RU2604576C1 - Pharmaceutical composition for treating infectious-inflammatory diseases of local application and method of its production and application - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to pharmaceutical composition for treating infectious-inflammatory diseases for local application, method of producing compositions and use thereof for treating or improving health in infectious-inflammatory diseases of mouth and throat. Composition contains as active agent combination of gramicidin C dihydrochloride, oxybuprocaine hydrochloride and cetylpyridinium chloride, as auxiliary substances - 96 % ethanol, sucralose, glycerol, citric acid monohydrate, sodium citrate, polysorbate, methylparaben, propylparaben, natural flavoring agent mint, purified water.

EFFECT: invention implementation allows to reduce side effects of using composition with gramicidin and increase uniformity of dosing.

4 cl, 3 tbl, 4 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).

For example, a topical anti-angina spray is known, 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).

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-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. 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 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.

Patent RU 2532027 C2 dated 10.27.2014 discloses a liquid composition for topical application containing a pharmaceutical active ingredient, a solvent mixture containing water, isopropanol in an amount of 5 wt. % to 20 weight. % and propylene glycol in an amount of 2 wt. % to 25 weight. %, and phospholipid blowing agent in an amount of from 2 wt. % to 25 weight. % As active components, an extensive list of substances of various pharmacological groups is listed, including gramicidin C, oxybuprocaine hydrochloride and cetylpyridinium chloride. However, specific formulations including at least one of these substances are not disclosed. The foam composition is suitable mainly for application to the skin and wounds, and there is no indication of the possibility of oral administration.

Currently, a combination drug in the form of resorption tablets for the treatment of infectious and inflammatory diseases of the pharynx and oral cavity "Grammidin with anesthetic neo" is available, which includes gramicidin C, oxybuprocaine hydrochloride and cetylpyridinium chloride (http://grls.rosminzdrav.ru /InstrImg.aspx?idReg=11177&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.

As the closest analogue, the composition in the form of a Septolete® Plus spray can be indicated containing active ingredients: Benzocaine and Cetylpyridinium chloride monohydrate in terms of cetylpyridinium chloride and excipients: ethanol 96%, glycerol, sodium saccharin, peppermint oil and water (http: : //www.krka.ru/media/products/ru/otc/exp_pdf/2015/Septolete_Plus_spray_Instruction.pdf). It is used to relieve pain in infectious and inflammatory diseases of the oral cavity and pharynx (pharyngitis, laryngitis, tonsillitis, inflammation of the gums and oral mucosa (gingivitis, stomatitis)), topically. During each procedure, 2 sprays (0.300 ml) are performed. It is recommended to take every 2-3 hours up to 8 times a day. The drug has good antibacterial effectiveness. However, it has side effects. So, with prolonged use of doses or with frequent use with a short time interval, the development of methemoglobinemia is possible. Allergic reactions and difficulty breathing, numbness of the oral mucosa are possible.

The objective is to develop a new effective drug based on gramicidin.

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

Gramicidin C 0.027-0.033 Oxybuprocaine hydrochloride 0,067-0,083 Cetylpyridinium chloride 0.045-0.055 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

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 the first solution is prepared by adding purified oxybuprocaine hydrochloride 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 prepare the second solution by stirring purified water, ethanol 96% and polysorbate 80, adding gramicidin C dihydrochloride, methyl parahydroxybenzoate, propyl parahydroxyb nzoata and stirring until complete dissolution followed by addition of mint flavor and mixing, then mixed first and second solutions and stirring until complete homogenisation was filtered and packaged as necessary.

The solution can be 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.

The composition of the drug includes the antimicrobial agent gramicidin C, a local anesthetic (analgesic) agent - oxybuprocaine 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. Anesthetic oxybuprocaine has a local anesthetic effect on the mucous membrane of the mouth and throat. It causes a reversible blockade of the propagation and conduction of nerve impulses through the axons of nerve cells.

The drug has an antimicrobial effect, anesthetic 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, in particular, by spraying on the mucous membrane of the mouth and throat.

