RU2667974C2 - Pharmaceutical combined composition for local and external use on basis of dioxidine - Google Patents

Abstract

FIELD: pharmaceuticals.SUBSTANCE: group of inventions refers to pharmaceutical compositions used in the treatment of extensive purulent-necrotic post-traumatic, postoperative wounds. Compositions for topical or topical application according to the invention contain 0.1–5 % by weight of dioxidine, a hydrophilic base and at least one target additive selected from the group: 0.5–6.5 % by weight anesthetic, 0.05–16 % by weight of a complex of proteolytic enzymes, 0.001–5 % by weight of a synthetic antibacterial agent that reduces the resistance of microorganisms, 0.5–5 % by weight of an antibiotic, 0.05–12.5 % by weight of synthetic immunomodulator, dimexidum, stimulator of reparative processes, antimycotic.EFFECT: invented combined composition creates optimal conditions for shortening the periods of systemic antimicrobial and antifungal therapy, allows to accelerate the healing process, improve the conditions for wound healing.19 cl, 43 ex, 1 tbl

Description

The invention relates to medicine and veterinary medicine, in particular to pharmaceutical preparations used in the treatment of extensive purulent-necrotic post-traumatic, postoperative wounds, extensive burns, as well as wounds after surgical treatment of acute purulent diseases of the skin and soft tissues (abscessing boils, carbuncles, mastitis, hydradenitis , erysipelas, etc.), in the treatment of patients with extensive atherosclerotic and venous trophic ulcers, with diabetic foot syndrome, complicated by the infection caused by vysokorez stentnymi Gram positive and Gram negative aerobic and anaerobic bacteria, fungi, resistant to the vast majority of antimicrobial and antifungal agents.

The developed combination composition for local and external use on the basis of dioxidine creates optimal conditions for reducing the time for systemic antimicrobial and antifungal therapy, accelerate the healing process, and improve the conditions for wound healing.

It is known that the development of infection can occur if the number of microbes exceeds 10 ⁵ per 1 g of wound tissue. The “critical” level of bacterial contamination can be significantly lower if there are dead tissues or foreign bodies in the wound, as well as in violation of the body's resistance factors, circulatory disorders, innervation (Blatun L.A. et al. “Clinical and laboratory effectiveness of modern polyethylene glycol ointments basis in the treatment of purulent wounds. ”Antibiotics and chemotherapy, 1999, No. N7, pp. 25-31).

The purulent-inflammatory process of soft tissue disease is a complex set of reactions that develop in the body in response to tissue damage. The course of the wound process is conditionally divided into three main phases.

Phase I is the phase of inflammation, consisting of two consecutive periods: vascular changes and wound cleansing due to the suppression of microflora and rejection (resorption) of non-viable tissues. In the vascular period of the phase of inflammation, the vessels in the tissues adjacent to the walls and the bottom of the wound expand; plasma exudation and the release of leukocytes from blood vessels begin and gradually increase. Exudate and cellular elements secreting proteolytic enzymes thin the areas of dead tissue.

The vascular period is replaced by a period of cleansing, liquefaction of necrotic tissues, with rejection together with small foreign bodies, removing them from the wound with an exudate current acquiring the character of pus (//feldsherstvo.ru/186.html). In the presence of pus, the focus of tissue decay in the wound, the concentration of para-aminobenzoic acid (PABA), which is necessary for the life of microorganisms, rises.

In the I phase of the wound process, a characteristic feature of a purulent wound is the presence of purulent-necrotic detritus in it. Primary necrosis in the wound occurs as a result of direct exposure to mechanical trauma and microbial toxins in the damage zone. The mechanism of formation of secondary necrosis is more complex. The purulent process in the wound develops by breaking down the immuno-leukocyte barrier by exo- and endotoxins of bacteria, which have a necrotizing effect on tissues, as well as their proteolytic enzymes and hyaluronidase, which causes depolarization of the main substance of the connective tissue.

Thus, the infection penetrates into deeper tissues, causing necrosis and thereby creating favorable conditions for the further life of microorganisms. When cells are destroyed, proteolytic and other hydrolytic enzymes are released into the tissue, which have a damaging effect on the walls of the wound.

The cause of "secondary" necrosis is also a disorder of regional microcirculation caused by purulent fusion. Violation of metabolic processes with the accumulation of underoxidized products and progressive local hypoxia cause the development of acidosis, hyperkalemia and an increase in osmotic pressure in the tissues. The result of these reactions is progressive tissue hyperhydration, the extreme degree of which leads to the development and spread of necrosis. Necrotic tissues in the initial phase of inflammation are usually tightly fixed to the bottom and edges of the wound, their number in case of an unfavorable course of the process can increase due to secondary necrosis.

In this case, a situation arises when the local treatment of a wound requires the selection of a drug that is highly active against the main pathogen (both the aerobic and anaerobic components of the purulent process), which has necrolytic properties, long osmotic activity, or, conversely, properties aimed at preventing drying of the wound surface , stimulation of the growth of granulations, and in the future, not interfering with the formation of the epithelium (Blatun L.A. et al. “Clinical and laboratory effectiveness of modern ointments on poly tylenglycol base in the treatment of purulent wounds. ”Antibiotics and chemotherapy, 1999, No. 7, pp. 25-31).

After cleansing the wound in the next day (on day 3), phase II of the wound process begins - the regeneration phase, which is characterized by the development of granulation tissue due to neoplasm of the capillaries and the migration of a significant number of fibroblasts. The maximum number of macrophages is reached on day 6 and remains at a high level for 2 weeks. Wound fibroblasts during this period actively produce fibronectin and type III collagen, replacing them with the lost matrix. Gradually, this process is being replaced by the production of type I collagen, the fibers of which are stabilized by the mucopolysaccharides of the interstitial substance of the connective tissue. The synthesis of collagen and protein-polysaccharide complexes of the connective tissue matrix is directly related to the process of capillary neoplasm.

The forming tissues are a kind of biological basis from which the migration of fibroblasts producing collagen occurs. In the early stages of wound healing, young microvessels provide oxygen to cells that actively synthesize protein in the wound, since the synthesis processes in the focus of inflammation require significant energy supply. Wound epithelization begins in the first hours after damage. Epithelial cells located along the edges of the wound are shifted towards the wound. During this period, they lose their differentiation. Granulation tissue becomes denser, the number of microvessels, macrophages, mast cells and fibroblasts decreases.

During the first day, 2-4 layers of basal epithelial cells are formed. In this case, the epithelium can creep onto fibrin covering the wound, leukocyte-necrotic masses or granulation tissue. Durable wound epithelization becomes only with the growth of the epithelium on granulation tissue, in other cases the epithelium dies. The epithelization of small-sized wounds is mainly due to cell migration starting from the basal layer. A wound larger than 0.1 cm is epithelized due to not only migration, but also mitotic division of epithelial cells. Differentiation of the migrating epidermis is detected already during the migration period. With the differentiation of the growing epithelium in its cells, granularity appears, the surface layers are keratinized, the basal layer of cells in its structure approaches the structure of cells of the transitional epithelium. The newly formed epithelial cover differs from the healthy one in the absence of sweat and sebaceous glands, as well as hair follicles.

Currently, due to an increase in the number of wounds with a slow healing process due to a decrease in the immune status and high allergization of patients, the treatment of wounds in the regeneration phase requires taking into account the possibilities of dressings. Dressings in the 2nd phase of the wound process, especially at an early stage of regeneration, should provide conditions for the normal course of proliferation of regenerative tissue cells, and have a beneficial effect on angiogenesis, motility and synthesis of epithelial cells.

Phase III - the phase of the organization of the scar and epithelization is characterized by a decrease in the number of fibroblasts, a decrease in the activity of enzymes, the ordering of collagen fibers under the influence of collagenase of the growing epidermis. Due to the contraction of smooth muscle cells, the edges of the wound come closer together. The primary tender collagen is replaced by more durable, resulting in a scar.

Normal wound healing with the formation of a full scar is completed in 25-29 days from the moment of their occurrence. At the same time, signs of the transition of an acute wound inflammatory process to a chronic one are often detected. In such a wound, an increase in the migration of mononuclear cells into the wound and a decrease in granulocyte cells, migration of T and B lymphocytes are noted. The slowed down course of the inflammatory process, the tendency to chronicity may be due to the progression of the autoimmune mechanism.

The listed phases of the wound healing process are observed for all wounds, but they are expressed to varying degrees, depending on the type of healing: primary intention, secondary intention or under the scab - the phase of regeneration, formation and maturation of granulation tissue.

There is no sharp boundary between the phases. Moreover, in extensive wounds with torn bruised edges, all three phases can be observed simultaneously, while in one area the wound has already been cleaned and filled with granulations, in the other, young granulation tissue at the bottom of the wound is still growing, and on the third it is still continuing prolonged period of purification, i.e. the first inflammatory phase, and clearly visible areas of necrotic tissue, limited from adjacent tissues by the growth of granulation tissue (http://feldsherstvo.ru/186.html).

Fresh wounds before they are coated with granulations are able to absorb toxins, bacteria, tissue breakdown products. Wounds covered with granulations practically have no suction ability.

Violation of the healing process is directly dependent not only on general and local factors, but also on the unlawful use of obsolete drugs for local treatment of wounds: a hypertonic solution of sodium chloride, ichthyol, streptocid, tetracycline, furacilin, gentamicin and other fat-based ointments.

In the first phase of the wound healing process, all medications must have a wide spectrum of antimicrobial activity (with antibacterial, anticandidar, and virucidal activity), high osmotic properties to ensure an intensive outflow of exudate from the depth of the wound into the dressing, rejection and melting of necrotic tissues and the evacuation of wound contents. They should also ensure that the drug penetrates into the damage zone to create therapeutic efficacy, as well as provide anti-inflammatory and analgesic effects. At the same time, absorption into the blood should be minimal in order to reduce the general toxic effects (“Pharmacocorrection of the wound process”, http://www.provisor.com.ua/archive/2007/N15/process.php).

In the second phase of the wound healing process, along with the suppression of a small number of microbes or newly emerged hospital strains, in the wound due to aseptic and antiseptic disorders at the time of dressings, the preparation should provide optimal conditions for the growth of granulations.

The drugs used for local treatment of wounds must meet the modern requirements for medicines of this pharmacotherapeutic group: have anti-inflammatory effect, inhibit the development of wound and perifocal inflammation in the tissues, inhibit the growth of microorganisms in the wound and, most importantly, have an antibacterial effect against hospital strains of bacteria resistant to antibiotics and antiseptics.

The polymer hydrophilic water-soluble bases of such preparations must have inherent osmotic and sorption properties, that is, they must adsorb necrotic cells, decay products and inflammation, thus cleaning the wound, but should not cause osmotic lysis of healthy cells and inhibit the growth of granulations.

Many modern drugs for local treatment of wounds have ceased to possess the necessary antimicrobial activity due to the formation of microorganism resistance to them. As numerous studies show, the structure of the pathogens of purulent complications of wounds has changed. Along with traditional gram-positive and gram-negative aerobic microorganisms, a significant proportion is accounted for by anaerobic microorganisms, fungi (http://bibliofond.ru/view. Aspx? Id = 556568).

The widespread, often uncontrolled and insufficiently justified use in medicine of antibiotics, antimycotics, corticosteroids and immunosuppressants, violation of the recommendations for their use led to the spread of strains with multiple resistance to antimicrobial agents.

Staphylococcus plasmids are known that carry genes for resistance to penicillin, gentamicin, tetracycline, methicillin, lincomycin, sulfanilamides, as well as new generation antibiotics: fluoroquinolones, cephalosporins II and III generations, glycopeptides and others. (“Modern approaches to the treatment of infectious skin diseases.” I.M. Kirichenko, http://old.consilium-medicum.com/media/consilium/06_01c/12.shtml).

There is a low sensitivity of proteas and staphylococci in association to the "old" antibiotics most widely used in practice (ampicillin, carbenicillin, erythromycin, lincomycin, ristomycin, chloramphenicol, tetracycline). At the same time, most strains of proteins and staphylococci isolated in monoculture were resistant to “old” antibiotics: penicillin, tetracycline and chloramphenicol.

With this in mind, it is justified to develop dosage forms for the treatment of wounds that contain not antibiotics, but antiseptics, the resistance of microorganisms to which is developing more slowly (“Development of the composition and technology for producing an ointment containing a biocomplex of cobalt with furazolidone.” Medicine, health, http: // uchi- referat.ru/medicina-zdorove/2921-razrabotka-sostava-i-tehnologii-polucheniya-mazi-soderzhashhey-biokompleks-kobalta-s-furazolidonom.html).

The use of antiseptics in local and systemic infectious processes is caused by a number of goals:

1) prevention of the generalization of the process;

2) a decrease in the population and suppression of the vital activity of microbes located in the infectious focus;

3) prevention of the transition of acute local infectious processes into a chronic form as a result of superinfection, reinfection and secondary infection, introduction of microorganisms from the external environment, from other areas of the patient’s body, or as a result of activation of local autoflora;

4) the preservation of normal microflora in the affected organ, and in case of change, its recovery.

For preventive and therapeutic wound antiseptics, there is a wide selection of antiseptics. However, for antiseptics, there is currently a decrease in bacterial sensitivity to them ("The effectiveness of the treatment of purulent-inflammatory diseases of the soft tissues with Absil1", abstract of the dissertation of Candidate of Medical Sciences (14.00.27) / L.A. Lacerus - Irkutsk , 1999).

Currently, there is a significant spread of biologically resistant forms to widely used antiseptics among hospital and community-acquired microorganism strains (“Development of the composition and technology for producing an ointment containing cobalt and furazolidone biocomplex”, “Medicine, Health”, http: // uchi-referat. com / medicina-zdorove / 2921-razrabotka-sostava-i-tehnologii-polucheniya-mazi-soderzhashhey-biokompleks-kobalta-s-furazolidonom.html).

By the 90s of the 20th century, publications appeared on microbial contamination of almost all types of antiseptics used in medicine and the detection of representatives of all systematic groups of bacteria and fungi in them (R. Sufiyarov, “Treatment of purulent-inflammatory diseases of soft tissues of protean staphylococcal nature” , abstract of the dissertation of the candidate of medical sciences (14.00.27) / R.S. Sufiyarov - Ufa, 1998).

A few years ago, the NDM-1 gene was discovered in India, which provides bacteria with resistance to a huge number of antibiotics, including carbapenems. The appearance of this gene has already been recorded in other countries, including the UK and the USA. Infections containing the NDM-1 gene become very dangerous and can only be treated with a complex mixture of drugs (https://nplus1.ru/news/2015/11/19/panresistance).

The formation of resistance of microorganisms to drugs widely used in clinics necessitates the development and introduction of new complex drugs with a wide range of therapeutic activity not only with respect to the aerobic, but also anaerobic component and fungi, as well as for the corresponding phases of the wound healing process.

It should be noted that all traumatic, most burn wounds and many surgical wounds are primarily microbially contaminated. Initial wound contamination consists of saprophytes with more than 200 species. Within 24 hours, hay bacilli and soil bacteria disappear from the contaminated wound and usually staphylococci remain as the dominant microflora. Streptococci and gram-negative bacteria penetrate a second time. Therefore, staphylococci should be considered the main object of the fight against suppuration of wounds in the initial stage of the first phase of the wound process.

In the past 30 years, in the practice of treating purulent wounds of various localization and genesis, multicomponent PEG-based ointments (levosin, levonorsin, metocaine, levomekol) have been successfully used, which include chloramphenicol, which shows a fairly high activity against hospital strains of gram-positive microorganisms and is not active enough against Ps. aeruginosa, Acinetobacter spp. Proteus spp., E coli.

This disadvantage is absent in ointments for the treatment of wounds in the first phase of the wound healing process, in which dioxidine is introduced (Dioxidin 5%, Dioxol ointment, Lidoxicol). For the treatment of purulent wounds in the second phase of the wound healing process, an ointment with dioxidine “Methyldioxilin” is known.

The composition of the above ointments is as follows.

Ointment “Dioxidine 5%”: dioxidine - 5%, nipagin - 0.08%, propyl ether paraoxybenzoic acid (propyl paraben) - 0.02%, PEO-400 - 74.9%, PEO-1500 - 20% (http: //www.piluli.ru/product525505/product_info.html).

Dioxicole ointment: dioxidine - 1%, methyluracil - 4%, trimecain - 4%, PEO-400 - 72.8%, PEO-1500 - 18.2% (“Theory and practice of local treatment of purulent wounds”, ed. B.M. Datsenko, Kiev, Health Publishing House, 1995, p. 241).

Lidoxicole ointment: dioxidine - 1%, methyluracil - 4%, lidocaine hydrochloride - 2%, PEO-400 - 73.8%. PEO-1500 - 19.2%. (TV Pushkina et al. “Experimental evaluation of the chemotherapeutic efficacy and toxicity of a new dosage form of dioxidine - Lidoksikol ointment”, Chemical and Pharmaceutical Journal, Volume 42, No. 7, 2008, pp. 34-37; RU patent 2283088, A61K 9/06, 09/10/2006, “Combined antimicrobial agent for the treatment of purulent wounds”).

Ointment “Methyldioxylin” - dioxidine - 1%, methyluracil - 10%, vinylin - 15%, PEO-400 - 31%, emulsifier No. 1 - 8%, distilled water - 35% (http://medlec.org/lek2- 63461.html).

In addition, on the basis of dioxidine, a gaseous pharmaceutical composition in the form of a dioxisole aerosol is known, in its composition (g / package): dioxidine - 0.6, trimecain - 3.0, proxanol-268 - 12.6, 1.2- propylene glycol - 20.3, purified water - 13.5, freon-12 - 10.0 ("Theory and practice of local treatment of purulent wounds" / Edited by B. M. Datsenko, Kiev, publishing house "Health", 1995 city, p. 260).

Known pharmaceutical combination compositions with dioxidine have the following disadvantages.

As indicated above, the structure of the pathogens of purulent complications of wounds has changed. Along with traditional gram-positive and gram-negative aerobic microorganisms, a significant proportion is accounted for by anaerobic microorganisms, which are highly sensitive to the action of dioxidine, as well as fungi and protozoa, which are mainly insensitive to the action of dioxidine.

Known pharmaceutical compositions with dioxidine have high antianerobic activity, but do not have a pronounced necrolytic effect, which is important in the treatment of purulent wounds in the first phase of the wound process.

In addition, the minimum inhibitory concentrations (MIC, μg / ml) of dioxidine in relation to P. aeruginosa (125.0-1000.0 μg / ml), S. aureus (62.5-1000.0 μg / ml), Streptococcus spp . (64.0-> 1000.0 mcg / ml) is significantly higher than for other aerobic and anaerobic bacteria (“Difficult issues of antimicrobial chemotherapy”, E.N. Padeiskaya, table 1 and table 2, journal “Infections and antimicrobial therapy ”, Volume 3 / No.5 / 2001, www.consilium-medicum.com/article/8003).

As a comparison composition, we chose a pharmaceutical composition in the form of a soft form - ointment according to patent RU 2283088, А61К9 / 06, 09/10/2006.

This patent describes an antimicrobial agent for the treatment of purulent wounds in the form of an ointment containing an antibacterial agent - dioxidine, an agent that accelerates cell regeneration processes - methyluracil, a local anesthetic, a base - polyethylene oxides, characterized in that it contains lidocaine hydrochloride as a local anesthetic, and the basis - polyethylene oxide 400 and 1500, with a mass ratio of dioxidine, methyluracil, lidocaine hydrochloride 1: 4: 2 and polyethylene oxide 400 and 1500 (3.5-3.6): 1.

This composition, like Dioxol ointment, is characterized by a wide antibacterial spectrum with respect to gram-positive and gram-negative aero- and anaerobic bacteria with a predominantly highest activity against obligate anaerobes. Moreover, it is identical in spectrum of action to Dioxikol ointment (TV Pushkina et al. “Experimental evaluation of the chemotherapeutic efficacy and toxicity of a new dosage form of dioxidine - Lidoksikol ointment”, Chemical and Pharmaceutical Journal, Volume 42, No. 7, 2008 g., pp. 34-37).

Selected as a prototype composition has all of the above disadvantages inherent in known compositions with dioxidine.

The most promising and real method that restricts the appearance and accumulation of resistant bacteria in the body or compensates for the decrease in the therapeutic activity of the pharmaceutical composition due to the resistance of pathogenic microorganisms to them is to increase the effectiveness of therapy through the use of combinations of various antimicrobial components in one pharmaceutical preparation.

