WO2017095266A1

WO2017095266A1 - Pharmaceutical composition for topical application for treating infectious inflammatory diseases, and method for producing and using same (variants)

Info

Publication number: WO2017095266A1
Application number: PCT/RU2016/000815
Authority: WO
Inventors: Кирилл Константинович Сыров; Владимир Викторович НЕСТЕРУК
Original assignee: Общество С Ограниченной Ответственностью "Валента-Интеллект"
Priority date: 2015-12-01
Filing date: 2016-11-24
Publication date: 2017-06-08
Also published as: UA124498C2

Abstract

The invention relates to the field of medicine and the pharmaceutical chemical industry. Proposed is a pharmaceutical composition for treating infectious inflammatory diseases, in the form of a solution for topical application, characterised in that it contains, as active ingredient, a combination of gramicidin S dihydrochloride and cetylpyridinium chloride and, as excipients, ethanol 96%, sucralose, glycerol, citric acid monohydrate, sodium citrate, polysorbate, methylparaben, propylparaben, natural mint flavouring and purified water. Also proposed is a method for producing and using same.

Description

Pharmaceutical composition for the treatment of infectious and inflammatory diseases of local application and method for its preparation and use (options)

The invention relates to the field of medicine and the pharmaceutical industry.

Infectious and inflammatory diseases of the oral cavity and pharynx (pharyngitis, glossitis, stomatitis and gingivitis) are among the most common reasons for patients to visit local therapists, otorhinolaryngologists, and pediatricians, which is associated with a high incidence among young people of working age and children. Therapeutic tactics for infectious and inflammatory diseases of the mucous membrane of the oral cavity and pharynx include the appointment of drugs with anti-inflammatory, analgesic, immunocorrective effects, local antiseptics, decongestants and hypersensitizing drugs [Morozova SV. “Pain in the throat: causes and possibilities of drug therapy” // breast cancer, volume 13, J e 21, 2005, p. 1447-1452].

As used herein, the term “peptide antibiotic” means cyclic or linear oligo- and polypeptides containing non-peptide substituents (residues of fatty acids, aliphatic amines and alcohols, hydroxyacids, as well as sugars and heterocycles), for example, gramicidins (A, B , C, S, etc.,), thyrotricin, polymyxins B, E and M, cycloserine, penicillin, valinomycin, alanosine, bacitracin A, distamycin. The group is not limited to this list.

The mechanism of action of gramicidin C is associated with an increase in the permeability of the cytoplasmic membrane of the microbial cell, which violates its stability and causes death. Gramicidin C has an antibacterial effect against a wide range of gram-positive and gram-negative microorganisms. Cetylpyridinium chloride is an antiseptic, inhibits the growth and reproduction of pathogens of infectious diseases of the oral cavity. The drug has an antimicrobial effect, reduces inflammation, softens the discomfort in the throat, and facilitates swallowing.

Indications for use: infectious and inflammatory diseases of the oral cavity and throat: pharyngitis, tonsillitis, Ontitis parody, gingivitis, stomatitis.

It is used after meals, topically by irrigation or by spraying on the mucous membrane of the mouth and throat.

For the maximum therapeutic effect in the case of a spray, you should gargle well. Immediately after using the drug, you should refrain from eating food and drinks for 1 hour. Dosage of 3-4 injections (1 injection = 200 μl) for 1 application, 3-4 times a day for 3-7 days.

Unlike other antibacterial agents, it is possible to combine with other antimicrobial agents of local and systemic action with an increase in their effect.

As used herein, the term "antiseptic" means quaternary ammonium salts, as well as other compounds: cetyl pyridinium, benzalkonium, benzetonium, cetalkonium chloride, cetrimonium chloride, cetrimide, chlorhexidine, didecyldimethylammonium chloride, domifen bromide, tetrafamide, dophenium.

As used herein, the term “flavoring” means flavoring agents related to flavoring agents. artificial, identical to natural or natural origin.

As used herein, the term “humectant” also means a thickener to slow the hydrolysis of components; as a humidifier, you can use: propylene glycol, hexylene glycol, butylene glycol, glyceryl, neoagarobiosis, sorbitol, xylitol, maltitol, maltol. The group is not limited to this list.

As used herein, the term “solvent” means ethanol.

