RU2633635C1 - Topical pharmaceutical composition for treating inflammatory infections and method of its production and application - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for treating inflammatory infections in the form of a topical solution is proposed, characterised in that it contains a combination of gramicidin C dihydrochloride and cetylpyridinium chloride as the active principle, ethanol 96%, sucralose, glycerol, citric acid monohydrate, sodium citrate, polysorbate, methylparaben, propylparaben, natural mint flavour, purified water as auxiliary substances.

EFFECT: implementation of the invention allows to develop an effective agent with enhanced therapeutic efficacy and safety.

4 cl, 1 dwg, 7 tbl, 5 ex

Description

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, 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 includes the appointment of drugs with anti-inflammatory, analgesic, immune corrective action of local antiseptics, decongestants and hypersensitizing drugs (Morozova S.V. Pain in the throat: causes and possibilities of drug therapy. BC, volume 13, No. 21, 2005, p. 1447-1452).

A 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, 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).

A known composition for the treatment and prevention of respiratory infections in the form of a solution containing from about 0.01% to about 1% cetylpyridinium chloride; from about 1% to about 3.4% sodium chloride, for inhalation or rinsing of the oropharynx. Other active substances can also be added, if desired, for example, mucolytics, antihistamines, antibiotics, antifungal drugs and the like (WO 2010054083 (A2) - 2010-05-14).

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

Gramicidin C - the first original domestic antibiotic-polypeptide of the thyrotricin group isolated from the culture of Bacillus brevis G.F. Gause and M.G. Brazhnikova in 1942, intended exclusively for local use, 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 a second time with an initially viral infection, Streptococcus spp., Staphylococcus spp., Streptococcus pneumoniae, neisseria, anaerobes and 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 infection can be predicted with a high degree of probability, it is recommended that these drugs be preferred. 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. - No. 48 (12). - S. 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.

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.rosminzdrav.ru/InstrImg.aspx ? idReg = 10625 & t = & isOld = 1). Resorption tablets have a short-term local effect. It is believed that sprays are much more effective due to a higher concentration of active components in the area of the pathological process.

A known pharmaceutical composition that can be in the form of a spray containing neomycin, gramicidin, a quaternary ammonium salt of tomsilamine, phenylephrine, a preservative (a mixture of p-hydroxy methyl benzoate and p-hydroxy propyl benzoate) 0.01%, phosphate buffer and water (US 2730483). 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 is to develop a new, more effective peptide-based antibiotic product with enhanced therapeutic efficacy and safety.

The problem is 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 for the treatment of infectious and inflammatory diseases in the form of a solution for topical application, characterized in that the peptide antibiotic is selected from the group consisting of 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 for the treatment of infectious and inflammatory diseases in the form of a solution for topical administration, 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 for the treatment of infectious and inflammatory diseases in the form of a solution for topical application, characterized in that it contains at least one flavoring and / or moisturizer and / or solvent and / or sweetener, and / or a preservative and / or solubilizer and / or buffering agent.

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

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

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 0.09-0.11 Glycerol 14.9-18.2 Peppermint flavor 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 rest

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

Gramicidin C 0,0319 Cetylpyridinium chloride 0,050 Methylparaben 0,092 Propylparaben 0.01 Ethanol 9.5 Sucralose 0.1 Glycerol 16.6 Peppermint flavor 0.41 Citric Acid Monohydrate 0,029 Sodium Citrate 0.011 Polysorbate 80 0.2 Purified water rest

In another embodiment, the invention relates to a method for producing a pharmaceutical composition for the treatment of infectious and inflammatory diseases for topical application, characterized in that the first solution is prepared by adding purified 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 prepare a second solution by stirring water hydrochloric acid, ethanol 96% and polysorbate 80, the addition of gramicidin C dihydrochloride, methyl paraben, propyl paraben and stirring until completely dissolved, followed by the addition of peppermint flavor and stirring, then the first and second solutions are mixed, stirred until complete homogenization and filtered.

In another embodiment, the invention relates to the use of a pharmaceutical composition for treating or improving an infectious and inflammatory disease of the oral cavity and throat, selected from the group: pharyngitis, tonsillitis, periodontitis, gingivitis, stomatitis, topically by irrigation or by spraying on the oral mucosa and throat.

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.

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.

Used in this document, the term "flavoring" means aromatic substances related to 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 triacetate (aka triacetin), 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 insoluble antibiotics, pluronics, polyethylene glycols are better soluble. The group is not limited to this list.