For the effective treatment of purulent wounds, combined preparations are currently widely used, which are available in fixed dosage forms. They usually include two to three antimicrobial agents. The choice of a combination of components of the combined compositions provides for:

1) increased activity of the combined composition compared with the action of the drug containing one active component;

2) the expansion of the spectrum of action of the combined composition, including activity in relation to resistant strains to one or another component in combination;

3) the ability to reduce the frequency of development of drug resistance to a specific group of antimicrobial agents in the composition;

4) improving drug tolerance, reducing the frequency and severity of adverse reactions, primarily due to lower therapeutic doses of the drug ("Antimicrobial agents in the series of derivatives of sulfanilamide, diaminopyrimidine, 5-nitroimidazole, di-N-hydroxyquinoxaline." Padeiskaya EN , Breast cancer №21 dated 04.11.1997, p. 1-6).

The objective of the invention is the creation of a pharmaceutical combination composition in the form of a liquid, soft, solid and gaseous dosage form based on dioxidine, a base and targeted additives that provide treatment for purulent wounds and burns, purulent-inflammatory skin diseases, etc. and improve the conditions for cleansing wounds from purulent - non-necrotic tissues, inhibiting the growth of microflora, resistant to the vast majority of antibacterial drugs, reducing the period of acute purulent process.

When using the invention, the following technical results can be obtained: an increase in therapeutic activity in comparison with known drugs, including strains of microorganisms that are resistant to individual components of the composition, improvement of the course of the wound process, quick wound cleansing, reduction of purulent discharge and signs of local inflammatory reactions, providing anesthetic effect, reducing convalescence time.

To solve this problem, the present invention proposes a pharmaceutical combination composition for external and local use containing dioxidine, a base, and at least one target additive selected from the range: anesthetic, stimulant of reparative processes, as well as from a number of additional target additives: bacteriolytic, proteolytic, collagenolytic enzyme or their complex, antibiotic, synthetic antibacterial agent (except antibiotic), including a substance that reduces resistance microorganisms, antimycotic, immunomodulator, in the following ratio of components (wt.%):

dioxidine 0.1-5.0 anesthetic 0.5-6.5 reparative stimulant 0.5-10.5 antibiotic 0.05-5.0 antimycotic 0.5-3.5 enzyme or enzyme complex 0.05-20.00 synthetic antibacterial 0.001-15.500 immunomodulator 0.05-12.50 the basis rest

The proposed pharmaceutical combination composition as an anesthetic contains lidocaine or trimecaine, but not limited to.

The proposed pharmaceutical combination composition as a stimulant of reparative processes contains substances selected from the range: xymedon, methyluracil, solcoseryl, pantothenic acid in the form of, for example, calcium pantothenate, etaden or their physiologically acceptable mixture, but not limited to.

The proposed pharmaceutical combination composition as an antibiotic contains substances selected from the series: ofloxacin, ciprofloxacin, netilmicin, amikacin, chloramphenicol, but not limited to.

The proposed pharmaceutical combination composition as an antimycotic contains clotrimozole or cyclopiroxolamine, but not limited to.

The proposed pharmaceutical combination composition as a bacteriolytic, proteolytic, collagenolytic enzyme or complex thereof contains, but is not limited to, lysoamidase, or ultralysin, or imosimase, or lysozyme.

The proposed pharmaceutical combination composition as a synthetic antibacterial agent, including reducing the resistance of microorganisms, contains a substance selected from the series: quinofuryl, ethylenediaminetetraacetic acid, its disodium salt - trilon B, a derivative of diaminopyrimidine trimethoprim, dimexide, a surface-active antiseptic or mixture, not limited to them.

As a synthetic antibacterial agent in the form of a surface-active antiseptic that reduces the resistance of microorganisms, the composition contains a substance selected from the series: miramistin, decamethoxin, catapol, polyhexanide, octenidine, sodium lauryl sulfate, but not limited to.

The proposed pharmaceutical combination composition as an immunomodulator contains substances selected from the range: polyoxidonium, cycloferon, tilorone, but not limited to.

In addition, the composition contains, if necessary, at least one of a number of components: preservative, stabilizer, nonionic detergent, solubilizer, or a mixture thereof.

The proposed pharmaceutical combination composition as a base contains hydrophilic substances selected from the range of: proxanol (emuxol), polyethylene oxide, propylene glycol, polyvinylpyrrolidone, gel of polyethylene oxide 1500, glyceride based on silicon glycerates, calcium or magnesium alginate, acrylic acid copolymer, sodium carboxymethyl cellulose cellulose, methyl cellulose, glycerin, or a physiologically acceptable mixture in various combinations providing the rheological requirements for the base depending ty of the dosage form of the pharmaceutical combination composition and, if necessary, in a mixture of at least one substance from the series: phosphate buffer solution, purified water, liquid paraffin, emulsifier, higher fatty synthetic alcohols, cetyl alcohol, stearyl alcohol, vinylin, povidone, or combinations thereof.

The proposed pharmaceutical combination composition is in the form of a liquid dosage form: solution, suspension, but not limited to, or a soft dosage form: ointment, gel, liniment, suppositories, but not limited to, or a solid dosage form: capsules for rectal or vaginal administration, or in the form of a gaseous dosage form: aerosol or spray.

As the main active substance of the proposed combination composition, together with the target additives, a synthetic antibacterial substance that is not an antibiotic is used - dioxidine (1,4-di-N-oxide-2,3-bis (oxymethyl) -quinoxaline), which is greenish - flavourless yellow crystalline powder, bitter taste. At room temperature, this substance is soluble in water up to 1%, at 37 ° C - up to 3%, decomposes under the influence of light with a decrease in activity ("Theory and practice of local treatment of purulent wounds", edited by prof. B.M.Datsenko, Kiev , publishing house "Health", 1995, p. 152).

The mechanism of action of dioxidine is based on damage to the DNA biosynthesis of a microbial cell with profound impairment of the nucleotide structure under the action of subinhibitory concentrations. Dioxidine selectively inhibits the formation of DNA in the cell of a microorganism, without affecting the formation of RNA and protein. It provokes structural violations of the cell membrane and the nucleotide of the microorganism, inhibits the action of bacterial nuclease and toxins.

Derivatives of diaminopyrimidine potentiate the activity of quinoxaline di-N-oxides, which include dioxidine. This allows you to reduce the concentration of dioxidine when used together. Derivatives of diaminopyrimidine are: pyrimethamine, trimethoprim, tetroxoprim, methioprim, brodimoprim, ormetoprim (“Antimicrobial agents in the series of derivatives of sulfanilamide, diaminopyrimidine, 5-nitroimidazole, di-N-hydroxyquinoxaline.” Padeiskaya E.N. 11, R.111, No. 11, 04.11.11, 11.11.11, 11 P. 11.11.11 g., p. 1-6).

In Russia, pyrimethamine and trimethoprim are registered as a medicine.

Derivatives of diaminopyrimidines selectively inhibit in the microbial cell dihydrofolate reductase (enzyme DFS), followed by impaired synthesis of tetrahydrofolate acid. Diaminopyrimidines have a wide antimicrobial spectrum. For example, trimethoprim is active against gram-positive and gram-negative aerobic bacteria (http://www.zdravosil.ru/lekarstvennye-sredstva-dlya-lecheniya-bakterialnyx/page/126/).

Dioxidin is characterized by a wide antibacterial spectrum, a bactericidal type of action. It is highly active against anaerobic bacteria with a predominantly highest activity against a wide range of obligate anaerobes - spore-forming and non-spore-forming (non-clostridial). In addition, the drug is active against gram-negative and gram-positive aerobic conditionally pathogenic bacteria - pathogens of purulent infection, as well as against some obligate pathogens - salmonella, shigella, cholera vibrio, yersinia.

In experiments with aerobic microorganisms, dioxidine is most active against gram-negative bacteria: neisseria, enterobacteria - salmonella, shigella, cholera vibrio, E. coli, Klebisiella. Pseudomonas aeruginosa strains and gram-positive bacteria - staphylococci, streptococci are more resistant to dioxidine (E.N.

Dioxidine is less active against certain gram-positive bacteria - Staphylococcus spp., S. aureus, S. pyogenes (Manual "Rational Antimicrobial Pharmacotherapy" / Edited by Dr. V.P. Yakovleva and Doctor of Medicine S. V. Yakovleva, Litterra Publishing House, 2003, pp. 750-752).

Dioxidin acts on bacterial strains that are resistant to other antibacterial drugs, including antibiotics. Perhaps the development of drug resistance of bacteria to it.

When applied topically, dioxidine does not have an irritating effect, in addition, it contributes to a more rapid course of reparative processes and epithelization of the wound (“Antibacterial preparation dioxidin: features of biological action and importance in the treatment of various forms of purulent infection.” Padeiskaya EN, “Infection and antimicrobial therapy ”, 2001, 5, pp. 150-155).

When treating burns and suppurating wounds, the drug effectively cleanses the surface of the wound and stimulates the tissue repair process (“All About Dioxidine”, www.tiensmed.ru/news/dioxidin-x2a.html).

Bactericidal concentrations of dioxidine depend on the type of bacteria, microbial load and exposure; they exceed 2–4 times the MPC (minimum inhibitory concentration). Clinical bacteria strains with antibiotic resistance are sensitive to dioxidine. With respect to the bacteroids, the IPC of dioxidine is 0.062-2,000 μg / ml, peptococcus 0.2-0.5 μg / ml, clostridia 1-2 μg / ml ("Theory and practice of local treatment of purulent wounds" / Ed. B. M. Datsenko, Kiev, Health Publishing House, 1995, p. 152, 153).

The development of bacterial resistance to dioxidine and the possibility of the emergence of hospital strains resistant to it are significantly lower than the development of microbial resistance to antibiotics. That is, drug resistance to dioxidine develops rather slowly. As a rule, there is no cross-resistance with other classes of antimicrobial agents.

Dioxidin goes well with antibacterial drugs of other pharmacological groups. It is advisable to introduce dioxidine in combination antibacterial therapy, when activity is required against anaerobic flora, Pseudomonas aeruginosa, multiresistant strains of staphylococci. Combined use of dioxidine with beta-lactams, vancomycin, aminoglycosides, fluoroquinolones is possible (Guide “Rational Antimicrobial Pharmacotherapy” / Edited by Doctor of Medical Sciences V.P. Yakovleva and Doctor of Medical Sciences S.V. Yakovleva, Iz- in Litterra, 2003, pp. 750-752).

Dioxidin exhibits bactericidal activity in the concentration range from 0.1% to 5%. It is available in the form of a 0.5% and 1.0% aqueous solution, 1% and 5% ointment, as well as aerosols. In combination with polyethylene oxides, the antibacterial activity of dioxidine is increased by 18-20 times. (“Theory and practice of local treatment of purulent wounds” / Edited by B. M. Dotsenko, Kiev, publishing house “Health”, 1995, p. 152).

The activity of dioxidine increases under anaerobic conditions, and the MPC values in this case can be reduced by 8-128 times, since free radical processes are activated under anaerobiosis conditions. An increase in activity under anaerobic conditions is characteristic of all derivatives of di-N-quinoxaline with antimicrobial activity, and is not described for other classes of antimicrobial substances. This is the fundamental difference between the mechanism of action of dioxidine and the mechanism of action of other antimicrobial agents. Under conditions of anaerobiosis, including in an infected body, dioxidine activates free radical processes, inducing the formation of reactive oxygen species. (EN Padeiskaya. “The Complicated Issues of Antimicrobial Chemotherapy.” “Infections and Antimicrobial Therapy,” Volume 3, No. 5, 2001).

Dioxidin induces gene mutations as well as lethal mutations in the germ cells of mammals. This indicates a potential genetic hazard of dioxidine. In this case, the toxic effects of dioxidine are manifested mainly with intravenous administration. The mutagenic activity of dioxidine is directly related to the DNA-tropic effect of the drug. The process is dose-dependent and manifests itself both in experiments with microorganisms and in relation to mammalian cells. The connection between the mutagenic and radical-stimulating activity of dioxidine has been established. Drugs with antiradical activity and other antimutagens (for example, bemitil) remove the mutagenic effect of dioxidine (E.N. Padeiskaya. “Difficult Issues of Antimicrobial Chemotherapy.“ Infections and Antimicrobial Therapy ”, Volume 3, No. 5, 2001).

With local and external use in the recommended therapeutic doses, dioxidine does not increase the frequency of mutations in human blood cells, and there are no contraindications for its external use.

First of all, dioxidine should be considered as a means for topical application in the form of ointment forms and for administration into the cavity, endobronchial or inhalation in the form of solutions. Dioxidine solution or ointment is effectively absorbed from the surface of the wound. Dioxidin has a wound healing effect. The mechanism of development of drug resistance to dioxidine has not been studied. (EN Padeiskaya. “The Complicated Issues of Antimicrobial Chemotherapy.” “Infections and Antimicrobial Therapy,” 2001, Volume 3, No. 5).

With local and intracavitary use of dioxidine, the possibility of a resorptive effect should be taken into account, especially with the extensive nature of the lesion ("Dioksidin: antimicrobial activity and prospects for clinical use at the present stage." DA Popov et al., "Antibiotics and chemotherapy", 2013. 58, p. 3-4).

Currently, acquired clinical resistance to dioxidine has been detected in 71.3% of community-acquired staphylococcus strains. Pseudomonas increased the percentage of clinically resistant strains of dioxidine ("Development of the composition and technology for producing an ointment containing a biocomplex of cobalt with furazolidone." Medicine, health, http://uchi-referat.ru/medicina-zdorove/2921-razrabotka-sostava-i -tehnologii-polucheniya-mazi-soderzhashhey-biokompleks-kobalta-s-furazolidonom.html).

In a preferred embodiment, the proposed composition contains from 0.1 to 5.0 wt. % dioxidine, more preferably from 0.5 to 1.0 wt. %

In a preferred embodiment, the composition has a ratio: diaminopyrimidine derivative (e.g. trimethoprim): dioxidine - from 1: 5 to 1:40, more preferably from 1: 5 to 1:10.

The requirements for a pharmaceutical combination composition with dioxidine can be formulated based on its properties.

1. Since dioxidine is less active against Pseudomonas aeruginosa strains and some gram-positive staphylococci and streptococci — Staphylococcus spp., S. aureus, S. pyogenes and others, than against gram-negative microorganisms, as well as acquired clinical resistance to 71.3 % of community-acquired strains of staphylococcus, the composition of the pharmaceutical combination composition should include components that compensate for the reduced activity of dioxidine to these pathogenic microorganisms.

To compensate for the reduced activity of dioxidine to gram-positive strains of staphylococci and streptococci, the composition of the composition contains a complex of lysoamidase enzymes, or the bacteriolytic enzyme lysozyme, or trimethoprim; or Trilon B, or quinifuryl, or a surfactant (sodium lauryl sulfate, catapol, chlorhexidine bigluconate, decamethoxin, miramistin, polyhexanide, octenidine), or netilmicin, which have an antibacterial effect against gram-positive bacteria.

To compensate for the reduced activity of dioxidine to Pseudomonas aeruginosa strains, Trilon B, or netilmicin, or amikacin, or ciprofloxacin was introduced into the composition.

2. Since dioxidine is practically inactive against fungi and protozoa, the composition of the proposed composition is administered active against protozoa trimethoprim, or active against fungi of the genus Candida quinifuril, or active against fungi and viruses dimexide, or active against fungi, mold , surfactant viruses, or clotrimazole or cyclopiroxolamine active against fungi.

3. Since there is a connection between the dioxidine mutagenicity and the effect of stimulating the formation of free radicals, a composition with antiradical activity, Trilon B or dimexide, is included in the composition.

4. To reduce the inflammatory process and reduce secondary tissue necrosis around the wound, Trilon B is introduced into the pharmaceutical composition with dioxidine, which reduces secondary tissue necrosis around the wound associated with excessive free radical oxidation, or dimexide, which can reduce anti-inflammatory and pain phenomena, or catapol, exhibiting anti-inflammatory effect.

5. Since dioxidine does not have a pronounced necrolytic effect, the composition of the composition, if necessary, is supplemented with a complex of lysoamidase enzymes, which, in addition to bacteriolytic action, has a proteolytic effect, or a proteolytic complex of enzymes - imosimase, or a collagenolytic and proteolytic complex of enzymes - ultralizine.

It should be noted that proteolytic enzymes are introduced, if necessary, into the composition of the proposed pharmaceutical combination composition with dioxidine, used in the first phase of the wound healing process.

The reason for this is that in different areas of extensive wounds, the second phase of the wound process, characterized by the appearance of young granulation tissue, may be present simultaneously with the first phase of the wound process. It is known that the use of proteolytic enzymes is not recommended in the second phase of the wound process due to the possible negative impact on young granulation tissue. Therefore, for extensive wounds that have simultaneously different phases of the wound process at different sites, the use of ointments with proteolytic enzymes is not recommended.

The composition of the proposed pharmaceutical composition together with dioxidine includes a complex of bacteriolytic enzymes that lyse gram-positive microorganisms, primarily antibiotic-resistant staphylococci, used in medicine under the name lysoamidase (patents RU 1549227, С12N 9/00, 1995.12.20; RU 2193063, С12N 9/00, publ. 2002.11.20), and veterinary medicine - lysomast (patent RU 2064299, А61К 35/74, publ. 1996.07.27).

The composition of lysoamidase includes: bacteriolytic enzymes: muramidase, muramoyalaninamidase, endopeptidase 0.1-2.0%; protease 0.5-2.0%; ballast components 4.0-8.0%, the rest is a polysaccharide. Three bacteriolytic enzymes have different substrate specificity for peptidoglycans of the cell walls of microorganisms: muramidase - an analogue of lysozyme in specificity, muramoyalaninamidase - cleaves the peptide part of the peptidoglycan from the polysaccharide, endopeptidase - destroys the bonds inside the interpeptide bridges of the cell wall.

Due to this, lysoamidase actively destroys cells of a wide range of gram-positive microorganisms, including pathogenic staphylococci and streptococci. Due to the presence of protease in lysoamidase and two bacteriolytic enzymes - endopeptidase and muramoalaninamidase, which also have proteolytic activity, the drug based on lysoamidase well cleans wounds from necrotic masses. Moreover, fragments of destroyed cells have an immunostimulating effect.

The polysaccharide included in the complex is a high polymer compound formed by a repeating unit consisting of N-acetylglucosamine, N-acetylmannuronic acid and N-acetylgalacturonic acid. It provides long-term - for several years - the preservation of the high activity of the enzymes included in it, as well as the immunostimulating properties of the drug lysoamidase.

It is especially important to note that the use of lysoamidase eliminates the likelihood of resistant strains of pathogenic microorganisms.

Lizoamidase is an amorphous powder of gray-brown color, odorless, tasteless, it is hygroscopic, slightly soluble in water, soluble in 0.01 M sodium phosphate buffer with a pH of 8.0; The pH of lysoamidase in solution is from 3.5 to 5.5.

The proteolytic activity of lysoamidase is expressed in PE; 1 mg of the substance contains at least 0.7 PE. The bacteriolytic activity of lysoamidase is expressed in LU; 1 mg of the substance contains at least 12 LU. Lizoamidase is thermophilic, heating is allowed no higher than + 37 ° C. It is stored in a dry, dark place at a temperature of no higher than + 10 ° C.

Based on this complex, a pharmaceutical preparation was developed, produced in the form of lyophilized powder, packaged in 10 ml 50 PE, 100 PE bottles with hermetically sealed rubber stoppers. At the same time, the delivery package includes a base - a solvent in ampoules of 5 ml per 1 ampoule per 50 PE (pharmacopoeial articles FS 42-3329-96 and FS 42-3332-96). The drug is used in liquid form in a phosphate buffer solution with a concentration of 5 PE (50 LE) in 1 ml; 10 PE (100 LE) in 1 ml; 25 PE (250 LE) in 1 ml.

Currently, the resistance of gram-positive microorganisms to lysoamidase is not detected. Gram-negative bacteria have a natural resistance to lysoamidase due to the structure of the cell membrane, which has an outer membrane that is resistant to any lytic enzymes. They cannot hydrolyze the peptidoglycan layer of the outer shell of bacteria without removing the outer membrane. This can be done using chelating agents, for example, ethylenediaminetetraacetic acid (EDTA) or its disodium salt Trilon B ("Theory and practice of local treatment of purulent wounds" / Edited by Prof. B.M. Datsenko, Kiev, publishing house "Health" , 1995, p. 139, 143), or surface-active substances (surfactants) when used together in one pharmaceutical combination composition.

Clinical studies of the drug showed that lysoamidase in the treatment of purulent wounds of soft tissues accelerates the course of the wound process compared to other traditional and non-traditional means: the microflora content decreases faster and the cytogram normalizes, the rejection of necrotic masses goes faster, granulations appear at the bottom of the wounds and the process begins epithelization of a wound defect.

