RU2601897C1 - Agent for treating pyoinflammatory processes in soft tissues and mucous membranes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers 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. Declared agent for treating pyoinflammatory processes in soft tissues and mucous membranes is a film and contains as therapeutic ingredients antiseptic chlorhexidine bigluconate 0.05 % and stimulator of regeneration methyluracil, comprises the base polyethylene oxide with molecular weight 400 (PEO-400) and carboxymethyl cellulose sodium salt (Na-CMC), also as a therapeutic component-metronidazole, as anaesthetic contains lidocaine hydrochloride, as a stabilizer - glycerine in the amounts specified in the patent claim.

EFFECT: technical effect consists in creation of effective remedy in the form of film, possessing antimicrobial, sorption, analgesic and wound healing action.

1 cl, 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.

In modern surgery, one of the urgent problems is the problem of treatment of purulent wounds, which is associated with the prevalence of wounds of various etiologies, purulent complications, high mortality, high material costs for treatment. According to some authors, purulent complications from all surgical diseases are 28-34%, and mortality from them reaches 22%.

Today, more and more attention is given to topical antiseptics, due to the fact that the frequent use of antibiotics leads to the predominance of microflora in the wound that is insensitive or insensitive to them. Without a doubt, modern drugs should have multidirectional effects: broad antimicrobial activity, high dehydrating ability, stimulation of tissue regeneration, local anesthesia.

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 drugs, such as wound dressings (sponges, films, etc.).

The prototype of our invention is considered a medicinal product that contains enterosgel as a base, as therapeutic components an antiseptic 0.05% solution of chlorhexidine bigluconate and a stimulator of methyluracil regeneration. (RF Patent No. 2445083 “MEANS FOR TREATMENT OF PURPOSITIVE INFLAMMATORY PROCESSES OF SOFT TISSUES AND Mucous membranes”).

However, this tool is an ointment that does not have anesthetic property and contains only one antiseptic, which reduces its area of application for mixed infections, which are increasingly found in wound discharge.

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

The technical result is achieved by the fact that the agent for treating purulent-inflammatory processes of soft tissues and mucous membranes is a film and contains, as therapeutic components, an antiseptic chlorhexidine bigluconate 0.05% and a stimulator of regeneration of methyluracil, contains polyethylene oxide with a molecular weight of 400 (PEO- 400) and the sodium salt of carboxymethyl cellulose (Na-CMC), also as a therapeutic component - metronidazole, contains lidocaine hydrochloride as an anesthetic, and glycerin following mass fractions:

Metronidazole 1,0 (FS 42-2283-93) Lidocaine hydrochloride 2.0 (FS 42-0251-07) Methyluracil 2.0 (FS 42-0256-07) Glycerol 1,0 (FS 42-2202-99) 400 molecular weight polyethylene oxide 1,0 (FS 42-1242-96) Carboxymethyl Cellulose Sodium 1.75 (TU 6-55-221-1453-96) A solution of chlorhexidine bigluconate (0.05%) 91.25 (TU 9158-002-76922630-2005)

Feature Description

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.

Methyluracil. Flavourless white crystalline powder. Slightly soluble in water (up to 0.9% at a temperature of + 200 ° C) and alcohol. By the chemical structure, methyluracil is a pyrimidine derivative. According to experimental data, a number of drugs of this group have anabolic and anti-catabolic activity, accelerates the processes of cell regeneration; accelerates wound healing, stimulates cellular and humoral defense factors. They also have anti-inflammatory effects. A characteristic feature of compounds of this series is the stimulation of erythro- and especially leukopoiesis, in connection with which they are usually assigned to the group of leukopoiesis stimulants.

Glycerin is colorless, odorless, sweetish in taste, a syrupy liquid of a neutral reaction, it is soluble 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.

Polyethylene oxides (PEO) have a dehydrating effect, and in a purulent wound it spreads not only to its tissues, but also to the microbial cells contained in it. The PEO base dehydrates the microbial cell, sharply reduces its biological activity and weakens its resistance to various drugs. As a result, the antimicrobial activity of many antibiotics, sulfonamides and antiseptics increases significantly. Due to the ability of PEO to absorb exudate, and with it microbial toxins, tissue breakdown products, biologically active substances - lysosomal enzymes and other inflammatory mediators, thereby “interrupting” its progressive course, they determine the potentiating effect on the therapeutic effect of the drug as a whole .

