RU2682171C2 - Pharmaceutical combined composition for the treatment of purulent wounds on the basis of fluoroquinolons (options) - Google Patents

Abstract

FIELD: medicine; veterinary.SUBSTANCE: invention relates to medicine and veterinary medicine, namely to pharmaceutical compositions used in the treatment of extensive purulent-necrotic post-traumatic, postoperative wounds, extensive burns, as well as wounds after the surgical treatment of acute purulent skin and soft tissue diseases (abscessed boils, carbuncles, mastitis, hydradenitis, erysipelas, etc.), in the 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 and gram-negative aerobic and anaerobic microorganisms, fungi resistant to the vast majority of antimicrobial and antifungal drugs. First option is a composition containing fluoroquinolones, more active than ofloxazole, in combination with appropriate target supplements that extend its spectrum of action. Second option is the composition of ofloxacin in combination with the corresponding target additives, expanding the range of its action. Third option is the composition of ofloxacin with a stimulator of the reparative process and an anesthetic in combination with appropriate target additives. Proposed compositions based on fluoroquinolones with the above target additives destroy both gram-positive and gram-negative microorganisms, including resistant to antibiotics, as well as fungi and protozoa.EFFECT: proposed fluoroquinolone-based compositions with the above targeted additives have a high therapeutic activity, improve usability, reduce the consumption of the active substance, help clean wounds from purulent-necrotic masses, give an anesthetic effect, further stimulate reparative processes in the wound, improve microcirculation, reduce secondary necrosis of tissues around the wound, reduce the likelihood of occurrence of strains resistant to the antimicrobial complex of the composition, have a local immunomodulatory effect.30 cl, 61 ex, 2 tbl

Description

The invention relates to medicine and veterinary medicine, namely to pharmaceutical compositions 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 (abscessed boils, carbuncles, mastitis, hydradenitis , erysipelas, etc.), in the treatment of patients with extensive atherosclerotic and venous trophic ulcers, with diabetic foot syndrome, complicated by an infectious process caused by high zistentnymi Gram positive and Gram negative aerobic and anaerobic bacteria, fungi, resistant to the vast majority of antimicrobial and antifungal agents.

The developed combined composition for local and external use on the basis of antibiotics of fluoroquinolones creates optimal conditions for reducing the time for systemic antimicrobial and antifungal therapy, can speed up the healing process, 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. 7, 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 phase of the inflammation phase, the vessels in the tissues adjacent to the walls and the bottom of the wound expand, the exudation of plasma begins and gradually increases, and the release of leukocytes from the blood vessels. 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 Tilenglycol base in the treatment of purulent wounds ”, Antibiotics and chemotherapy, 1999, N7, 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. Slow inflammatory process, 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, delimited 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 do not have a suction capacity.

In this regard, 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 evacuation wound contents, drug penetration into the damage zone to create therapeutic efficacy, while absorption into the blood should be minimal to reduce the total current ble effects, and provide anti-inflammatory and analgesic effects ( "Farmakokorrektcija wound process». http.//www.provisor.com.ua/archive/2007/N15/process.php).

In the second phase of the wound 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. There are frequent cases when surgical closure of the wound is impossible without the stage of drug treatment of the wound, taking into account the phase of the wound process.

The drugs used for local treatment of wounds must comply with 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 in the ratio of hospitalized bacterial strains multiresistant to antibiotics and antiseptics.

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

Many modern drugs for local and external 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. The association of aerobes and anaerobes in purulent post-traumatic wounds, bedsores, in patients with a diabetic foot reaches 98.8%. Moreover, from 80 to 100% of the isolated strains are insensitive to penicillin, cephalotin, cefazolin, tetracycline, kanamycin, gentamicin and several other antibiotics ("Biopharmaceutical aspects of the creation of ointments", 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. This resistance is due to plasmids. Staphylococcus plasmids are known that carry genes of resistance to penicillin, gentamicin, tetracycline, methicillin, lincomycin, sulfanilamides, as well as new generation antibiotics: fluoroquinolones, cephalosporins II and III generations, glycopeptides, etc. (Modern approaches to the treatment of infectious diseases, infections) 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 cobalt biocomplex with furazolidone.” Medicine, health, http: // uchi- referat.ru/medicina-zdorove/2921-razrabotka-sostava-i-tehnologii-polucheniya-mazi-soderzhashhev-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 to a chronic form as a result of superinfection, reinfection and secondary infection, as a result of the introduction of microorganisms from the environment, from other areas of the patient’s body, or as a result of activation of local autoflora;

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

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 the Absil drug", abstract of the dissertation for 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. The initial contamination of the wound consists of saprophytes, numbering more than 200 species. Within 24 hours, hay bacilli and soil bacteria disappear from the contaminated wound and usually staphylococci remain, as the prevailing 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.

Previously, there were so-called “reserve antibiotics” for combating staphylococcus, such as, for example, vancomycin, fusidic acid, rifampicin, and fluoroquinolones. However, strains resistant to these antibiotics are currently emerging.

Resistance to fluoroquinolones (ciprofloxacin and ofloxacin) is a real problem in the treatment of nosocomial infections. Resistance is most likely to form in P. aeruginosa strains. (Resistance. Quinolones / Fluoroquinolones. Http://www.antibiotic.ru/ab/001-07.shtml).

Known pharmaceutical combination compositions in the form of ointments for the treatment of purulent wounds in the first phase of the wound healing process based on fluoroquinolone of the second generation - ofloxacin.

These ointments include Oflokain-Darnitsa ointment, ofloxacin ointment according to patent RU 2145497, A61K 9/06, 02/20/2000, Oflomelid ointment according to patent RU 2349302, A61K 9/06, 03/20/2009.

The composition of the above ointments is as follows.

Ointment “Oflokain - Darnitsa”: ofloxacin - 0.1%, lidocaine - 3%, hydrophilic base - up to 100% (http://compendium.com.ua/info/28698).

Ointment with ofloxacin: ofloxacin - 0.05-0.5%, trimecaine or lidocaine - 1.00-6.00%, protease C enzyme - 0.5-3.0%, proxanol-268 - 15-25%, propylene glycol - 25.0-78.4%, PEO-400 - 5-20%, the rest is purified water to 100% (patent RU 214549, A61K 9/06, 20.02.2000).

Oflomelide ointment: ofloxacin - 0.1-5.0%, methyluracil - 0.5-7.0%, lidocaine hydrochloride - 0.5-6.0%, PEO-1500 - 1-40%, PEO- 400 - 10-95%, nipagin - 0.01-1.0%, nipazole - 0.005-1.0%, propylene glycol (plasticizer) - 1.0-20.0%, while the preservatives nipagin and nipazole are used in the ratio 4: 1 (patent RU 2349302).

On the basis of the materials of this patent, Oflomelide ointment is industrially produced, containing in its composition: ofloxacin - 1%, methyluracil - 4%, lidocaine hydrochloride monohydrate - 3% (in terms of lidocaine hydrochloride), excipients: nipagin, nipazole, propylene glycol, PEO-1500, PEO-400 (http://www.kurgansintez.ru/catalog/medicine/oflomelid_ofloksatsin_1_metiluratsil_4_lidokain_3_/).

Known pharmaceutical combination compositions with ofloxacin have the following disadvantages.

Ofloxacin is less active against strains of bacteria P. aeruginosa and Acinetobacter spp than ciprofloxacin (NN Kozachok et al. “Fluoroquinolones - a look into the future”, table 3, www.mit-ua.com/arhive/article/3015).

The increase in the activity of fluoroquinolone used in ointment compositions for the treatment of chronic purulent wounds in relation to P. Aeruginosa strains is relevant, since up to 68.8% of the strains of these bacteria are determined in the composition of wound microflora in these diseases. (“Wounds and wound infection”, M. I. Kuzin, B. M. Kostyuchenko, Moscow, “Medicine” publishing house, 1981, chapter 5, pages 149-156).

As noted above, resistance to fluoroquinolones (ciprofloxacin and ofloxacin) is a problem in the treatment of nosocomial infections. Resistance is most likely to form in P. aeruginosa strains. 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, as well as fungi and protozoa, which are mostly moderately sensitive or not sensitive to the action of fluoroquinolones.

The activity of fluoroquinolones in relation to gram-positive microorganisms is less pronounced than in relation to gram-negative (NN Kozachok et al. “Fluoroquinolones - a look into the future”, table 3, www.mit-ua.com/arhive/article/3015; http: / /www.medi.ru/doc/2602402a.htm).

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.

As a comparison composition, we selected a pharmaceutical composition in the form of a mild form of Oflomelide (patent RU 2349302, A61K 9/06, 03/20/2009), for the treatment of purulent wounds, having the above disadvantages. The composition of this pharmaceutical composition includes fluoroquinolone - ofloxacin, a hydrophilic base and excipients in the form of methyluracil, lidocaine and preservatives in a certain weight ratio.

To eliminate the above disadvantages of the known pharmaceutical composition selected as a prototype, three options are possible.

The first option is the use in the proposed pharmaceutical combination composition instead of ofloxacin of more active fluoroquinolones in combination with appropriate target additives, expanding its spectrum of action in comparison with analogues and prototype.

The second option is the use of ofloxacin in the proposed pharmaceutical composition in combination with the corresponding target additives, which are absent in the analogues and prototype, expanding the spectrum of its action in comparison with analogues and prototype.

The third option is the use of ofloxacin in the proposed pharmaceutical combination composition together with a reparative process stimulant and anesthetic in accordance with the prototype of patent RU No. 2349302 in combination with the corresponding target additives that are absent in the prototype, compensating for the disadvantages of the prototype.

These options are considered by us in the proposed application for the invention.

The objective of the invention is the creation of pharmaceutical combined compositions (options) in the form of liquid, soft, solid and gaseous dosage forms based on antibiotics of fluoroquinolones, the basis and targeted additives that provide treatment for purulent wounds and burns, purulent-inflammatory skin diseases, etc., reducing the time period of acute purulent process, improving the conditions for cleansing wounds from purulent-necrotic tissues, inhibiting the growth of microflora, resistant to the vast majority of antibacterial drugs .

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 an anesthetic effect, reducing convalescence time.