In the treatment of purulent wounds of soft tissues under dressings with lysoamidase, the time required for cleansing of necrotic tissues was reduced by 2 times in many cases.

Lizoamidase stimulates reparative processes, exerting, in addition to non-proliferative and bacteriolytic effects, an influence on the course of the 2nd phase of inflammation, not only due to a reduction in the 1st phase, which is typical for all enzyme preparations (used for treatment in such cases), but also due to the directly stimulating effect on the cells of granulation tissue. Lizoamidase acts directly on proliferate cells.

In a preferred embodiment, the proposed composition contains from 0.01 to 5.00 wt. % lysoamidase, more preferably from 0.5 to 1.5 wt. %

In the proposed composition, dioxidine is used with a complex of bacteriolytic and proteolytic enzymes for the treatment of wounds with polyvalent microflora, which includes gram-positive and gram-negative microorganisms. Since some strains of gram-positive bacteria - staphylococci, streptococci are more resistant to dioxidine, and bacteriolytic enzymes that are part of lysoamidase lyse a wide range of gram-positive pathogenic microorganisms, such as staphylococci and streptococci, the combined use of lysoamidase and dioxidine expands its therapeutic combination , including including activity in relation to resistant strains to one or another component in combination, in comparison with with drugs used separately.

To compensate for the reduced activity of dioxidine to Pseudomonas aeruginosa strains, Trilon B or surfactant (catapol, chlorhexidine bigluconate, decamethoxin, miramistin, polyhexanide, octenidine), or streptocid, or netilmicin, or amikrofacin, or cypic is introduced into the composition of the dioxidine bacillus strains.

When used together in one combined composition, wound cleansing and acceleration of the wound healing process are enhanced.

In the composition of the proposed pharmaceutical composition, along with dioxidine, the bacteriolytic enzyme lysozyme is used.

Lysozyme - (ukopolysaccharidase) is an enzyme of protein nature, which is obtained in crystalline form. Its physico-chemical properties and lytic activity vary widely. The molecular weight of animal lysozyme is 14800, from plants - 24000, from bacteriophage - 13900.

It is a single polypeptide chain consisting of 130-150 amino acid residues, does not contain sulfhydryl groups, and is resistant to heating to 100 ° in an acidic environment. For use as a medicine, it is obtained from protein of chicken eggs (http://piluli.kharkov.ua/drugs/drug/2495/).

The drug has a bacteriolytic effect, has the ability to destroy polysaccharides of the microbial membrane. Along with antibacterial properties, it shows the ability to stimulate the nonspecific reactivity of the body, to provide anti-inflammatory and mucolytic (thinning) effects.

Lysozyme activity is determined by the degree of lysis of the micrococcus Micrococcus lysodeikticus highly sensitive to it. Gram-positive microbes are sensitive to lysozyme, gram-negative are resistant. The mechanism of action of lysozyme is reduced to enzymatic cleavage of the rigid murein layer of the bacterial cell wall, which is accompanied by the release of muramic, diaminopimelic, glutamic and aspartic acids, glucosamine, alanine, serine and lysine. As a result of this, the cell takes on the shape of a ball (protoplast) and in a hypertonic environment it preserves it, and in an iso- or hypotonic one it breaks.

Lysozyme is used in the treatment of chronic septic conditions and purulent processes, with burns, frostbite, etc. The drug is non-toxic, does not irritate tissues and can be used with poor tolerance to other antibacterial drugs.

Lysozyme has only bacteriolytic activity. At the same time, the efficiency of lysis, for example, of E. coli increases when lysozyme is combined with Trilon B (“Theory and practice of local treatment of purulent wounds.” / Edited by Professor B.M. Datsenko, Kiev, publishing house “Health”, 1995 p. 144).

In a preferred embodiment, the proposed composition contains from 0.05 to 2.00 wt. % lysozyme, more preferably from 0.15 to 1.00 wt. %

To ensure the proteolytic properties of the composition of dioxidine with lysozyme, a complex of proteolytic enzymes is added to it.

As part of the proposed pharmaceutical combination composition, a complex of proteolytic enzymes, imosimase, is used together with dioxidine.

Due to the proteolytic effect, imozyme is used in acute and chronic purulent-necrotic processes. Imosimase is available in the form of a liquid or dry porous mass in 10 ml vials. 1 ml of liquid in a bottle is 50 PE. After drying, in a volume of dry porous mass of 1 ml contains 6.4 mg of lyophilized protein with an activity of 300 PE, or 13 mg of lyophilized protein, with an activity of 660 PE. This drug is stored at a temperature of +4 - + 8 ° C.

The method of preparation preparation is based on the radiation modification of bacterial proteases with polyethylene oxide. Imosimase is an enzyme obtained by immobilizing bacterial proteases (proteinases) from Bacillus subtilis bacteria (hay bacillus) on a chemically inert water-soluble polymer - polyethylene oxide 1500, with an activity of (100 ± 30) PE / cm ³ . It is obtained in the form of a clear, light liquid (opalescence is permissible), a yellowish tint, odorless and tasteless (patent RU No. 2137835, C12N 11/00, 09/20/1999).

Imosimase is highly active in the pH range from 6.0 to 10.0, thermostable in the presence of a substrate (up to + 80 ° C). Imosimase is resistant to endogenous proteolysis inhibitors. It hydrolyzes rapidly denatured proteins, including various amino acid sequences, including fibrin and collagen, has anti-inflammatory activity, does not cause allergic reactions (http://www.bionet.nsc.ru/booklet/Rus/RusApplied/RazrabotkiImozimazaRus.html )

The active components of imimazase provide enzymatic lysis of proteins of non-viable necrotic tissues, regardless of the location and etiology of the inflammatory pathological process. As a result, purulent wounds are cleansed and accelerated purulent detritus is evacuated, inflammation is stopped by enzymatic lysis of peptide inflammatory mediators, pain, swelling and hyperemia pass. The detoxification effect is due not only to enzymatic lysis, but also to the inactivation of toxins secreted by most pathogenic microorganisms, as well as toxins formed during tissue breakdown.

As a result of the use of imosimase, its immunomodulating effect is observed, causing an increase in the general resistance of the body and an increase in resistance to bacterial, viral and fungal infections.

Inactivation of imosimase occurs under the influence of mineral salts, alkalis, high doses of x-rays and UV rays, as well as when drying in air at room temperature.

Imosimase is used for purulent-necrotic processes of various etiologies and localization: suppuration of postoperative wounds, purulent wounds after opening abscesses, phlegmon, infected wounds, burns, frostbite, non-healing wounds, etc. (http://www.bionet.nsc.ru /booklet/Rus/RusApplied/RazrabotkiImozimazaRus.html).

The consumption of the drug when applied to a wound is from 0.5 cm ³ / cm ² to 1.0 cm ³ / cm ² .

In a preferred embodiment, the proposed composition contains from 0.5 to 8.0 wt. % imosimase in the form of a dry concentrate, more preferably from 1.0 to 5.0 wt. %

In the composition of the proposed pharmaceutical combination composition, together with dioxidine, ultralysin is used containing enzymes collagenase and protease.

Ultralizine as a biologically active substance is a strain of bacteria Streptomyces ivendulae VPKM S-910 ultrafiltrate isolated from the culture fluid with collagenolytic activity of 1800-2500 KEA / ml and proteolytic activity of 120-200 PE / ml. It selectively acts on soft tissues and skin integuments. Ultralizin (patent RU 2340371, А61Р 17/00, 10.12.2008) is used for the production of medicines, cosmetic creams.

Ultralizin is a part of Streptolaven ointment and Lavenderula ointment according to patent RU 2484811, А61K 9/06, 06/20/2013. It has not only proteolytic activity. Influencing mainly on collagen fibers, it promotes the melting of scabs (hardened blood layer and / or dead tissue covering the skin defect) and necrotic tissue.

In a preferred embodiment, the proposed composition contains from 2 to 16 wt. % ultralizine, more preferably from 4 to 8 wt. %

In the composition of the proposed composition, together with dioxidine, a synthetic antibacterial substance is used that reduces the resistance of microorganisms, - quinifuryl - N- (5-diethylaminopentyl-2) -2- [2 '- (5 "- nitrofuryl-2") - vinyl] - 4-quinoline carboxamide. This is a greenish-yellow amorphous powder, which is practically insoluble in water, very slightly soluble in alcohol. It relates to nitrofurans, which, by the mechanism of action on the microbial cell, act as acceptors through the restoration of the nitro group with the generation of biologically active intermediates. This process leads to effects on DNA.

Nitrofurans are more active against aerobic bacteria. They relate to compounds that suppress the transfer of the determinant of resistance (preventing the spread of resistance plasmids) during conjugation of bacteria. Being oxygen acceptors, nitrofurans disrupt the cellular respiration of bacteria and inhibit the biosynthesis of nucleic acids. Depending on the concentration, they have a bacteriostatic or bactericidal effect. At a concentration of 0.5% or more, quinifuril has a bactericidal effect.

Nitrofurans rarely develop drug resistance of microorganisms. They are characterized by a fairly wide spectrum of action and in high concentrations in vitro are active against many aerobic gram-negative (E. coli, K. pneumoniae, etc.) and gram-positive bacteria, some anaerobes, and Candida fungi. Enterococci are insensitive to nitrofurans, P. aeruginosa strains are resistant, most of the protea, serration, providence, and acinetobacter strains (“Theory and practice of local treatment of purulent wounds” / Edited by prof. B.M.Datsenko, Kiev, “Health”, 1995 , p. 163).

The use of quinifuril is known only locally in the form of 0.5% ointment.

In a preferred embodiment, the proposed composition contains from 0.1 to 1.0 wt. % quinifuryl, more preferably from 0.2 to 0.5 wt. %

In the proposed pharmaceutical combination composition, quinifuril is used together with dioxidine for the treatment of purulent wounds with polyvalent microflora, containing strains of staphylococci, streptococci, to which dioxidine activity is reduced, and also containing fungi to which dioxidin has no activity.

In the composition of the proposed composition, together with dioxidine, synthetic antibacterial substances are used that reduce the resistance of microorganisms: ethylenediaminetetraacetic acid (EDTA, complex II), its disodium salt (Trilon B), or a mixture thereof.

Ethylenediaminetetraacetic acid, a tetrabasic carboxylic acid, is a white fine crystalline powder that is slightly soluble in water, insoluble in most organic solvents, soluble in alkalis, and forms ethylene diamine tetraacetate salts with metal cations. It has a detoxifying, antioxidant effect (http://medside.ru/edta).

Trilon B (disodium EDTA, complexon III, chelaton III) is a white crystalline powder or white crystals that dissolves well in water and alkalis, very slightly soluble in alcohol, pH of a 1% aqueous solution is 4.5, pH the drug with a mass fraction of 5% - 4.0-5.5. It forms very stable complex compounds with most cations, reacts with strong oxidizing agents.

EDTA and Trilon B are substances that alter the structure of the cytoplasmic membrane of microorganisms. They violate the integrity of the membranes of the bacterial cell wall, which reduces the resistance of bacteria to antibiotics and other antibacterial substances, especially those for which calcium and magnesium ions are antagonists of their antimicrobial effects, for example, polymyxins and aminoglycosides.

As a result of a sufficiently long contact of the EDTA solution with various types of microorganisms in the cells of the latter, nucleic acids are destroyed, which leads to their lysis. In addition to influencing the cell wall and bacterial metabolism, EDTA induces the loss of plasmids in the staphylococcus transductant strains, and also inhibits the genetic transfer of R plasmids in in vivo experiments in staphylococcus.

The impact of EDTA and Trilon B on the membrane of the microbial cell leads to the lysis of genital pyli, providing plasmid transfer. In this regard, in a resistant population of microorganisms, the number of sexually transmitted R + cells responsible for the bacterial transmission of plasmids during conjugation is primarily reduced.

The main difference in the structure of the cell membrane of gram-positive and gram-negative microorganisms is the presence of an outer membrane in gram-negative forms. Any lytic enzymes cannot hydrolyze the peptidoglycan layer of the outer shell of bacteria without destroying the outer membrane, which can be done using chelating agents and detergents included in the combination preparations.

Trilon B is a chelating agent that binds divalent metal ions, which causes the membrane to lose the lipopolysaccharide complex. As a result, the cell wall becomes fragile, its permeability to various substances, including antimicrobial action, increases. This has a pronounced damaging effect on the microbial cell.

For the treatment of wounds with polyvalent microflora, this drug can be used in combination with targeted antimicrobial agents. In such cases, Trilon B, increasing the permeability of the microbial cell, enhances the sensitivity of microorganisms to antibacterial drugs, for example, chloramphenicol.

Trilon B exhibits a bacteriostatic effect in relation to strains of gram-negative and gram-positive pyogenic bacteria: staphylococcus and bacillus of blue-green pus in a concentration of more than 0.075%, protein and Escherichia coli in a concentration of more than 0.15%. The minimum bactericidal concentration (MBC) of Trilon B with respect to Staphylococcus aureus ATCC 25923 is 2%, to Pseudomonas aeruginosa ATCC 27858 - 0.5%.

Trilon B can be used topically as a bacteriostatic substance in the treatment of wounds infected with blue-green pus stick, as well as for the preservation of drugs. E. coli is effectively lysed by combining trilon B and lysozyme (“Theory and practice of local treatment of purulent wounds” / Edited by prof. B.M. Datsenko, Kiev, publishing house “Health”, 1995, p. 143, 144) .

The stick of blue-green pus, as well as protea, is less sensitive to cationic antiseptics than staphylococci, streptococci, pneumococci, intestinal and typhoid bacilli, etc. The combination of trilon B with cationic surfactants increases the bactericidal effect on these microorganisms.

The combination of Trilon B with cationic antiseptics is promising for use as part of pharmaceuticals as preservatives.

Given the data on the dependence of histamine activity on Ca ^{2+ ions} , it is rational to introduce complexones, in particular Trilon B, in the composition of preparations for treating wounds in the first phase of the wound healing process to improve microcirculation in wound tissues.

Trilon B refers to water-soluble antioxidants that reduce secondary tissue necrosis around the wound associated with excessive free radical oxidation (“Theory and practice of local treatment of purulent wounds” / Edited by Professor B.M. Datsenko, Kiev, publishing house “Health” , 1995, p. 146, 180, 185, 228).

In a preferred embodiment, the proposed composition contains from 0.001 to 0.500 wt. % EDTA.

In a preferred embodiment, the composition contains from 0.005 to 10,000 wt. % Trilon B, more preferably from 0.01 to 4.00 wt. %

In the proposed pharmaceutical combination composition, Trilon B is used in conjunction with dioxidine for the treatment of purulent wounds with polyvalent microflora containing strains of staphylococci, streptococci and Pseudomonas aeruginosa, to which dioxidine activity is reduced.

EDTA or Trilon B in the proposed composition reduces the resistance of strains of staphylococcus and Pseudomonas aeruginosa to antibiotics and other antibacterial substances, including dioxidine.

Secondary tissue necrosis in the circumference of a wound is partially associated with excessive free radical oxidation. Since Trilon B is a water-soluble antioxidant, its use in the proposed combination composition with dioxidine reduces secondary tissue necrosis around the wound.

In the composition of the proposed combination composition, a synthetic antibacterial substance that reduces the resistance of microorganisms, dimexide (dimethyl sulfoxide, DMSO), is used together with dioxidine.

Dimexide is a bipolar aprotic solvent. It has been widely used in various fields of chemistry, as well as as a medicine. Dimexide is a viscous colorless liquid or colorless crystals, melting at a temperature of 18.5 ° C, with a specific odor. When mixed with water, it becomes very hot. The drug is hygroscopic, mixes in all proportions with water and alcohol.

Dimexide has a local anesthetic, local anti-inflammatory, antimicrobial (antiseptic) and fibrinolytic effects. In addition, it has an antiviral, antifungal, vasodilating effect, reduces the level of free radicals, and stimulates various types of immunity.

Dimexide quickly penetrates through biological membranes, including through the skin and mucous membranes, increases their permeability to other drugs. Its molecular bond with water is 1.3 times stronger than the molecular bond of water with water. As a result, it replaces water when moving through cell membranes, and carries with it substances that usually themselves cannot penetrate through the membrane into the cell. Due to this, the therapeutic effect of some transported drugs, for example, antibiotics, is enhanced. In this case, the latter can be used in smaller doses than usual, without reducing their therapeutic efficacy and with a decrease in their undesirable side effects.

Dimexide hydrates cells, causing changes in the fluid structure of cell water. It changes the sensitivity of antibiotic-resistant microflora. Dimexide acts on the membrane of the microbial cell, which leads to the lysis of genital pyli, providing the transfer of plasmids. In this regard, in a resistant population of microorganisms, the number of sexually transmitted R + cells responsible for the bacterial transmission of plasmids during conjugation is primarily reduced.

In most cases, dimexide is used in combination with other medicinal substances (previously dissolved in it) for better and deeper penetration into tissues (http://www.rlsnet.ru/mnn_index_id_64.htm). It is used as a component of hydrophilic bases. The introduction of more than 5% of readily penetrating dioxide into the base causes a significant deterioration in tissue cell viability.

In a preferred embodiment, the proposed composition contains from 0.5 to 5.0 wt. % dimexide, more preferably from 1.0 to 3.0 wt. %

In the proposed combination composition, dimexide is used together with dioxidine for the treatment of purulent wounds with polyvalent microflora containing strains of staphylococci, streptococci and Pseudomonas aeruginosa, to which dioxidine activity is reduced, and also containing fungi and viruses, in relation to which dioxidine is not active.

The use of dimexide in the proposed composition also has a local anesthetic, local anti-inflammatory, vasodilating effect, and also reduces the level of free radicals, stimulates various types of immunity.

The composition of the proposed combination composition with dioxidine uses synthetic antibacterial substances that reduce the resistance of microorganisms in the form of surface-active substances (surfactants).

A surfactant is a large group of substances with a diphilic structure of molecules that are capable of adsorbing from a solution to a phase interface in a liquid medium (for example, the surface of microbial cells) with a decrease in free surface energy. The use of cationic and anionic surfactants in medical practice is associated with their ability to break the microbial cell permeability barriers. In this case, surfactants destroy the membrane by binding internal proteins or, lining up between lipid molecules, increase their mobility.

Binding to the membranes of bacteria of ionic surfactants causes the exit from bacterial cells of vital metabolites, potassium ions, inorganic phosphorus, sugars, purines and pyrimidine bases. From staphylococcus and E. coli cells treated with both cationic and anionic surfactants, an intensive release of substances with a maximum absorption of 260 nm characteristic of nucleic acids is observed. At the same time, the amount of antibiotic staphylococcus "absorbed" by the cells increases by 3 (cationic) and 2 (anionic) times. Intracellular accumulation of antibiotics is accompanied by a significant increase in their antimicrobial action, including in relation to resistant forms of bacteria.

Surfactants are able to independently perform the function of an antimicrobial substance, which is most characteristic of cationic surfactants. Especially important for clinical practice is the ability of surfactants to influence the elimination and transfer of drug resistance plasmids in bacteria.

There are two types of plasmid elimination: one due to suppression of plasmid DNA replication, the other due to the preferential inhibition of the growth of bacterial cells that are plasmid carriers, which leads to the selection of bacteria that spontaneously lose extrachromosomal factors.

The active center of penicillinase contains essential amino acids. Therefore, substances that actively interact with its amino groups are effective inhibitors of this enzyme. These requirements are most satisfied by anionic surfactants, which are sodium salts of alkyl sulfates and alkyl sulfonates of higher fatty acids (VGS) with carbon atoms of alkyl chains from 12 to 16. Anionic surfactants include sodium salts of sulfonates of higher fatty alcohols, for example, sodium lauryl sulfate. Anionic surfactants contain polar groups in the molecule and dissociate in water with the formation of negatively charged long-chain organic ions that determine their surface activity. Sodium, ammonium and triethanolamine salts are soluble in water.

Some anionic and nonionic surfactants are inhibitors of enzymes - inactivators of antibiotics. In in vivo experiments on a model of purulent-inflammatory process in rats, it was found that sodium lauryl sulfate at a concentration of 0.1% inhibited staphylococci transduction of the plasmid Em-resistance (in some cases completely). Anionic surfactants completely suppress the genetic transfer of R-plasmids in Escherichia coli both during conjugation and transduction (“Theory and practice of local treatment of purulent wounds” / Edited by prof. B.M.Datsenko, Kiev, publishing house “Health”, 1995, pp. 144-146).

Effective inhibitors of enzymes that inactivate aminoglycosides (neomycin, kanamycin, streptomycin) are anionic surfactants: sodium lauryl sulfate, sodium alkylbenzenesulfonate (C ₁₀ -C ₁₆ ). Sodium lauryl sulfate is also an effective inhibitor of chloramphenicol acetyltransferase ("Theory and practice of local treatment of purulent wounds" / Edited by prof. BM Datsenko, Kiev, publishing house "Health", 1995, p. 142, 143).