As used herein, the term “sweetener” means sucralose, potassium acesulfame, sodium saccharin. The group is not limited to this list.

As used herein, the term “preservatives” means propyl paraben, methyl paraben, benzoic acid, ethyl paraben, sodium benzoate, potassium. The group is not limited to this list.

As used herein, the term “solubilizer” means polysorbate, a surfactant in the presence of which are readily soluble, insoluble antibiotics, pluronics, polyethylene glycols. The group is not limited to this list.

A well-known topical spray is dosed Anti-angina containing Chlorhexidine gluconate in the form of a 20% solution, Tetracaine hydrochloride and excipients: glycerol 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, citric acid anhydrous - 0.02 mg / 0.01 g, purified water - up to 200 mg / up to 100 g (http://medi.ru/doc/a2901 s.htm.

A known composition for the treatment and prevention of respiratory infections in the form of a solution for inhalation or rinsing of the oropharynx containing from about 0.01% to about 1% cetylpyridinium chloride, from about 1% to about 3.4%) sodium chloride. Other active substances can also be added, if desired, for example, mucolytics, antihistamines, antibiotics, antifungal drugs, and the like [WO2010054083 A2, publ. 05/14/2010, IPC A61K9 / 08, A61K9 / 36, A61P1 / 02].

For the treatment of infectious diseases of the throat and oral cavity, Gramicidin C has been successfully used for decades.

Gramitsidin C - the first original domestic antibiotic - the polypeptide of the thyrotricin group isolated from the culture of Bacillus brevis G.F. Gause and M.G. Brazhnikova in 1942, is intended exclusively for local use and has no analogues for systemic use.

The drug has a pronounced bactericidal effect against pathogenic gram-positive and gram-negative bacteria, which in most cases are either directly the cause of diseases of the throat and oral cavity, or they attach secondarily with an initially viral infection, Streptococcus spp., Staphylococcus spp., Streptococcus pneumoniae, neisseria, anaerobes 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 with a high degree probabilities of the causative agent of the infection can be predicted; preference is given to such drugs. Resistance to polypeptides is rare. There are very few reports in the literature on the isolation of gramicidin-resistant microorganism strains from patients or from natural sources. It is very difficult to obtain strains resistant to this antibiotic in laboratory conditions [Polin AN, Egorov NS “Structural and functional features of gramicidin C in connection with its antibiotic activity” // Antibiotics and chemotherapy, 2003, T. 48 (12), S. 29-32]. Due to the originality of the chemical structure and mechanism of action of gramicidin, resistance to it is not accompanied by an increase in the level of antibiotic resistance for systemic use.

Currently, a combined preparation is being produced in the form of resorption tablets for the treatment of infectious and inflammatory diseases of the pharynx and oral cavity, which includes the antimicrobial agent gramicidin C and the antiseptic agent cetylpyridinium chloride (http: //grls.rosmir-zdrav.m/InstrImg .aspx? idReg = 10625 & t = & isOld = n.

Resorption tablets have a short-term local effect. It is believed that sprays act much more efficiently due to a higher concentration of active components in the area of the pathological process.

Known pharmaceutical composition, which can be made in the form of a spray containing neomycin, gramicidin, Quaternary ammonium salt of tomsylamine, phenylephrine, preservative (a mixture of p-hydroxy methyl benzoate and p-hydroxy propyl benzoate) 0.01%, phosphate buffer and water [US2730483 publ. 01/10/1956, IPC C07H15 / 232]. This source can be indicated as the closest analogue of the prototype. The solution can cause a decrease in the effect due to the emergence of resistance resistance due to neomycin, which is part of the antibiotic. In addition, side effects, such as dizziness, tachycardia, hearing loss, may occur.

The objective of the present invention is to develop a new, more effective means based on peptide antibiotics with increased therapeutic efficacy and safety.

