RU2713884C1 - Liquid composition for producing a spray for forming an antimicrobial wound dressing in skin microtrauma - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to pharmacology and represents a liquid composition for preparing a dosage form for forming an antimicrobial wound dressing in microtrauma of skin, containing as active agents benzalkonium chloride and oligohexamethylene hydrochloride, having branched structure:

n₁, n₂ and n₃ are equal to 1–3, z is equal to 0.15–1, auxiliary substances including PVP and PEG or collagen stabilized with polysorbate, as well as solvent selected from water, ethyl alcohol and isopropyl alcohol, with the following components content: antimicrobial agent 0.80–1.70 g; excipients 3–25 g; solvent up to 100 g.

EFFECT: invention provides extending the range of products for treating microtrauma of skin.

7 cl, 4 dwg, 7 ex, 9 tbl

Description

FIELD OF THE INVENTION

The invention relates to the field of pharmacology. More specifically, it provides a liquid composition containing one or more antimicrobial agents, one of which is oligohexamethylene hydrochloride having branched molecules, excipients and a solvent. The invention can find application in everyday life and in medical practice for the treatment of minor damage to the skin (microtrauma), such as, for example, scratches or abrasions.

State of the art

Getting microtrauma (cuts, scratches, abrasions) is an unpleasant, but integral part of any person’s life. The most common cause of microtrauma is inaccurate handling of cutting and piercing objects in the home and during work. Scratches can be the result of careless handling of pets, resulting from scratching. Cuts can occur as a result of trauma, manifestations of aggression. Bacteria that can cause an inflammatory process or more serious consequences can enter the bloodstream through damaged skin.

Scratches and abrasions are surface damage to one or more layers of the skin. An infection can enter the body with any damage to the skin, even with a small scratch. With complications of infection, inflammation, pain, purulent formations may appear, and in severe cases, sepsis. The most dangerous infection is Gram-positive bacillus Clostridium tetani causing tetanus, which is a spore-forming obligate anaerobic.

All accidental microtraumas are infected, no matter how they are inflicted. Moreover, the primary infection is introduced into the tissue by a foreign object that was wounded. With deep microtraumas, pieces of foreign objects get inside, which cause the primary infection of the wound. A secondary infection can enter the wound from the surrounding areas of the skin and mucous membranes, clothing, from infected body cavities (such as the esophagus), at the time of dressing, etc.

Most often, wound infection occurs with a purulent infection caused by streptococci and staphylococci. Therefore, the fight against such microorganisms and the prevention of their secondary entry into the wound are important aspects of microtrauma therapy.

Various medical devices are used to close microtraumas, for example, plasters and bandage dressings, as well as adhesive dressings and tissue adhesives, which may contain bacteriostatic or bactericidal components. As the latter, triphenylmethane dye Brilliant Green and the biguanide derivative, chlorhexidine, are most widely used. Wound healing adhesive dressings containing herbal extract compositions are currently being developed. So, for example, in the international application WO 2014/120700 (published 07.08.2014) a synergistic medical combination is disclosed containing from 5 to 1000 parts of an extract of Hydrastis canadensis, from 5 to 1000 parts of an extract of representatives of the genus Panax and from 5 to 1000 parts of Aloe extract barbadensis L.

In the description of the invention to patent CN 108392672 (publ. 08/14/2018) a gel dressing is disclosed containing (in parts by weight) calcium chloride 1-10, sodium alginate 1-10, ginseng root powder 10-50 and water 30-90, and also the alga Sargass (representative of the genus Panax), which has a wide spectrum of biological activity, in particular bacteriostatic and wound healing. The advantages of this technical solution compared to commercially available non-woven alginate materials are great flexibility, softness, stickiness and breathability.

Film-forming compositions for closing wounds have been known for quite some time. So, in the description of the invention to patent CH 530795 (publ. 30.11.1972) a film-forming composition for closing wounds, such as cuts, scratches, postoperative wounds, preferably used from a spray container containing a film-forming synthetic polymer, in particular PVA, dissolved in a mixture that does not irritate the skin and consists of MeAc, EtOH and BzOH. Preferably, the solution contains 16.94 wt.% PVA, 43.66 wt. % MeAc, 35.2 wt.% EtOH and 4.2 wt. % BzOH, and a packaged spice composition is prepared by mixing 33 g of a solution with 50 g of acetone and 67 g of CCl ₂ F ₂ as a propellant.