The properties of surfactants - change the permeability of cell walls and inhibit the action of β-lactamases - are not related to each other. However, they both enhance the action of antibiotics against resistant bacteria. Moreover, the amplification effect does not depend on the type of bacterial resistance - chromosomal or plasmid.

In the proposed combined composition, an anionic surfactant is used in the form of, for example, sodium lauryl sulfate.

Cationic surfactants dissociate in water with the formation of positively charged organic ions that determine their surface activity. Penetrated into the cytoplasm of the cell, cationic surfactants cause the deposition of intracellular proteins and nucleic acids, which leads to irreversible disruption of the vital functions of microorganisms. The spectrum of their action includes staphylococci, streptococci, pneumococci, Escherichia coli and typhoid bacilli, cholera vibrio, etc. The stick of blue-green pus and Proteus are less sensitive to cationic antiseptics. Cationic surfactants, especially salts of quaternary ammonium and pyridine compounds, have a strong bactericidal property (“Theory and practice of local treatment of purulent wounds” / Edited by prof. B.M. Datsenko, Kiev, publishing house “Health”, 1995, pp. . 145-147).

In the proposed combined composition with dioxidine, low-toxic cationic surfactants are used: catapol, chlorhexidine, miramistin, decamethoxin, polyhexanide (lavacept), octenidine.

Catapol - n-alkyldimethylbenzylammonium chloride + polyvinylpyrrolidone + crotonic acid (benzalkonium chloride + povidone copolymer with crotonic acid). Catapol, which is a complex of Catamine AB with a polymer, belongs to the group of cationic surfactants and is a broad-spectrum antiseptic approved for use in medicine, veterinary medicine and poultry farming, in the food and fish processing industries. Catapol is available as a 10% aqueous solution containing, in addition to the basic substance, sodium chloride. In medical, veterinary and sanitary practice, the drug is used in the form of dilute solutions with concentrations of 0.01-1.00 wt. %

Catapol is an antiseptic for external use of a wide spectrum of action, shows bactericidal activity against staphylococci, streptococci, gram-negative bacteria (including E. coli and Pseudomonas aeruginosa, Proteus, Klebsiella), anaerobic bacteria, fungi and molds. It acts on strains of bacteria resistant to antibiotics and other chemotherapeutic drugs. Catapol enhances the effect of various antibiotics when used together, inhibits bacterial pathogenicity enzymes (plasmocoagulase and staphylococcal hyaluronidase) (www.recipe.ru; “Theory and practice of local treatment of purulent wounds” / Edited by Professor B.M. Datsenko, Kiev, ed. in Health, 1995, pp. 145-147). Catapol stimulates tissue regeneration. In addition, it has anti-inflammatory, anti-burn and antiseptic effects (http://www.recipe.ru/docs/ls/index.php?filter=bysearch&filter_param=Katapol&action=descr-drug-table&drugid=5777).

In a preferred embodiment, the proposed composition contains from 0.01 to 1.00 wt. % catapol.

In this composition, catapol is used together with dioxidine for the treatment of purulent wounds with polyvalent microflora, containing strains of staphylococci, streptococci and Pseudomonas aeruginosa, to which dioxidine activity is reduced, and also containing fungi and mold, in relation to which dioxidine is not active.

The use of catapol in the proposed composition also stimulates tissue regeneration and anti-inflammatory effect.

Chlorhexidine - N, N '' - bis (4-chlorophenyl) -3,12-diimino-2,4,11,13-tetraazatetra-decanediimidamide. It is an odorless white crystalline powder that is poorly soluble in water and alcohol. Chlorhexidine gluconate contains a larger percentage of the active substance itself, namely, 1 g of the drug accounts for 0.2 g, and 1 ml of the drug chlorhexidine bigluconate accounts for 0.5 mg of the active substance (20.00% and 0.05%, respectively).

Chlorhexidine is bactericidal against most gram-positive and gram-negative aerobic and anaerobic bacteria, treponem, gonococcus, trichomonas, it does not act on viruses and spores.

Chlorhexidine bigluconate is an effective penicillinase inhibitor. It also inactivates chloramphenicol acetyl transferase of Escherichia coli and staphillococcus. Chlorhexidine bigluconate has a pronounced antimicrobial effect against the main pathogens of purulent wound infection already in concentrations of 10-50 μg / ml. At its higher concentrations, a rapid bactericidal effect occurs. Due to its low toxicity and weak irritating effect, chlorhexidine biglucon is used in the form of a 0.01-0.50% solution in 70% ethanol. ("Theory and practice of local treatment of purulent wounds" / Edited by prof. B.M. Datsenko, Kiev, publishing house "Health", 1995, p. 142, 143, 147).

In a preferred embodiment, the proposed composition contains from 0.01 to 1.00 wt. % chlorhexidine bigluconate.

In such a chlorhexidine composition, bigluconate is used together with dioxidine for the treatment of purulent wounds with polyvalent microflora containing strains of staphylococci, streptococci and Pseudomonas aeruginosa, to which dioxidine activity is reduced, and also containing fungi in relation to which dioxidine is not active.

Decamethoxin - 1,10-decamethylene bis (N, N-dimethylmethoxycarbonylmethyl) ammonium dichloride - is a white crystalline powder with a faint characteristic odor that is readily soluble in water, ethanol and chloroform with the formation of slightly opalescent solutions, very slightly soluble in acetone, practically insoluble in ether and benzene.

Decamethoxin is a low-toxic cationic antiseptic. It is an antiseptic of a group of quaternary ammonium compounds. The drug concentrates on the cytoplasmic membrane (CPM) of the microbial cell and combines with the phosphatide groups of the lipids of the membrane, disrupting the permeability of the CPM of microorganisms. The basis of its action is the following mechanism - the destruction of the upper membrane layer, loosening of the membrane and increase its permeability to large molecular substances. Since most enzymes are fixed on the membrane structures, decamethoxin changes the enzymatic activity of the cell, inhibiting the enzymatic systems.

The hydrophobic radical of decamethoxin contributes to the maximum binding of the drug to the cell membrane of microorganisms, and the cationic one first reduces and then neutralizes the charge of the microbial cell wall.

Decamethoxin does not act on the membranes of human cells, since they have a significantly greater length of lipid radicals and therefore hydrophobic interaction does not occur.

The pharmacological action of decamethoxin is antimicrobial, antifungal. It has a pronounced bactericidal effect on staphylococci, streptococci, diphtheria and Pseudomonas aeruginosa, capsular bacteria and fungicidal effects on yeast, yeast-like fungi, causative agents of epidermophytosis, trichophytosis, microsporia, erythrasma, some types of mold fungi, protergillocytes, aspergillocytes, aspergillocycles, aspergillocytes, aspergillocycles, aspergillocycles, protergicides, Giardia, virusocidal effect on viruses. Decamethoxin is highly active against antibiotic-resistant microorganisms. But the formation of forms resistant to decamethoxin with prolonged use occurs slowly and does not exceed effective concentrations of the drug.

Bacteriostatic, fungistatic concentrations of decamethoxin are similar to its bactericidal, fungicidal, virusocidal, protistocidal concentrations. In the course of treatment with decamethoxin, the sensitivity of antibiotic-resistant microorganisms to antibiotics increases, and the action of other antimicrobial agents is also potentiated with complex treatment.

With purulent and fungal diseases, a 0.01-0.50% aqueous solution of decamethoxin is used for washing. The composition of the solution also includes other ingredients: ethanol 96%, glycerol, citral alcohol solution 1%, purified water (http://www.rlsnet.ru/mnn_index_id_689.htm; http://compendium.com.ua/akt/68 / 610 / decametoxinum).

In a preferred embodiment, the proposed composition contains from 0.01 to 0.50 wt. % decamethoxin.

In the proposed pharmaceutical combination composition, decamethoxin is used together with dioxidine for the treatment of purulent wounds with polyvalent microflora, containing strains of staphylococci, streptococci and Pseudomonas aeruginosa, to which dioxidine activity is reduced, and also containing fungi, yeast, protozoa and viruses, in relation to which dioxidine is not active.

Miramistin - benzyldimethyl- [3- (myristoylamino) propyl] ammonium chloride monohydrate - odorless white crystalline powder, readily (slowly) soluble in water, 95% alcohol, chloroform. Miramistin is a low-toxic cationic antiseptic. It is an antiseptic of a group of quaternary ammonium compounds, has an antimicrobial effect against gram-positive microorganisms, and acts worse on gram-negative flora. The strength of the bactericidal efficacy of miramistin is slightly inferior to catamine AB, which is part of catapol. Their MBC in relation to staphylococcus and bacillus of blue-green pus are respectively 0.003% and 0.008%, 0.1% and 0.63%. In addition, miramistin is used as a stabilizer of dispersed systems that serve as the basis for foams and ointments.

Miramistin has a wide spectrum of antimicrobial activity, including hospital strains resistant to antibiotics. The drug has a pronounced bactericidal effect against gram-positive, gram-negative aerobic and anaerobic bacteria, defined as monocultures and microbial associations, including hospital strains with antibiotic resistance. It has an antifungal effect on ascomycetes and yeast-like fungi, dermatophytes, as well as on other pathogenic fungi in the form of monocultures and microbial associations, including fungal microflora with resistance to chemotherapeutic drugs.

In addition, it has an antiviral effect, is active against complex viruses (herpes viruses, human immunodeficiency virus, etc.). Miramistin suppresses microbial associations (staphylococci and Escherichia, staphylococci and Pseudomonas aeruginosa), penicillin-producing hospital strains.

This compound increases the functional activity of immune cells, stimulates a local nonspecific immune response, accelerates the healing process of wounds, reduces the resistance of microorganisms to antibacterial drugs, effectively prevents infection of wounds and burns, activates regeneration processes, stimulates protective reactions at the site of application by activating the absorption and digestion function phagocytes, potentiates the activity of the monocyte-macrophage system. Miramistin has a pronounced hyperosmolar activity, as a result of which it stops wound and perifocal inflammation, absorbs purulent exudate, contributing to the formation of a dry scab, does not damage granulation and viable skin cells, does not inhibit edge epithelization, does not have a locally irritating effect and allergenic properties.

The drug is available in the form of a 0.01% aqueous solution (http://www.rlsnet.ru/ tn_index_id_4800.htm), 0.5% ointment Miramistin and Streptolaven. On the ointment with miramistin "Lavendula" there is RU 2484811, A61K 9/06, 06/20/2013.

In a preferred embodiment, the proposed composition contains from 0.01 to 1.00 wt. % miramistina.

In this composition, miramistin is used together with dioxidine for the treatment of purulent wounds with polyvalent microflora containing strains of staphylococci, streptococci and Pseudomonas aeruginosa, to which dioxidine activity is reduced, and also containing fungi, yeast, protozoa and viruses, against which dioxidine is not active.

The use of miramistin in the proposed composition increases the functional activity of immune cells, stimulates a local nonspecific immune response, accelerates the healing process, reduces the resistance of microorganisms to antibacterial drugs, suppresses wound and perifocal inflammation, absorbs purulent exudate, contributing to the formation of a dry scab.

Guanidines are cationic surfactants. Representatives of this group are guanidine derivatives: chlorhexidine bigluconate, chlorhexidine dihydrochloride, chlorhexidine diacetate, polymer derivatives of guanidine - polyhexamethylene guanidine hydrochloride, (PHMG-x), polyhexamethylene guanidine phosphate (PGDG-ganidine-catanedihydrogen dihydrogen).

Guanidines have stability, low toxicity and a sparing effect on objects. In its pure form, guanidines are active against gram-negative and gram-positive microorganisms, do not show activity against viruses, fungi, spores. The expansion of the spectrum of their antimicrobial activity occurs when combined with other surfactants, alcohol (acquire virucidal properties), etc.

The optimal environment for these compounds is alkaline, pH 10.0-11.0. Guanidines are part of the preparations intended for disinfection, as well as in the composition of skin antiseptics.

Polyhexanide (lavasept) - a derivative of biguanide and amide (cationic diguanidine) - is chemically stable, non-volatile, odorless, soluble in water, ethanol, glycerin, propylene glycol and other solvents.

Polyhexanide is a membrane-specific molecule with numerous active sites that provide an effective antimicrobial effect at a low concentration. Active biguanide sections of the molecule have high molecular efficiency against bacteria, while remaining non-toxic to the plasma membranes of human cells. Polyhexanide has a broad spectrum antibacterial effect and low toxicity (http://www.lsgeotar.ru/pharma_mnn/1928.html).

Polyhexanide is used in the form of a 0.1% or 0.2% Lavasept solution, as well as 0.1% Prontosan gel (http://www.piluli.ru/product/Prontosan).

The use of polyhexanide is effective for chronic wounds.

In a preferred embodiment, the proposed composition contains from 0.05 to 2.00 wt. % polyhexanide, more preferably from 0.1 to 0.5 wt. %

In this composition, polyhexanide is used with dioxidine in one composition for the treatment of purulent wounds with polyvalent microflora containing strains of staphylococci, streptococci and Pseudomonas aeruginosa, to which dioxidine activity is reduced.

Octenidine (octenidine dihydrochloride) - N, N 'dihydrochloride - 1,10-decanediyl-di-1- [4H] pyridinyl-4-ylidene) bis (1-octamine) is a cationic surfactant with antimicrobial activity against a wide range of microorganisms. Octenidine is similar in its action to quaternary ammonium compounds, but has a wider spectrum of activity. Being a derivative of guanidines, octenidine differs from them in that it has a wider spectrum of microcidal action: microorganisms, viruses, fungi. Octenidine is used as an antiseptic for the skin and mucous membranes, does not have a cumulative (accumulating) effect. He became a complete substitute for traditional antiseptics - iodine and alcohol (http://www.epidemiolog.ru/anti/disinfection/SECTION_ID=&ELEMENT_ID-466).

Octenidine is more active than chlorhexidine (http://mmtd.kz/sravnitelnaya_ocenka_h).

The industrially produced preparation "Octenisept" in the form of a solution in which 0.1% octenidine dihydrochloride and 2% 2-phenoxyethanol (http://www.rlsnet.ru/tn_index_id_2418.htm) exhibits pronounced antibacterial properties, namely, activity in relation to to gram-positive and gram-negative bacteria, some lipophilic viruses, fungi and dermatophytes (http://medside.ru/fenoksietanol).

In a preferred embodiment, the proposed composition contains from 0.005 to 5,000 wt. % octenidine hydrochloride, more preferably from 0.01 to 2.00 wt. %

In a preferred embodiment, the composition contains from 0.5 to 4.0 wt. % 2-phenoxyethanol, more preferably from 1.0 to 2.0 wt. %

In this composition, octenidine is used with dioxidine for the treatment of purulent wounds with polyvalent microflora containing strains of staphylococci, streptococci and Pseudomonas aeruginosa, to which dioxidine activity is reduced, as well as microflora containing fungi and viruses, in relation to which dioxidine is practically inactive.

Sodium lauryl sulfate (sodium dodecyl sulfate) - the sodium salt of lauryl sulfuric acid, an anionic surfactant - is a white powder. It is combustible, spontaneous combustion temperature 310.5 ° С, solubility in water - not less than 130 g / l (13%) at 20 ° С. In aqueous solutions, it forms a stable foam. Sodium lauryl sulfate is part of the ointment, which involves prolonged contact with the skin. In this case, the concentration will be no higher than 1.0% (https://ru.wikipedia.org/wiki/%D0%9B%D0%B0%D1%83%D1%80%D0%B8%D0%BB% D1% 81% D1% 83% D0% BB% D1% 8C% D1% 84% D0% B0% D1% 82_% D0% BD% D0% B0% D1% 82% D1% 80% D0% B8% D1% 8F).

Sodium lauryl sulfate is an effective inhibitor of aminoglycoside inactivating enzymes and an effective inhibitor of chloramphenicol acetyltransferase.

In a preferred embodiment, the proposed composition contains from 0.001 to 2,000 wt. % sodium lauryl sulfate, more preferably from 0.1 to 1.0 wt. %

In this composition, sodium lauryl sulfate is used as an inhibitor of the resistance of microorganisms in combination with dioxidin and aminoglycoside antibiotics (netilmicin, amikacin) and chloramphenicol.

With the combined use of aminoglycosides with dioxidine in one composition, their antibacterial effect is enhanced (http://gn24.net/publ/therapy/tablitsa-sovmestimosti-antibiotikov.html).

The proposed pharmaceutical combination composition along with dioxidine uses the antibiotic netilmicin, which refers to aminoglycosides.

Netilmicin has minimal ototoxicity and nephrotoxicity compared with other aminoglycosides (G.K. Reshedko. Netilmicin. Clinical Microbiology of Antimicrobial Chemotherapy, 2007, Volume 9, No. 3, pp. 253-267).

Netilmicin (netilmicin sulfate) is a semi-synthetic antibiotic from the group of generation III aminoglycosides, a derivative of sisomycin. It is soluble in water, has a wide bactericidal spectrum of action. Netilmicin binds to the 30S subunit of ribosomes and disrupts protein synthesis, preventing the formation of a complex of transport and messenger RNA, and the genetic code is erroneously read and non-functional proteins are formed. In high concentrations, it violates the permeability of the cytoplasmic membrane and causes the death of microorganisms.

Avoid the use of netilmicin in conjunction with polymyxin B, other aminoglycosides, ethacrylic acid, furosemide, muscle relaxants, anesthetics (www.rlsnet.ru/mnn_index_id_196.htm), vancomycin, colistin, platinum preparations, methotrexate, phosphamide, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphamide, phosphate sodium, some antiviral agents (acyclovir, ganciclovir, adefovir, cidofovir, tenofovir), amphotericin B, immunosuppressants such as cyclosporine or tacrolimus, and iodine-contrasting substances (www.medi.ru/doc/x1338.htm).

Netilmicin is active even in low concentrations against a wide range of pathogenic bacteria, including Escherichia coli, Klebsiella spp., Enterobacter spp., Serratia spp., Citrobacter spp., Proteus spp. (indole-positive and indole-negative), including Proteus mirabilis, Proteus morganii, Proteus rettgeri, Proteus vulgaris, Pseudomonas aeruginosa and Neisseria gonorrhoeae. In vitro netilmicin is also active against strains of Haemophilus influenzae, Salmonella spp., Shigella spp. and in relation to penicillinase and non-penicillinase forming strains of Staphylococcus, including methicillin-resistant. Some strains of Providencia spp., Acinetobacter spp. and Aeromonas spp. also susceptible to netilmicin.

Many microbial strains resistant to other aminoglycosides, such as kanamycin, gentamicin, tobramycin and sisomycin, are in vitro sensitive to netilmicin. In some cases, amikacin-resistant strains are sensitive to netilmicin (www.medi.ru/doc/x1338.htm).

Netilmicin is not active against anaerobes (G.K. Reshedko. "Netilmicin. Clinical Microbiology of Antimicrobial Chemotherapy, 2007, Volume 9, No. 3, pp. 253-267, Table 6 and 7). It is available as a solution of netilmicin for intravenous and intramuscular administration of 25 mg / ml (2.5%) and 100 mg / ml (10%) (www.medi.ru/doc/x1338.htm), as well as 0, 3% eye ointment and eye drops. Composition per 1.0 g: the active substance is netilmicin sulfate - 4.55 mg, in terms of netilmicin - 3.00 mg. (Www.ros-med.info/reestr-ls/info.php?action=info&id=18900 )

In a preferred embodiment, the proposed composition contains from 0.1 to 4.0 wt. % netilmicin, more preferably from 0.2 to 2.0 wt. %).

In the composition of the proposed composition, along with dioxidine, the antibiotic amikacin (amikacin sulfate), which refers to aminoglycosides, is used. Amikacin is a semi-synthetic broad-spectrum antibiotic that acts bactericidal, binds to the 30S subunit of ribosomes and blocks protein synthesis. It is an amorphous powder of white or white color with a yellowish tint, which is easily soluble in water, it is hygroscopic (20 mg in 1 ml of water). For a solution obtained by dissolving 10 mg of amikacin per ml of water, the pH value is 2.0-4.0.

It acts on many strains of gram-negative bacteria, including bacterial strains of P. aeruginosa, resistant to gentamicin and other generation II aminoglycosides, is active against some strains of gram-positive microorganisms - Enterococcus faecalis, Staphylococcus spp. (including those resistant to penicillin), not active against streptococci / pneumococci, E. faecium, methicillin-resistant strains of staphylococci.

Amikacin is used mainly in combination with other antibacterial agents. It is used for infectious and inflammatory diseases caused by gram-negative microorganisms or associations of gram-positive and gram-negative microorganisms, including for the treatment of infected burns, purulent infections of the skin and soft tissues, wound infection.