The problem is solved by a pharmaceutical composition for the treatment of infectious and inflammatory diseases in the form of a solution for topical application, which contains, as an active principle, a combination of Gramycidin C dihydrochloride and cetylpyridinium chloride, as auxiliary substances - ethanol 96%, sucralose, glycerol, citric acid monohydrate, sodium citrate , polysorbate, methylparaben, propylparaben, natural mint flavoring, purified water at the following content of components, in wt.%:

Gramicidin C dihydrochloride 0.027 - 0.033

Cetylpyridinium chloride 0.045 - 0.055

Ethanol 96% 7.3 - 10.9

Sucralose 0.09 - 0, 1 1

Glycerol 14.9 - 18.2

Natural mint flavoring 0.37-0.44

Citric Acid Monohydrate 0.026 - 0.032

Sodium Citrate 0.0099 - 0.012

Polysorbate 80 0, 18 - 0.22

Methyl parahydroxybenzoate (methyl paraben) 0.0736 - 0.1 104

Propyl parahydroxybenzoate (propyl paraben) 0.0080 - 0.0120 Purified water the rest

The pharmaceutical composition may be in the form of a solution, preferably in the form of a spray.

The preparation method is characterized in that a solution of cetylpyridinium chloride is prepared by adding cetylpyridinium chloride to purified water and mixing until it is completely dissolved, then glycerol is added and mixed, followed by citric acid monohydrate, sodium citrate and sucralose, stirring until complete dissolution. A solution of gramicidin C dihydrochloride is separately prepared by mixing purified water, ethanol 96% and polysorbate 80, adding gramicidin C dihydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate and mixing until complete dissolution, followed by adding natural mint flavoring and stirring. The resulting solutions are stirred until complete homogenization and filtered.

If necessary, the finished solution is packaged in aluminum or glass bottles, coated with plastic, equipped with a pump and a pressure device with a folding cannula, followed by insertion into a cardboard box. These types of packaging ensure safety during the declared shelf life, which is confirmed by the results of the study of the stability of the drug.

The problem is also solved by creating a pharmaceutical composition for the treatment of infectious and inflammatory diseases in the form of a solution for topical use, which contains:

peptide antibiotic 0.027-0.200

antiseptic 0,045-0,200

Excipients, including purified water 99.6-99.928,

wherein said composition has a pH of from 4 to 8.

In a more preferred embodiment, the invention relates to a pharmaceutical composition in the form of a topical solution for the treatment of infectious and inflammatory diseases, characterized in that the peptide antibiotic is selected from the group comprising gramicidin, thyrotricin, polymyxins B, E and M, cycloserine, penicillin, valinomycin, Alanosine, Bacitracin A, Distamycin.

In a more preferred embodiment, the invention relates to a pharmaceutical composition in the form of a topical solution for the treatment of infectious and inflammatory diseases, characterized in that the antiseptic is selected from the group consisting of cetylpyridinium, benzalkonium, benzetonium, cetalkonium chloride, cetrimonium chloride, cetrimide, chlorhexidine, didecyl dimethyl dimethyl dimethyl , domifen bromide, dophania chloride, tetraethylammonium bromide.

In a more preferred embodiment, the invention relates to a pharmaceutical composition in the form of a solution for topical application for the treatment of infectious and inflammatory diseases, characterized in that it contains at least one flavoring and / or moisturizer and / or solvent and / or sweetener and / or preservative and / or solubilizer and / or buffering agent.

In a more preferred embodiment, the invention relates to a pharmaceutical composition in the form of a topical solution for the treatment of infectious and inflammatory diseases, characterized in that it is in the form of a spray.

In a more preferred embodiment, the invention relates to a pharmaceutical composition in the form of a solution for topical use for the treatment of infectious and inflammatory diseases, characterized the fact that it contains as an active principle a combination of Gramycidin C, Cetylpyridinium chloride, and as auxiliary substances ethanol 96%, sucralose, glycerol, citric acid monohydrate, sodium citrate, polysorbate, methyl paraben, propyl paraben, natural mint flavoring, water purified at the following components in wt.%:

Gramicidin C 0.027-0.2

Cetylpyridinium chloride 0.045-0.2

Methylparaben 0.0736-0, 1104

Propylparaben 0.0080-0.0120

Ethanol 7.3-10.9

Sucralose 0.09-0.1 1

Glycerol 14.9-18.2

Natural mint flavoring 0.37-0.44

Citric Acid Monohydrate 0.026-0.032

Sodium Citrate 0.0099-0.012

Polysorbate 80 0, 18-0.22

Purified water the rest

In a more preferred embodiment, the invention relates to a pharmaceutical composition in the form of a topical solution for the treatment of infectious and inflammatory diseases, characterized in that it contains, as an active principle, a combination of Gramycidin C, Cetylpyridinium chloride, and 96% ethanol as excipients , sucralose, glycerol, citric acid monohydrate, sodium citrate, polysorbate, methylparaben, propylparaben, natural mint flavoring, purified water with the following components in ACC%.:

Gramicidin C 0.03 19 Cetylpyridinium chloride 0.050

Methylparaben 0.092

Propylparaben 0.01

Ethanol 9.5

Sucralose 0.1

Glycerol 16.6

Natural Mint Flavor 0.41

Citric Acid Monohydrate 0.029

Sodium Citrate 0.01 1

Polysorbate 80 0.2

Purified water the rest

In another embodiment, the invention relates to a method for producing a pharmaceutical composition for topical use in the treatment of infectious and inflammatory diseases, characterized in that the first solution is prepared by adding purified and cetylpyridinium chloride to the water, stirring until complete dissolution, adding glycerol and mixing, followed by addition citric acid monohydrate, sodium citrate and sucralose and stirring until completely dissolved. A second solution is prepared separately by mixing purified water, ethanol 96% and polysorbate 80, adding gramicidin C dihydrochloride, methyl paraben, propyl paraben and mixing until complete dissolution, followed by adding mint flavoring and mixing the first and second solutions, mix until complete homogenization and filter.

In another embodiment, the invention relates to the use of a pharmaceutical composition for treating or improving a condition with an infectious and inflammatory disease of the oral cavity and throat, such as tonsillitis, periodontitis, gingivitis, stomatitis, locally - by irrigation or by spraying on the mucous membrane of the oral cavity and throat.

The preparation method is characterized in that a solution of cetylpyridinium chloride is prepared by adding cetylpyridinium chloride to purified water and mixing until it is completely dissolved, then glycerol is added and mixed, followed by the addition of citric acid monohydrate, sodium citrate and sucralose, stirring until complete dissolution. Separately, a solution of gramicidin C dihydrochloride is prepared by mixing purified water, ethanol 96% and polysorbate 80, adding gramicidin C dihydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate and stirring until it is completely dissolved, followed by adding peppermint flavor and stirring, and the resulting solutions are stirred until stirring.

If necessary, the finished solution is packaged in aluminum or glass bottles, coated with plastic, equipped with a pump and a pressure device with a folding cannula, followed by insertion into a cardboard box. These types of packaging ensures safety during the declared shelf life, which is confirmed by the results of the study of the stability of the drug.

In one embodiment, the preparation may include an antimicrobial agent, gramicidin C and an antiseptic agent, cetylpyridinium chloride. Although the invention is presented in this document taking into account various typical practical methods of application, it should be borne in mind that these practical applications are only a description of the principles of the existing invention and its application. Specialists who are experts in this field of knowledge can see that there may be many modifications of typical variants of the practical application of the invention, not beyond the scope of the invention.

In addition, it should be borne in mind that various features and / or characteristics of different methods of practical application of the invention can be combined. Therefore, it should be understood that numerous modifications may exist in addition to the described practical applications, and other methods of use may be devised that are not outside the scope of the invention.

In addition, specialists in a specific field of specialized knowledge can see other options for the practical application of the invention after reading the description of the invention, as well as after the practical use of the invention presented in this document. It is assumed that the sections of the description and examples will be taken only as an illustration of a typical application, in accordance with this field of knowledge and the guidelines presented in this application for invention.

Song Options

Options 1-3

Composition Amount of substance mass%

Option 1 Option 2 Option 3

Grammicidin C 0.028 0.0319 0.2

Cetylperidinium 0.046 0.05 0.2 chloride

Methylparaben 0.1 1 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3 Sucralose 0.1 1 0, 1 0.09

Glycerol 18 16.6 15

Flavor 0.44 0.41 0.37 mint

Citric acid 0.032 0.029 0.026 monohydrate

Sodium citrate 0.012 0.01 1 0.0099 polysorbate 0.22 0.2 0.18 water the rest the rest

Options 4-6

Composition Amount of substance mass%

Option 4 Option 5 Option 6

Cycloserine 0.028 0.0319 0.2

Cetylperidinium 0.046 0.05 0.2 chloride

Methylparaben 0.1 1 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3 Sucralose 0.1 1 0, 1 0.09