Description of the invention to patent CN 107174573 (publ. 09/19/2017) discloses a film-forming spray for wound protection, which is prepared from the following components (in mass parts): glycyl-glycine endopeptidase 0.005-0.05, chlorxylene 0.1-0.3 , polyvinylpyrrolidone-K90 4-7, polyvinyl alcohol 2-10, sodium carboxymethyl cellulose 0.2-0.8, ethyl alcohol 20-30 and water 49-65. The disclosed film-forming protective spray is characterized by a short film-forming time, high film strength and long-term antibacterial action.

In the description of patent RU 2312658 (publ. 20.12.2007) a film-forming aerosol for protecting wounds in the treatment based on a synthetic polymer is disclosed, characterized in that it consists, wt. hours:

1) polysiloxane-polycarbonate block copolymer (PS-PC) with the ratio of PS: PC blocks = (35-55) :( 65-45), as the basis for the formation of a coating film 3-10;

2) chloroform - a solvent of a block copolymer and as an anesthetic substance 97-90;

3) an antiseptic drug in an alcohol solution of 0.1-0.2;

4) halocarbon or mixtures thereof as a propellant 100-120.

Getting on the skin, liquid chloroform causes a feeling of cold, then burning and redness of the skin. Chloroform vapors are not so irritating, but if they are inhaled, respiratory activity, heart function (a violation of the frequency, rhythm and sequence of contractions of the heart muscle, myocardial dystrophy) and other organs, for example, the liver (dystrophy, cirrhosis), are possible. This is a significant drawback of such a composition, which is present on the market under the trade name Pentazol (Penta Med LLC, RF).

As a development of the technical solution described above, we can consider the commercially available Aktoviderm drug (LLC Millor Pharma, RF), which contains polycarbonatesiloxane, chloroform, chlorhexidine, and propellant (Freon 406a). This drug has the same drawback due to the presence of chloroform in its composition. In addition, halogenated hydrocarbons damage the ozone layer of the Earth.

Branched copolymers of guanidine and hexamethylenediamine - oligohexamethylene guanidines (OHMG) are known. In the patent RU 2443684 (publ. February 27, 2012), branched oligomers of hexamethylenediamine and guanidine of the formula (I) are disclosed

an ₁ , n ₂ and n ₃ are 1-3, az is 0.15-1.10 with a molecular weight distribution of M _w / M _n from 5.4 to 9.3 with a weight average molecular weight of M _w ranging from approximately 3800 to 6300 and a number average molecular weight M _n ranging from about 600 to 1100, as a salt. The description indicates that the preparation of the base can be carried out in the presence of an alcohol, such as ethanol or isopropanol, taken in an amount of 0.5-1.0 volume of the total volume of the reaction mass, consisting of equal volumes of approximately 50% aqueous solutions of the oligomer and alkali. This allows you to reduce the residual content of HMDA to 0.02-0.1% of the mass. depending on the time and temperature of the process, as well as the ratio of reagents and alcohol. A product of this purity is quite suitable as a pharmaceutical substance.

In patent RU 2513997 (publ. 04/27/2014) an ophthalmic preparation is disclosed in the form of drops containing a combination of active components, a promoting component, excipients and water, characterized in that the combination of active components consists of a branched polyhexamethylene guanidine of the formula (I) shown above, where R, n ₁ , n ₂ and n ₃ , z, M _w / M _n , M _w and M _n have the above meanings, present in the form of hydrochloride, and taurine; the promoting component is selected from succinic acid or a pharmaceutically acceptable salt thereof, excipients are selected from the group consisting of physiologically tolerated alkaline or acid agents present in amounts required to maintain the pH of the drug in the range from 6.0 to 7.8, and saline tonic an agent selected from physiologically tolerated sodium or potassium salts and mixtures thereof, present in an amount providing a tonicity of the drug comparable to the tonicity of a natural tear fluid healthy vogo person.

The drug has a healing effect on eye injuries. In vitro also shows its bactericidal effect against E. coli, Staphylocuccus spp. and Candida spp. The described description of the invention indicates the bactericidal action of OGMG-GC against Staphylocuccus spp., Which can infect microtrauma of the skin, but relates to ophthalmic preparations.

Thus, there is a need to develop new drugs and dosage forms to fight infections with microtrauma and prevent re-infection.