With the interaction of amikacin with anesthetics, muscle relaxants, polymyxins, the neuromuscular blocking effect is enhanced. Amikacin is produced in the form of a solution for injection and gel 5.0% (Guide “Rational Antimicrobial Pharmacotherapy” / Edited by Doctor of Medical Sciences V.P. Yakovleva and Doctor of Medical Sciences S.V. Yakovleva, publishing house Litterra, 2003, pp. 708-709).

In a preferred embodiment, the proposed composition contains from 0.5 to 5.0 wt. % amikacin sulfate.

In this composition, netilmicin and amikacin are used together with dioxidine to treat purulent wounds with polyvalent microflora containing strains of gram-positive and gram-negative bacteria, including anaerobic ones, to which netilmicin and amikacin are not active. To reduce the resistance of microorganisms to netilmicin and amikacin, the composition of the composition includes an inhibitor of enzymes that inactivate aminoglycosides, sodium lauryl sulfate.

Since gram-negative bacteria and to a lesser extent gram-positive and anaerobes are especially sensitive to the above aminoglycosides (Guide “Rational Antimicrobial Pharmacotherapy” / Edited by Doctor of Medical Sciences V.P. Yakovleva and Doctor of Medical Sciences S.V. Yakovleva, Litterra Publishing House, 2003, p. 95), it is advisable to use them in a combined pharmaceutical composition together with lysoamidase or lysozyme, which suppress a wide range of gram-positive microorganisms, and with dioxidine, highly active against anaerobes.

The proposed pharmaceutical combination composition together with dioxidine uses the ofloxacin antibiotic, which refers to fluoroquinolones.

Ofloxacin is a crystalline powder of a slightly yellowish color, odorless, bitter taste, which is slightly soluble in water and alcohol.

Ofloxacin has a bactericidal effect due to the blockade of DNA gyrase in bacterial cells. DNA gyrase is necessary for the replication, transcription, reparation, and recombination of bacterial DNA. Its inhibition leads to unwinding and destabilization of bacterial DNA and, as a result, to the death of a microbial cell. The bactericidal efficacy of ofloxacin is manifested quite quickly, the resistance of microorganisms to this drug is rare. This is due to its mechanism of action, affecting only one gene of DNA gyrase and topoisomerase.

Ofloxacin is most active against some gram-positive and most gram-negative bacteria (including the Enterobacteriaceae family, hemophilic bacillus, neisseria), staphylococci and intracellular pathogens (chlamydia, mycoplasmas, ureaplasmas). With respect to streptococci, pneumococci, Pseudomonas aeruginosa and mycobacteria, it is less active, inactive or does not show activity against enterococci and most anaerobes (Guide “Rational Antimicrobial Pharmacotherapy” / Edited by Dr. V.P. Yakovleva and D.M. S.V. Yakovleva, publishing house "Literra", 2003, p. 846-849).

Ofloxacin is active against a narrow spectrum of surgical pathogens. It has a moderate antimicrobial effect when applied topically. It is positioned as a replacement for drugs with chloramphenicol (V.V. Privolnev. “The choice of drug for the local treatment of infected wounds.” Journal named after Prof. B. M. Kostyuchenko “Wounds and wound infections”, 2015, vol. 2, p. 13 -18, table 3).

Ofloxacin is inferior to ciprofloxacin in terms of its effect on gram-negative bacteria (especially P. aeruginosa), and in some cases it is superior to staphylococcus.

The drug can be used for severe infections of the skin, soft tissues, bones, joints. Ofloxacin can be prescribed simultaneously with many antibacterial drugs (macrolides, b-lactam antibiotics, cephalosporins, etc.). Due to this property, the drug is widely used in combination therapy for infectious diseases. Ofloxacin, unlike ciprofloxacin, remains active when used simultaneously with chloramphenicol (chloramphenicol) and rifampicin - inhibitors of RNA polymerase synthesis. It is produced in the form of tablets, solution, 1.0% Oflomelide ointment and 0.1 Oflokain-Darnitsa ointment.

In a preferred embodiment, the proposed composition contains from 0.05 to 2.00 wt. % ofloxacin.

The composition of the proposed pharmaceutical composition along with dioxidine uses the antibiotic ciprofloxacin, which refers to fluoroquinolones.

Ciprofloxacin is a crystalline powder of a slightly yellowish color, odorless, bitter taste, which is sparingly soluble in water and alcohol, soluble in 0.1 N hydrochloric acid. It is almost completely absorbed in the digestive tract, bioavailability - 80%, T1 / 2 = 4-6 hours.

Ciprofloxacin has a bactericidal effect due to the inhibition of DNA gyrase (topoisomerase II and IV, responsible for the folding of chromosomal DNA into the supercoil around nuclear RNA), disruption of DNA biosynthesis, growth and division of bacteria, as well as by the application of pronounced morphological changes (i.e. including cell wall and membranes) and rapid cell death. It acts on microorganisms during their growth and dormancy.

Ciprofloxacin is most active against aerobic gram-negative bacteria, less active against non-fermenting gram-negative microbes, in particular bacterial strains P. aeruginosa, Acinetobacter. However, of all the fluoroquinolones permitted in Russia for medical use, it is most active against P. aeruginosa. With respect to gram-positive microbes (staphylococci and streptococci), the activity of ciprofloxacin is lower than with respect to gram-negative. It is inactive against enterococci and most anaerobes (Manual “Rational Antimicrobial Pharmacotherapy” / Edited by Doctor of Medical Sciences V.P. Yakovleva and Doctor of Medical Sciences S.V. Yakovleva, publishing house “Literra”, 2003 g., pp. 952-956). In an acidic environment, its activity decreases.

Most methicillin-resistant staphylococci are resistant to ciprofloxacin. Intracellular strains of bacteria Streptococcus pneumoniae, Enterococcus faecalis, Mycobacterium avium are moderately sensitive to ciprofloxacin.

Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia, as well as Bacteroides fragilis, Pseudomonas cepacia, Pseudomonas maltophilia, Ureaplasma urealyticum, Clostridium difficile, Nocardia are resistant to ciprofloxacin. Ciprofloxacin is not effective against Treponema pallidum. Resistance to the drug develops slowly and gradually ("multi-stage" type). There is no cross-resistance with penicillins, cephalosporins, aminoglycosides.

The activity of ciprofloxacin increases when combined with beta-lactam antibiotics, aminoglycosides, vancomycin, clindamycin, metronidazole.

It can be used for severe infections of the skin, soft tissues, bones, joints. The drug is released in the form of tablets, solutions, eye drops of 0.3%.

In a preferred embodiment, the proposed composition contains from 0.1 to 5.0 wt. % ciprofloxacin.

Derivatives of diaminopyrimidine (pyrimethamine, trimethoprim, tetroxoprim, methioprim, brodimoprim) potentiate the activity of fluoroquinolones, which include ofloxacin and ciprofloxacin (Antimicrobials in the series of derivatives of sulfanilamide, diaminopyrimidine, 5-nitroimide, 5-nitroimide, 5-nitroimide, 5-nitroimide). E.N., breast cancer №21 dated 04.11.1997, p. 1-6).

Essential in the combination of fluoroquinolones and diaminopyrimidine derivatives is the possibility of reducing the dosages of each of the drugs.

In a preferred embodiment, the composition has a ratio: diaminopyrimidine derivative: fluoroquinolone ≈ 1: 5 to 1:40, more preferably 1: 5 to 1:10.

Since ofloxacin and ciprofloxacin have little activity against enterococci and most anaerobes (NN Kozachok et al. “Fluoroquinolones - a look into the future.” Table 3, www.mit-ua.com/arhive/article/3015), it is advisable to use them in combined pharmaceutical composition together with dioxidine, highly active against anaerobes, as well as with other components active against gram-positive microorganisms and fungi.

In the composition of the proposed pharmaceutical combination composition, along with dioxidine, the antibiotic chloramphenicol (chloramphenicol), which refers to phenols, is used. This is a synthetic antibiotic that is identical to the natural product of the microorganism Streptomyces venezuelae, which is a crystalline powder, white or white with a slight yellowish-green tinge, bitter in taste, slightly soluble in water, easily in ethanol, soluble in ethyl acetate, practically insoluble in chloroform.

This is a broad-spectrum antimicrobial drug that is active against most gram-positive and gram-negative aerobic and anaerobic bacteria, chlamydia, spirochetes and rickettsia.

Chloramphenicol is a protein synthesis inhibitor at the 70S ribosome level. This target consists of two subunits: large 50S and small 30S. It inhibits protein synthesis by binding to the protein of the 50S ribosome subunit, disrupts the protein synthesis at the stage of amino acid transfer from aminoacyl t-RNA to ribosomes, inhibits the enzymatic reaction - it inhibits the peptidyl transferase enzyme, which catalyzes the formation of peptide bonds during protein synthesis. RNA of bacterial cells changes under the action of chloramphenicol and differs from normal cells.

Chloramphenicol inhibits protein synthesis in proliferating cells and in stationary culture. In relation to most sensitive microorganisms, the drug has a bacteriostatic effect. In high concentrations or in relation to highly sensitive microorganisms, chloramphenicol may have a bactericidal effect. The drug penetrates well into the cells of the microorganism, which ensures its activity against a number of pathogens with intracellular localization: rickettsia, chlamydia, legionella (Manual “Rational Antimicrobial Pharmacotherapy” / Edited by Dr. V.P. Yakovleva and D.M. S.V. Yakovleva, publishing house "Literra", 2003, pp. 921-927).

Chloramphenicol is an antagonist of penicillin, aminoglycoside, reduces the antibacterial effect of penicillins and cephalosporins. With simultaneous use with erythromycin, clindomycin, lincomycin, a mutual weakening of action is noted due to the fact that chloramphenicol can displace these drugs from a bound state or prevent their binding to the 50S subunit of bacterial ribosomes.

With the combined use of chloramphenicol with dioxidine, their antibacterial effect is slightly increased (http://gn24.net/publ/therapy/tablitsa-sovmestimosti-antibiotikov.html).

Chloramphenicol is active against a narrow spectrum of surgical infections. It has a weak antimicrobial effect when applied topically. Recommended for the treatment of superficial infections of the skin (VV Privolnev. “The choice of the drug for the local treatment of infected wounds.” Journal named after prof. BM Kostyuchenko “Wounds and wound infections”, 2015, vol. 2, p. 13 -18, table 3).

On pneumococcus, meningococcus and hemophilic bacillus, chloramphenicol acts bactericidal, on another sensitive microflora - bacteriostatically. The drug does not affect acid-resistant bacteria, Pseudomonas aeruginosa, clostridia, methicillin-resistant strains: staphylococci, Acinetobacter, Enterobacter, Serriatia marcescent, indigenous strains Proteus spp., Pseudomonas aeruginosa spp., Protozoa and fungi. It is used to a limited extent due to severe adverse reactions and secondary resistance of many pathogens (“Development of the composition and technology for the preparation of an ointment containing a cobalt bio-complex with furazolidone.” Medicine, health, http://uchi-referat.ru/medicina-zdorove/2921- razrabotka-sostava-i-tehnologii-polucheniya-mazi-soderzhashhey-biokompleks-kobalta-s-furazolidonom.html).

Resistance to chloramphenicol develops most often in enterobacteria (20-60% of strains), less often in meningococci, neisseria, gram-positive cocci (0.25-1.00% of strains). The process is directly dependent on the breadth of use and duration of use of the drug in the respective regions and hospitals, the transmission mechanism is plasmid.

In most cases, the resistance of microorganisms to chloramphenicol is due to the bacterial enzyme chloramphenicolacetyltransferase encoded by plasmid genes, which is inactivated by the drug. Strains synthesizing chloramphenicolacetyltransferase are increasingly found among staphylococci. The prevalence of such strains varies, in some hospitals it reaches 50% or more, especially among methicillin-resistant staphylococci. Other mechanisms of resistance to chloramphenicol have been described - a decrease in the permeability of bacterial membranes (in Escherichia coli and Pseudomonas spp.), A decrease in the affinity of ribosomes for the drug, due to a mutation (http://sportwiki.to/%D0%9В%D0%В5%D0% B2% D0% BE% D0% BC% D0% B8% D1% 86% D0% B5% D1% 82% D0% B8% D0% BD (% D1% 85% D0% BB% D0% BE% D1% 80 % D0% B0% D0% BC% D1% 84% D0% B5% D0% BD% D0% B8% D0% BA% D0% BE% D0% BB).

As already indicated, Trilon B, increasing the permeability of the microbial cell, enhances the sensitivity of microorganisms to antibacterial drugs, for example, chloramphenicol. An effective inhibitor of chloramphenicol acetyltransferase is sodium lauryl sulfate and chlorhexidine bigluconate (“Theory and practice of local treatment of purulent wounds” / Edited by prof. B.M. Datsenko, Kiev, Health, 1995, p. 142, 143 , 144-146).

Chloramphenicol is widely used for the treatment of purulent wounds and infiltrates ("Theory and practice of local treatment of purulent wounds" / Edited by prof. B.M. Datsenko, Kiev, from Health, 1995, p. 155, 235).

Locally, chloramphenicol is used for purulent-inflammatory diseases of the skin and soft tissues: purulent wounds, infected burn surfaces, etc. It is produced in the form of tablets, capsules, solutions for external use 0.25%, 1%, 2%, 2.5%, 3%, 5%, eye drops 0.25%, oral suspensions 5%, liniment for external use - 1%, 5%, 10%, ointments 0.75% and 1%, suppositories, aerosols.

In a preferred embodiment, the proposed composition contains from 0.1 to 10.0 wt. % chloramphenicol, more preferably from 0.5 to 5.0 wt. %

In such a composition, chloramphenicol is used together with dioxidine for the treatment of purulent wounds with polyvalent microflora, including those containing microorganisms to which dioxidine is active, and chloramphenicol is inactive.

It is advisable in the proposed combination composition with dioxidine and chloramphenicol to use components - Trilon B, catapol, decamethoxin, miramistin, active against Pseudomonas aeruginosa, Proteus spp., Pseudomonas aeruginosa spp., Protozoa and fungi, to which chloramphenicol is also not very active.

It also seems useful in this composition to use chloramphenicol acetyltransferase inhibitors — sodium lauryl sulfate or chlorhexidine bigluconate to reduce the resistance of microorganisms to chloramphenicol.

One of the shares in the wound polyvalent microflora is a fungal infection. Certain types of fungi competing with bacteria for food sources produce antibiotics that inhibit the vital activity of bacteria, which leads to an increase in the proportion of fungal infection in the wound. To ensure the suppression of fungal infection in the composition of the proposed combination composition, the following antimycotics are used together with dioxidine: clotrimazole or cyclopiroxolamine.

Clotrimazole, an imidazole derivative, is an antifungal drug for topical and topical use. The mechanism of its action is to inhibit the synthesis of ergosterol, which is necessary for the construction of the cell membrane of fungi, which leads to a violation of its permeability and subsequent cell lysis. The drug also causes an increase in the permeability of the phospholipid membrane of liposomes, vacuolization of the cytoplasm, and a decrease in the number of ribosomes. In addition, clotrimazole inhibits the activity of peroxidases, which facilitates the accumulation of hydrogen peroxide in the fungal cell, which takes part in its destruction.

It has a wide spectrum of action: effective against dermatophytes, yeast fungi, has an antibacterial effect on staphylococci and streptococci.

Clotrimazole after application to the skin is absorbed in an amount not exceeding 1.0%, but penetrates the stratum corneum of the epidermis and accumulates there. (//medi.ru/doc/g2713.htm). The drug is used in the form of 1% ointment, 1% cream, 2% gel and 1% solution for external use.

In a preferred embodiment, the proposed composition contains from 0.5 to 3.0 wt. % clotrimazole.

Cyclopiroxolamine is a broad-spectrum antimycotic that is highly active against dermatomycetes, as well as yeast, gram-positive and gram-negative bacteria, mycoplasmas and trichomonads. The fungicidal effect of this drug is associated with the suppression of transmembrane transport of amino acids, K ⁺ and phosphates in growing fungal cells (www.medicreferat.com.ru/pageid-1053-4.html). The drug is available in the form of a 1% solution for external use, 1% cream (www.yarapteka.ru/modules.php?name=spr&inf=283).

In a preferred embodiment, the proposed composition contains from 0.2 to 1.0 wt. % cyclopiroxolamine.

In the pharmaceutical combination composition, clotrimazole or cyclopiroxolamine is used with dioxidine in one composition for the treatment of purulent wounds with polyvalent microflora, including those containing fungi to which dioxidine is not active.

To provide additional stimulation of the repair processes in the wound, the proposed pharmaceutical combination composition based on dioxidine contains a wound healing substance: xymedon, methyluracil, calcium patonate, solcoseryl, etaden, or a physiologically acceptable mixture thereof.

Xymedon - N- (β-hydroxyethyl) - 4, 6-dimethyldihydropyrimedone - 2, the 3rd generation pyrimidine derivative, which has high regenerative activity (ed. St. SU 1685454, A61K 31/513, publ. 23.10.1991). The preparation is a crystalline powder of white color or with a pink tint, odorless, bitter taste, with a melting point of 139-143 ° C, easily soluble in water, alcohol, physiological saline.

Xymedon stimulates metabolic processes, primarily due to protein biosynthesis. The drug also affects the regulation of active calcium transport in the cell, affects the processes of tissue respiration, lipid peroxidation and the activity of the antioxidant system.

Xymedon has an effect on the sulfhydryl status of immunocompetent cells, has antimutagenic activity, antimicrobial effect. The stimulating effect of xymedon is most fully manifested in the first 5-7 days, wound healing is much faster than in the control group (methyluracil), the forming scar ripens faster, the growth of granulation tissue is less pronounced, the process of collagenogenesis starts earlier.

Xymedon in reparative activity surpasses the methods of medication and physiotherapy known to date. However, it does not change the normal course of wound healing: the same phases of the wound healing process are observed, but they are significantly shortened. An interesting feature of the effect of the drug is its ability to regulate collagenogenesis, preventing the formation of keloid scars.

Unlike many drugs that inhibit the inflammatory reaction, xymedon has a regulatory effect on the inflammatory process. In the first stage of inflammation, the drug has a protective effect at the cellular level due to membrane-stabilizing (including leukocyte lysosome membranes), antioxidant, adaptogenic, antibacterial effects. In the membrane-stabilizing effect, the antioxidant effect of xymedon is manifested (http: //www.medicum.nnov.m/nmj/2002/3/18.php).

Xymedon interferes with most necrobiotic processes of the alteration phase, in addition, this period is significantly shortened. In the second phase of inflammation, xymedon has a pronounced decongestant effect, improves microcirculation. The exudation period is sharply shortened. The powerful effect of the drug manifests itself in the early beginning of the proliferation phase, the rapid activation of collagenogenesis, the best vascularization, accelerated epithelization of the suture zone. All of the above is of great importance for increasing the strength of sutured wounds of hollow organs during the "dangerous" days of the postoperative period known to surgeons.

In the treatment with xymedon, the phagocytic index and the completeness of phagocytosis increase by 2 times compared with their values in control animals treated with methyluracil.

The antibacterial effect of xymedon compares it favorably with methyluracil. When exposed to a bacterially contaminated medium, a 5% solution has a bacteriostatic effect, and a 10% concentration of xymedon solution has bactericidal activity. Other dosage forms of xymedon (powder, ointment) also have antibacterial properties.

In a preferred embodiment, the proposed composition contains from 1 to 10 wt. % xymedon, more preferably from 4 to 10 wt. %

Methyluracil, being a pyrimidine derivative, has anabolic and anti-catabolic activity. The substance does not have a local irritant effect, accelerates the processes of cell regeneration, reducing the healing time of wounds, stimulates cellular and humoral defense factors, has an anti-inflammatory effect, and stimulates erythro- and leukopoiesis.

In a preferred embodiment, the proposed composition contains from 1 to 10 wt. % methyluracil, more preferably from 4 to 10 wt. %

Pantothenic acid in the form of calcium pantothenate (vitamin B ₅ ) is a promising wound healing agent. It is used to treat burns and sluggishly healing wounds. In the body, pantothenic acid is part of coenzyme A, which plays an important role in the processes of acetylation and oxidation. Vitamin B ₅ , as a component of coenzyme A, plays a key role in the metabolism of carbohydrates, proteins and fats, and is therefore important for the maintenance and restoration of all tissue cells (“Essentials about Vitamins”, DSV Nutritional Products, www.dsm.com/ru_RU/html /dnpru/hnh_maininfovit_index_basics_panto.htm).