Glycerol 18 16.6 15

Flavor 0.44 0.41 0.37 mint

Citric acid 0.032 0.029 0.026 monohydrate

Options 7-9

Composition Amount of substance mass%

Option 7 Option 8 Option 9

Polymyxin B 0.028 0.0319 0.2

Cetylperidinium 0.046 0.05 0.2 chloride

Methylparaben 0.1 1 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3 Sucralose 0.11 0.1 0.09

Glycerol 18 16.6 15

Flavor 0.44 0.41 0.37 mint

Citric acid 0.032 0.029 0.026 monohydrate

Options 10-12

Composition Amount of substance mass%

Option 10 Option 11 Option 12

Tyrotricin 0.028 0.0319 0.2

Cetylperidinium 0.046 0.05 0.2 chloride

Methylparaben 0.1 1 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3 Sucralose 0.1 1 0.1 0.09

Glycerol 18 16.6 15

Flavor 0.44 0.41 0.37 mint

Citric acid 0.032 0.029 0.026 monohydrate

Options 13-15

Composition Amount of substance ass%

Option 13 Option 14 Option 15

Grammicidin C 0.028 0.0319 0.2

benzalkonium 0.046 0.05 0.2

Methylparaben 0.1 1 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3 Sucralose 0.1 1 0.1 0.09

Glycerol 18 16.6 15

Flavor 0.44 0.41 0.37 mint

Citric acid 0.032 0.029 0.026 monohydrate

Options 16-18

Composition Amount of substance ass%

Option 16 Option 17 Option 18

Grammicidin C 0.028 0.0319 0.2 Cetrimony 0.046 0.05 0.2

chloride

Methylparaben 0.1 1 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3 Sucralose 0.1 1 0, 1 0.09

Glycerol 18 16.6 15

Flavor 0.44 0.41 0.37 mint

Citric acid 0.032 0.029 0.026 monohydrate

Options 19-21

Composition Amount of substance mass%

Option 19 Option 20 Option 21

Grammicidin C 0.028 0.0319 0.2

chlorhexidine 0.046 0.05 0.2

Methylparaben 0.1 1 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3 Sucralose 0.1 1 0.1 0.09

Glycerol 18 16.6 15

Flavor 0.44 0.41 0.37 mint

Citric acid 0.032 0.029 0.026 monohydrate

Options 22-24

Composition Amount of substance mass%

Option 22 Option 23 Option 24

Grammicidin C 0.028 0.0319 0.2

Cetylperidinium 0.046 0.05 0.2 chloride

Benzoic acid 0.12 0.012 0.0780

Ethanol 10.9 9.5 7.3

Acesulfame potassium 0.1 1 od 0.09

Propylene glycol 18 16.6 15

Flavor 0.44 0.41 0.37 mint

Citric acid 0.032 0.029 0.026 monohydrate Sodium citrate 0.012 0.01 1 0.0099 polysorbate 0.22 0.2 0.18

water rest the rest rest

Options 25-27

Composition Amount of substance mass%

Option 25 Option 26 Option 27

Grammicidin C 0.028 0.0319 0.2

Cetylperidinium 0.046 0.05 0.2

chloride

Methylparaben 0.1 1 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3

Sodium saccharinate 0.1 1 od 0.09

Sorbitol 18 16.6 15

Flavor 0.44 0.41 0.37

mint

Citric acid 0.032 0.029 0.026

monohydrate

Sodium citrate 0.012 0.01 1 0.0099 polysorbate 0.22 0.2 0.18

water rest the rest rest

Options 28-30

Composition Amount of substance mass%

Option 28 Option 29 Option 30

Grammicidin C 0.028 0.0319 0.2

Cetylperidinium 0.046 0.05 0.2

chloride

ethyl paraben 0.11 0.092 0.0740

Propylparaben 0.012 0.01 0.0080

Ethanol 10.9 9.5 7.3

Sodium saccharinate 0.11 0.1 0.09

xylitol 18 16.6 15

Flavor 0.44 0.41 0.37

mint

Citric acid 0.032 0.029 0.026

monohydrate

Sodium citrate 0.012 0.01 1 0.0099 polysorbate 0.22 0.2 0.18

water rest the rest rest

Effect: reduction of side effects. Example 1. The composition

Active substances:

Gramicidin C dihydrochloride 0.319 mg ND firm

0.30 mg

Cetylpyridinium chloride 0.50 mg ND firm, Heb. Pharm.