Disclosure of the invention

The aim of the invention is the creation of a medicinal product in the form of a solution to obtain a sprayable dosage form for isolating microtraumas from an external, potentially containing pathogens, environment and their treatment, which does not cause resistance and is effective against a wide range of pathogenic microorganisms. Thus, the arsenal of funds for this purpose can be expanded. In addition, the technical result is the exclusion of chloroform from the solvent, which will avoid the locally irritating and allergenic effects of the nebulized dosage form.

In well-known technical solutions, OGMG-GC exhibits bactericidal properties in dilute aqueous solutions. Its activity in medicines presented in the form of a wound dressing formed on the skin by spraying a liquid composition containing an alcoholic or aqueous-alcoholic solvent is not obvious from the prior art.

As a result of extensive research, the inventors have found that the objective of the invention can be achieved by creating a liquid composition for producing a sprayable dosage form for forming an antimicrobial wound dressing for skin microtraumas, containing an antimicrobial agent, excipients and a solvent in which the antimicrobial agent is selected from the group consisting of oligohexamethylene guanidine hydrochloride (OHMG-GC), benzalkonium chloride (BA-X) and rosin, excipients include polyvinylpyrrolide n (PVP) as the polymer base, a plasticizer selected from the group consisting of polyethylene glycol (PEG) and polysorbate stabilized collagen, and the solvent is selected from the group consisting of distilled water, ethyl alcohol and isopropyl alcohol, while the molecules of oligohexamethylene guanidine hydrochloride have branched structure represented by the formula

n ₁ , n ₂ and n ₃ are 1-3, az is 0.15-1.10 with a molecular weight distribution of M _w / M _n from 5.4 to 9.3 with a weight average molecular weight of M _w ranging from approximately 3800 to 6300 and the number average molecular weight M _n in the range from about 600 to 1100, with the following component contents (in g):

antimicrobial agent 0.80-1.70; Excipients 3-25; solvent up to 100.

In a first preferred embodiment, the liquid composition has the following composition (in g):

OGMG-GC 0.80 Benzalkonium chloride 0.02 PVP with an average molecular weight of 27 kDa 20 PEG with an average molecular weight of 400 kDa 5 Ethyl alcohol (96%) up to 100.

In a second preferred embodiment, the liquid composition has the following composition (in g):

OGMG-GC 0.80 Benzalkonium chloride 0.02 Rosin 0.85 PVP with an average molecular weight of 27 kDa 10 PEG with an average molecular weight of 400 kDa 3 Isopropyl alcohol 3.4 Ethyl alcohol (96%) up to 100.

In a third preferred embodiment, the liquid composition has the following composition (in g):

OGMG-GC 0.80 Benzalkonium chloride 0.02 Rosin 0.85 PVP with an average molecular weight of 27 kDa 8 PEG with an average molecular weight of 400 kDa 3 g Fish Collagen 0.5 Polysorbate Monooleate (Tween 80) 0.5 Distilled water thirty Ethyl alcohol (96%) up to 100.

Preferably, the liquid composition is for spraying without using a propellant to form a spray.

Alternatively, preferably the liquid composition is intended to be sprayed without using a propellant to form an aerosol.

Also in accordance with the invention, there is provided a mechanical device for producing an propellant-free spray, including a reservoir with a liquid composition and a spray unit hermetically attached to it, connected by a flow of the liquid composition to the reservoir by a sampling tube, the lower part reaching the bottom of the reservoir, and connected to the atmosphere by air flow . Preferably, the reservoir is made of an organic polymer for medical use, metal or glass, and the spray unit is actuated by a limited stroke of its drive in the direction of the reservoir. Accordingly, 40 ml aluminum monoblock cylinders with an inner lacquered coating with a microdoser and a protective cap made of high density polyethylene are preferred.

The invention also provides a mechanical device for producing an aerosol containing a propellant, including a reservoir with a liquid composition and a spray assembly hermetically attached to it, which is connected downstream of the liquid composition to the reservoir by a sampling tube, the lower part of which reaches the bottom of the reservoir, in which the liquid composition is located under excessive pressure, the propellant and the spray unit are driven by the limited stroke of its drive in the direction of the tank. Accordingly, aluminum cylinders with an internal lacquer coating are preferred as a reservoir.

Brief Description of the Drawings

In FIG. 1 shows the dynamic viscosity of a liquid composition prepared in accordance with Example 1 as a function of strain rate.