To solve this problem, the present invention provides a pharmaceutical combination composition for external and local use, containing an antibiotic from the class of fluoroquinolones, in addition to ofloxacin, a base, and at least one substance in the form of a target additive selected from the series: an additional antibiotic from the class of fluoroquinolones , an antibiotic that does not belong to the class of fluoroquinolones, a synthetic antibacterial agent, including a substance that reduces the resistance of microorganisms, an antimycotic, an enzyme or comp enzyme Lex, immunomodulator, excipient, or their physiologically acceptable combination, in the following ratio of components (wt.%):

fluoroquinolone class antibiotic - 0.05-5.00; non-fluoroquinolone antibiotic - 0.5-5.5 synthetic antibacterial - 0.01-5.50; antimycotic - 0.2-3.5; enzyme or enzyme complex - 0.05-16.00; immunomodulator - 0.05-12.50; excipient - 0.005-20,000 the basis - the rest.

The proposed composition as an antibiotic from the fluoroquinolone class contains at least one substance selected from the series: ciprofloxacin, levofloxacin, sparfloxacin, moxifloxacin or their physiologically acceptable compounds (e.g. salts), or a combination of these two substances, but not limited to, and as an antibiotic not belonging to the class of fluoroquinolones, it contains netilmicin, or amikacin, or sisomycin, but not limited to.

The proposed composition as a synthetic antibacterial agent contains a substance dioxidine, or nitazole, or metronidazole, but not limited to, and as a synthetic antibacterial agent that reduces the resistance of microorganisms, it contains at least one substance selected from the series: Trilon B, a derivative diaminopyrimidine trimethoprim, dimexide, surface-active antiseptic, or a physiologically acceptable mixture thereof, but not limited to.

The proposed composition as a synthetic antibacterial agent in the form of a surface-active antiseptic that reduces the resistance of microorganisms, contains at least one substance selected from the series: miramistin, decamethoxin, sodium lauryl sulfate, but is not limited to, and contains clotrimozole or cyclopiroxolamine as an antimycotic , not limited to them.

The proposed composition as an enzyme or complex of enzymes contains at least one substance selected from the series; lidase, asperase, protease, collagenase, lysoamidase, imosimase, ultralysin, but not limited to.

The proposed composition as an immunomodulator contains at least one substance selected from the series: tilorone, cycloferon, polyoxidonium, but not limited to.

The proposed composition, if necessary, contains at least one excipient selected from the series: anesthetic, stimulant of reparative processes, preservative, stabilizer, detergent, solubilizer, or a mixture thereof in various physiologically acceptable combinations.

As a basis, the proposed pharmaceutical combination composition contains at least one hydrophilic substance selected from the series: proxanol (emuxol), polyethylene oxide, propylene glycol, polyvinyl pyrrolidone, polyethylene oxide 1500 gel, glycerohydrogel based on silicon glycerates, calcium or magnesium alginate, acrylic acid copolymer , sodium carboxymethyl cellulose, oxidized cellulose, methyl cellulose, glycerin, or a physiologically acceptable mixture thereof in various combinations providing rheological requirements depending on the dosage form of the pharmaceutical combination composition and, if necessary, in a mixture with at least one substance from the series: phosphate buffer solution, purified water, liquid paraffin, emulsifier, higher fatty synthetic alcohols, cetyl alcohol, stearic 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.

A variant of the pharmaceutical combination composition containing the antibiotic ofloxacin, a base, and at least one substance selected from the series is also proposed: an additional antibiotic from the class of fluoroquinolones, a non-fluoroquinolone antibiotic, a synthetic antibacterial agent, including reducing the resistance of microorganisms, antimycotics, an enzyme or complex of enzymes, an immunomodulator, excipient, or a physiologically acceptable combination thereof in the following ratio (wt.%):

ofloxacin - 0.05-5.00; fluoroquinolone class additional antibiotic - 0.05-5.00; non-fluoroquinolone antibiotic - 0.5-5.5; synthetic antibacterial - 0.01-5.50; antimycotic - 0.2-3.5; enzyme or enzyme complex - 0.05-16.0; immunomodulator - 0.05-12.5; excipient - 0.005-10.00 the basis - the rest.

The proposed composition as an additional antibiotic from the class of fluoroquinolones contains at least one substance selected from the series: ciprofloxacin, levofloxacin, sparfloxacin, moxifloxacin or their physiologically acceptable compounds (e.g. salts), but not limited to, but as an antibiotic, not belonging to the class of fluoroquinolones, contains netilmicin, or amikacin, or sisomycin, but not limited to.

The proposed composition as a synthetic antibacterial agent contains a substance dioxidine, or nitazole, or metronidazole, but not limited to, and as a synthetic antibacterial agent that reduces the resistance of microorganisms, it contains at least one substance selected from the series: Trilon B, a derivative diaminopyrimidine trimethoprim, dimexide, surface-active antiseptic, or a physiologically acceptable mixture thereof, but not limited to.

The proposed composition as a synthetic antibacterial agent in the form of a surface-active antiseptic that reduces the resistance of microorganisms, contains at least one substance selected from the series: miramistin, decamethoxin, sodium lauryl sulfate, but is not limited to, and contains clotrimozole or cyclopiroxolamine as an antimycotic , not limited to them.

The proposed composition as an enzyme or complex of enzymes contains at least one substance selected from the series; asperase, collagenase, lysoamidase, imosimase, ultralizine, not limited to.

The proposed composition as an immunomodulator contains at least one substance selected from the series: tilorone, cycloferon, polyoxidonium, but not limited to.

The proposed composition, if necessary, contains at least one excipient selected from the series: preservative, stabilizer, detergent, solubilizer, or a mixture thereof in various physiologically acceptable combinations.

As a basis, the proposed pharmaceutical combination composition contains at least one hydrophilic substance selected from the series: proxanol (emuxol), polyethylene oxide, propylene glycol, polyvinyl pyrrolidone, polyethylene oxide 1500 gel, glycerohydrogel based on silicon glycerates, calcium or magnesium alginate, acrylic acid copolymer , sodium carboxymethyl cellulose, oxidized cellulose, methyl cellulose, glycerin, or a physiologically acceptable mixture thereof in various combinations providing rheological requirements depending on the dosage form of the pharmaceutical combination composition and, if necessary, in a mixture with at least one substance from the series: phosphate buffer solution, purified water, liquid paraffin, emulsifier, higher fatty synthetic alcohols, cetyl alcohol, stearic 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.

A variant of a pharmaceutical combined composition containing an antibiotic ofloxacin, a stimulant of reparative processes, an anesthetic, a base, and at least one substance selected from the series: an additional antibiotic from the class of fluoroquinolones, an antibiotic that is not fluoroquinolone, a synthetic antibacterial agent, including reducing the resistance of microorganisms, antimycotic, enzyme or complex of enzymes, immunomodulator, excipient, or their physiologically acceptable combination of following ratio (wt.%):

ofloxacin - 0.05-5.00; reparative stimulant - 0.5-10.0; anesthetic - 0.5-6.0; fluoroquinolone class additional antibiotic - 0.05-5.00; non-fluoroquinolone antibiotic - 0.5-5.5; synthetic antibacterial - 0.01-5.50; antimycotic - 0.2-3.5; enzyme or enzyme complex - 0.05-16.0; immunomodulator - 0.05-12.5; excipient - 0.005-10.00 the basis - the rest.

The proposed composition as an additional antibiotic from the class of fluoroquinolones contains at least one substance selected from the series: ciprofloxacin, levofloxacin, sparfloxacin, moxifloxacin or their physiologically acceptable compounds (e.g. salts), but not limited to, but as an antibiotic, not belonging to the class of fluoroquinolones, contains netilmicin, or amikacin, or sisomycin, but not limited to.

The proposed composition as a synthetic antibacterial agent contains a substance dioxidine or nitazole or metronidazole, but not limited to, and as a synthetic antibacterial agent that reduces the resistance of microorganisms, it contains at least one substance selected from the series: Trilon B, a derivative of diaminopyrimidine trimethoprim, dimexide, surface-active antiseptic, or a physiologically acceptable mixture thereof, but not limited to.

The proposed composition as a synthetic antibacterial agent in the form of a surface-active antiseptic that reduces the resistance of microorganisms, contains at least one substance selected from the series: miramistin, decamethoxin, sodium lauryl sulfate, but is not limited to, and contains clotrimozole or cyclopiroxolamine as an antimycotic , not limited to them.

The proposed composition as an enzyme or complex of enzymes contains at least one substance selected from the series; asperase, collagenase, lysoamidase, imosimase, ultralizine, not limited to.

The proposed composition as an immunomodulator contains at least one substance selected from the series: tilorone, cycloferon, polyoxidonium, but not limited to.

The proposed composition, if necessary, contains at least one excipient selected from the series: preservative, stabilizer, detergent, solubilizer, or a mixture thereof in various physiologically acceptable combinations.

As a basis, the proposed pharmaceutical combination composition contains at least one hydrophilic substance selected from the series: proxanol (emuxol), polyethylene oxide, propylene glycol, polyvinyl pyrrolidone, polyethylene oxide 1500 gel, glycerohydrogel based on silicon glycerates, calcium or magnesium alginate, acrylic acid copolymer , sodium carboxymethyl cellulose, oxidized cellulose, methyl cellulose, glycerin, or a physiologically acceptable mixture thereof in various combinations providing rheological requirements depending on the dosage form of the pharmaceutical combination composition and, if necessary, in a mixture with at least one substance from the series: phosphate buffer solution, purified water, liquid paraffin, emulsifier, higher fatty synthetic alcohols, cetyl alcohol, stearic 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.

For the effective treatment of purulent wounds, combined preparations are currently widely used, which are available in fixed dosage forms, including in the form of mild forms for external and local use. 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 with 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 the tolerability of drugs, 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”, E. Padeiskaya, breast cancer No. 21 dated November 4, 1997, p. 1-6).

As the main component of the proposed combined pharmaceutical composition, together with the target additives, one or more antibiotics from the class of fluoroquinolones are used in the form of a monocomponent or a mixture thereof. The use of one of them in the form of a monocomponent, namely, ofloxacin, is known in pharmaceutical compositions for external or local treatment of purulent wounds.