For maximum therapeutic effect, gargle well before use. Dosage for adults and children over 12 years of age: 3-4 injections (1 injection 200 μl) for 1 application, 3-4 times a day for 3-7 days.

Effect: reduced side effects, higher uniformity of dosage.

Example 1 Spray Composition

Active substances: Gramicidin C dihydrochloride - 0.319 mg Company ID Oxybuprocaine hydrochloride - 0.75 mg Company ID 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 Brit.Pharm./Hev.Pharm. or Farm.USA-NF mg 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 paraben - 0.92 mg Brit.Pharm./Hev.Pharm. or Farm.USA-NF propyl paraben - 0.10 mg Brit.Pharm./Hev.Pharm. or Farm.USA-NF Purified water - up to 1 ml Brit.Pharm./Hev.Pharm. or Farm.USA-N

Example 2 A method of obtaining a finished pharmaceutical composition

Stage 1: Purified water is introduced into the production tank.

Step 2: Oxybuprocaine hydrochloride and cetylpyridinium chloride are 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 (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 according to 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 dosage form or 7.5 + 12.5 + 18, 75 mg / kg in active substances, which is 500 times more than the therapeutic dose (when using tablets Grammidine with Neo anesthetic 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;

- 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. In particular, in tests of repeated use locally in doses exceeding the equitherapy, the hemoglobin content according to the invention is 139 g / l, according to the prototype -125 g / l, control 137 g / l;

- 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.

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 μl / 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 proposed solution does not have a resorptive effect, the solution of the prototype has a slight resorptive effect (table 2).

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 3)

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.

Example 4 Dosing Uniformity

The test is carried out in accordance with the requirements of the European Pharmacopoeia, monograph 1807 and article 2.9.40.

Evaluation of the drug for uniformity of dosage is carried out by weight.

The test is performed as follows. Press the pressure device several times until air is removed from the cannula. After at least 5 s, shake the vial for 5 s. Then press on the pressure device and the released contents are discarded. Repeat these steps three more times. The vial is weighed, pressed onto the pressure device and the vial is weighed again, weighing is carried out to the nearest 0.001 g. The mass of the released contents is determined by the difference. Repeat this operation for nine more vials.

The allowable value (AV) is calculated in the same way as for determining the uniformity of dosing by quantitative determination (see Heb. Pharm., Table 2.9.40.-2), replacing the individual contents of the active substances in product units with the calculated individual content obtained, as indicated below.

x1, x2 ... xn are the individual values of the content of gramicidin C, oxybuprocaine hydrochloride and cetylpyridinium chloride in the tested vials;

,Where

,

wi - mass of released contents from the i-th bottle, in grams;

A is the quantitative content of gramicidin C, oxybuprocaine hydrochloride or cetylpyridinium chloride in the preparation, as a percentage of the amount indicated on the label;

W is the average mass of released content, in grams.

The individual content of dosage units (xi) of the claimed composition is in the range from 0.75 M to 0.85 M, of the prototype 0.85 M - 1.25 M, that is, although both solutions meet the requirements, the dosage uniformity of the claimed composition is higher.

Claims (4)

1. A pharmaceutical composition for the treatment of infectious and inflammatory diseases for topical application, characterized in that it contains, as an active principle, a combination of Gramycidin C, Oxybuprocaine hydrochloride, 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 0.027-0.033 Oxybuprocaine hydrochloride 0,067-0,083 Cetylpyridinium chloride 0.045-0.055 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 use according to claim 1, characterized in that the first solution is prepared by adding purified oxybuprocaine hydrochloride and cetylpyridinium chloride to the water, mixing until complete dissolution, adding glycerol and mixing, followed by by adding 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, the addition of gramicidin C dihydrochloride, methyl paraben, propyl paraben and stirring until completely dissolved, followed by the addition of mint flavoring and stirring, then the first and second solutions are mixed, mixed until completely homogenized and filtered. 4. The use of the pharmaceutical composition according to claim 1 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 oral mucosa and throat.