In FIG. 2 shows the dynamic viscosity of a liquid composition prepared in accordance with Example 2 as a function of strain rate.

In FIG. 3 shows the dynamic viscosity of a liquid composition prepared in accordance with Example 3 as a function of strain rate.

In FIG. 4 is a photograph of a static imprint of a spray torch of a liquid composition prepared in accordance with Example 2.

The implementation of the invention

Further, the possibility of carrying out the invention with the achievement of its technical results will be shown in non-limiting examples.

Examples 1 and 2. Preparation of collagen-free liquid compositions

30 ml of ethyl alcohol (96%) is poured into a measuring cup and 0.80 g of OGMG-GC is added with stirring at 40 ° C; after its dissolution, 0.02 g BA-X is added to the solution. Then, PVP is added with stirring, and after its dissolution, PEG 400 is added, followed by stirring the solution for 20 minutes at the same temperature.

In Example 2, a solution of rosin in isopropyl alcohol is separately prepared and added after dissolving the PVP. The mass of liquid compositions was adjusted to 100 g by adding ethyl alcohol (96%) and the solutions were cooled.

в течение 10 минут. Полученные составы стерилизуют, последовательно пропуская под давлением через мембранные фильтры с размером пор 0,8 мкм, 0,45 мкм и 0,22 мкм в стерильные флаконы объемом 100 мл. Флаконы закрывают резиновыми пробками и укупоривают алюминиевыми крышками с помощью устройства для обжима.After cooling, the solutions are degassed in an ultrasonic bath at a temperature

for 10 minutes. The resulting compositions are sterilized by successively passing under pressure through membrane filters with pore sizes of 0.8 μm, 0.45 μm and 0.22 μm into sterile 100 ml vials. The vials are closed with rubber stoppers and sealed with aluminum caps using a crimping device.

Example 3. The preparation of a liquid composition containing collagen

30 g of water is poured into a measuring cup and 0.5 g of polysorbate-80 is added with stirring. The resulting mixture was stirred at a temperature of 40 ° C until the polysorbate was completely dissolved. 3.0 g of PEG 400 was added to the resulting solution, followed by stirring the solution for 10 minutes at the same temperature. Rabbi collagen is added to the mixture and mixing is carried out until the components are completely dissolved, after which 0.80 g OGMG-GC and 0.02 g BA-X are added to the mixture and mixed until they are completely dissolved.

Then the mass of the composition is adjusted to 100 g by adding ethyl alcohol (96%) and left under stirring for one hour without changing the temperature. Then the glass with the solution is covered with cling film and allowed to cool to room temperature. The solution is sterilized by successively passing under pressure through membrane filters with pore sizes of 0.8 μm, 0.45 μm and 0.22 μm into sterile 100 ml vials. The vials are closed with rubber stoppers and sealed with aluminum caps using a crimping device.

Example 4. Confirmation of the antibacterial activity of the liquid composition

The antimicrobial activity of the liquid composition is determined against the methylotrophic bacterium Methylophilus quaylei (strain MT; VKM B-2338T), which is a gram-negative, non-spore-forming, immobile short bacillus propagating by simple division, with ribulose-monophosphate utilization of methanol (Doronina N., Ivanova E. , Trotsenko Y., Pshenichnikova A., Kalinina E., Shvets V. Methylophilus quaylei sp. Nov., A new aerobic obligately methylotrophic bacterium. Syst. Appl. Microbiol. 2005 June; 28 (4): 303-309).

Preparation of culture media. For the cultivation of bacteria Methylophilus quaylei prepare the environment of the following composition:

The medium is sterilized at 115 ° C for 30 minutes in a steam sterilizer (GK-10-1, OJSC TZMOI, RF). Separately, under the same conditions, a phosphate solution is sterilized. After natural cooling to room temperature, the solutions, observing sterility, are mixed and 1 vol. % methanol.

Cultivation of bacteria Methylophilus quaylei. To obtain the inoculum, the bacteria are transferred from the mown agar to a liquid nutrient medium and cultured for 24 hours at 28 ° C on a thermostatic shaker (100 rpm) in 150 ml flasks. The volume of liquid in the flasks is 20-40 ml. 200-400 μl of methanol is added. Cultivated crops are used as seed.