Over the years, the following fluoroquinolones have been registered in Russia (http://grls.rosminzdrav.ru/grls.aspx):

I generation of quinolones - no fluoroquinolones;

II generation of quinolones: ciprofloxacin, ofloxacin, pefloxacin, lomefloxacin, norfloxacin;

III generation of quinolones: levofloxacin, sparfloxacin;

IV generation of quinolones: moxifloxacin, hemifloxacin.

In the proposed composition, ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, moxifloxacin in the form of a monocomponent or a mixture of components are considered.

For 30 years of clinical use, fluoroquinolones have taken one of the leading places among antimicrobial agents. Moreover, they are considered as a serious alternative to highly active antibiotics with a wide bactericidal spectrum of action in the treatment of severe infections of various localization.

All fluoroquinolones selectively inhibit one of the key enzymes of the microbial cell, DNA gyrase, which is responsible for the normal biosynthesis and replication of bacterial DNA.

Fluoroquinolones - drugs with a wide bactericidal spectrum of action active against gram-positive and gram-negative, aerobic and anaerobic microorganisms, chlamydia, mycoplasmas, legionella, mycobacteria.

Despite the similarity of the antibacterial spectrum of fluoroquinolones, there are differences in the sensitivity of microorganisms to representatives of different generations of fluoroquinolones, as well as to certain drugs within the generation. The second generation of fluoroquinolones is active against a wide range of gram-negative aerobic microorganisms, including multiple-resistant, as well as Staphylococcus aureus. The disadvantage of the second generation of fluoroquinolones is their low activity against pneumococci, chlamydia, mycoplasmas and anaerobes.

Fluoroquinolones of the third and fourth generations with respect to gram-negative microorganisms are not inferior to the action of second-generation drugs (except for Pseudomonas aeruginosa). As for gram-positive flora, as well as chlamydia, mycoplasmas, mycobacteria, in this case they are superior to fluoroquinolones of the second generation. In addition, fluoroquinolones of the fourth generation are also effective against certain non-spore forming anaerobes, including strains resistant to the action of second generation drugs.

The activity of fluoroquinolones in relation to gram-positive microorganisms is less pronounced than in relation to gram-negative. On staphylococci, drugs have approximately the same effect. Streptococci are less sensitive to fluoroquinolones than staphylococci. Only ciprofloxacin and ofloxacin are active against most types of streptococci (MPC up to - 2 mg / l or less).

S. pneumoniae and beta-hemolytic streptococci are more sensitive to drugs than alpha-hemolytic and non-hemolytic streptococci and enterococci. In relation to gram-positive cocci, including pneumococci, sparfloxacin has the highest activity, which is 1-3 orders of magnitude superior to the activity of other mono-, di- and trifluoroquinolones.

The activity of levofloxacin and sparfloxacin exceeds the activity of ciprofloxacin and ofloxacin 2-4 times.

Ciprofloxacin has activity against various mycobacteria; other drugs affect only certain species.

Fluoroquinolones are active against atypical bacteria: chlamydia, mycoplasmas, legionella, against which sparfloxacin is the most active.

Most anaerobes, with the exception of B. urealyticus, are resistant or moderately sensitive to fluoroquinolones.

Fungi, viruses, treponema, most protozoa are resistant to the action of fluoroquinolones.

The activity of some fluoroquinolones is described in the works - “New fluoroquinolones: features of antimicrobial action and pharmacokinetics http://nature.web.ru/db/msg.html?mid=1176799&uri=index.html#h2Enr/Bf7Vy8kP/7w6T0bw, Bda ., Budanov SV. State Scientific Center for Antibiotics, State Institute of Preclinical and Clinical Expertise of Medicines of the Ministry of Health of the Russian Federation, Moscow; "Fluoroquinolones http://www.provisor.com.ua/archive/2002/N19/art_36.php"; http://www.medi.ru/doc/2602402a.htm "; N.N. Kozachok et al. “Fluoroquinolones - a look into the future”, table 3, www.mit-ua.com/arhive/article/3015).

Fluoroquinolones have a certain post-antibiotic effect, which is expressed in the manifestation of an antimicrobial effect after removal of the drug from the medium. The duration of the post-antibiotic effect depends on the type of microorganism and the magnitude of the previously acting concentration (http://www.medi.ru/doc/2602402a.htm).

Bacterial resistance to fluoroquinolones develops relatively slowly: single mutations, due to which bacteria become resistant to fluoroquinolones, occur infrequently (10 ^-9 -10 ^-11 ); in some strains, the mutation frequency is 10 ^-7 . In the absence of contact of the drug with the microbial cell, spontaneous mutants often again become sensitive.

The development of the resistance of microorganisms to fluoroquinolones (quinolones) is based on three main mechanisms: a change in the structure of target enzymes (DNA gyrase and topoisomerase IV), impaired penetration into the cell, and active excretion from the cell.

Changing the structure of target enzymes is the leading mechanism of resistance to fluoroquinolones (quinolones). In this case, two bacterial enzymes of DNA gyrase (topoisomerase II) and topoisomerase IV are modified, which mediate conformational changes in the bacterial DNA molecule necessary for its normal replication.

Considering that the genes of both enzymes are localized on the bacterial chromosome, resistance to fluoroquinolones is of a chromosomal nature, which is cross-sectional within the quinolone group. The emergence of resistance to non-fluorinated quinolones, which is especially important from a practical point of view, extends to fluoroquinolones. However, the level of resistance to fluoroquinolones is much lower, which determines the high clinical activity of fluoroquinolones in relation to most bacterial strains resistant to non-fluorinated quinolones.

The formation of resistance to fluoroquinolones occurs stepwise. Initially, mutations occur in the genes of one of the topoisomerases, which in this case is the primary target of the action of quinolones. This is accompanied by a 4–8-fold increase in the MPC (minimum inhibitory concentration) of the drug, while the antibacterial effect is retained due to the suppression of the activity of the second enzyme. With the further action of quinolones on the microorganism, mutations can occur in the genes encoding the second enzyme, which will cause an increase in BMD by another 4-8 times. At the same time, when using fluoroquinolones, which have a similar affinity for both enzymes, the selection of resistant strains is slower due to the lower likelihood of double mutations.

It is important to note that, with some exceptions, mutations in the topoisomerase genes lead to approximately the same decrease in enzyme affinity for all quinolones. However, this acquires clinical significance only if the BMD becomes higher than the pharmacodynamically substantiated sensitivity criterion. So, for example, with the initial MPC values of levofloxacin and moxifloxacin in relation to the pneumococcus strain of 1.0 and 0.12 mg / l, respectively, a 8-fold decrease in the affinity of quinolones for topoisomerase IV will increase the MPC to 8.0 and 1.0 mg / l According to pharmacodynamically justified criteria, the mutant strain will be resistant to levofloxacin, but will remain sensitive to moxifloxacin.

The second mechanism providing a decrease in the activity of quinolones is a decrease in the permeability of the outer membrane of bacteria due to damage to the permeability of porin channels or the lipopolysaccharide layer. In this case, the membrane permeability decreases not only for quinolones, but also for antibacterial drugs of other classes (aminoglycosides, beta-lactams).

In recent years, evidence has emerged of the spread of quinolone resistance due to the ejection phenomenon. The implementation of this mechanism, associated with the function of certain cellular enzymes, leads to a sharp decrease in the intracellular concentration of the drug. In some cases, this mechanism is combined with modification of targets.

In different types of bacteria, the formation of resistance to quinolones varies significantly. Resistance is most rapidly formed in P. aeruginosa, Staphylococcus aureus strains (the main hospital strains in the microflora of purulent wounds) and some others. (Resistance of bacteria to quinolones (fluoroquinolones). Http://www.mednovosti.by/journal.aspx?article=1611).

The combination of fluoroquinolones with other antibacterial drugs in most cases leads to an additive or indifferent effect, less often a synergistic, but not antagonistic effect. The antagonistic effect is noted with drugs that inhibit the synthesis of protein or RNA (tetracycline, chloramphenicol). In general, the combined use of fluoroquinolones with clindamycin, erythromycin, metronidazole, vancomycin, penicillins, cephalosporins or aminoglycosides is possible (http://www.medi.ru/doc/2602402a.htm).

Combined use of dioxidine with aminoglycosides, fluoroquinolones is possible (Manual “Rational Antimicrobial Pharmacotherapy” edited by Doctor of Medical Sciences V.P. Yakovleva and Doctor of Medical Sciences S.V. Yakovleva, pp. 750-752).

Fluoroquinolones exhibit antagonism with nitrofuran derivatives (e.g., quinifuril), so combinations of these drugs should be avoided.

The half-life of T _1/2 in various fluoroquinolones is as follows:

norfloxacin - 3-4 hours; ciprofloxacin - 4-6 hours; ofloxacin - 4.5-7 hours; levofloxacin - 6-8 hours; lomefloxacin - 7-8 hours; pefloxacin - 8-13 hours; moxifloxacin - 10.5 - 13.5 hours (average 12 hours);

(Group of quinolones / fluoroquinolones http://www.antibiotic.ru/ab/038-42.shtml)

sparfloxacin - 16-30 hours (http://www.rlsnet.ru/mnn_index_id_1876.htm).

By analogy with sulfanilamides, fluoroquinolones can be classified by the elimination sex period: short-acting at T _1/2 <8 hours; average duration of action T _1/2 - 8 ÷ 13 hours; long-acting T _1/2 - 13 ÷ 30 hours.

This classification of fluoroquinolones allows you to combine fluoroquinolones with different half-lives in one pharmaceutical combination composition, achieving a prolonged effect of the composition and expanding its antibacterial activity.

The known composition according to patent RU 2349302, A61K 9/06, 03/20/2009 with ofloxacin having a half-life of not more than 7 hours, is used in the treatment of wounds 1 time per day.

Ciprofloxacin from all fluoroquinolones used in the proposed pharmaceutical combination composition has significantly greater activity against bacterial strains of P. aeruginosa and Acinetobacter spp than moxifloxacin (NN Kozachok et al. “Fluoroquinolones - a look into the future”, table 3, www.mit-ua.com/arhive/article/3015), having a half-life of 4-6 hours. At the same time, moxifloxacin is more active against gram-positive microorganisms and anaerobes than ciprofloxacin, having an average half-life of about 12 hours.