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.

Chlorhexidine bigluconate. It is one of the most active local antiseptic agents. Chemically, it is a dichloro-containing derivative of biguanide. Chlorhexidine has a fast and strong bactericidal effect on gram-positive and gram-negative bacteria. Not valid for viruses and spores. The drug is stable and after treating it with the skin, it remains on it in a certain amount, which continues to give a bactericidal effect. The drug remains active in the presence of blood, pus. Chlorhexidine is also effective against pathogens of sexually transmitted diseases.

The method is carried out as follows.

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

1. A portion of the polymer of carboxymethyl cellulose sodium salt (Na-CMC) was poured with a solution of chlorhexidine bigluconate, in which lidocaine hydrochloride was previously dissolved, glycerin was added and left to swell the polymer, the mass was homogenized by slowly mixing and divided into two equal parts;

2. Pre-ground methyluracil was dispersed with the first part of the prepared polymer solution on chlorhexidine bigluconate containing lidocaine hydrochloride;

3. The pre-ground metronidazole was dispersed with polyethylene oxide with a molecular weight of 400 (PEO-400) and the second part of the polymer solution on chlorhexidine bigluconate containing lidocaine hydrochloride was added in portions to the resulting suspension;

4. The resulting compositions were mixed and after deaeration of the mass it was poured into Petri dishes on the prepared substrate (a thin layer of liquid paraffin). 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

1. A portion of the polymer of the carboxymethyl cellulose sodium salt (Na-CMC) (1.75 mass fractions) was poured with a 0.05% chlorhexidine bigluconate solution (91.25 mass fractions) in which lidocaine hydrochloride (2.0 mass fractions) was previously dissolved; glycerol (1.0 mass fractions) and left to swell the polymer, the mass was homogenized by slowly mixing and divided into two equal parts.

2. Pre-ground methyluracil (2.0 mass fractions) was dispersed with the first part of the polymer solution prepared according to paragraph 1.

3. Pre-ground metronidazole (1.0 mass fractions) was dispersed with polyethylene oxide with a molecular weight of 400 (1.0 mass fractions) and the second part of the polymer solution prepared according to paragraph 1 was added in parts to the resulting suspension.

4. The resulting compositions were mixed and after deaeration of the mass it was poured into Petri dishes on the prepared substrate (a thin layer of liquid paraffin). 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 method (GF XII, 2007) in relation to St. test strains. aureus ATCC 6538-P, you. 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 test strains St. aureus ATCC 653 8-P, you. cereus ATCC 10702, E. coli ATCC 25922, Proteus vulgaris, which significantly 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 first 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 faster decrease in the area of wounds in the experimental series compared with the model and control (the initial area of the wounds was 250 ± 2.35 mm ² ). So, from 10 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 on average by 99.2%, which was 1.5 times higher than the rate of wound healing on average 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 10th day, the microbial contamination of wounds is 1.4 times less than in the control series. Thus, it was found that the tool we developed reduces the microbial contamination of wounds by 1.4 times compared to 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 a prototype, a powerful layer of infiltrate, consisting in the vast majority of granulocytes, was found on the surface of the wound immediately below the drug layer, and foci of hemorrhage in the upper layers were also noted. On the 15th day, complete granulation coverage with epidermis was observed in almost all animals, the epidermis consisted of 2 layers of cells (the upper layer being somewhat infiltrated by polymorphonuclear leukocytes), and epidermal derivatives were absent over the entire area of the wound defect.

On the 3rd day, during treatment using the agent developed by us (experimental series), insignificant infiltration of fresh granulations with polymorphonuclear leukocytes is noted. On the 15th day, the wound was completely epithelized, complete restoration of the skin was observed with the exception of its derivatives.

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 film and contains, as therapeutic components, an antiseptic chlorhexidine bigluconate 0.05% and a stimulator of regeneration of methyluracil, contains as a base polyethylene oxide with a molecular weight of 400 and sodium carboxymethyl cellulose, also as a therapeutic the component is metronidazole, contains lidocaine hydrochloride as an anesthetic, and glycerol in the following mass fractions as a stabilizer:
Metronidazole 1,0 Lidocaine hydrochloride 2.0 Methyluracil 2.0 Glycerol 1,0 400 molecular weight polyethylene oxide 1,0 Carboxymethyl Cellulose Sodium 1.75 A solution of chlorhexidine bigluconate (0.05%) 91.25