Evaluation of antibacterial activity. Bacteria are cultured in flasks with a capacity of 150 ml in 40 ml of culture medium on a thermostatically controlled shaker (28 ° C, 100 rpm). The daily culture of M. quaylei MG with absorption in a cuvette with an optical path length of 10.01 mm at a wavelength of 660 nm (A ₆₆₀ ) equal to 2.155 (spectrophotometer Coleman 575, Perkin-Elmer, USA) was used as an inoculum. 1 ml of a daily culture is added to 7 flasks (flask 1 - control of bacterial growth) with a sterile growth medium and 400 μl of methanol is added, 400 μl is added.

After a day, 1 ml samples were taken in the burner flame and the absorbance of the culture fluid was measured at a wavelength of 600 nm. An increase in biomass concentration corresponds to an increase in absorption. The test results to confirm the antibacterial activity of the liquid compositions in accordance with the invention by the method of measuring the absorption of radiation of a cell suspension are shown in table 1.

The research results show that all liquid compositions in accordance with the invention have antibacterial activity, while the composition of example 3 is most active. Rosin has insignificant bactericidal properties, and in the absence of OHMG-GC and BA-X, the compositions do not exhibit such properties.

Example 5. Determination of physico-chemical properties of films obtained from liquid compositions in accordance with the invention

1) Preparation of samples for research. Petri dishes are lined with food-grade plastic wrap and press it tightly over the entire area of the inner surface of the cups. Samples of liquid compositions prepared in accordance with examples 1-3 (30 ml of each composition) are poured into Petri dishes, tighten the cups with a cloth and left for 2 days at room temperature.

2) Determination of adhesion to metal. Half-length metal spatulas are covered with plastic wrap and cut to the size of a spatula. 10 ml of experimental composition is carefully poured onto the spatula so as to ensure uniform distribution of the composition over the entire area of the spatula, and left for 2 days at room temperature.

From a half of a spatula coated with a plastic film, the film obtained from the liquid composition is peeled off until its length is sufficient to secure the film to the sponge of the upper clamp of the Instron 3343 tensile testing machine (Instron, UK). The spatula is fixed to the sponge of the lower clamp exactly in the center of its length. Under the control of the built-in computer, a tensile testing machine is turned on, which captures the moment when the plastic film is completely peeled off from the spatula and displays the adhesion value (in N / m).

для металла (сталь) и для кожи принимают равными 1 Дж/м² и 0,037 Дж/м² соответственно. Далее производят пересчет адгезии образцов к металлу на работу адгезии к коже человека, решив систему уравнений (1-2):Determine the wetting angle of the fluid samples of the test solutions on a metal spatula and skin. Values

for metal (steel) and for leather, they are taken equal to 1 J / m ² and 0.037 J / m ^2, respectively. Next, recalculate the adhesion of the samples to the metal on the work of adhesion to human skin, solving the system of equations (1-2):

- работа адгезии,Where

- adhesion work,

- поверхностная энергия твердого тела к газу,

- surface energy of a solid to a gas,

- поверхностное натяжение твердого тела на границе с жидкостью,

- surface tension of a solid at the interface with the liquid,

- поверхностное натяжение жидкости на границе с газовой средой,

- surface tension of the liquid at the boundary with the gas medium,

- краевой угол смачивания.

- contact angle of wetting.

As a result of determining adhesion to a metal spatula medical (steel 12X18H10T), the following values were obtained (table 2):

The calculated work of adhesion of the compounds to the skin is presented in table 3.

The adhesion value for compositions 1 and 2 is in the first half of the acceptable interval (12-120 N / m), and the adhesion of composition 3 is close to its lower acceptable border, which is satisfactory.

3) Determination of vapor permeability of films. Films for studies are prepared according to the procedure described in section 1) of Example 5. From the obtained films, samples are cut with a scalpel, the diameter of which coincides with the diameter of the lower part of the chamber for testing.

25 ml of distilled water is poured into the lower part of the chamber. A rubber gasket is placed on the upper section of the chamber, on top of which an experimental sample is applied. The chamber is tightly closed with a threaded cap with a hole for connecting the experimental sample with the atmosphere, which makes up most of the surface of the cap.

Chambers with samples prepared in accordance with examples 1-3 are weighed to the nearest 0.0001 g. All cameras are placed in a desiccator, which is installed in a thermostat and kept at a temperature of 37 ° C for an hour. The mass difference of the chambers is recorded before and after thermostating. Next, calculate the mass of water in the chamber before (m _initial ) and after (m _final ) exposure and calculate the number of water vapor passing through the film of the samples (vapor permeability) as specified in GOST 22900-78. Artificial leather and film materials. Methods for determination of vapor permeability and moisture absorption: - M .: IPK. Publishing house of standards. 1979. - amend. from 10/18/2016. - 8 p.