The combined use of these fluoroquinolones in the proposed pharmaceutical combination composition increases its activity against strains of bacteria P. aeruginosa and Acinetobacter spp, gram-positive microorganisms and anaerobes in comparison with the action of each of the fluoroquinolones separately. In this case, the half-life of fluoroquinolones in this composition will be at least 12 hours, which allows the use of this composition in the treatment of wounds 1 time in 1.5-2 days. A similar composition is with ciprofloxacin and sparfloxacin, the average half-life of which is about 23 hours, which allows the use of this composition in the treatment of wounds once every 2-2.5 days.

The main pharmacokinetic properties of fluoroquinolones are their large distribution and their good penetration into various fluids and tissues, as well as into the cells of microorganisms (NN Kozachok et al. “Fluoroquinolones - a look into the future”, table 3, www.mit-ua. com / arhive / article / 3015). This provides a high concentration of fluoroquinolones in the wound content and tissues surrounding the wound during their external and local application.

Since the fluoroquinolones in the proposed composition exhibit a bactericidal effect depending on the concentration, higher maximum concentrations of fluoroquinolones in the wound lead to more rapid death of sensitive microorganisms and prevent the selection of resistant strains.

The bacterial strains Staphylococcus spp., Streptococcus spp., P. aeruginosa, Proteus spp., Including those included in the wound infection of purulent wounds in various groups of patients at different stages of treatment, are moderately sensitive microorganisms with respect to fluoroquinolones. The strains of Sacteroides spp., Clostridium spp., Mycobacterium belong to resistant microorganisms in relation to fluoroquinolones, (table 3. http://www.medi.ru/doc/2602402a.htm).

To increase the sensitivity of these microorganisms to the proposed pharmaceutical composition, in addition to fluoroquinolone, antibacterial components are included that have high bactericidal or bacteriostatic activity to them (microorganisms). So, for example, for Clostridium difficile, Clostridium spp - nitazole, metronidazole, etc .; for P. aeruginosa, Proteus spp. - dioxidine, amikacin, etc .; for Staphylococcus spp., Streptococcus spp. - a lidase enzyme or a complex of lysoamidase enzymes, or nitazole, or trimethoprim, or Trilon B, or surfactants.

Derivatives of diaminopyrimidine (pyrimethamine, trimethoprim, tetroxoprim, methioprim, brodimoprim, ormetoprim) potentiate the activity of fluoroquinolones ("Antimicrobial agents in the series of derivatives of sulfanilamide, diaminopyrimidine, 5-nitroimidazole, di-N-hydroxyquinoxamine N., N." November 4, 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.

Derivatives of diaminopyrimidines selectively inhibit the enzyme DFS in a microbial cell, followed by impaired synthesis of tetrahydrofolate. Diaminopyrimidines have a wide antimicrobial spectrum. For example, trimethoprim is active against gram-positive and gram-negative aerobic bacteria.

In Russia, pyrimethamine and trimethoprim are registered as a medicine (http://www.zdravosil.ru/lekarstvennye-sredstva-dlya-lecheniya-bakterialnyx/page/126/).

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

To enhance the activity of fluoroquinolones and other antibacterial components that make up the composition, the activity of which depends on the permeability of the outer membrane of bacteria, substances that increase the permeability of the membrane or lyse it are introduced into the composition. Such substances include anionic surfactants (surfactants), for example, sodium lauryl sulfate or sodium alkyl benzene sulfonate (C ₁₀ -C ₁₆ ); cationic surfactants that increase the permeability of cell walls, for example, decamethoxin, miramistin, catapol, ethylenediaminetetraacetic acid (EDTA) and its disodium salt trilon B ("Theory and practice of local treatment of purulent wounds", edited by B. M. Datsenko, Kiev, " Health ”, 1995, pp. 140, 143-145).

Since fluoroquinolones are inactive against fungi and protozoa, active substances can be introduced into the composition of the proposed composition. Such substances include trimethoprim, active against protozoa, or active against fungi and viruses, dimexide, or surfactants, active against fungi, mold, viruses, as well as active against fungi clotrimazole or cyclopiroxolamine.

To reduce the inflammatory process and reduce secondary tissue necrosis around the wound, nitazole is introduced into the pharmaceutical composition with fluoroquinolones, which reduces the degree of edema in exudative inflammation, or Trilon B, which reduces secondary tissue necrosis in the circumference of the wound, associated with excessive free radical oxidation, or dimexide, which reduces anti-inflammatory and pain phenomena.

Since fluoroquinolones do not show a necrolytic effect, proteolytic protease or asperase enzymes, or collagenolytic enzyme collagenase, or a complex of lysoamidase enzymes, which, in addition to bacteriolytic action, has a proteolytic effect, or proteolytic complex of imosimase or collagenolytic enzymes, are added to the composition, if necessary and proteolytic complex of enzymes - ultralysin.

It should be noted that proteolytic enzymes are introduced, if necessary, into the composition of the proposed pharmaceutical combination composition with fluoroquinolones used in the first phase of the wound healing process. In the second phase of the wound process, their use is not recommended because of the possible negative impact on young granulation tissue.

Fluoroquinolones included in the proposed pharmaceutical composition, in the form of a monocomponent or a mixture of components, have the following properties.

Ofloxacin is a crystalline powder of a slightly yellowish color, odorless, bitter taste. Slightly soluble in water and alcohol. It dissolves in water when heated in the presence of trimecaine or in combination with Trilon B and sodium chloride (patent RU No. 2245134).

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). In relation to streptococci, pneumococci, Pseudomonas aeruginosa and mycobacteria, it is less active. It is inactive or does not show activity 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 "Litterra ", 2003, pp. 846-849).

Ofloxacin is active against a narrow spectrum of pathogens of surgical infection, it has a moderate antimicrobial effect when applied topically, is positioned as a replacement for drugs with chloramphenicol (V.V. Privolne “Choosing a drug for the local treatment of infected wounds,” journal named after prof. B.M. “Wounds and Wound Infections,” 2015, Volume 2, pp. 13-18, Table 3).

The drug can be used for severe infections of the skin, soft tissues, bones, joints. Due to the fact that ofloxacin can be prescribed simultaneously with many antibacterial drugs, the drug is widely used as part of combination therapy for infectious diseases. Ofloxacin, unlike ciprofloxacin, remains active when used simultaneously with chloramphenicol (chloramphenicol) and rifampicin - inhibitors of RNA polymerase synthesis.

Ofloxacin is available in the form of 0.1 g and 0.5 g tablets, 0.2% infusion solution, 0.3% eye and ear drops, 0.3% eye ointment (Quinolone / Fluoroquinolone Group http: //www.antibiotic. ru / ab / 038-42.shtml), 0.1% ointment and 1% ointment for the treatment of infected wounds of various localization.

In a preferred embodiment, the proposed composition contains from 0.05 to 5, 0 wt. % ofloxacin, in a more preferred embodiment, from 0.1 to 1.0%.

In sources known to the authors, the use of ofloxacin was not found in any pharmaceutical composition for the treatment of infected wounds of various localization with the indicated target additives, except methyluracil, lidocaine or trimecaine, and protease C.

Ciprofloxacin is a crystalline powder of a slightly yellowish color, odorless, bitter taste. Slightly soluble in water and alcohol, soluble in 0.1N hydrochloric acid.

Ciprofloxacin is most active against aerobic gram-negative bacteria, it is less active against non-fermenting gram-negative microbes, in particular P. aeruginosa, Acinetobacter. Nevertheless, it is the most active fluoroquinolone of the blue-green pus (P. aeruginosa) strains registered in Russia in relation to strains. Its activity against P. aeruginosa strains is two times higher than that of ofloxacin. With respect to gram-positive microbes (staphylococci and streptococci), the activity of ciprofloxacin is lower than with respect to gram-negative, it is not very active against enterococci and most anaerobes (Guide “Rational Antimicrobial Pharmacotherapy” edited by Doctor of Medical Sciences V.P. Yakovlev and D.M. S.V. Yakovleva, ed. Litterra, 2003, pp. 952-956).

Most methicillin-resistant staphylococci are resistant to ciprofloxacin. Bacterial strains Streptococcus pneumoniae, Enterococcus faecalis, Mycobacterium avium (located intracellularly) 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. It is not effective against Treponema pallidum.

In in vitro experiments, synergism was observed with a combination of ciprofloxacin with aminoglycosides, with the most pronounced increase in the bactericidal activity of fluoroquinolone observed using subinhibitory concentrations of sisomycin (http://www.medi.ru/doc/2602402a.htm).

Ciprofloxacin can be used for severe infections of the skin, soft tissues, bones, joints.

The drug is available in the form of tablets 0.1 g, 0.25 g, 0.5 g, 0.75 g; 0.2% infusion solution and 1% concentrate for its preparation, 0.3% eye and ear drops, 0.3% eye ointment (Group of quinolones / fluoroquinolones http://www.antibiotic.ru/ab/038-42. shtml).

In a preferred embodiment, the proposed composition contains from 0.05 to 5.0 wt. % ciprofloxacin, more preferably from 0.05 to 2.5%.

Levofloxacin is a synthetic chemotherapeutic agent, fluorinated carboxyquinolone, free from impurities of the S-enantiomer of the racemic compound - ofloxacin LS. It is a crystalline powder or crystals, light from yellowish-white to yellow-white, which is readily soluble in water at a pH of 0.6-6.7. Its molecule has the ability to form stable compounds with ions of many metals. The ability to form chelate compounds in vitro decreases in the following order: Al + 3> Cu + 2> Zn + 2> Mg + 2> Ca + 2.

The pharmacological effect of levofloxacin is a broad-spectrum antibacterial, and in concentrations equivalent to or slightly higher than the inhibitory concentrations, it most often has a bactericidal effect.

In vitro, levofloxacin resistance resulting from spontaneous mutations is rare. Although cross-resistance was observed between levofloxacin and other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be sensitive to levofloxacin. Some strains of Pseudomonas aeruginosa can quickly become resistant during treatment with levofloxacin, as well as when using other drugs of this class.

