; gramicidin - 1.5-4.5 mg / day. 68. Use according to claim 63, characterized in that the active substances in said combination, composition or agent are used in daily dosages: ambroxol - 7.5-22.5 mg / day; gramicidin - 1.5-4.5 mg / day. 69. Use according to claim 63, characterized in that said combination, composition or agent is intended for topical application in the oral cavity and pharynx. 70. Use according to claim 63, characterized in that said combination, composition or agent is administered from 1 to 6 times a day. 71. Use according to claim 63, characterized in that said combination, composition or agent is administered from 1 to 4 times a day. 72. Use according to claim 63, characterized in that said combination, composition or agent is administered from 1 to 3 times a day.