The vapor permeability values of films prepared from samples of the tested compositions are presented in table 4.

The results of the study show that all samples are sufficiently vapor permeable.

4) Determination of breathability of films. Films for studies are prepared according to the procedure described in section 1) of Example 5. From the obtained films, samples are cut with a scalpel whose diameter slightly exceeds the diameter of the surface of the working platform of the clamping arm of the TesTex TF164E Air Permability Tester (TesTex Testing Equipment, USA) used for testing . The pressure of the supplied air is set equal to 200 Pa, the device is turned on under the control of the built-in computer and the pressure hand is pressed until the air permeability value determined during the study is displayed (table 5).

* at a pressure of supplied air equal to 400 Pa

The research results show that, only the film obtained from the sample in accordance with example 2, sufficiently passes air. Samples of films of compositions 1 and 4 cannot be used for long-term stay of the film on the surface of the skin.

5) Assessment of the strength and elasticity of the films. Films for studies are prepared according to the procedure described in section 1) of Example 5. Then, strips of films 10 mm wide and 50 mm long are cut with a scalpel.

The ends of the strips are securely fixed in the upper and lower jaws of the Instron 3343 tensile testing machine (Instron, UK) and include it in the work under the control of the built-in computer. At the end of the measurements (after the strip is broken), the values of the forced elastic and tensile load, and the relative elongation are given in table 6.

The load at a break of 0.38-0.5 MPa are considered sufficient for the use of films as wound dressings. A sample of the film from the composition prepared in accordance with example 3 showed low elasticity with a high value of strength necessary for tearing, which will not allow its use in areas of the skin in places of its natural bend. The film from the composition in accordance with example 2 showed acceptable values of elasticity and strength. Sample composition 1 has the highest elasticity, but a satisfactory low value for tensile strength.

6) Determination of the rheological properties of liquid compositions. The rheological properties of liquid compositions prepared in accordance with Examples 1-3 are characterized based on the dependence of the dynamic viscosity on the strain rate, which is recorded using a rotational viscometer (Brookfield viscometer). During the study, the device measures the torque required to rotate the immersion element (spindle) into the liquid. At each dynamic viscosity value, the hydraulic resistance is proportional to the spindle speed of a given shape and size.

15 ml of the test liquid composition are poured into the sample chamber. A spindle (SC4-18) is mounted on the viscometer shaft, the sample chamber is placed in a thermostat and fixed. The sample is thermostated for 15 minutes at a temperature of 25 ° C. Then, in the control program, a set of spindle speed values (1 / min) is set so as to obtain viscosity data in the range corresponding to from 10% to 90% of the maximum deflection of the calibrated viscometer spring.

The rheological behavior of liquid compositions prepared in accordance with examples 1-3 was characterized as follows (table 7):

Example 6. Assessment of the stability of liquid compositions during storage

1) Bookmark samples for stability studies by the method of “accelerated aging”. Liquid compositions prepared in accordance with examples 1-3 are poured into vials of penicillin FO-10 with a nominal capacity of 10 ml into sterile conditions. Eight vials are filled with each liquid composition, introducing 7.0 ml of the composition into them. The vials are corked with sterile rubber stoppers, marked and stored in a climate chamber KBF115 (Binder, Germany) with a difference in test temperature and storage temperature (25 ° C) equal to 35 ° C.

2) Visual stability assessment. In studies using the “accelerated aging” method, the shelf life of 30, 45, and 60 days corresponds to a shelf life of 2, 3, and 4 years. Every 7 days, the bottles are inspected for separation of the compositions. After 56 days, no stratification was observed in any of the liquid compositions prepared in accordance with the examples.

Thus, the shelf life of liquid compositions in accordance with the invention is confidently evaluated for 3 years.

3) Measurement of the pH of liquid compositions at the stages of research by the method of “accelerated aging”. The pH value of healthy human skin is in the range of 5.2-5.7. Finding the pH of the liquid compositions in accordance with the invention in the specified interval prevents the manifestation of discomfort and possible skin burn when applying the composition to the wound surface.