In vitro, the minimum inhibitory concentrations of levofloxacin (2 μg / ml or less) were established for most (≥90%) strains of the following microorganisms: gram-positive aerobes - Staphylococcus haemolyticus, Streptococcus (group C / F), Streptococcus (group G), Streptococcus agalactiae, Streptococcus milleri, Streptococcus viridans; Gram-negative aerobes - Acinetobacter lwoffii, Acinetobacter baumannii, Bordetella pertussis, Citrobacter (diversus) koseri, Citrobacter freundii, Enterobacter aerogenes, Enterobacter sakazakii, Klebsiella provergensergensergensergomeriergensergomeriergensergomeriergensergens,,,,, ; gram-positive anaerobes - Clostridium perfringens.

Levofloxacin can be effective against microorganisms resistant to aminoglycosides, macrolides and beta-lactam antibiotics (including penicillin).

In in vitro and in vivo studies, levofloxacin within therapeutic concentrations did not induce or inhibit enzyme systems, thus, its enzyme-mediated effect on the metabolism of other drugs is not expected. (http.//www.rlsnet.ru/mnn_index_id_2681.htm).

Levofloxacin, the levorotatory isomer of ofloxacin, combines the high efficacy of ofloxacin with the resistance of the molecule to biotransformation in the body. At the same time, levofloxacin is 2 times more active than ofloxacin against the background of better tolerance (http://www.provisor.com.ua/archive/2002/N19/art_36.php).

The drug is available in the form of tablets of 0.25 g, 0.5 g, 0.5% solution for infusion, 0.5% eye drops (http://www.tiensmed.ru/news/levofloxacin-wd8.html).

In a preferred embodiment, the proposed composition contains from 0.05 to 2.00 wt. % levofloxacin. In a more preferred embodiment, from 0.02 to 1.00%.

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

Sparfloxacin is a broad-spectrum bactericidal antimicrobial with respect to both gram-positive and gram-negative flora. The advantage of the drug is a high activity against gram-positive cocci and anaerobes compared with fluoroquinolones of previous generations. With respect to gram-negative flora, it exhibits activity similar to aminoglycosides.

Sparfloxacin has a bactericidal effect on gram-positive microorganisms only during the division period, on gram-negative organisms - willow dormancy, since it affects not only DNA gyrase, but also causes lysis of the cell wall.

It prevents the transcription of the genetic material of bacteria, leading to a rapid decrease in the ability of bacteria to divide. As a result of its action, there is no parallel development of resistance to other antibiotics that do not belong to the group of gyrase inhibitors, which makes it highly effective against bacteria that are resistant, for example, to aminoglycosides, penicillins, cephalosporins, tetracyclines and many other antibiotics.

The following pathogens are highly sensitive to sparfloxacin: Escherichia coli, Shigella spp., Salmonella spp., Citrobacter spp., Klebsiella spp., Enterobacter spp., Serratia spp., Hafnia spp., Edwardsiella spp., Proteus spp. Indole (indole) indole , Providencia spp., Morganella spp., Yersinia spp., Vibrio spp., Aeromonas spp., Plesiomonas spp., Pasteurella spp., Haemophilus spp., Campylobacter spp., Pseudomonas cepacia, Pseudomonas aeruginosa , Moraxella spp., Acinetobacter spp., Brucella spp .; Staphylococcus spp., Streptococcus pneumoniae, Mycoplasma pneumoniae, Listeria spp., Corynebacterium spp., Chlamydia spp., Xanthomonas maltophilia.

Sparfloxacin is characterized by high activity against Mycobacterium tuberculosis, including the multi-resistant strains of Enterococcus faecalis, Ureaplasma urealyticum, Nocardia asteroides, which are usually sensitive to sparfloxacin. The following microorganisms have moderate sensitivity: Gardnerella spp., Flavobacterium spp., Alcaligenes spp., Streptococcus agalactiae, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus viridans, Mycoplasma hominis, Mycobacterium fortuitum.

With some exceptions, anaerobic microorganisms are moderately sensitive (Peptococcus spp., Peptostreptococcus spp.) Or resistant (Bacteroides spp) to sparfloxacin, it is not effective against Treponema pallidum.

Sparfloxacin resistance develops extremely slowly, because, on the one hand, there are practically no persistent microorganisms left after its action, and, on the other hand, bacterial cells have no enzymes that inactivate it.

Sparfloxacin showed no cross-resistance to other antimicrobials. In relation to Pseudomonas aeruginosa and other gram-negative bacteria, it is inferior in activity to ciprofloxacin.

With respect to S. aureus (including MRSA), Enterococcus spp. Sparfloxacin is superior in activity to ofloxacin, ciprofloxacin, levofloxacin and moxifloxacin.

It has a postantibiotic effect: microorganisms do not multiply within 0.5 -4 hours after the disappearance of the drug from plasma.

When a combination of sparfloxacin with other antimicrobials is usually observed synergism (aminoglycosides, metronidazole, etc.). (http://www.rlsnet.ru/mnn_index_id_1876.htm).

Sparfloxacin is available in 0.2 g tablets.

In a preferred embodiment, the proposed composition contains from 0.05 to 2.0 wt. % sparfloxacin.

Moxifloxacin in the form of moxifloxacin hydrochloride is a yellowish or yellow crystalline substance, poorly soluble in water.

Pharmacological action - broad-spectrum antibacterial, bactericidal.

Moxifloxacin is active both in vitro and according to the results of clinical studies in the treatment of a number of infections against most strains of the following microorganisms: aerobic gram-positive microorganisms - Enterococcus faecalis (only strains sensitive to vancomycin and gentamicin), Staphylococcus aureus (only methicillin-sensitive strains), Stregin Streptococcus constellatus; Streptococcus pneumoniae, including multiresistant strains; Streptococcus pyogenes; aerobic gram-negative microorganisms - Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, anaerobic microorganisms, microorganisms, microorganisms, microorganisms, microorganisms, microorganisms pneumoniae.

In vitro moxifloxacin is active (MPC ≤2 μg / ml) against most - more than 90% - strains of the following microorganisms: aerobic gram-positive microorganisms - Staphylococcus epidermidis (methicillin-sensitive strains only), Streptococcus agalactiae, Streptococcus viridans; aerobic gram-negative microorganisms - Citrobacter freundii, Klebsiella oxytoca, Legionella pneumophyla; anaerobic microorganisms - Fusobacterium spp., Prevotella spp.

Cross-resistance between moxifloxacin and other classes of antimicrobials, including macrolides, beta-lactam antibiotics, aminoglycosides, tetracyclines, is unknown.

Resistance to moxifloxacin develops slowly and is associated with multistage mutations. Moxifloxacin resistance in Gram-positive bacteria occurs with a frequency of up to 1,8⋅10 ^-9 1⋅10 ^-11 or less.

Cross-resistance between moxifloxacin and other fluoroquinolones was observed in gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may be susceptible to moxifloxacin.

Studies in healthy volunteers (n = 32) showed that moxifloxacin does not cause photosensitization (compared with placebo), unlike other fluoroquinolones.

The moxifloxacin solution is compatible with the following solutions: 0.9% sodium chloride, 1 M sodium chloride, 5% dextrose, water for injection, 10% dextrose, Ringer-lactate solution (http://www.rlsnet.ru/mnn_index_id_2812.htm) .

It is not compatible with 10% and 20% sodium chloride solutions, 4.2% and 8.4% sodium bicarbonate solution.

Moxifloxacin is available in the form of 400 mg tablets, an intravenous solution of 400 mg per 250 ml (0.16%), eye drops in the form of a 0.5% solution of 5 ml in plastic dropper bottles (http: //www.tiensmed. com / news / moxifloxacin-ab1.html).

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

In the proposed combined pharmaceutical composition, ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, moxifloxacin are used as a monocomponent or together with other fluoroquinolones, as well as antibiotics that are not in the class of fluoroquinolones, and synthetic antibacterial agents for the treatment of purulent microflora, multivalent containing strains of anaerobes to which some of the indicated fluoroquinolones are inactive, and also containing fungi and protozoa to which they are not active.

In sources known to the authors, the use of ciprofloxacin, levofloxacin, sparfloxacin and moxifloxacin in any pharmaceutical composition for the treatment of infected wounds of different localization together with these target additives was not found.

The attached table 1 presents IPC90 fluoroquinolones (from literature) in relation to the main gram-positive and gram-negative microorganisms that are part of the hospital microflora of purulent wounds.

From table 1 it is seen that moxifloxacin has maximum activity against S. aureus (including MRSA), S. epidermidis, Acinetobacter spp., E. coli spp., Enterobacter spp. Sparfloxacin has high activity against S. aureus, including MRSA, Enterococcus spp., S. epidermidis; ciprofloxacin has maximum activity against P. aeruginosa, Klebsiella spp., Proteus spp., and also a fairly high activity against E. coli spp., Enterobacter spp., Acinetobacter spp.

Ha based on this table and taking into account the half-life of T _1/2 , combinations of fluoroquinolones are used in the form of components of the proposed composition.

Such combinations include, but are not limited to: ciprofloxacin and sparfloxacin, ciprofloxacin and moxifloxacin, levofloxacin and sparfloxacin. These components complement each other in activity when used together in the same pharmaceutical composition, and also extend the cycle of its active action.

The composition of the proposed pharmaceutical combination composition together with fluoroquinolones uses aminoglycosides: netilmicin, amikacin, sisomycin. With the combined use of aminoglycosides with fluoroquinolones in one composition, their antibacterial effect is synergistically enhanced (http://www.medi.ru/doc/2602402a.htm).

Aminoglycosides penetrate the microbial cell and bind to specific receptor proteins on the 30 S subunit of the ribosome: they disrupt the formation of the initiating complex (messenger RNA — the 30S subunit of the ribosome), alter the reading of information from DNA, facilitating the synthesis of defective proteins, and also cause the disconnection of polyribosomes, which makes synthesis difficult squirrel. At higher concentrations, they damage the cytoplasmic membranes and cause cell death.

Netilmicin has minimal ototoxicity and nephrotoxicity compared to other aminoglycosides (G.K. Reshedko "Netilmicin," Antimicrobials, 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. Soluble in water. It has a wide bactericidal spectrum of action.

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. Are also sensitive 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).

Available in the form of 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 of 0.3% eye drops: 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. %

Amikacin in the form of amikacin sulfate is an amorphous powder of a 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 per ml of water, the pH value is 2.0-4.0.