The pharmaceutical composition may be in the form of a solution, or 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 the addition of citric acid monohydrate, sodium citrate and sucralose, stirring until complete dissolution, a solution of gramicidin is separately prepared With dihydrochloride by mixing purified water, ethanol 96% and polysorbate 80, adding gramicidin C dihydrochloride, methyl parahydroxybenzoate, ropilparagidroksibenzoata and stirring until complete dissolution followed by addition of mint flavor and mixing 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 composition of the drug may include an antimicrobial agent - gramicidin C, and an antiseptic agent - cetylpyridinium chloride. 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, periodontitis, 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.

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 options for practical application 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 description sections and examples will be taken only as an illustration of a typical application, in accordance with this field of knowledge and the indications of this application for invention.

Song Options

Options 1-3

Options 4-6

Options 7-9

Options 10-12

Options 13-15

Options 16-18

Options 19-21

Options 22-24

Options 25-27

Options 28-30

Example 1

Active substances: Gramicidin C dihydrochloride - 0.319 mg Company ID - 0.30 mg Cetylpyridinium chloride - 0.50 mg ND firms, Heb. Pharm. Excipients: Ethanol 96% - 95.00 mg Brit.Pharm./Hev.Pharm. or Farm.USA-NF Sucralose - 1.00 mg Brit.Pharm./Hev.Pharm. or Farm.USA-NF Glycerol - 166.00 mg Brit.Pharm./Hev.Pharm. or Farm.USA-NF Peppermint flavor - 4.10 mg Company ID Citric Acid Monohydrate - 0.29 mg Brit.Pharm./Hev.Pharm. or Farm.USA-NF Sodium Citrate - 0.11 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 Farm.USA-NF Propyl parahydroxybenzoate - 0.10 mg Brit.Pharm./Hev.Pharm. (propylparaben) or Farm.USA-NF Purified water - up to 1 ml Brit.Pharm./Hev.Pharm. or Farm.USA-NF

Example 2. The method of obtaining

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.

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

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: Transfer to a temporary storage tank.

Step 11: Filter, fill and pack.

Internal production control: control the volume of filling (table 1).

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. The LD50 for rats was not achieved with the maximum possible dose of 25.0 ml / kg in the dosage form or 7.5 + 12.5 mg / kg in active substances, which is 500 times more than the therapeutic dose (when using Grammidine Neo tablets - 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 5);

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

- the content of hemoglobin, erythrocytes, ESR did not differ from the indicators in the control group, while prototype studies showed changes (see table 6);

- 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.

Research data on the oral mucosa when stained with hematoxylin and eosin are presented in FIG. 1, where A is a slice of the control group, B is the claimed solution, C is the prototype. In the prototype with prolonged use, a slight locally irritating effect is noted. 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 solution does not have a resorptive effect.

Example 4

The antibacterial effect of the compositions (options 1-21) 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 2, 3, 4).

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.

Example 5. Stability Test

Tested the stability of the pharmaceutical compositions, options 22-30, in the form of a solution according to this invention. 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 7.

The results shown in table 7 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 are stable for a period of at least two weeks even when stored at ambient temperature.

Claims (5)

1. The pharmaceutical composition for the treatment of infectious and inflammatory diseases in the form of a solution for topical application, characterized in that it contains a combination of gramicidin C, cetylpyridinium chloride as an active principle, 96% ethanol, sucralose, glycerol, citric acid monohydrate as excipients , sodium citrate, polysorbate, methylparaben, propylparaben, natural mint flavoring, purified water, with the following content of components, mass. %: 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 0.09-0.11 Glycerol 14.9-18.2 Peppermint flavor 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 rest 2. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a spray. 3. A method of obtaining a pharmaceutical composition for the treatment of infectious and inflammatory diseases for topical application according to claim 1, characterized in that the first solution is prepared by adding purified 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 prepare a second solution by mixing purified water, ethanol 96% and polysorbate 80, at ION gramicidin C dihydrochloride, methyl paraben, propyl paraben, and stirring until complete dissolution followed by addition of mint flavor and mixing, then mixed first and second solutions are stirred until complete homogenization and filtered. 4. The use of the pharmaceutical composition according to paragraphs. 1, 2 for the treatment or improvement of an infectious and inflammatory disease of the oral cavity and throat, selected from the group: pharyngitis, tonsillitis, periodontitis, gingivitis, stomatitis, topically by irrigation or by spraying on the mucous membrane of the oral cavity and throat.

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