Excipients:

Ethanol 96% - 95.00 mg Brit. Farm. / Heb. Farm

or Farm.USA-NF

Sucralose - 1, 00 mg Brit. Farm. / Heb. Farm

or Pharm.USA-NF Glycerol - 166.00 mg Brit.Pharm./Hev.Pharm.

or Farm.USA-NF

Peppermint flavoring - 4, 10 mg company ND

Citric Acid Monohydrate 0.29 mg Brit.Pharm./Hev.Pharm.

or Farm.USA-NF

Sodium citrate 0, 1 1 mg Brit.Pharm./Hev.Pharm.

or Farm.USA-NF

Polysorbate 80 2.00 mg Brit.Pharm./Hev.Pharm.

or Farm.USA-NF

Methyl parahydroxybenzoate 0.92 mg Brit.Pharm./Hev.Pharm.

(methylparaben) or Pharm.USA-NF

Propyl parahydroxybenzoate 0.10 mg Brit.Pharm./Hev.Pharm.

(propylparaben) or Pharm.USA-NF

Purified water up to 1 ml Brit.Pharm./Hev.Pharm.

or Farm.USA-NF

Example 2. A method of obtaining a composition

Stage 1: Purified water is introduced into the production tank. Step 2: Cetylpyridinium chloride is added to the production tank and mixed until completely dissolved. Internal production control: carry out visual inspection until complete dissolution.

Step 3: Glycerol is added to the production tank and mixed.

Step 4: Citric acid monohydrate, sodium citrate and sucralose are added to the production tank and mixed until completely dissolved.

Internal production control: carry out visual inspection until complete dissolution.

Step 5: Purified water, ethanol 96% and polysorbate 80 are added to the pre-mixing tank and mixed.

Step 6: Gramicidin C hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate are added to the pre-mixing tank and mixed until completely dissolved.

Step 7: Mint flavor is added to the pre-mixing tank and mixed.

Step 8: Transfer the solution obtained in step 7 to the production tank.

Step 9: The final bulk product is mixed in the production tank until complete homogenization.

In-house control:

- characteristics

- pH

- density

Step 10: The resulting product is transferred to a temporary storage tank. Stage 1 1: The resulting product is filtered, filled and packaged.

Internal production control: control the filling volume of the packaging.

(Table 1).

Table 1. Internal production control

Example 3. Pharmacological studies.

Studies have been conducted of the general toxic effect, as well as the specific pharmacological activity and resorptive action of the composition in the form of a spray for topical application in example 1.

In the experiments, sexually mature outbred white rats were used. With a single intraventricular administration, it was found that the drug is a low-toxic substance. Rat LD50 was not achieved with the highest possible dose of 25.0 ml / kg in dosage form or 7.5+ 12.5 mg / kg for active ingredients, which is 500 times more than the therapeutic dose (when using Grammidine Neo tablets, the therapeutic dose was exceeded by 350 times).

The results of a study of the subchronic toxicity of the proposed pharmaceutical composition in rats showed that repeated topical administration by spraying in the mouth and throat at an equi-therapeutic dose and exceeding the therapeutic dose for 30 days did not cause functional disorders of the main organs and systems of the body:

- within 30 days there were no changes in horizontal and vertical activity in the open field test compared to the control group (spraying with water);

- the height and duration of the QRS complex, the duration of the PQ interval within the species norm, while prototype studies showed changes (see table 3);

- data on the analysis of urine did not reveal significant differences compared with the control;

- the content of hemoglobin, red blood cells, ESR did not differ from the indicators in the control group, while prototype studies showed changes (see table 4);

- local application did not cause changes in the myelogram in experimental animals.

Long-term local use of the claimed composition did not reveal a locally irritating effect according to histological examination of the mucous membranes of the oral cavity, esophagus and stomach.

The research data of the oral mucosa when stained with hematoxylin and eosin are presented in figure 1, where A is a section of the control group, B is the claimed solution, C is the prototype. AT prototype with prolonged use there is a slight local irritating effect.