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

The average therapeutic concentration of the substance with intravenous and intramuscular administration is detected within 12 hours. Amikacin is used mainly in combination with other antibacterial agents. The most justified use of amikacin in infections associated with P. aeruginosa. Amikacin 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 not pharmaceutically compatible with B and C vitamins, amphotericin, heparin, potassium chloride, nitrofurans, penicillin, chlortiazide, cephalosporins, erythromycin. The interaction of amikacin with diuretics, NSAIDs, penicillins, sulfanilamides, cephalosporins increases the concentration of amikacin in the blood serum and there is an increase in nephro- and neurotoxicity.

Amikacin is available in the form of a solution for injection of 250 mg / ml and 5% gel (Manual "Rational Antimicrobial Pharmacotherapy" edited by Doctor of Medical Sciences V.P. Yakovleva and Doctor of Medical Sciences S.V. Yakovleva, ed. in Litterra, 2003, pp. 708-709; http://www.vidal.ru/drugs/amikacin_20878).

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

Sisomycin in the form of sisomycin sulfate is a white or white powder with a yellowish or pinkish tint that is readily soluble in water and organic solvents (http://www.submed.ru/#!untitled/c3od).

It acts on most gram-positive and gram-negative microorganisms, including Staphylococcus spp. (including resistant to penicillin and antibiotics of other groups), Escherichia coli, Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., Proteus spp, does not affect Bacteroides spp. and other anaerobes, viruses, protozoa.

Sisomycin resistance develops slowly. Cross-resistance to all aminoglycosides also occurs. Sizomycin is used mainly for severe diseases caused by gram-negative microorganisms resistant to other antibiotics, or associations of gram-positive and gram-negative pathogens.

Sizomycin cannot be used (jointly or sequentially) with drugs with oto- and nephrotoxic effects (streptomycin, kanamycin, gentamicin, viomycin, monomycin, ristomycin, polymyxin B), as well as simultaneously with diuretics and curariform agents (http: // www. zdorovieinfo.ru/spravochnik-lekarstv/Sisomicin/).

Sisomycin is used as a 1% or 5% solution.

In the proposed pharmaceutical combination composition, netilmicin or amikacin or sisomycin is used with fluoroquinolones in one composition for the treatment of purulent wounds with polyvalent microflora, including those containing streptococcal strains, as well as methicillin-resistant staphylococcus strains, Pseudomonas aeruginosa strain. To reduce the resistance of microorganisms to netilmicin, amikacin, or sisomycin, an aminoglycoside enzyme inhibitor, for example, sodium lauryl sulfate, is included in the composition.

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), as well as some fluoroquinolones, are not very active against enterococci and most anaerobes, it is advisable to use them in a combined pharmaceutical composition based on fluoroquinolones in combination with lysoamidase that suppresses s range of staphylococcal and streptococcal microflora and Dioxydinum, highly active towards anaerobes. At the same time, lysoamidase and dioxidine in one combined composition provide, due to their properties, cleansing the surface of suppurating wounds and stimulate the tissue repair process.

The proposed pharmaceutical composition together with fluoroquinolones uses a synthetic antibacterial substance - dioxidine (1,4-di-N-oxide-2,3-bis- (hydroxymethyl) -quinoxaline), which is a greenish-yellow crystalline powder, odorless, 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 ("Antimicrobial agents in the series of derivatives of sulfanilamide, diaminopyrimidine, 5-nitroimidazole, di-N-hydroxyquinoxaline", Padeiskaya EN, breast cancer No. 21 dated 04.11.1997, p. 1- 6).

Dioxidin is characterized by a wide antibacterial spectrum, a bactericidal type of action. 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 (sensitive to diatomic oxygen) 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. Padeiskaya, “Complicated Issues of Antimicrobial Chemotherapy,” “Infections and Antimicrobial Therapy,” 2001, Volume 3, No. 5)

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

Dioxidine acts on strains of bacteria that are resistant to other antibacterial drugs, including antibiotics. It does not have a local irritant effect. Perhaps the development of drug resistance of bacteria to it.

The dioxidine treatment of burn and purulent-necrotic wounds promotes faster cleaning of the wound surface, stimulates reparative regeneration and marginal epithelization, and favorably affects the course of the wound process. Bactericidal concentrations of dioxidine depend on the type of bacteria, microbial load and exposure; they exceed the IPC by 2-4 times. Clinical bacteria strains with antibiotic resistance are sensitive to dioxidine. (“Theory and practice of local treatment of purulent wounds” under the editorship of B.M. Dotsenko, Kiev, from “Health” 1995, p. 152). For bacteroids, the IPC of dioxidine is 0.062-2.0 μg / ml, peptococcus 0.2-0.5 μg / ml, clostridium 1-2 μg / ml. 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, p. 750 -752).

Dioxidin exhibits bactericidal activity in the concentration range from 0.1% to 1%. Available in the form of 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” under the editorship of B. M. Dotsenko, Kiev, from “Health”, 1995, p. 152).

Dioxidine activity increases under anaerobic conditions, and the MPC values in this case can be reduced by 8-128 times. The activation of free radical processes occurs under conditions of anaerobiosis. 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 the infected body, dioxidine activates free radical processes, inducing the formation of reactive oxygen species (E.N. Padeiskaya, “Difficult 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. A connection is observed between the mutagenicity of dioxidine and the effect of stimulating the formation of free radicals. Drugs with antiradical activity and other antimutagens remove the mutagenic effect of dioxidine. 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.

The main disadvantage of dioxidine is the damaging effect on the adrenal glands. In addition, its disadvantage is its small therapeutic breadth, which requires strict adherence to the recommended doses. The daily therapeutic dose of dioxidine for systemic (intravenous) use for humans should not exceed 10 mg / kg. 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. When treating burns and suppurating wounds, the drug effectively cleanses the surface of the wound and stimulates the tissue repair process. The mechanism of development of drug resistance to dioxidine has not been studied. (EN Padeiskaya, “Difficult Issues of Antimicrobial Chemotherapy,” “Infections and Antimicrobial Therapy,” Volume 3, No. 5, 2001) Currently, acquired clinical resistance has been detected in 71.3% of community-acquired staphylococcus strains to dioxidine. The percentage of clinically resistant strains of pseudomonads to dioxidine has increased ("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 composition comprises from 0.1 to 5.0% dioxidine by weight, more preferably from 0.5 to 1.0% by weight.

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

The proposed pharmaceutical combination composition together with fluoroquinolones uses synthetic antibacterial substances related to nitroimidazole derivatives, metronidazole and nitazole.

Metronidazole is a white or yellowish-green crystalline powder, slightly soluble in water and alcohol.

The pharmacological action that he exhibits is antimicrobial, antibacterial, antiprotozoal, trichomonacid, antiulcer, anti-alcohol.

The nitro group of the molecule, which is an electron acceptor, is built into the respiratory chain of protozoa and anaerobes (competes with electron transporting proteins - flavoproteins, etc.), which disrupts the respiratory processes and causes cell death. In addition, in some types of anaerobes it has the ability to suppress DNA synthesis and cause its degradation (http://www.rlsnet.ru/mnn_index_id_756.htm).

It is known as an antiprotozoal agent, and is also widely used as a bactericidal drug against anaerobic bacteria. Its rather wide spectrum of action covers many protozoa, in particular trichomonads, giardia, amoeba, balantidia, etc. It is also highly active against most anaerobic bacteria: bacteroids, anaerobic cocci and fusobacteria, as well as clostridia. But aerobic bacteria (staphylococcus, Escherichia coli and other enterobacteria, Pseudomonas aeruginosa, etc.) practically do not have an antimicrobial effect.

The selective effect of metronidazole on anaerobic bacteria is due to the fact that in their cells there are conditions for the interaction of the drug with RNA, which leads to cell death. Metronidazole is resistant to purulent exudate enzymes. Therefore, it is indicated for local use in purulent wounds and in the cavities of abscesses, while maintaining activity under anaerobic conditions. In addition, it has an anti-edematous effect, stimulates the regeneration of the intestinal mucosa, is effective in diseases caused by clostridia, in particular with gas gangrene. In case of mixed anaerobic-aerobic infections (and even if this is suspected), metronidazole can be prescribed together with other chemotherapeutic drugs shown to this patient from among the more active ones (http.//www.net-olezniam.ru/publ/khimioterapevticheskieratemieratzhepma / 53-1-0-974).

Release form: tablets of 0.25 g and 0.5 g, rectal suppositories and vaginal tablets of 0.5 g and 0.1 g, ointment "Metrokain" containing 1% chloramphenicol and 2% metronidazole, cream for external use 1 %, gel for external use 1%, gel for vaginal use 0.75% and 1%, solution for infusion 0.5%.

In a preferred embodiment, the proposed composition contains from 0.1 to 4.0 wt. % metronidazole, more preferably from 0.5 to 2.0 wt. %

Nitazole (aminitrosol) - N- (5-Nitro-2-thiazolyl) acetamide is a crystalline powder, yellow with a greenish tint. It is practically insoluble in water, slightly soluble in alcohol. Nitazole is an anti-anaerobic drug, and resistance to it by anaerobes is rare. This is an antibacterial drug of a specific action, since it is active only against bacteria with an anaerobic mechanism. The drug selectively acts on anaerobes that function at a relatively low oxidation-reduction potential sufficient to ensure the restoration of the nitro group of nitazole, which is accompanied by the generation of unstable intermediate products biologically active against DNA. Reduced nitazole binds to DNA and causes chain disruption, resulting in cessation of DNA replication and transcription.

Nitazole is highly active not only against asporogenous anaerobes (bacteroids, peptococci, peptostreptococci) and spore-forming anaerobes of clostridia, but also against facultative anaerobes: staphylococcus, Escherichia coli, Klebsiella and others that are insensitive to metronidazole.

Nitazole gives a pronounced inhibitory effect on both antibiotic-sensitive and bacterial strains resistant to them. Suppresses the development of Trichomonas vaginalis and other protozoa. It also has an antimicrobial effect against Staphylococcus spp., Streptococcus spp., Escherichia coli and some other pathogenic microorganisms. Inactive against Proteus spp. and Pseudomonas aeruginosa.

Nitazole has a direct anti-inflammatory effect: the drug reduces the degree of edematous reaction with exudative inflammation, both in cases of its systemic use and local application. The use of hydrophilic nitazole is preferred. The decongestant effect of nitazole is higher than hydrocortisone acetate. In the composition of combined preparations, the anti-inflammatory effect can be enhanced due to the synergistic action of a number of components that show their activity by various mechanisms. ("Theory and practice of local treatment of purulent wounds", edited by prof. B.M. Datsenko, 1995, publishing house "Health", p. 164, 165, 181).

