RU2603490C1 - Agent for treating pyoinflammatory processes in soft tissues and mucous membranes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to agents possessing antimicrobial, sorption, analgesic and wound healing action on local pyoinflammatory processes in soft tissues and mucous membranes, used in surgery, dermatology, obstetrics and gynecology, otorhinolaryngology. Agent for treating pyoinflammatory processes in soft tissues and mucous membranes is two-layer film and contains combination of antiseptic, benzalkonium chloride and metronidazole as therapeutic components, sodium carboxymethyl cellulose (Na-CMC) is used as base, anaesthetic is lidocaine hydrochloride, transdermal transfer accelerator of active substance is dimethyl sulphoxide, stabilizer is glycerine.

EFFECT: technical result consists in creation of effective remedy in form of two-layer film, possessing antimicrobial, sorption, analgesic and wound healing action.

1 cl, 2 ex, 3 tbl

Description

The invention relates to medicine, namely to agents having antimicrobial, sorption, analgesic and wound healing effects on local purulent-inflammatory processes of soft tissues and mucous membranes used in surgery, dermatology, obstetrics and gynecology, otorhinolaryngology.

The problem of treatment of purulent wounds is still relevant in modern medical practice. According to some authors, purulent complications from all surgical diseases are 28-34%, and mortality from them reaches 22%.

To achieve a positive result, modern drugs should have a multidirectional effect and combine such properties as broad antimicrobial activity, high dehydrating ability, stimulation of tissue regeneration, local anesthesia.

To date, to treat the variety of microorganisms that cause a purulent-inflammatory process in the soft tissues, topical antibiotics are used. However, it should be noted that their massive, and in some cases their uncontrolled use leads to the predominance of microflora in the wound that is insensitive or insensitive to them. In this regard, in surgical practice in the treatment of local purulent-inflammatory processes, interest in antiseptics and chemotherapeutic drugs is increasing.

In order to absorb purulent exudate and drain the wound surface in drugs (ointments, gels, etc.) for external use, polyethylene oxides (PEO), carbon sorbents, cellulose derivatives, etc. are currently widely used. Moreover, modern trends dictate the need to develop convenient forms of drugs, such as wound dressings (sponges, films, etc.).

The prototype of our invention is considered a medicinal product that contains an alloy of polyethylene oxides with a molecular weight of 400 and 1500 and includes a combination of benzalkonium chloride antiseptics and metronidazole as therapeutic components (RF Patent No. 2542373 "MEANS FOR THE TREATMENT OF PULMONARY INFLAMMATORY TREATMENT ").

However, this tool is an ointment that does not have anesthetic property and does not contain a component that increases the transdermal transfer of active substances.

The technical result of the invention is the creation of an effective tool in the form of a two-layer film with antimicrobial, sorption, analgesic and wound healing effects.

The technical result is achieved in that the agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes is a two-layer film and contains as a therapeutic component a combination of the antiseptic benzalkonium chloride and metronidazole, sodium carboxymethyl cellulose (Na-CMC) is used as a base, as an anesthetic - lidocaine hydrochloride, as an accelerator of transdermal transfer of the active substance - dimethyl sulfoxide, as a stabilizer - glycerin in the following mass olyah:

Metronidazole 1,0 (FS 42-2283-93) Lidocaine hydrochloride 2.0 (FS 42-0251-07) Benzalkonium chloride 0.02 (Ph Eur monograf 0372) Glycerol 1,0 (FS 42-2202-99) Dimethyl sulfoxide 1,0 (TU 6-09-3818-89) Carboxymethyl Cellulose Sodium 1.75 (TU 6-55-221-1453-96) Purified water 93.23 (FS 42-0324-09)

Feature of the objects:

Metronidazole. An antibacterial chemotherapeutic drug derived from 5-nitroimidazole has high activity against a wide range of bacteria and protozoa. It is proved that anaerobes retained 100% sensitivity to it. The mechanism of action is the biochemical reduction of the 5-nitro group of metronidazole by intracellular transport proteins of anaerobic microorganisms and protozoa. The reduced 5-nitro group of metronidazole interacts with the DNA of the cell of microorganisms, inhibiting the synthesis of their nucleic acids, which leads to the death of bacteria.