Pantothenic acid stimulates skin regeneration, normalizes cellular metabolism, increases the strength of collagen fibers. Optimum molecular weight, hydrophilicity and low polarity make it possible to penetrate into all layers of the skin. It has a regenerative, weak anti-inflammatory effect.

In a preferred embodiment, the proposed composition contains from 1 to 10 wt. % calcium pantothenate, more preferably from 4 to 10 wt. %

Solcoseryl is a cattle blood extract freed from proteins and lacking antigenic activity. It is a deproteinized hemodialysate containing a wide range of low molecular weight components of the cell mass and blood serum of dairy calves with a molecular weight of 5000 D. The pharmacological action of solcoseryl is antihypoxic, cytoprotective, regenerating, membrane-stabilizing, angioprotective, wound healing.

It promotes the formation of granulation tissue and the elimination of exudate.

In a preferred embodiment, the proposed composition contains from 0.2 to 5.0 wt. % solcoseryl.

Etaden stimulates reparative processes in the epithelial and hematopoietic tissues, activates the metabolism of nucleic acids. It is indicated for the treatment of thermal and radiation injuries of the skin, rectal mucosa, and nonhealing granulating wounds.

In a preferred embodiment, the proposed composition contains from 0.5 to 2.0 wt. % etaden.

One of the main tasks of local treatment of wounds and burns is the problem of suppressing pain. To solve this problem, the proposed combination composition uses a local anesthetic substance, which is used as lidocaine or trimecain.

Lidocaine - (2-diethylamino) -N- (2,6-dimethylphenyl) acetamide (and in the form of hydrochloride) is a white or almost white crystalline powder, poorly soluble in water. It is used in the form of hydrochloric acid, readily soluble in water. The mechanism of its local anesthetic effect is to stabilize the neuronal membrane, reducing its permeability to sodium ions, which prevents the emergence of an action potential and impulses. Its antagonism with calcium ions is possible. Lidocaine is rapidly hydrolyzed in a slightly alkaline tissue environment and, after a short latent period, acts for 60-90 minutes. With inflammation (tissue acidosis), the anesthetic activity of lidocaine decreases. It is effective in all types of local anesthesia, dilates blood vessels. It does not irritate tissue. To prolong the action of the anesthetic, it is possible to add 1 drop of a 0.1% adrenaline solution to 5-10 ml of lidocaine (in this case, the maximum allowable dose is increased to 500 mg) (http://www.rlsnet.ru/mnn_index_id_843.htm).

Lidocaine has a lower toxicity than trimecaine (patent RU 2283088, A61K9 / 06, 09/10/2006).

Trimecaine - 2- (Diethylamino) -N- (2,4,6-trimethylphenyl) acetamide in the form of a hydrochloride is a crystalline powder, white or white with a yellowish tint, which is soluble in water and alcohol. Possessing sufficient lipophilicity, it penetrates the nerve fiber membrane, binds to receptors and disrupts depolarization processes, blocking the conduction of a nerve impulse. (http://www.rlsnet.ru/mnn_index_id_1292.htm).

Anesthetics in the composition of the polymer bases contribute to the release and absorption of antiseptics. For example, trimecain enhances the antimicrobial properties of miramistin, which is part of a hydrophilic-based ointment (I. M. Kirichenko. “Modern approaches to the treatment of infectious skin diseases.” Http://old.consilium-medicum.com/media/consilium/06_01c/ 12.shtml).

In the proposed composition, the acceptable range of application of anesthetic from 0.5 to 6.0 wt. % However, the most optimal content of anesthetic in it is in the range from 1.0 to 3.0 wt. %

The local inflammatory reaction is a multifactorial reaction of the body to trauma and microbial invasion.

Disruption of microcirculation is one of the main factors in the pathogenesis of the inflammatory process. Microcirculation includes not only blood flow through arterioles, capillaries and venules, but also transcapillary exchange, which provides tissue homeostasis necessary for life. Her disorders are divided into intravascular changes, disorders of the vessels themselves and extravascular changes. The therapeutic range of drugs used to improve microcirculation in wound tissues can be largely realized due to their antihistamine, anti-inflammatory and dehydrating effects.

The use of trilon B in the proposed pharmaceutical combination composition with dioxidine provides improved microcirculation in the tissues of the wound, since trilon B reduces the activity of histamine. In addition, the use of a hyperosmolar base also improves microcirculation in the tissues of the wound due to its dehydrating effect. In this case, the applied base, consisting of hyperosmolar substances, has an indirect anti-inflammatory effect due to the absorption of fluid and reduction of edema of the wound tissue or in the subcutaneous lesion.

It is known that patients with severe signs of immune dysfunction during microbial infection are shown synthetic immunomodulators, such as tilorone, polyoxidonium (http: //uhonos.m/infekcii/stafilokokk/), cycloferon, etc.

Tiloron effectively increases the body's resistance to infections caused by viruses, bacteria, fungi and protozoa. It has an activating effect on macrophages. At the same time, not only the absorptive capacity of phagocytes increases, but also the production of reactive oxygen species by these cells that have a bactericidal effect. Tiloron has a stimulating effect on the phagocytic and bactericidal functions of macrophages, while reducing the intensity of lipid peroxidation.

The immunomodulatory activity of tilorone is especially pronounced against the background of immunosuppressive conditions caused by various reasons, including surgical interventions. Tiloron also exhibits anti-inflammatory activity and antipyretic effect, inhibits platelet aggregation. Moreover, it is not inferior to aspirin in the magnitude of the effect, and surpasses it in duration (T.O. Filippova et al. “Tiloron: profile of biological activity. I. Pharmacological properties.” Pp. 19-21, http // magazine.odmu .od.ua / antropo / 2006/1 / 18pdf).

It is well known that tilorone is used in oral form (Amixin, Lavomax tablets) for systemic use. Known pharmaceutical compositions with tilorone in the form of a solution for injection (patents RU 2359664, A61K 31/06 06/27/2009, RU 2364390, A61K 31/06, 08/20/2009), as well as soft forms in the form of ointments, suppositories, etc. for local and external use (patents RU 2351322, A61K 31/06 04/10/2009, RU 2352330, A61K 31/06, 04/20/2009, RU 2353354 A61K 31/06, 04/20/2009, RU 2348400, A61K 31/06, 03/10/2009 )

The studies revealed the anti-inflammatory and reparative effect of tilorone in the form of an ointment for inflammation and trophic skin disorders in a model of pathological changes in the skin of the foot of the hind limb in rats caused by transection of the tibial nerve and ligation of the popliteal artery.

Tiloron accelerated the healing of skin damage with its ointment application and subcutaneous chipping and had no effect when the probe was inserted into the stomach. In this case, healing took place with ointment applications for 14 days, with chipping - for 18 days, with the introduction of tilorone into the stomach and control (applications with an ointment base without tilorone) - 42 days (“Study of the therapeutic activity of tilorone in various forms with pathological skin conditions "," Cytokines and inflammation ", 2011, volume 10, No. 3, pp. 98-101; patent RU 2423971, A61K 31/06, 07/20/2011).

These studies show that for traumatic wounds associated with impaired tissue innervation and blood supply, a pharmaceutical combination composition containing tilorone and dioxidine can be used to heal them, which, in addition to its antibacterial effect, stimulates the tissue repair process and has a wound healing effect.

In a preferred embodiment, the proposed composition contains from 0.05 to 10.00 wt. % tilorone, more preferably from 0.5 to 5.0 wt. %

In this case, tilorone is used with dioxidine in the same composition for the treatment of purulent wounds with polyvalent microflora as an immunomodulator of local (local) action, accelerating wound healing in phase II of the wound process.

Cycloferon (meglumine acridone acetate) is a low molecular weight inducer of endogenous interferon (patent RU 2036198, С07Н 5/06, 05/27/1995) obtained by mixing acridonoacetic acid with N-methylglucamine. According to the chemical structure, acridonoacetic acid is a planar tricyclic heteroaromatic system with an N-carboxymethyl substituent. This compound simultaneously combines high lipophilicity due to a flat heteroaromatic ring and hydrophilicity due to the ring keto group and the side residue of acetic acid at the nitrogen atom. This chemical structure of acridonoacetic acid ensures that it has a high biological activity, due to both easy penetration into the organs and tissues of the body, and a possible effect on the receptor apparatus of the cell and on the metabolic reactions in the body.

N-methylglucamine is a compound used to solubilize and stabilize various biological compounds, a derivative of a linear polyalcohol (D-sorbitol). This is a chemically stable hygroscopic crystalline substance, readily soluble in water and most organic solvents (Acridonoacetic acid is an active component of drugs with N-methylglucamine, www.ama.dp.ua / Info / Lidraru / CycloSrPed / p2.asp).

The immunomodulatory effect of cycloferon is expressed in the correction of the body's immune status in immunodeficiency states of various origins. The drug has a low toxicity. It has no mutagenic, teratogenic, embryotoxic and carcinogenic effects.

Cycloferon is available in tablet form, with 0.15 g of acridonoacetic acid and 0.146 g of N-methylglucamine in 1 tablet (Description of the drug, www.regmed.ru/InstrShow2.asp?InstrLinkNx=a83ba87ba88ba75b).

Cycloferon is used as a 12.5% aqueous solution for intramuscular and intravenous administration (Description of the drug, www.biomedservis.ru/preparat/pr_cycloferon_liniment.htm) containing 0.125 g of acridonoacetic acid and 0.0963 g of N-methylglucamine in 1 ml of solution.

In addition, cycloferon is produced in the form of a liquid ointment - 5% of the liniment of cycloferon containing 0.05 g of acridonoacetic acid, 0.0385 g of N-methylglucamine in 1 g of ointment, as well as an additional target additive in the form of 0.1% catapol antiseptic and 1, 2-propylene glycol as a base (Cycloferon ^® http://www.e-apteka.ru/doc/Vidal_docs/drug_info_24196.asp).

A high antibacterial and anti-chlamydial effect of the drug in the form of a liniment due to the activation of the immune system, as well as anti-inflammatory and antiproliferative effect of the drug was established.

The immunomodulatory effect of cycloferon in the form of a liniment is expressed in the correction of local immunity in immunodeficiency states of various origins and autoimmune diseases. The main producing cells of interferon after administration of the drug in the form of a liniment are the lymphoid elements of the mucous membrane: macrophages, T and B lymphocytes, as well as epithelial cells (http://www.biomedservice.ru/preparat/pr_cycloferon_liniment.htm).

In a preferred embodiment, the proposed composition contains from 2 to 15 wt. % cycloferon, more preferably from 5.0 to 12.5 wt. % In such an embodiment of the composition, the ratio of the components of cycloferon: acridonoacetic acid / N-methylglucamine = 1 ÷ 1.5, more preferably ≈1.3.

In the proposed combined pharmaceutical composition, cycloferon is used with dioxidine in one composition for the treatment of purulent wounds with polyvalent microflora as an immunomodulator of local (local) action, accelerating wound healing in phases I and II of the wound process.

Polyoxidonium - a copolymer of N-hydroxy 1,4-ethylene piperazine and (N-carboxyethyl) -1,4-ethylene piperazine bromide - an immunomodulator with a molecular weight of 60,000 to 100,000 significantly increases the body's immune resistance against various infections, has a non-specific protective effect against a wide spectrum pathogens. It activates the migration of motile macrophages of tissues, their ability to phagocytose and digest pathogenic bacteria, increases the efficiency of cooperative interaction of T and B lymphocytes in antibody formation reactions in response to foreign antigens, activating immune responses. The introduction of polyoxidonium leads to the activation of the synthesis of IgG and IgM antibodies that protect against infections, but not IgE antibodies that are responsible for allergic reactions (Polyoxidonium. Www.mtu-net.ru/doctor99/5nklassifi1 polioxidoniy 2905.htm).

Polyoxidonium is a water-soluble polymer having in its polymer chain a large number of weakly charged N-oxide groups, which provide a high adsorption capacity of the polymer. Each polyoxidonium molecule is capable of forming a complex with many small molecules and, in particular, with toxin molecules. This ensures its pronounced detoxification activity. It increases the resistance of cell membranes to the cytotoxic effect of drugs and chemicals, reducing their toxicity. The antitoxic potential of polyoxidonium is very high, it is hundreds of times higher than the antitoxic properties of hemodisis.

Polyoxidonium has a high bioavailability of 89%, reaching a maximum concentration in the blood when administered intramuscularly after 40 minutes, is rapidly distributed to all organs and tissues. The half-life in the body (fast phase) is about 25 minutes, the half-life (slow phase) is 36.2 hours with intramuscular administration and 25.4 hours with intravenous administration.

For suppositories, bioavailability is 70%, the maximum concentration of polyoxidonium in the blood is reached 1 hour after administration, its half-life (fast phase) is about 30 minutes, the half-life (slow phase) is 36.2 hours. In the body, the drug undergoes biodegradation and is excreted mainly through the kidneys.

Polyoxidonium is combined with all antibiotics, antiviral and antifungal agents, etc. Its use in complex therapy allows to increase the effectiveness and reduce the duration of treatment, significantly reduce the use of antibiotics, and extend the period of remission.

Polyoxidonium can be introduced into the body in various ways, including non-injection methods for focusing in the pathological process. This allows you to activate local immunity, that is, parts of the immune system that are closest to a diseased organ or tissue.

The life time of polyoxidonium in the human body is several days. This determines the high efficiency of polyoxidonium, as well as its prolonged effect.

Polyoxidonium does not cause side or toxic effects. The drug is available in the form of tablets of 0.012 g, injection for 3-4% and 6-8%, as well as suppositories weighing 1.3 g, containing 0.006 g and 0.012 g of polyoxidonium (http://polioxidonii.lek-va.ru/ )

In a preferred embodiment, the proposed composition contains from 0.4 to 10.0 wt. % polyoxidonium, more preferably from 5 to 10 wt. %

Polyoxidonium is used with dioxidine in one pharmaceutical composition for the treatment of purulent wounds with polyvalent microflora as an immunomodulator of local (local) action with detoxification activity, accelerating wound healing in phases I and II of the wound process.

As a preservative, the proposed composition contains Trilon B (see above), as well as parabens: nipagin, nipazole or a mixture thereof.

Nipagin or methyl paraben - methyl ester of paraoxybenzoic acid actively inhibits the growth of gram-positive bacteria, it is less active against gram-negative bacteria and molds. Better than other para-hydroxybenzoic acid esters, it dissolves in water, but is less effective for antibacterial purposes. Nipagin is mainly used in combination with other preservatives (for example, phenoxyethanol). Nipagin is slightly soluble in water - 0.25% at 20 ° C and gives good results as a preservative already at a concentration of 0.05%. It is used at a concentration of 0.25%, in which its bactericidal effect exceeds that of phenol by 2.6 times.

Nipazole or propyl paraben (propyl parahydroxybenzoate) - p-hydroxybenzoic acid propyl ester. Nipazole is slightly soluble in water - 0.03% at 20 ° C. Its bactericidal activity is more than 5 times higher than the bactericidal activity of nipagin. Due to its low solubility in water, it is recommended to use its 0.07% solution.

These preservatives are compatible with almost all medicines, with the exception of sodium bicarbonate, sodium tetraborate and silver nitrate. The proposed composition may contain a mixture of nipagin and nipazole, in particular in a ratio of 1: 3.

The low toxicity of parabens allows them to be used in topical drugs - suspensions, liniments, solutions, suppositories of gelatin capsules, etc. (S. I. Marchenko. "Lecture notes on the course of technology of dosage forms and galenical preparations." Lecture No. 6 t. www.opu.odessa.ua/konsp/KI.229.doc).

Non-inogenic detergents with high surface activity, not creating ions in aqueous solutions, have a dissolving and disinfecting effect. The proposed pharmaceutical composition as a nonionic detergent contains tween-80 or tween-20.

Twins are monoesters of polyoxyethylated sorbitan (spen) and higher fatty acids. Twins dissolve in water and organic solvents. In pharmaceuticals, they are used to stabilize emulsions and suspensions. In addition, tween-80 is used as a solubilizer - a substance that increases the solubility of insoluble or insoluble drugs.

Solubilization is the process of spontaneous transition of a water-insoluble substance into an aqueous solution of a surfactant. As a solubilizer can also be used, for example, a surfactant - sodium dodecyl sulfate (sodium lauryl sulfate).

The proposed pharmaceutical composition as a stabilizer may contain substances selected from the group: etonium, citric acid, miramistin.

Etonium gives a bacteriostatic and bactericidal effect, is effective against streptococci, staphylococci and other microorganisms. It has local anesthetic activity, stimulates wound healing.

Citric acid is an important metabolic product in living organisms, participates in the tricarboxylic acid cycle and glyoxylate cycle. It has the properties of both a stabilizer and an antioxidant, as well as a chelating agent.

Hydrophilic bases are more preferable for pharmaceutical compositions, since they serve as vehicles for delivering drugs to the microbial cell due to the presence of external polysaccharide membranes and hydrophilic capsules in gram-negative and gram-positive bacteria, which prevent the penetration of hydrophobic antibacterial substances into microbial cells.

Hydrophilic bases that can be used in the proposed pharmaceutical combination composition are divided into two groups:

- water-soluble bases, which usually contain purified water, hydrophilic non-aqueous solvents: polyethylene oxide, for example, PEO-400, 1,2-propylene glycol, glycerin, ethyl cellosolve, dimexide, polyvinylpyrrolidone, water-soluble polymers: polyethylene oxide, for example PEO-1500, proxanol for example proxanol-268;

- water-washable bases, which in addition to water-soluble polymers and hydrophilic non-aqueous solvents contain lipophilic substances: higher fatty alcohols, petroleum jelly, paraffin oil, lanolin, waxes. These bases are typically oil / water emulsions and require the presence of an oil / water emulsifier.

Basics with hyperosmolar properties play an important role in local therapy of purulent wounds. They provide an outflow of purulent exudate from the wound, have an anti-inflammatory effect due to the absorption of fluid and reduce swelling of the wound tissue, and also protect the tissue from overhydration. Often they contribute to enhancing the action of antibacterial substances.

Substances with high hyperosmolar properties include polyethylene oxides - water-soluble products of the polymerization of ethylene oxide, which are physiologically indifferent compounds.

Polyethylene oxides and polyethylene glycols have a similar chemical structure. The differences are that polyethylene oxides are obtained by polymerization of ethylene oxide, and polyethylene glycols during the polycondensation of ethylene glycol molecules. Given the fact that ethylene oxide in water easily opens the epoxy cycle, turning into ethylene glycol, we can conclude that these polymer systems are identical.

The class of hyperosmolar substances includes hydrophilic non-aqueous solvents (PEO-400, 1,2-propylene glycol, glycerin, ethyl cellosolve, dimexide) and polymers (polyethylene oxide, for example PEO-1500, proxanol-268 or emuxol-268).

They are easily applied to the wound surface and evenly distributed on it, improving the contact of the ointment with the tissues and contents of the wound, mix well with wound exudate and maintain their uniformity, low toxicity and do not irritate tissues, do not violate their physiological functions.

In a purulent wound, PEOs of different molecular weights behave differently. So, PEO-1500 molecules stably maintain their primary localization: they remain in the wound cavity and actively bind the inflammatory exudate, giving it to the dressing with which the liquid evaporates. The released PEO-1500 molecules reattach water to themselves, and the process repeats.

Smaller PEO-400 molecules have the ability to penetrate deep into the tissues and after 2 hours are determined in the bottom and walls of the wound. Forming complexes with antibacterial substances, PEO-400 conducts them into wound tissues, where microorganisms are localized. The ability of polyethylene oxides to provide an antimicrobial drug with an interstitial action fundamentally distinguishes this ointment base from fatty bases or solutions of antibiotics (antiseptics), the antimicrobial effect of which is limited only by the wound surface, although it is the deep microflora that determines the severity and direction of the purulent process.

The main property of PEO is that they have a pronounced dehydrogenating (moisture-absorbing) effect on the tissue. Due to the high ability to hydrate, these polymers actively absorb wound exudate, and with it microbial toxins, tissue breakdown products, as well as various biologically active substances - lysosomal enzymes and other inflammatory mediators, thereby interrupting its progressive course. Of fundamental importance is the fact that in a purulent wound, the dehydrating effect of PEO extends not only to the tissues that form the bottom and walls of the wound cavity, but also to the microbial cells contained in the wound. Dehydration of microbial cells leads to a significant decrease in its biological activity and, in particular, resistance to the action of certain drugs.

Therefore, in the presence of PEO, the antimicrobial effect of antibiotics is increased tenfold. It is also important that the dissolution of antibiotics, sulfanilamides and other substances in PEO leads to an increase in their dispersion with an increase in therapeutic activity, which is also facilitated by a faster release of antimicrobial substances from the base. PEO is an active conductor of drugs across the skin barrier. The important thing is that this penetrating without damage to the cells ability of PEO is enhanced in conditions of inflammation.