The formation of drug resistance to nitazole is associated with a decrease in the activity of nitroreductases and the degree of intracellular transformation of compounds, a decrease in the formation of complexes with DNA and the concentration of cytotoxic metabolic products. It is also possible to reduce the permeability of the cell wall of microorganisms to nitazole.

In a preferred embodiment, the composition contains from 0.5 to 4 wt. % nitazole

Some fluoroquinolones (e.g., ofloxacin, ciprofloxacin) are inactive against enterococci and most anaerobes.

In the proposed pharmaceutical combination composition, dioxidine, metronidazole and nitazole are used with fluoroquinolones for the treatment of purulent wounds with polyvalent microflora containing, among other things, anaerobes, protozoa and other microorganisms to which fluoroquinolones are moderately active or inactive, or to which microorganisms have developed resistance.

In the composition of the proposed composition, together with fluoroquinolones and other antibacterial components, synthetic antibacterial substances are used that reduce the resistance of microorganisms, which include the disodium salt of ethylenediaminetetraacetic acid (Trilon B), trimethoprim, dimexide and surface-active antiseptics.

Ethylenediaminetetraacetic acid - tetrabasic carboxylic acid, complexon II, a white crystalline powder, slightly soluble in water, insoluble in most organic solvents, soluble in alkalis, forms ethylene diamine tetraacetates with metal cations. It has a detoxifying, antioxidant effect (http://medside.ru/edta)

The disodium salt of ethylenediaminetetraacetic acid (complexon III, Trilon B, chelaton III) is a white crystalline powder or white crystals. It is well soluble in water and alkalis, very slightly soluble in alcohol; the pH of a 1% aqueous solution is 4.5; The pH of the drug with a mass fraction of 5% is 4-5.5. 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 for which calcium and magnesium ions are antagonists of the manifestation of their antimicrobial effects, for example, polymexins and aminoglycosides.

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 transfer 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 removing the outer membrane, which can be done using chelating agents and detergents included in the combination preparations. Trilon B - is a chelating substance that binds ions of divalent metals, 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 these cases, Trilon B, increasing the permeability of the microbial cell, enhances the sensitivity of microorganisms to antibacterial drugs.

Trilon B exhibits a bacteriostatic effect in relation to strains of gram-negative and gram-positive pyogenic bacteria: to staphylococcus and bacillus of blue-green pus - in a concentration of more than 0.075%; Proteus and Escherichia coli - more than 0.15%. MBC Trilon B in relation 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.

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 of these microbes. 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 (EDTA), into 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 Prof. B.M. Datsenko, 1995, Health ”, P. 139, 143, 144, 146, 180, 185, 228).

In a preferred embodiment, the proposed composition contains from 0.005 to 10,000 wt. % Trilon B, more preferably from 0.01 to 2.00 wt. %

In such a combination composition, trilon B (as a substance with a bacteriostatic effect) is used together with fluoroquinolones for the treatment of purulent wounds with polyvalent microflora, including those containing strains of staphylococci, streptococci, Pseudomonas aeruginosa and other microorganisms to which the activity of some fluoroquinolones is for one reason or another lowered.

In the proposed pharmaceutical combination composition, Trilon B reduces the resistance of strains of staphylococci, Pseudomonas aeruginosa and other microorganisms to antibiotics and other antibacterial substances, including fluoroquinolones.

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 pharmaceutical combination composition with fluoroquinolones reduces secondary tissue necrosis around the wound.

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

Dimexide is a chemical with the formula - (CH3) 2SO. This is an important bipolar aprotic solvent. It is 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 heats up strongly, is hygroscopic, mixes with water and alcohol in all ratios. Dimexide is used both in undiluted form and in the form of solutions (10-30-50-70%) in doubly distilled water to reduce inflammatory and pain phenomena during complex therapy.

Dimexide has a local anesthetic, local anti-inflammatory, antimicrobial (antiseptic) and fibrinolytic effects. In addition, dimexide has an antiviral, antifungal, vasodilating effect, reduces the level of free radicals, and stimulates various types of immunity. Dimexide quickly and well penetrates biological membranes, including through the skin and mucous membranes, and 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 while moving through cell membranes, and carries with it substances that usually cannot penetrate through the cell themselves. Due to this, it enhances the therapeutic effect of some transported medicinal substances, for example, antibiotics, corticosteroids, insulin. In this case, they 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 transfer 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). Dimexide 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 composition contains from 0.5 to 5 wt. % dimexide, more preferably from 1 to 3 wt. %

In the proposed pharmaceutical combination composition, dimexide is used together with fluoroquinolones for the treatment of purulent wounds with polyvalent microflora, containing strains of staphylococci, streptococci, Pseudomonas aeruginosa and other microorganisms to which the activity of fluoroquinolones is reduced for one reason or another, and also containing fungi, in relation to which fluoroquinolones are 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 fluoroquinolones 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.

It has also been proved that surfactants are capable of independently performing 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 properties of surfactants - to change the permeability of cell walls and inhibit the action of b-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.

Antibiotic inactivator enzyme inhibitors are some anionic and nonionic surfactants. In subbacteriostatic concentrations, anionic surfactant alkyl sulfates in vitro experiments reduced the frequency of transmission of Em resistance in staphylococci by 100 or more times, while cationic surfactants (rockcal, catamine AB, chlorhexidine bigluconate) did not have this ability. 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 (in some cases completely) transduction of the plasmid Em-resistance. Anionic surfactants completely suppress the genetic transfer of R-plasmids in Escherichia coli during conjugation and transduction.

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 sulphates and alkyl sulphonates of higher fatty acids (VGS) with the number of carbon atoms in the alkyl chains from 12 to 16. Anionic surfactants contain polar groups in the molecule and dissociate in water to form negatively charged long-chain organic ions determining their surface activity. Sodium, ammonium and triethanolamine salts are soluble in water.

Effective inhibitors of enzymes that inactivate aminoglycosides (neomycin, kanamycin, streptomycin) are anionic surfactants: sodium lauryl sulfate, sodium alkylbenzenesulfonate (C ₁₀ -C ₁₆ ). These surfactants completely suppress the activity of the corresponding enzymes in doses 2.5 times lower than cationic surfactants. For example, sodium alkylbenzenesulfonate is an inactivator of E. coli 6-lactamase. An effective inhibitor of chloramphenicol acetyltransferase is sodium lauryl sulfate. ("Theory and practice of local treatment of purulent wounds", edited by prof. B.M. Datsenko, Kiev, publishing house "Health", 1995, p. 142, 143, 144-146).

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. Less sensitive to cationic antiseptics are cyanobacterium pus, as well as Proteus. The bactericidal effect of cationic surfactants against gram-negative bacteria can be increased by combining with Trilon B.

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, 1995, publishing house "Health", p. 145 -147).

In the proposed combined composition with fluoroquinolones, low-toxic cationic surfactants are used - decamethoxin, miramistin.

Decamethoxin is a white crystalline powder with a weak characteristic odor, it is soluble in water, ethanol and chloroform with the formation of slightly opalescent solutions, it is very slightly soluble in acetone, practically insoluble in ether and benzene.

Decamethoxin is an antiseptic of the Quaternary Ammonium Group. It 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 the action is the following mechanism - decamethoxin destroys the upper membrane layer, loosens the membrane and increases 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. It is highly active against microorganisms resistant to antibiotics (chloramphenicol, streptomycin, monomycin, kanamycin, neomycin, etc.). The formation of decamethoxin-resistant forms with prolonged use occurs slowly and does not exceed effective concentrations of the drug. Bacteriostatic (fungistatic) concentrations are similar to its bactericidal (fungicidal), virucidal, protistocidal concentrations. In the course of treatment with decamethoxin, the sensitivity of antibiotic-resistant microorganisms to antibiotics increases, and also potentiates the effect of other antimicrobial agents with complex treatment.

With purulent and fungal diseases, a 0.01-0.5% aqueous solution for washing is used.

The composition of the solution 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 0.5 wt. % decamethoxin.

Miramistin is an odorless white crystalline powder, readily (slowly) soluble in water, 95% alcohol, and 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. By the strength of the bactericidal effectiveness of miramistin, it 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. ("Theory and practice of local treatment of purulent wounds", edited by prof. B.M. Datsenko, 1995, Kiev, publishing house "Health", p. 147, 148).

Miramistin has a wide spectrum of antimicrobial activity, including hospital strains resistant to antibiotics. The drug has a pronounced bactericidal effect against gram-positive and 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, yeast 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. 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. It increases the functional activity of immune cells, stimulates a local non-specific immune response, accelerates the healing process of wounds, reduces the resistance of microorganisms to antibacterial drugs, and effectively prevents infection of wounds and burns.

Miramistin activates the regeneration processes, stimulates protective reactions at the site of application by activating the absorbing and digesting functions of phagocytes, and potentiates the activity of the monocytic macrophage system. It 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. It does not have a local irritant effect and allergenic properties. Available in the form of a 0.01% aqueous solution (http://www.rlsnet.ru/tn_index_id_4800.htm). Previously produced in the ide of 0.5% ointment Miramistin and ointment Streptolaven. There is a patent RU 2484811 for ointment with miramistin "Lavender".

In a preferred embodiment, the composition contains from 0.01 to 1 wt. % miramistina.

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.

In the proposed pharmaceutical combination composition, cationic surface-active antiseptics (miramistin, decamethoxin) are used together with fluoroquinolones for the treatment of purulent wounds with polyvalent microflora containing strains of staphylococci, streptococci, Pseudomonas aeruginosa and other microorganisms, for which the activity of certain fluoroquinolones is lower by one or the other , as well as containing mushrooms, yeast and protozoa, in relation to which fluoroquinolones are not active.

Sodium lauryl sulfate (sodium dodecyl sulfate) is the sodium salt of lauryl sulfuric acid, an anionic surfactant. This is a white powder, which is combustible, its spontaneous combustion temperature is 310.5 ° С, solubility in water is not less than 130 g / l at 20 ° С. The color of the aqueous solution of sodium lauryl sulfate is from yellow to tan. 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, its concentration will not be higher than 1%.