Lidocaine hydrochloride has a local anesthetic effect, blocks voltage-dependent sodium channels, which prevents the generation of impulses in the ends of sensory nerves and the conduction of impulses along nerve fibers. Suppresses the conduct of not only pain impulses, but also impulses of other modalities. The anesthetic effect of lidocaine is 2-6 times stronger than procaine (acts faster and longer - up to 75 minutes). When applied topically, it dilates blood vessels, does not have a locally irritating effect.

Benzalkonium chloride. It has a microbostatic and microbicidal effect on gram-positive, in large doses - on gram-negative bacteria and fungi of the genus Candida. It is also known as a preservative, which is used to prevent microbial contamination during prolonged storage of dosage forms, in particular ointments, gels, etc. In addition to antiseptic, it has a deodorizing effect. In addition, benzalkonium chloride is a cationic surfactant that can affect the degree of grinding of medicinal substances, thereby increasing their bioavailability and effectiveness.

Glycerin is a colorless, odorless, sweetish-tasting, syrupy liquid of a neutral reaction, it dissolves in all proportions in water and alcohol, and is very hygroscopic. It has a softening effect on the skin and scabs formed on its surface. In high concentrations it has antiseptic properties, due to which it is used as a preserving medium. Glycerin belongs to the group of stabilizers with the properties to maintain and increase the degree of viscosity and consistency.

Dimethyl sulfoxide is a colorless transparent liquid or colorless crystals, melting at a temperature of 18.5 ° C, with a specific odor. Hygroscopic. Miscible in all proportions with water and alcohol. The molecular weight is 78.13. As a medicine, purified dimethyl sulfoxide is used in the form of aqueous solutions as a local anti-inflammatory and analgesic, as well as in ointments - to increase the transdermal transfer of active substances, since it penetrates the skin and transfers other substances in a few seconds.

The sodium salt of carboxymethyl cellulose (Na-CMC) is soluble in water, in aqueous solutions of alkalis, in organic solvents and mineral oils - it is not soluble. In this case, the sodium salt of carboxymethyl cellulose forms viscous transparent solutions characterized by pseudoplasticity, and for some varieties of the product, by thixotropy (i.e., the ability to spontaneously restore the original structure destroyed by mechanical action). In the form of a gel, Na-CMC interacts with tissues and wound contents, is evenly distributed over the wound surface, provides fast and complete delivery of drugs to the lesion site, and exhibits an osmotic effect when applied to the wound, absorbing the wound discharge.

Purified water (Aqua purificata) is a colorless, clear, odorless and tasteless liquid, pH 5.0-6.8. Water was used as a solvent.

The method is carried out as follows.

The technology was carried out under aseptic conditions and included several stages.

A portion of the polymer of the sodium salt of carboxymethyl cellulose (Na-CMC), glycerol and the calculated amount of water were divided into two equal parts and used to prepare each separate layer of films.

1. Preparation of the first film layer

1.1. A portion of the Na-CMC polymer was poured with purified water, leaving a small amount to dissolve lidocaine hydrochloride and benzalkonium chloride. Glycerin, a solution of lidocaine hydrochloride and benzalkonium chloride were added, left to swell the polymer, then carefully mixed until a homogeneous mass was obtained.

1.2. After deaeration of the resulting mass, it was poured into Petri dishes on the prepared substrate (a thin layer of liquid paraffin). Dried to a residual moisture content of 10%.

2. Preparation of the second film layer

2.1. A portion of the Na-CMC polymer was poured with purified water, glycerin was added and left to swell the polymer, then it was carefully mixed until a homogeneous mass was obtained.