Hydrophilic bases on polyethylene oxides are able to dissolve in the secrets of the mucous membranes, completely release medicinal substances, do not irritate the mucosa; they have a long shelf life, high physiological indifference, which contributes to their use in liquid, ointment-like and formulated soft dosage forms.

An important biomedical requirement for ointment soft dosage forms is the ability to wet the wound surface and spread over it, which is due to the surface-active properties of solvents, polymers, surfactants and the base as a whole.

The most pronounced surface activity are alcohols and ethyl cellosolve, which are unsuitable for inclusion in the composition of the base in high concentrations. Of the glycols, it is preferable to use 1,2-propylene glycol and PEO-400 compared to glycerol having weak surface-active properties.

In the State Register of Medicines 5 polyethylene oxides (PEO) with different molecular weights are registered: PEO-400. PEO-1000, PEO-1500, PEO-2000 and PEO-4000.

When mixing the PEO-400 solvent with PEO-1500 polymer, the latter acts as a thickener, which, depending on the amount in the total mass, provides the required consistency of the created dosage form. In addition, PEO-1500 is an osmotically active substance that absorbs purulent exudate due to the binding of water molecules to hydroxyl and ether groups. This basis is recommended for ointment dosage forms used in the local treatment of wounds in the first phase of the wound process.

Proxanol-268 (emuxol-268) is a block copolymer of propylene and ethylene oxides. Proxanol-268 as an osmotically active substance provides a more uniform absorption pattern and has a longer period of osmotic action. The total mass of absorbed water with proxanol-268 solutions in 24 hours significantly exceeds that in the case of PEO-1500. This is due to the higher mass of proxanol-268 (8.7 times more than PEO-1500).

The kinetics of water absorption by solvents and polymers depends on their molecular weight, concentration and molecular structure. So PEO-400 absorbs more water than 1,2-polyethylene glycol, and has a longer period of osmotic action. Sorption activity of 1,2-propylene glycol is maintained for 4-6 hours. This is due to both its lower molecular weight in comparison with PEO-400 and the lower hydrophilic-lipophilic balance (HLB), which for propylene glycol is 9.38.

The magnitude of the hydrophilic-lipophilic balance is greater, the greater the hydrophilicity of a substance. Therefore, the higher the HLB and the molecular weight, the stronger and longer the osmotic effect of the substance will appear at a given concentration.

HLB values for some substances: 1,2-propylene glycol - 9.375; glycerin - 11.275; ethyl cellosolve - 8.3; PEO-400 - 12.49; PEO-1500 - 20.74.

1,2-Propylene glycol, PEO-400, PEO-1500, proxanol-268 can serve as preservatives in the developed soft dosage forms.

The polyethylene oxide base of ointments has a number of disadvantages, which include the risk of damage to cell membranes, excessive dehydration of tissue cells, osmotic shock leading to their death.

The use of hydrophilic solvents and polymers individually adversely affects tissue cells. Moreover, penetrating, semi-penetrating and completely penetrating hydrophilic substances have a cytotoxic effect. With a combination of solvents and polymers, the situation changes dramatically. Cells remain viable with dilutions 1-3 orders of magnitude lower. Moreover, when comparing the effect on the cells, it was found that instead of PEO-1500, proxanol-268 is more preferable to use in basics. To address these shortcomings, bases have been developed that have the mildest cytotoxic effect on tissue cells.

These basics include:

1) a mixture of 1,2-propylene glycol, PEO-400 and proxanol-268 in the ratios 48:32:20;

2) PEO-400 and proxanol-268 in a ratio of 8: 2;

3) PEO-400 and PEO-1500 in a ratio of 8: 2 (the basics are indicated by the degree of increase in the cytotoxic effect on tissue cells).

The least toxic is base 1). The ratio between 1,2-propylene glycol and PEO-400 in a hydrophilic basis is considered an important biopharmaceutical factor, which not only affects the release of drugs through a semipermeable membrane and osmotic properties, but also on which the zones of growth inhibition of bacteria depend. The prevalence of a PEO-400 base in a dispersed medium (more than 50%) adversely affects the antibacterial properties of the ointment.

Bases with proxanol-268 penetrate under the scab better than bases with PEO-1500. This is explained by the better ability to wet the wound surface and spread proxanol-268 along it, which has higher surface-active properties than PEO-1500.

The results of the studies made it possible to substantiate the compositions of hydrophilic bases with a pronounced osmotic effect, but not damaging the tissue. From this perspective, perspectives are foundations consisting of proxanol-268, PEO-400 and 1,2-propylene glycol, to which water can be added, for example, the above basis: a mixture of 1,2-propylene glycol, PEO-400 and proxanol-268 in ratios 48:32:20. This base has the mildest effect on cells.

Despite the significant concentration of low molecular weight 1,2-propylene glycol, the cytotoxic effect of this base is minimal, since its diffusion rate is reduced due to the formation of hydrogen bonds between the hydroxyl groups of propylene glycol and the ether groups of proxanol-268 and PEO-400 ("Theory and practice of local treatment of purulent wounds "under the editorship of professor B.M. Datsenko, Kiev," Health ", 1995, pp. 255-260).

Polymer systems such as polyethylene glycols and polyethylene oxides, regardless of the method of preparation and molecular weight, can have a noticeable amount of terminal aldehyde groups. Since glycol aldehyde is formed during the oxidation of ethylene glycol, a fragment of the glycol aldehyde can complete the chain of the polyethylene oxide molecule. The presence of terminal aldehyde groups in high polymer systems that are not able to overcome the transdermal barrier is not dangerous.

Conversely, aldehyde fragments, due to their high biocidal properties, can have a beneficial effect, for example, in the treatment of burn wounds and other types of skin disorders accompanied by the development of microflora (monograph by A. N. Decina, “Theory of Soft Cosmetic Effects. Modern Cosmetology,” Novosibirsk, "Science", 2000, www.golkom.ru/book/48_1.htm, p. 217, 218).

In the proposed pharmaceutical combination composition, a hydrophilic base of polyethylene glycols (polyethylene oxides) is used to make ointments for the I and II phases of the wound healing process.

Currently, pharmacologically-conjugated (immobilized) pharmacological agents are actively used in pharmacology. It is known that hydrophilic polymers such as PEG, hydroxyethylene starch, polyvinyl pyrrolidone and others can be associated with biologically active substances by adsorption on their surface or by the formation of chemical bonds. In this case, a significant modification of the properties of the active substance can occur, which can lead to its stability, increase in half-life, decrease in toxicity, and increase in selectivity of action due to qualitative changes in pharmacokinetic and pharmacodynamic parameters.

One of the options for obtaining this kind of conjugated active substances is the pegylation reaction (pegylation) - the addition of PEG molecules using ionizing radiation. Moreover, the presence of hydrogen atoms allows one PEG molecule to bind 2-3 water molecules, and thus, when several PEG molecules are attached, a “water cloud” is formed around the pegylated particle, increasing its hydrodynamic radius.

If the pharmacologically active substance remains stable during irradiation, the process of formation of conjugates is carried out in one step by irradiation with ionizing radiation of a mixture of an aqueous solution of a polymer carrier and a drug substance. If, after radiation exposure, a biologically active compound loses its pharmacological properties, a two-step approach is used: only the polymer carrier is irradiated and then mixed with the active form of the drug substance (Nanotechnology in Pharmacology. AM Dygay et al., Moscow, 2011, pg. 39-41, p. 49).

Using the technology of processing a solution of polyethylene oxide 1500 in water with accelerated electrons, a gel was obtained containing from 1 to 4% polyethylene oxide. This gel is the Geko hydrogel, a colorless gel mass. The gel obtained by this technology, in addition to being the safest, has some unique properties. Under the influence of ionizing radiation, as a result of the formation of intermolecular cross-links, a multilayer polymer network (in the form of a gel with water) is obtained having a cellular structure — cells of type A (determine the hydrophilicity of the system) and type B (determine the affinity for fats - lipophilicity).

The presence of such fragments in the gel structure determines the properties of the system as a whole, which, along with the possibility of introducing water-soluble additives (salts, alcohol, glycerin, etc.), retains a good amount of lipophilic systems (for example, oil) without the addition of emulsifiers. On the other hand, a polyethylene oxide gel, which is a mixture of water and large molecules of cross-linked or cross-linked polyethylene oxide in a sufficiently low concentration, when used as a base for ointments and cosmetic preparations does not form a dense film that could interfere with the respiration processes and the release of cellular metabolism products. The presence of free and bound water in the structure of the gel makes it possible to classify the polyethylene oxide gel as a moisturizing base. Geko hydrogel has a widely varying structural viscosity. It is prone to liquefaction with the addition of alcohol, glycerol, with intense mechanical stress.

The chemical composition of the gel: distilled water - 96%, polyethylene oxide - 1500 - 3.5%, sodium benzoate - 0.5%. Physico-chemical properties of the gel: pH of a 20% aqueous suspension - 4.0-8.0; dynamic viscosity at 30 ° C at a shear rate of 16 s -1 - 2.0-6.0 Pa⋅s.

Geko hydrogel is used in the proposed pharmaceutical combination composition as a base with dissolution of dioxidine and other components in it during the manufacture of an ointment (gel) for the treatment of wounds in the second phase of the wound process.

In 2000, Russia developed silicon glycerates and glycerohydrogels based on them. By its physical properties, silicon glycerohydrogel (KGG-gel) is transparent or translucent, colorless or white, odorless, and stable during storage. KGG-gel is non-toxic, safe to use, has no local irritating effect on the skin and mucous membranes, does not have allergenic properties, has anesthetic properties, decongestant, antipyretic and antioxidant effects. KGG-gel can be used as a source of an essential trace element - silicon for the regulation of silicon metabolism in the body. KGG-gel has transcutaneous activity, promotes transdermal penetration of low molecular weight substances.

In the proposed pharmaceutical combination composition, silicon glycerohydrogel is used for the manufacture of ointments (creams) for the second phase of the wound process.

Hyaluronic acid - a polysaccharide from the glucosaminoglycan family, has the ability to bind 1000 times more water than it weighs. Hyaluronic acid has the highest hygroscopicity compared to other moisturizing agents, such as glycerin and sorbitol. In this case, the absorbed water is retained inside the gel and does not evaporate even when the relative humidity of the surrounding air decreases. Due to its high hydrophilicity, hyaluronic acid forms highly viscous gels with water that moisturize the skin and mucous membranes. Hyaluronic acid is non-toxic.

As part of the gels, hyaluronic acid has an antimicrobial, wound healing and anti-inflammatory effect, promotes the regeneration of the epithelium, prevents the formation of granulation tissues, adhesions, scars, normalizes blood circulation, and does not cause clinical complications. Hyaluronic acid has a positive effect on the course of local inflammatory processes, binds the microflora, as well as the products of its decay and vital activity, has a pronounced anti-inflammatory effect and a local anesthetic effect.

At the same time, hyaluronic acid also provides mechanical protection for wounds, as it forms a thin film that prevents the penetration of environmental factors, pathogenic agents, into the wound. Hyaluronic acid gels are used to treat local and general purulent-inflammatory processes, thermal and chemical burns, trophic ulcers in chronic venous insufficiency, skin radiation injuries, cracks, abrasions, as well as for the treatment of long-term healing wounds of various etiologies (patent RU 2195262, A61K 9/06, 12/27/2002).

Sodium hyaluronate - the sodium salt of hyaluronic acid, is readily soluble in water with the formation of a viscous colorless gel with a pH of 6.0-7.5 (0.1% solution). In its activity, sodium hyaluronate, the sodium salt of hyaluronic acid, promotes tissue regeneration without scarring, has the ability to stimulate cell migration and proliferation, and is used in concentrations ranging from 0.01 to 0.5.00%.

In the proposed pharmaceutical combination composition, hyaluronic acid or sodium hyaluronate are used to make ointments (creams) for the second phase of the wound healing process.

The hydrophilic component of the bases is polyvinylpyrrolidone, a synthetic polymer inert to the body and not degraded by enzyme systems. It is part of a detoxification blood substitute fluid that binds toxic substances of various structures and removes them from the body (blood substitute fluids, www.nedug.ru/libraru/doc.aspx?item=38053).

The composition of the solvents allows you to adjust the melting temperature of ointment bases, as well as the rheological properties of ointments.

The above analysis of the known properties of hyperosmolar substances and their combinations for soft dosage forms made it possible to propose the above bases with hyperosmolar properties for a pharmacological composition containing dioxidine.

Using these bases for liquid, soft and soft formulated dosage forms, as well as dioxidine, enzymes or a complex of enzymes, antibiotics, anesthetics, reparative stimulants, synthetic antibacterial agents, antimycotics, immunomodulators, pharmaceutical combined compositions of hydrophilic liquid preparations, ointments, creams, gels, capsules and suppositories for rectal administration, aerosols and sprays.

The type of dosage form of the proposed pharmaceutical composition depends on the molecular weight of the used hyperosmolar substances, their ratio in the composition of the mixture, as well as the quantitative ratio of the hyperosmolar base with other components of the composition. Based on these quantitative ratios, the dosage form of the proposed pharmaceutical composition may be a liquid, gel, cream, ointment, suppository.

The ointment form is most preferable for external use, since it is well fixed and held on the wound surface, has longer therapeutic activity, cheaper to manufacture, and is convenient to use, which enhances the patient's motivation for treatment.

Hydrophilic ointments are hyperosmolar, as a result of which, when used, they can absorb a significant amount of exudate.

Hydrophilic creams are prepared on the basis of a water / oil or water / oil / water emulsion stabilized with suitable emulsifiers or ready to use hydrophilic bases. These also include colloidal dispersed systems consisting of water-dispersed or mixed in-glycol solvents of higher fatty alcohols or acids stabilized by hydrophilic surfactants. Creams are biphasic or multiphase disperse systems, the dispersion medium of which at the set storage temperature, as a rule, has a Newtonian type of flow and low values of rheological parameters.

Hydrophilic gels (hydrogels) are prepared on the basis of water, a hydrophilic mixed or non-aqueous solvent (glycerin, 1,2-propylene glycol, PEO-400 polyethylene oxide) and a hydrophilic gelling agent (carbomers, cellulose derivatives, sodium hyaluronate, hyaluronic acid, etc.) . Gels are single, double, or multiphase disperse systems with a liquid disperse medium, the rheological properties of which are due to the presence of gelling agents in relatively low concentrations. In this dosage form, the gellants can additionally play the role of stabilizers of disperse systems: suspensions or emulsions.

Hydrophilic suppositories prepared on the above bases easily dissolve in the intestine, evenly distributing medicinal substances throughout the mucosa, which have both local and resorptive effects on the body.

Rectal gelatine capsules are more promising compared to suppositories from a technological, biopharmaceutical and economic point of view. The gelatin shell protects the drug from environmental factors and has advantages over suppositories, since it can encapsulate substances in the form of ointment, liniment, cream, gel, emulsion, suspension, etc.

The release of the drug substance occurs faster and easier than in suppositories, since under the influence of a weakly alkaline medium (pH 7.3-7.6) of the contents of the rectum, the gelatinous membranes swell, and in this state even a slight peristalsis of the rectal wall is sufficient to rupture and releasing content. The amount of drug substance in the capsule, which has the necessary therapeutic effect, is a double dose of suppositories.

Thus, the production of rectal agents in a gelatin shell allows you to save expensive biologically active ingredients and reduce the cost of drugs. Rectal gelatin capsules with the proposed pharmacological preparation meet all the requirements for ideal suppositories and can be used in medicine for the treatment of proctologic diseases.

Aerosols are liquid foam preparations in aerosol packaging for topical treatment of wounds and burns. Given the osmotic activity of the foam bases and the breadth of their antibacterial action, these drugs are indicated for use in the I or II phase of the wound process, however, by the same criteria they can also be used to treat wounds during the transition of the wound process from phase I to phase II.

The main advantages of the dosage form of the spray are as follows:

- the use of aerosols is convenient, hygienic;

- exact dosage when using metering devices;

- quick therapeutic effect at a relatively low cost of drugs;

- the aerosol can is hermetically closed, which eliminates contamination of the drug from the outside;

- an aerosol can protects the drug from drying out, the effects of light and moisture;

- aerosols remain sterile throughout the expiration date.

Aerosols have some disadvantages:

- relatively high cost;

- the possibility of a balloon explosion upon impact or high temperature;

- indoor air pollution with drugs and propellants during manipulations (“Industrial Technology of Medicines.” Vol. 2, VI Chueshov et al., Kharkov, 2002, p. 640).

Sprays as a dosage form are now actively used in medical practice. This is due to the development of high-performance and high-quality micropumps that provide the creation of a gas-liquid jet with certain parameters. Spray as a dosage form actually replaces aerosols. The main fundamental difference is that in the aerosol, the supply of the drug is due to overpressure, and extraction occurs through the valve. This creates a fine suspension with a particle size of 1-5 microns with high kinetic energy. When using a spray, the drug is supplied due to its mechanical extrusion by the piston of the micropump, while the pressure in the bottle is close to atmospheric. The particle size of the spray is larger than that of the aerosol (10-50 microns), their speed is not high. Medications in the form of a spray are used for local, external, intranasal use.

The main advantages of the dosage form of the spray are as follows:

- quick therapeutic effect;

- therapeutic effect can be obtained with a lower dose of the drug, since when dispersed, the chemical and, therefore, pharmacological activity of the drug increases;

- a high degree of penetration into the folds, pockets, cavity of the wound or mucous membrane and other inaccessible places due to the small particle size;

- there is no danger of contamination of the drug from the outside, as the container is hermetically sealed, this also prevents the preparation from drying out and protects hygroscopic substances from moisture;

- accurate dosage is ensured when using metering valves;

- the method of application is convenient and fast.

(http://pharmspray.vipsmed.ru/publikacii/novaja-lekarstvennaja-forma-sprej/)

Dioxidine in the proposed pharmaceutical combination composition as a basic component suppresses anaerobic bacteria, gram-negative and, to a lesser extent, gram-positive aerobic conditionally pathogenic bacteria in the treatment of purulent wounds. In addition, it helps to clean the wound surface, stimulates reparative regeneration and marginal epithelization, favorably affects the course of the wound process.

The lack of dioxidine in the proposed composition is its reduced activity to Pseudomonas aeruginosa strains, to gram-positive staphylococci and streptococci, as well as the resistance to it of certain staphylococcus strains. In addition, dioxidine is not active against fungi, mold and protozoa, it does not have analgesic, anti-inflammatory, proteolytic, immunomodulatory and pronounced reparative effects.

To compensate for the shortcomings of dioxidine, special targeted additives have been introduced into the proposed pharmaceutical composition: bacteriolytic and proteolytic enzymes, antibacterial substances active against Pseudomonas aeruginosa strains and staphylococci, resistance inhibitors, antimycotics, reparative process stimulants, anesthetics and immunomodulators.

The combined use of dioxidine and other antibacterial components in one pharmaceutical composition enhances the activity of the composition due to different mechanisms of action on the pathological wound microflora, and in some cases at different periods of healing time.

The combined use of dioxidine with antibacterial components of various nature, some of which reduces the resistance of pathogenic microflora, significantly enhances the antibacterial effect of the proposed pharmaceutical composition.

The use of antimycotics in the proposed drug, together with dioxidine, provides a complex effect of the proposed pharmaceutical composition for fungal infections of the skin and wounds.

Other positive effects from the use of antibacterial components in the proposed composition are an improvement in microcirculation in wound tissues due to a decrease in histamine activity, a decrease in secondary tissue necrosis around the wound circumference, a decrease in the degree of edema reaction with exudative inflammation, an additional improvement in cleaning the wound surface and stimulation of the tissue repair process.

The use in the proposed pharmaceutical combination composition of anesthetics in the form of monocomponents or their mixtures significantly suppresses pain in the treatment of wounds and burns.

To provide additional stimulation of the repair processes in the wound, substances stimulating the healing processes in the wound are introduced into the proposed pharmaceutical composition, both in the form of a monocomponent and as a mixture of components. One of them is Xymedon. In addition to stimulating metabolic reparative processes in the wound, it additionally provides an antibacterial effect, an immunostimulating effect, regulating the effect on the inflammatory process due to the membrane-stabilizing, antioxidant, adaptogenic and antibacterial effects, has a pronounced decongestant effect, and improves microcirculation. In addition, it regulates collagenogenesis, preventing the formation of keloid scars.

The use of immunomodulators in the proposed composition provides local stimulation of immunity in the tissues surrounding the wound, which accelerates the course of the wound process and shortens the healing time.