Resorptive effects have been studied in rabbits. The drug was applied by spraying on the mucous membrane of the oral cavity and throat of a rabbit at a therapeutic dose of 280 μg / rabbit (the declared dose was converted from person to rabbit) once. Blood samples were taken 15, 45 and 90 minutes after application of the solution. Blood analysis was performed using an LC-20 Prominance chromatograph, Japan.

The analysis results showed that the solution does not have a resorptive effect.

The antibacterial effect was investigated on strains of Streptococcus pyogenes, Escherichia coli. The sensitivity to the drug was determined by serial dilution. It was found that the solution showed a pronounced antibacterial effect against both gram-positive and gram-negative bacteria (table 2)

The distribution of the active principle on the surface of the glands and in the blood was studied on the model of Smirnov, Belashev, Demin and showed a higher concentration at the injection site compared to tablets.

Table 2.

"-" lack of bacterial growth, "+" visible bacterial growth Table 3.

Table 4.

Example 4. The antibacterial effect of the compositions (options 1-21)

The antibacterial effect of the compositions was studied on strains of Streptococcus pyogenes, Escherichia coli.

The sensitivity to the drug was determined by serial dilution. It was found that the solution showed a pronounced antibacterial effect against both gram-positive and gram-negative bacteria (tables 5, 6 and 7)

Table 5.

“-” lack of bacterial growth, “- +” weak growth, “- ++” moderate growth, “- +++” strong growth, “++++” copious growth

Table 6.

Escherichia - ++ - ++ - ++ - + - + - + coli strain

18M

Streptococcus - ++ - ++ - ++ - + pyogenes,

strain 415

Table 7.

strain Variants of compositions

15 16 17 18 19 20 21

Escherichia - + - ++ - ++ - + - + coli strain

18M

Streptococcus - + - ++ - + - +

pyogenes

strain 415

Example 5. Stability Test

Stability tests were conducted for the pharmaceutical compositions of this invention, options 22-30, in the form of a solution. Samples of the preparations in accordance with options 22-30 were stored at 25 ° C, humidity 60 ± 5%. On days 7 and 14, a portion of each sample was taken, the purity and concentration of gramicidin C in each portion was measured by reverse phase HPLC. The amounts of gramicidin C, measured on the seventh and fourteenth day in accordance with the stability tests, are shown in table 8.

Table 8.

[Original count After 1 week After 2 weeks

Option 22 100.0% 100.0% 100.0%

Option 23 100.0% 100.1% 100.0%

Option 24 100.0% 100.0% 99.8%

Option 25 100.0% 99.7% 99.5%

Option 26 100.0% 100.0% 99.7%

Option 27 100.0% 100.0% 99.9%

Option 28 100.0% 100.0% 99.5%

Option 29 100.0% 99.7% 99.7%

Option 30 100.0% 99.8% 99.9%

Comparative example, option 1 100.0% 99.8% 99.8%

Comparative example, option 2 100.0% 99.8% 100.0%

Comparative example, option 3 100.0% 99.9% 99.7%

The results shown in table 8 confirm that the stability of gramicidin C was maintained in the compositions of options 22-30 and in the compositions in accordance with comparative examples.

The above results show that the compositions of this invention remain stable for a period of at least two weeks even when stored at ambient temperature.

Claims

Claim

1. The pharmaceutical composition in the form of a solution for topical use for the treatment of infectious and inflammatory diseases, characterized in that it contains as an active principle a combination of Gramycidin C dihydrochloride and cetylpyridinium chloride, and as excipients - ethanol 96%, sucralose, glycerol, lemon acid monohydrate, sodium citrate, polysorbate, methyl paraben, propyl paraben, natural mint flavoring, purified water at the following content of components, in wt.%:

Gramicidin C dihydrochloride 0.027-0.033

Cetylpyridinium chloride 0.045-0.055

Ethanol 96% 7.3-10.9

Sucralose 0.09-0, 1 1

Glycerol 14.9-18.2

Natural mint flavoring 0.37-0.44

Citric Acid Monohydrate 0.026-0.032

Sodium Citrate 0.0099-0.012

Polysorbate 80 0.18-0.22

Methyl parahydroxybenzoate (methyl paraben) 0.0736-0.1 104

Propyl parahydroxybenzoate (propyl paraben) 0.0080-0.0120

Purified water the rest

2. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a spray.