For pH measurements, an Expert-pH pH meter (NPP Ekoniks LLC, RF) is used, equipped with a single-key glass combined semi-microelectrode ESK-10313/4 (0-14 pH, 20-100 ° С, d 8 mm, L 30 mm; LLC “Measuring equipment”, RF), calibrated with standard buffer solutions with pH 4.01 and 6.86 (LLC “Scientific and Technical Company Analit-Neva, RF).

Before and at the end of each measurement, the electrode is washed with distilled water, and a drop of washing water is removed from the bottom of the electrode with filter paper. After every 7 days from the climate chamber, one bottle is removed with a sample for liquid compositions prepared in accordance with examples 1-3. The bottles are alternately placed in a thermostatic cell, incubated for 30 minutes and pH measurements are made by immersing the electrode in them. The measurement results are presented in table 8.

All liquid compositions prepared in accordance with the examples satisfy the requirement for pH throughout the duration of the study. The maximum deviation of the pH value from the value for a freshly prepared composition is 1.6%, which is comparable with the measurement error.

Example 7. The choice of spray nozzles

When spraying a liquid composition from a package, a so-called static imprint of a spray torch is formed, which is usually divided into three zones: 1) internal, consisting of large aerosol particles, 2) central or working, consisting of medium and small aerosol particles, and 3) external, into which small aerosol particles fall.

The composition prepared in accordance with example 2, fill the vials and cork them alternately with different spray nozzles (LLC Estrocom, Russia). From a distance of 20 cm on a white sheet of paper, laid out vertically, release one dose of the composition. The diameters of the inner, working and outer zones are measured and presented as a percentage of the diameter of the spray torch. The results are presented in the table.

Thus, it will be understood by one of ordinary skill in the art that for each formulation prepared in accordance with the invention, a suitable spray nozzle can be selected.

Claims (13)

1. A liquid composition for producing a sprayable dosage form for the formation of an antimicrobial wound dressing for skin microtraumas, containing an antimicrobial agent, excipients and a solvent, characterized in that the antimicrobial agent is a mixture of oligohexamethylene guanidine hydrochloride (OHMG-GC) and benzalkonium chloride (BA) excipients include polyvinylpyrrolidone (PVP) as the polymer base, a plasticizer selected from the group consisting of polyethylene glycol (PEG) and collagen is stabilized th polysorbate and the solvent is selected from the group consisting of distilled water, ethyl alcohol and isopropyl alcohol, the hydrochloride oligogeksametilenguanidina molecules have a branched structure represented by the formula

n ₁ , n ₂ and n ₃ are 1-3, az is 0.15-1.10 with a molecular weight distribution of M _w / M _n from 5.4 to 9.3 with a weight average molecular weight of M _w ranging from approximately 3800 to 6300 and the number average molecular weight M _n in the range from about 600 to 1100, with the following component contents (g): antimicrobial agent 0.80-1.70 Excipients 3-25 solvent up to 100. 2. The liquid composition according to claim 1, characterized in that the antimicrobial agent further comprises rosin. 3. The liquid composition according to p. 1, characterized in that it has the following composition: OGMG-GC                                                     0.80 g Benzalkonium chloride 0.02 g PVP with an average molecular weight of 27 kDa  20 g PEG with an average molecular weight of 400 kDa    5 g Ethyl alcohol (96%)                                      up to 100 g 4. The liquid composition according to p. 1, characterized in that it has the following composition: OGMG-GC                                                    0.80 g Benzalkonium chloride                                          0.02 g Rosin                                                    0.85 g PVP with an average molecular weight of 27 kDa  10 g PEG with an average molecular weight of 400 kDa    3 g Isopropyl alcohol                                            3.4 g Ethyl alcohol (96%)                                      up to 100 g 5. The liquid composition according to p. 1, characterized in that it has the following composition: OGMG-GC                                                   0.80 g Benzalkonium chloride                                         0.02 g Rosin                                                   0.85 g PVP with an average molecular weight of 27 kDa  8 g PEG with an average molecular weight of 400 kDa  3 g Fish Collagen                                                    0.5 g Polysorbate Monooleate (Tween 80)                    0.5 g Distilled water                                30 g Ethyl alcohol (96%)                                    up to 100 g 6. The liquid composition according to paragraphs. 1-4, characterized in that the liquid composition is intended for spraying without the use of a propellant with the formation of a spray. 7. The liquid composition according to paragraphs. 1-4, characterized in that the liquid composition is intended for spraying using a propellant with the formation of an aerosol.

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