The use of a hydrophilic base, consisting of a mixture of polyethylene oxides and proxanol, in the proposed pharmacological composition provides fast delivery of active substances to both microbial cells and tissue cells, which increases the therapeutic activity of the composition. In addition, the dehydrogenation of the hydrophilic base of cells of gram-positive and gram-negative microorganisms reduces their resistance to the destructive effect of the antibacterial substances that make up the proposed pharmaceutical composition. It also enhances its therapeutic activity.

The use of a hyperosmolar base additionally improves microcirculation in wound tissues due to its dehydrating effect, and also has an additional anti-inflammatory effect due to the absorption of fluid and reduction of edema of wound tissues. The hypreosmolar base provides an outflow of purulent exudate from the wound and protects the tissue from overhydration. It is easy to apply to the wound surface, it is well kept on it, evenly distributed on it, improving the contact of the ointment with tissues and wound contents, penetrates well under the scab, mixes well with wound exudate, while maintaining its uniformity, low toxicity and does not irritate tissue does not violate their physiological functions. The dissolution of the active substances in a polyethylene oxide base increases their dispersion and the ability to more quickly release from the base, which also increases the therapeutic activity of the proposed pharmaceutical combination composition.

This base is a conductor of active substances through the skin barrier, while such a penetrating without damage to cells is enhanced in conditions of inflammation. The hydrophilic base on polyethylene oxides is able to dissolve in the secrets of the mucous membranes, completely releasing medicinal substances without irritating the mucous membrane, has a long shelf life and high physiological indifference.

Preservatives, stabilizers provide long-term storage of the pharmaceutical composition with preservation of its activity in case the active substances of the composition and its target additives, including the base, can be subject to degradation or the action of microorganisms.

Nonionic detergents and solubilizers provide the dissolution of poorly soluble substances in the base.

The proposed pharmaceutical composition employs substances approved for the manufacture of medicines.

The proposed pharmaceutical composition is obtained by mixing the components by known methods.

The possibility of implementing the invention is illustrated by the following examples, but is not limited to.

Examples of compositions for the first phase of the wound healing process.

Liquid dosage forms for external and local use

Example 1

Solution for external and local application No. 1

Example 2

Solution for external and local application No. 2

Example 3

Solution for external and local application No. 3

Example 4

Liniment for external and local use No. 1

Example 5

Liniment for external and local use No. 2

Example 6

Liniment for external and local use No. 3

Example 7

Suspension for external and local use No. 1

Example 8

Suspension for external and local use No. 2

Soft dosage forms for external and local use

Example 9

Ointment for external and local application No. 1

Example 10

Ointment for external and local application No. 2

Example 11

Ointment for external and local application No. 3

Example 12

Ointment for external and local application No. 4

Example 13

Ointment for external and local application No. 5

Example 14

Ointment for external and local application No. 6

Example 15

Ointment for external and local application No. 7

Example 16

Ointment for external and local application No. 8

Example 17

Ointment for external and local application No. 9

Example 18

Ointment for external and local application No. 10

Example 19

Ointment for external and local application No. 11

Example 20

Ointment for external and local application No. 12

Example 21

Ointment for external and local application No. 13

Example 22

Ointment for external and local application No. 14

Example 23

Ointment for external and local application No. 15

Example 24

Ointment for external and local application No. 16

Example 25

Ointment for external and local application No. 17

Examples for phase II wound healing

Example 26

Ointment for external and local application No. 18

Example 27

Gel for external and local application No. 19

Example 28

Gel for external and local application No. 20

Example 29

Gel for external and local application No. 21

Example 30

Gel for external and local application No. 22

Example 31

Ointment for external and local application No. 23

Example 32

Gel for external and local application No. 24

Example 33

Gel for external and local application No. 25

Example 34

Gel for external and local application No. 26

Examples of pharmaceutical combination compositions for soft formable forms (suppositories, capsules)

Example 35

Composition for the preparation of suppositories No. 1

100 pieces of rectal suppositories in the form of hydrophilic suppositories in the form of suppositories are made up of no more than 1 hour at a temperature of (37 ± 1) ° С, which meets the requirements of the Global Fund XI (Art. Suppositories, p. 151-153).

Example 36

Composition for the preparation of suppositories No. 2

100 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm, 32 mm long, and a weight of 2.9 g were made from this mixture. The solubility of the suppositories on a hydrophilic basis is no more than 1 hour at a temperature of (37 ± 1) ° С, which meets the requirements GF XI (Art. Suppositories, p. 151-153).

Example 37

Composition for the preparation of suppositories No. 3

100 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm, 32 mm long, and a weight of 3.1 g were made from this mixture. The solubility of the hydrophilic suppositories is no more than 1 hour at a temperature of (37 ± 1) ° С, which meets the requirements GF XI (Art. Suppositories, p. 151-153).

Example 38

Ointment from example No. 10 (ointment for external and local use No. 2) was filled with 100 pieces of gelatin capsules No. 00, a volume of 0.95 ml. The disintegration of the obtained capsules is less than 20 min, which meets the requirements of the Global Fund XI (St. Capsules, p. 143).

Examples of pharmaceutical combination composition for filling aerosol cans

Example 39

Aerosol composition No. 1

Example 40

Aerosol composition No. 2

Examples of pharmaceutical combination compositions used in the form of a spray

Example 41

Composition for spray No. 1

Example 42

Composition for spray No. 2

Example 43

Composition for spray No. 3

Testing the activity of pharmaceutical compositions with proteolytic enzymes is carried out as follows (for example, lysoamidase).

All solutions for determining the proteolytic activity of lysoamidase, except for solutions of the studied compositions, are prepared in accordance with the requirements of FS 42-3330-96 and FS 42-3329-96.

Solutions of the studied lysoamidase compositions are prepared in graduated plastic tubes with a capacity of 1.5 ml, 300 mg of ointment compositions of lysoamidase and 700 mg of phosphate buffer (30% solution, w / w) are added. After thoroughly mixing and shaking for 2 minutes on a Vortex, the tubes are centrifuged for 5 minutes at 5000 rpm to precipitate insoluble components.

To determine the proteolytic activity, the initial solution is diluted 15 times (to obtain a 2% solution of the lysoamidase composition, 0.024% of the active substance).

In microcentrifuge tubes with a capacity of 1.5 ml add 250 μl of 1% casein solution (3 experimental and 3 control tubes for each test composition). Then they are heated in a solid-state thermostat at 37 ° C for 10 minutes. 250 μl of a 2% solution of the lysoamidase composition are added to each of the three test tubes and the tubes are heated at 37 ° C for 10 minutes. In all tubes, 1 ml of a 5% solution of TCA is added, and in the control, an additional 250 μl of a 2% solution of the lysoamidase composition. Heated at 37 ° C for 10 min, then centrifuged for 5 min at 15000 rpm to precipitate denatured protein under the influence of TCA.

The optical density of the obtained supernatants was measured at 260 nm on a Beckman Coulter DU800 spectrophotometer.

The calculation of proteolytic activity is carried out according to the formula from FS 42-3330-96, taking into account the features of the experiment

PA = (D ₀ -D _k) / 20

where D ₀ and D _K are the optical densities of the supernatants in the experimental and control tubes, respectively; 20 is the amount of the lysoamidase composition in mg taken for analysis per 1 ml of casein solution).

Testing the activity of pharmaceutical compositions with bacteriolytic enzymes is carried out as follows (for example, lysoamidase).

A suspension of bacterial cells of Micrococcus luteus and all solutions, except for solutions of the studied compositions, are prepared in accordance with the requirements of FS 42-3330-96 and FS 42-3329-96.

To determine the bacteriolytic activity, a suspension of bacterial cells of Micrococcus luteus is added 1 ml in microcentrifuge tubes with a capacity of 1.5 ml (3 tubes for each test sample and 3 tubes - control). After heating in a solid-state thermostat at 37 ° С for 5 min, 25 μl of phosphate buffer are added to control tubes, and 25 μl of the initial (30%) solution of lysoamidase compositions are added to experimental tubes. After heating at 37 ° C for 5 min, 50 μl of 4 M NaCl are added to all tubes. Measurement of optical density is carried out at 540 nm on a Beckman Coulter DU800 spectrophotometer, the tubes are thoroughly shaken immediately before the measurement sample is introduced into the cuvette.

The calculation of bacteriolytic activity is carried out according to the formula from FS 42-3330-96, taking into account the features of the experiment:

LA, units / mg = (D _k -D ₀ ) × 0.44,

where D _k and D ₀ - optical density values into control and test tube, respectively; 0.44 is a coefficient taking into account the amount of the added composition, reaction time and conversion factor, taking into account the reaction conditions.

The measurement of protein is carried out according to the method of Bradford. To 2 ml of Bradford reagent, 40 μl of undiluted supernatant was added. The measurement of optical density is carried out at 595 nm on a Beckman Coulter DU800 spectrophotometer. The calibration curve is built according to data obtained for bovine serum albumin (10-100 μg of protein per 100 μl of solution).

The preparation of the Ultralizin enzyme complex and the determination of its proteolytic and collagenolytic activity are described in patent RU 2340371, А61Р 17/00, 2340371.

Obtaining the enzyme complex "Imozimaza" is given in patent RU 2137835, C12N 11/00, 09/20/1999. The proteolytic activity of the enzyme preparation Protosubtilin, which is part of the Imozimaz complex, is determined in accordance with GOST 20264.2-88 “Enzyme preparations. Methods for determining proteolytic activity. "

The antimicrobial activity of ointments based on some of the proposed pharmaceutical combined compositions was studied according to the "Methodological recommendations for the experimental study of drugs for the treatment of purulent wounds", M, 1989.

Hospital strains of gram-positive and gram-negative microorganisms isolated from patients who were treated were used as test cultures. Microbial suspension was prepared in concentrations of 10 ⁵ -10 ⁶ CFU in 1 ml and introduced into a Petri dish with agar. Following the instructions, when determining the activity of antibacterial agents by agar diffusion method (well method), the following criteria were used to assess the sensitivity of microorganisms to the studied drugs:

- the absence of growth retardation zones around the well, as well as the growth retardation zone of up to 10 mm were considered as a lack of sensitivity to the drug;

- growth inhibition zones with a diameter of 11-15 mm were considered as low sensitivity;

- growth retardation zones with a diameter of 15-20 mm were considered as an indicator of good sensitivity;

- growth inhibition zones with a diameter of more than 25 mm were considered as an indicator of high sensitivity.

The attached to the description of table 1 shows the results of experimental verification of antimicrobial activity against hospital strains of known ointments in comparison with some combined ointment compositions on a hydrophilic basis according to the invention. From this table it is seen that the antimicrobial activity of some of the proposed combined ointment compositions in relation to hospital strains has a high sensitivity, and in some cases is higher than that of known ointments.

Clinical testing of an ointment sample for external and local application No. 1 (example 9 in the application description) was carried out in animals with severe resistant purulent-necrotic lesions. The ointment was used for purulent-necrotic processes localized in the epidermal tissues, phlegmonous lesions of the subcutaneous fat and deep layers of muscle tissue caused by trophic disorders, traumatic injuries with contamination by microorganisms, including an isolated culture of Pseudomonas aeruginosa, contaminated lesions of unknown etiology.

The clinical effect of the use of ointment with dioxidine and lysoamidase was significantly higher than that of Suralan preparations (in the composition per 1 g: miconazole nitrate - 23 mg, polymyxin B sulfate - 0.696 mg, prednisolone acetate 0.5 mg, auxiliary ingredients), "Panologist" (in the composition per 1 g: triamycinolone acetonide - 1 mg; neomycin sulfate - 2.5 mg, thiostrepton - 2500 ME, nystatin - 100000 ME, auxiliary ingredients); "Levomekol" (in the composition per 1 g: chloramphenicol - 7.5 mg; methyluracil - 40 mg, auxiliary ingredients).

The use of ointments with dioxidine and lysoamidase gave a positive effect. The introduction of this ointment into the treatment regimen improved the course of the wound process, led to a quick cleansing of the wound, a decrease in purulent discharge and signs of local inflammatory reactions, and reduced the time of convalescence.

Based on the proposed solution, a number of new drugs can be created in the form of liquid dosage forms, soft dosage forms, including those being formed, as well as aerosols and sprays containing dioxidine and targeted additives.

The proposed pharmaceutical combination composition based on dioxidine with the above target additives destroys both gram-positive and gram-negative microorganisms, including those resistant to antibiotics; has a high therapeutic activity; improves usability; reduces the consumption of the active substance; helps to cleanse wounds from purulent-necrotic masses, gives an anesthetic effect; additionally stimulates reparative processes in the wound; improves microcirculation; reduces secondary tissue necrosis around the wound associated with excessive free radical oxidation, reduces the likelihood of resistant strains to the antimicrobial complex of the composition, has a local immunomodulating effect.

The search for information did not reveal identical and similar technical solutions.

The above set of features of the proposed pharmaceutical composition (composition, quantitative ratio of the components in it and its dosage form) was not previously known, which indicates the novelty of the proposed solution.

This set of essential features of the claimed composition for external use on the basis of dioxidine and the above target additives does not follow explicitly from the studied prior art, has significant differences from the considered analogues.

Moreover, the set of distinctive essential features of the proposed pharmaceutical combination composition does not follow obviously from the current level of technology, since it was not previously known that some active target additives indicated in the considered technical solution retain their activity when combined with dioxidine in one composition on hydrophilic basis.

Thus, the proposed composition meets the criterion of "inventive step", as it was unexpectedly shown that its antibacterial activity is not less, and in some cases higher than that of existing analogues.

The proposed pharmaceutical combination composition for local and external use based on dioxidine and target additives can be used for industrial serial production of liquid dosage forms, for example, such as solutions, liniments, suspensions; soft ointment forms, for example, such as ointments, gels; as well as for the industrial production of formed soft dosage forms (suppositories and gelatin capsules for rectal administration) and gaseous dosage forms (aerosols, sprays).

The inventive pharmaceutical combination composition can be recommended in the treatment of extensive purulent-necrotic post-traumatic, postoperative wounds, burns, and also wounds after surgical treatment of acute purulent diseases of the skin and soft tissues (abscessed boils, carbuncles, mastitis, hydradenitis, erysipelas, etc.), with treatment of patients with extensive atherosclerotic and venous trophic ulcers, with diabetic foot syndrome complicated by an infectious process caused by highly resistant gram-positive Gram-negative and aerobic and anaerobic microorganisms, fungi resistant to the vast majority of systemic antimicrobial and antifungal drugs.

The proposed compositions can be used in surgical, traumatological, obstetric, gynecological, proctological hospitals, as well as to assist victims of industrial and natural disasters, in the treatment of patients at the outpatient stage.

Thus, it is shown that when using the present invention, the following technical results can be obtained: an increase in therapeutic activity in comparison with known preparations, including strains of microorganisms resistant to individual components of the composition, improvement of the course of the wound process, quick wound cleansing, and reduction of time convalescence, i.e. optimal conditions are created for reducing the time for systemic antimicrobial and antifungal therapy, accelerating the healing process, and improving the conditions for wound healing.

Claims (23)

1. A pharmaceutical combination composition for external and local use, comprising dioxidine, hydrophilic base, lidocaine or trimecaine as an anesthetic, characterized in that it additionally contains lysoamidase, or imosimase, or ultralizine as a complex of proteolytic enzymes, in the following ratio of components, wt .%: dioxidine 0.1-5.0 anesthetic 0.5-6.5 complex of proteolytic enzymes 0.05-16.00 hydrophilic base rest 2. The pharmaceutical composition according to claim 1, characterized in that it further comprises dimexide in an amount of from 0.5 to 5.0 wt.%. 3. The pharmaceutical composition according to claim 1, characterized in that it further includes a stimulant of the reparative process, limited to a substance selected from the range: xymedon, methyluracil, calcium pantothenate, solcoseryl, etaden, in an amount of from 0.5 to 10.5 wt. % 4. A pharmaceutical combination composition for external and local use, including dioxidine, hydrophilic base, lidocaine or trimecaine as an anesthetic, characterized in that it additionally contains a substance selected from the series: ethylenediaminetetraacetic acid, trilon B, trimethoprim, sodium lauryl sulfate, catapol, decamethoxin, polyhexanide or a mixture thereof, as a synthetic antibacterial agent that reduces the resistance of microorganisms, in the following ratio of components, wt.%: dioxidine 0.1-5.0 anesthetic 0.5-6.5 synthetic antibacterial agent microbial resistance 0.001-5.00 hydrophilic base rest 5. The pharmaceutical composition according to claim 4, characterized in that it further comprises dimexide in an amount of from 0.5 to 5.0 wt.%. 6. The pharmaceutical composition according to claim 4 or 5, characterized in that it further includes a stimulant of the reparative process, limited to a substance selected from the range: xymedon, methyluracil, calcium pantothenate, solcoseryl, etaden, in an amount of from 0.5 to 10.5 wt.%. 7. The pharmaceutical composition according to claim 4, 5, or 6, characterized in that it further comprises a complex of proteolytic enzymes, which includes at least one substance from the series: lysoamidase, imosimase, ultralysin, in an amount of from 0.05 to 16 , 00 wt.%. 8. A pharmaceutical combination composition for external and local use, comprising dioxidine, hydrophilic base, lidocaine or trimecaine as an anesthetic, characterized in that it additionally contains a substance selected from the series: ofloxacin, ciprofloxacin, netilmicin, amikacin, chloramphenicol, as an antibiotic as well as a substance selected from the series: ethylenediaminetetraacetic acid, Trilon B, trimethoprim, sodium lauryl sulfate, catapol, miramistin, decamethoxin, chlorhexidine, polyhexanide, as a synthetic of the antibacterial agent which reduces the resistance of microorganisms, with the following component ratio, wt.%: dioxidine 0.1-5.0 anesthetic 0.5-6.5 antibiotic 0.05-5.00 synthetic antibacterial agent microbial resistance 0.001-5.00 hydrophilic base rest 9. The pharmaceutical composition of claim 8, characterized in that it further comprises dimexide in an amount of from 0.5 to 5.0 wt.%. 10. The pharmaceutical composition according to claim 8 or 9, characterized in that it further includes a stimulant of reparative processes, limited to a substance selected from the range: xymedon, methyluracil, calcium pantothenate, solcoseryl, etaden, in an amount of from 0.5 to 10.5 wt.%. 11. The pharmaceutical composition according to claim 8, 9, or 10, characterized in that it further comprises a complex of proteolytic enzymes, limited to a substance selected from the range: lysoamidase, imosimase, ultralizine, in an amount of from 0.05 to 16.00 wt. .%. 12. A pharmaceutical combination composition for external and local use, comprising dioxidine, hydrophilic base, lidocaine or trimecaine as an anesthetic, characterized in that it additionally contains a substance selected from the series: polyoxidonium, cycloferon, tilorone or a mixture thereof, as a synthetic immunomodulator , in the following ratio of components, wt.%: dioxidine 0.1-5.0 anesthetic 0.5-6.5 synthetic immunomodulator 0.05-12.50 hydrophilic base rest 13. The pharmaceutical composition according to p. 12, characterized in that it further includes a synthetic antibacterial agent that reduces the resistance of microorganisms, an antibiotic or a mixture thereof, in an amount of from 0.001 to 10,000, wt.%. 14. The pharmaceutical composition according to p. 13, characterized in that as a synthetic antibacterial agent that reduces the resistance of microorganisms, it includes at least one substance selected from the series: ethylenediaminetetraacetic acid, trilon B, trimethoprim, sodium lauryl sulfate, cationic surfactant a substance, dimexide or a mixture thereof, in an amount of from 0.001 to 5.00 wt.%. 15. The pharmaceutical composition according to p. 13, characterized in that the antibiotic includes at least one substance from the series: ofloxacin, ciprofloxacin, netilmicin, amikacin, chloramphenicol, in an amount of from 0.05 to 5.0 wt.%. 16. The pharmaceutical composition according to 14, characterized in that the cationic surfactant includes at least one substance from the series: catapol, miramistin, decamethoxin, chlorhexidine or polyhexanide, in an amount of from 0.01 to 2.0 wt.% . 17. The pharmaceutical composition according to p. 12 or 13, characterized in that it further includes a stimulant of reparative processes, limited to a substance selected from the range: xymedon, methyluracil, calcium pantothenate, solcoseryl, etaden, in an amount of from 0.5 to 10.5 wt.%. 18. The pharmaceutical composition according to p. 12, or 13, or 17, characterized in that it further comprises a complex of proteolytic enzymes, limited to a substance selected from the range: lysoamidase, imosimase, ultralizine, in an amount of from 0.05 to 16.00 wt. .%. 19. The pharmaceutical composition according to p. 12, or 13, or 17, or 18, characterized in that it further includes an antimycotic, in which it contains cyclopiroxolamine or clotrimazole, in an amount of from 0.5 to 3.0 wt.%.