3. The method of obtaining the pharmaceutical composition according to claim 1 in the form of a solution for topical use for the treatment of infectious and inflammatory diseases, characterized in that a solution of cetylpyridinium chloride is prepared by adding cetylpyridinium chloride in purified water and stirring until it is completely dissolved, then glycerol is added and stirring, followed by the addition of citric acid monohydrate, sodium citrate and sucralose, stirring until complete dissolution, a solution of gramicidin C dihydrochloride is prepared separately by mixing purified water, ethanol 96% and polysorbate 80 by adding gramicidin C dihydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate and stirring until completely dissolved, followed by the addition of natural mint and stirring, the resulting solutions are mixed until completely homogenized and filtered.

4. The use of the pharmaceutical composition according to claim 1 locally by irrigation or by spraying on the mucous membrane of the oral cavity and throat to treat or improve the condition of an infectious and inflammatory disease of the oral cavity and throat, such as: pharyngitis, tonsillitis, periodontitis, gingivitis, stomatitis ,.

5. The pharmaceutical composition in the form of a solution for topical use for the treatment of infectious and inflammatory diseases, characterized in that it contains (wt.%):

peptide antibiotic 0.027-0.200

antiseptic 0,045-0,200

Excipients,

including purified water 99.6-99.928,

wherein said composition has a pH of from 4 to 8.

6. The pharmaceutical composition according to p. 5, characterized in that the peptide antibiotic is selected from the group comprising gramicidin, thyrotricin, polymyxins B, E and M, cycloserine, penicillin, valinomycin, alanosine, bacitracin A, distamycin.

7. The pharmaceutical composition according to claim 5, characterized in that the antiseptic is selected from the group consisting of cetylpyridinium, benzalkonium, benzetonium, cetalkonium chloride, cetrimonium chloride, cetrimide, chlorhexidine, didecyldimethylammonium chloride, domifen bromide, tetrafonium chloride.

8. The pharmaceutical composition according to p. 5, characterized in that it contains at least one flavoring and / or humectant, and / or a solvent, and / or a sweetener, and / or a preservative, and / or a solubilizer, and a buffering agent.

9. The pharmaceutical composition according to claim 5, characterized in that it is made in the form of a spray.

10. The pharmaceutical composition in the form of a solution for topical use for the treatment of infectious and inflammatory diseases, characterized in that it contains, as an active principle, a combination of Gramycidin C, Cetylpyridinium chloride, and 96% ethanol, sucralose, glycerol, citric acid as excipients monohydrate, sodium citrate, polysorbate, methyl paraben, propyl paraben, natural mint flavoring, purified water with the following components in wt.%:

Gramicidin C 0.027-0.2

Cetylpyridinium chloride 0.045-0.2

Methylparaben 0.0736-0, 1 104

Propylparaben 0.0080-0.0120

Ethanol 7.3-10.9

Sucralose 0.09-0,

eleven Glycerol 14.9-18.2

Natural mint flavoring 0.37-0.44

Citric Acid Monohydrate 0.026-0.032

Sodium Citrate 0.0099-0.012

Polysorbate 80 0.18-0.22

Purified water the rest

And. The pharmaceutical composition of claim 10, characterized in that it is made in the form of a spray.

12. The method of obtaining the pharmaceutical composition according to PP. 5-1 1, characterized in that the first solution is prepared by adding purified and cetylpyridinium chloride to the water, stirring until complete dissolution, adding glycerol and mixing, followed by the addition of citric acid monohydrate, sodium citrate and sucralose and stirring until complete dissolution, separately prepared the second solution by mixing purified water, ethanol 96% and polysorbate 80, adding gramicidin C dihydrochloride, methyl paraben, propyl paraben and stirring until completely dissolved, followed by ION natural mint flavoring agent and mixing, then mixed first and second solutions are stirred until complete homogenization and filtered.

13. The use of the pharmaceutical composition according to claim 5-12 locally by irrigation or by spraying on the mucous membrane of the oral cavity and throat to treat or improve the condition for an infectious and inflammatory disease of the oral cavity and throat selected from the group: pharyngitis, tonsillitis, periodontitis, gingivitis stomatitis.