2.2. The pre-ground metronidazole was dispersed with dimethyl sulfoxide and the second part of the Na-CMC polymer was added to the resulting suspension, mixed to a homogeneous mass.

2.3. After deaeration of the resulting mass, it was poured onto a dried and formed surface of the film with lidocaine hydrochloride and benzalkonium chloride.

2.4. It was dried to a residual moisture content of 10%, after which it was cut into 2 × 2 cm plates and hermetically packed in a sterile plastic bag.

EXAMPLE ON THE METHOD FOR PRODUCING

A portion of the polymer of the sodium salt of carboxymethyl cellulose (Na-CMC), glycerol and the calculated amount of water were divided into two equal parts and used to prepare each separate layer of films.

1. Preparation of the first film layer

1.1. A portion of the Na-CMC polymer (0.875 mass fractions) was filled with purified water (40.615 mass fractions), lidocaine hydrochloride (2.0 mass fractions) and benzalkonium chloride (0.02 mass fractions) were dissolved in 6.0 mass fractions of purified water. Glycerin (0.5 mass fractions) was added to a solution of lidocaine hydrochloride and benzalkonium chloride, left to swell the polymer, then carefully mixed until a homogeneous mass was obtained.

1.2. After deaeration of the resulting mass, it was poured into Petri dishes on the prepared substrate (a thin layer of liquid paraffin). Dried to a residual moisture content of 10%.

2. Preparation of the second film layer

2.1. A portion of the Na-CMC polymer (0.875 mass fractions) was poured with purified water (46.615 mass fractions), glycerin (0.5 mass fractions) was added and left to swell the polymer, then it was carefully mixed until a homogeneous mass was obtained.

2.2. The pre-ground metronidazole (1.0 mass fractions) was dispersed with dimethyl sulfoxide (1.0 mass fractions) and the polymer obtained in paragraph 2.1 was added to the resulting suspension, mixed to a homogeneous mass.

2.3. After deaeration of the resulting mass, it was poured onto the dried and formed surface of the film obtained in paragraph 1.2.

2.4. It was dried to a residual moisture content of 10%, after which it was cut into 2 × 2 cm plates and hermetically packed in a sterile plastic bag.

DETERMINATION OF THE MICROBIOLOGICAL ACTIVITY OF A MEANS FOR TREATMENT OF PURPOSITIVE INFLAMMATORY PROCESSES OF SOFT TISSUES AND Mucous membranes

The antimicrobial effect of the developed agent was studied by agar diffusion (GF XII, 2007) in relation to the test strains St.aureus ATCC 6538-P, Bacillus cereus ATCC 10702, E. coli ATCC 25922, Proteus vulgaris and Pseudomonas aeruginosa ATCC 9027, Candida albicans ATCC 885-653. The results of the determination are presented in table. one.

From the data presented in table. 1, it follows that the product we developed has a fairly strong antimicrobial effect in relation to all the studied test strains. The growth inhibition zone when studying the spectrum of antimicrobial activity is most pronounced in relation to the test strains St.aureus ATCC 6538-P, Bacillus cereus ATCC 10702, Candida albicans ATCC 885-653, E. coli ATCC 25922, Proteus vulgaris, which is not inferior, but in a number of indicators, it even exceeds the zone of growth inhibition in the study of the prototype.

The local anesthetic activity of the agent we developed was studied in vivo experiments (20 chinchilla rabbits) using the Rainier-Valet method, which is based on the change in the sensitivity of the rabbit’s cornea when a test sample is applied to it, which is expressed in response to the stimulus as closing century.

A test film (developed by us) of 2 × 2 cm in size was introduced into the conjunctival sac of a rabbit’s eye. Using calibrated hairs, rhythmic irritations were applied to the cornea at a frequency of 100 beats per minute after 1, 2, 5, 8, 10, 12, 15 minutes and then every 5 minutes until the closure of the eyelids (Table 2).

Based on the statistically processed data presented in table 2, it can be noted that the greatest indicators of strength and duration of anesthesia occur when we use the tools developed by us.

EXAMPLE OF EXPERIMENTAL APPLICATION

The study of the wound healing activity of the developed product was carried out in an experiment on male rats of the Wistar breed, weighing 180-200 g, in which a purulent wound was modeled according to the method of P.I. Tolstoy. The experimental animals were divided into three series, 36 animals each:

In the 1st series (model), treatment was not carried out.

In the 2nd series (control), prototype treatment was performed.

In the 3rd series (experimental), treatment was carried out with the agent developed by us (films 2 × 2 cm in size).

The course of the wound process in experimental animals was evaluated by planimetric (method of L.I. Popova), microbiological, histological methods. The research results were processed statistically (calculated average values, reliability criteria).

Animals were withdrawn from the experiment by an overdose of ether anesthesia on days 1, 3, 5, 8, 10, 15.

After modeling on the 1st day, in all series there was hyperemia of the wound edges, swelling of the surrounding tissues, the bottom of the wounds was covered with fibrin deposits with necrosis, purulent discharge was observed.

During treatment, the wound surface was cleansed of purulent necrotic masses, edema was stopped, granulations and marginal epithelization appeared.

The results of a planimetric study indicate a more rapid decrease in the area of wounds in the experimental series compared with the model and control (the initial area of the wounds was 250 mm ² ). So, from 3 days the area of the wounds in the control and experimental series had statistically significant differences. The healing process was faster in the experimental series compared with the control and model. The results of a planimetric study are presented in table. 3.

Thus, the obtained data of a planimetric study confirm the high efficiency of the agent we developed (experimental series) in the treatment of purulent wounds. By the 15th day, the area of wounds in the experimental series decreased by an average of 95.5%, which was higher than the rate of wound healing by an average of 1.3 times compared with the control series.

The data of microbiological studies showed that in the experimental series microbial contamination of wounds was significantly less than in the control series, starting from 8 days and throughout the observation period. In the experimental series on the 8th day, the microbial contamination of the wounds is 1.6 times less than in the control series, on the 10th day - 2.1 times less than in the control series. Thus, it was found that the tool developed by us 1.6-2.1 times reduces the microbial contamination of wounds in comparison with the prototype.

For a complete assessment of the state of the wound in dynamics, the histological method of studying wound biopsy samples was used, which makes it possible to objectively assess the dynamics of the course of the wound process.

On the 3rd day, during treatment using the agent we developed (experimental series), a rather weak infiltration of fresh granulations with polymorphonuclear leukocytes is noted. On the 10th day, the epithelial shaft creeps from the edges and bottom of the wound. On the 15th day, the wound was epithelized, almost complete restoration of the skin was observed with the exception of its derivatives.

Thus, in the series where the treatment was carried out by the agent developed by us (experimental series). more rapid cleansing of the surface of the wound from leukocyte-necrotic masses, an active growth of granulations. By the 10th day, a significant part of the wound or its entire surface is epithelized.

The use of the developed agent in the treatment of purulent wounds in the I and II phase of the wound process increases the speed of wound healing, reduces microbial contamination of wounds, accelerates the formation and maturation of granulation tissue, and promotes early and rapid epithelization of the wound surface compared to the prototype treatment. Moreover, the use of a film-developed product that we developed greatly facilitates the dressing process; when applying a film, young epithelium and granulation are not injured, as happens when smearing an ointment on a wound.

Claims (1)

The agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes is a two-layer film containing as a therapeutic component a combination of benzalkonium chloride antiseptic and metronidazole, sodium carboxymethyl cellulose as a base, lidocaine hydrochloride as an anesthetic, and an accelerator of transdermal transfer agent - dimethyl sulfoxide, as stabilizer glycerin in the following mass fractions:
Metronidazole 1,0 Lidocaine hydrochloride 2.0 Benzalkonium chloride 0.02 Glycerol 1,0 Dimethyl sulfoxide 1,0 Carboxymethyl Cellulose Sodium 1.75 Purified water 93.23