Sodium lauryl sulfate is an effective inhibitor of enzymes that inactivate aminoglycosides (netilmicin, amikacin, sisomycin).

In a preferred embodiment, the composition contains from 0.001 to 2 wt. % sodium lauryl sulfate, more preferably from 0.1 to 1 wt. %

In the proposed pharmaceutical combination composition, sodium lauryl sulfate is used as an inhibitor of the resistance of microorganisms when fluoroquinolones are combined with aminoglycoside antibiotics (netilmicin, amikacin, sisomycin) in this composition.

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 fluoroquinolones: clotrimazole, or cyclopiroxolamine.

Clotrimazole is an imidazole derivative, an antifungal drug for external and local 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. For external use, the concentration of the drug in the epidermis is higher than in the dermis and subcutaneous tissue.

Clotrimazole after application to the skin is absorbed in an amount not exceeding 1%, but penetrates the stratum corneum of the epidermis and accumulates there. To a small extent absorbed from the mucous membranes (3%). The absorbed drug is metabolized in the liver and excreted by the kidneys; The half-life is 3-5 hours (//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 composition contains from 0.5 to 3.5 wt. % clotrimazole.

Cyclopiroxolamine is a broad-spectrum antimycotic, highly active against dermatomycetes, as well as yeast, gram-positive and gram-negative bacteria, mycoplasmas and trichomonads. The fungicidal effect of the drug is associated with the suppression of transmembrane transport of amino acids, K + and phosphates in growing fungal cells. This drug has almost no toxic effect on the body, is well released from the base, selectively accumulates in the epidermis and its derivatives (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 composition contains from 0.2 to 2% (mass) of cyclopiroxolamine.

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

In the composition of the proposed pharmaceutical composition, along with fluoroquinolone with reduced activity against gram-positive microorganisms, including those resistant to fluoroquinolones, for example, with ciprofloxacin and others, the bacteriolytic enzyme lysozyme is used.

Lysozyme - (ukopolysaccharidase) is an enzyme of protein nature, obtained in crystalline form. Its physico-chemical properties and lytic activity vary widely. Lysozyme 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, lysozyme is obtained from protein of chicken eggs (relative molecular weight of about 15,000) (http://www.piluli.kharkov.ua/drugs/drug/2495/).

The drug has a bacteriolytic effect. It has the ability to destroy the polysaccharides of the microbial membrane. Along with antibacterial properties, the drug has 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.

Lysozyme is used in the treatment of chronic septic (associated with the presence of microbes in the blood) 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 Prof. B.M. Datsenko, Kiev, publishing house “Health”, 1995, p. 144).

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

In the proposed composition, fluoroquinolones are used with lysozyme for the treatment of wounds with polyvalent microflora, which includes gram-positive and gram-negative microorganisms. Since some strains of gram-positive bacteria are staphylococci (MRSA), streptococci (CNS) (see table 1) are resistant to certain fluoroquinolones (ofloxacin, ciprofloxacin, levofloxacin), and lysozyme lyse gram-positive pathogens, such as staphylococci and lysozyme and some fluoroquinolones in one combined composition expands its therapeutic activity in comparison with monopreparations used separately.

The presence of necrotic tissue in the wound not only prevents the development of granulations, but also supports the activity of pathogenic microflora, being the optimal substrate for its nutrition. A gentle (bloodless) technique for cleansing wounds from necrotic tissues was developed on the basis of local application of various kinds of enzymes to the wound. They are able to thin the wound exudate and dissolve purulent-necrotic deposits by hydrolytic decomposition of cellular residues, protein bodies, fibrin, casein and denatured collagen.

In the composition of the proposed pharmaceutical composition for cleaning wounds from necrotic tissue, if necessary, at least one proteolytic or collagenolytic enzyme or complex of enzymes selected from the range of: asperase, protease, collagenase, lysoamidase, imosimase, ultralysin is used.

To date, the most promising and biologically acceptable method of wound cleansing is the method associated with the local use of proteolytic enzymes due to the following advantages:

1. Selectivity of action, since enzymes lyse only dead tissue and, unlike surgical or chemical necrectomy, they do not violate healthy areas of the skin, which can be foci of islet granulation and epithelization.

2. Enzymatic cleansing of wounds is the most physiological method, since under natural conditions, proteolytic enzymes are also released during tissue alteration.

3. Proteolytic enzymes usually have a fibrinolytic effect, which plays a large role in wound healing, as long-healing wounds of various etiologies are characterized by a low level of fibrinolytic activity.

4. The use of enzymes in the treatment of purulent wounds reduces the antibiotic resistance of their microflora, reduces their virulence.

Local application of proteolytic enzymes provides quick and painless wound cleansing, has anti-inflammatory and anti-edematous effects on tissues. By splitting devitalized proteins, proteolytic enzymes deprive microorganisms of the substrate for nutrition and reproduction, and increase their accessibility to antibacterial drugs. This method allows to reduce the treatment time for patients with purulent wounds by 1.5-2 times.

Local use of necrolytic drugs is rational for treating wounds in the first phase of the wound process. In the wound repair phase, proteolytic enzymes can inhibit the formation and growth of granulation tissue. Therefore, the basis for ointments with necrolytic substances should be hydrophilic and absorb wound exudate.

The first phase of the wound process is characterized by a pronounced inflammatory reaction, which is largely due to the activity of enzymatic processes in the wound. The activation of proteolysis enzyme systems resulting from inflammation is associated with damage to lysosomal membranes, which leads to the release of lysosomal proteases, which destroy proteins and other components of tissue cells. Thus, enzymes of bacterial and tissue genesis, catalyzing inflammation reactions, can have a damaging effect on tissues and contribute to the development of infection. Excessive proteolysis is one of the factors aggravating the severity of the inflammatory process up to the development of secondary necrosis in the wound. Under these conditions, the use of proteolytic enzymes in the treatment of the first phase of the wound process is impractical, since in a purulent-necrotic wound, the activity of the lysosomal proteases contained in it can be extremely high. Therefore, it is necessary to first determine the activity of lysosomal proteases in the wound, and only taking this analysis into account, should additional proteolytic enzymes or inhibitors of excess lysosomal proteases, for example, aminocaproic acid, be used (Theory and Practice of Local Treatment of Purulent Wounds, edited by Prof. B. M. Datsenko , 1995, the publishing house "Health", pp. 165-169).

It follows from this that not every ointment composition for the treatment of the first phase of the wound process should include a proteolytic enzyme or a complex of enzymes.

Direct introduction into the wound of native proteolytic enzymes in the form of powders, powders or solutions into the wound leads to their rapid inactivation, which makes enzyme therapy ineffective, while a long-term effect in the lesion is desirable. In addition, soluble enzymes that enter the bloodstream can cause side effects (for example, allergic and pyrogenic reactions).

Protolytic enzymes used in therapeutic practice (trypsin, chymopsin, chymotrypsin, terrilitin, collagenase, alpha-amylase, protease-C, etc.) for the treatment of purulent wounds remain active for no more than 4-6 hours. Eliminate this deficiency of enzymes by including them in soft external dosage forms: ointments, gels, creams (Bernikovsky VV Biotechnological development of necrolytic ointment and its research: diss. Cand. Biol. Sciences. - Pyatigorsk, 2007); (Bernikovsky V.V., Stepanova E.F. Research on the osmotic activity of some hydrophilic bases / Development, research and marketing of new pharmaceutical products: collection of scientific papers - Pyatigorsk, 2006. - Issue 61. - 632 p.).

The immobilization of proteases, for example, in ointment bases, leads to a significant reduction in the time of cleansing and healing of wounds compared to native enzymes. In this case, it is rational to combine enzymes with antimicrobial agents, keratolics and antioxidants ("Theory and practice of local treatment of purulent wounds", edited by prof. B.M.Datsenko, 1995, publishing house "Health", p. 170).

The most accessible proteases (serine, cysteine and aspartic) are inactive with respect to collagen, the main structural protein of connective tissue. Despite this, it is precisely such proteases that are most widely used in medical practice (Enzyme preparations. (Http://www.rusmedserver.ru/ojogi/36.html).

Proteases are one of the most numerous groups of enzymes; they are found in all animal and plant tissues and in microorganisms. Proteases are involved in protein metabolism, breaking down proteins to free amino acids. A large number of proteases are currently isolated in crystalline form.

Proteases (for example, protease C) are enzymes that break down peptide bonds in proteins and their breakdown products. Belong to the class of hydrolases, i.e. enzymes that break intramolecular bonds with the addition of water elements. Protease C has a proteolytic effect on purulent and necrotic masses. It is obtained by microbiological synthesis in the form of a powder (substance) packed in 0.5 kg plastic bags (http://www.mosmedclinic.ru/pharmacology/prepdesc/67125).

In a preferred embodiment, the proposed composition contains from 0.5 to 3.00% protease C by weight, more preferably from 1.0 to 2.0% by weight.

Asperase is an enzyme of plant origin; it is an amorphous powder of light brown color with a grayish tint, with a faint characteristic odor. It has a proteolytic effect (lysis / dissolution / surface of necrosis / areas of dead tissue), fibrous and purulent deposits of various origin. Previously, 2% ointment with asperase on an emulsion hydrophilic basis was produced (http://www.piluli.kharkov.ua/drugs/drug/1433/).

In a preferred embodiment, the composition of the invention comprises from 0.5 to 3.0% by weight of asperase, more preferably from 1.0 to 2.0% by weight.

Dead tissue in a burn wound is represented mainly by coagulated proteins of the dermis (collagen, elastin, etc.), as well as damaged components of the extracellular matrix. On the surface of the wounds may be fibrinous plaque. The visible effects of wound cleansing are most often associated with the breakdown of fibrin by proteolytic enzymes, but not with the destruction of collagen. Therefore, it is advisable in this case to use enzymes with collagenolytic activity.

Collagenase is an enzyme preparation obtained from the pancreas of slaughter cattle. A porous mass, white or white with a yellowish tint. Collagenase is readily soluble in water and isotonic sodium chloride solution. Solutions are stored at temperatures from 0 to + 8'C for no more than a day; when inactivated, it is inactivated. The activity of the drug is expressed in units of action (ED). In 1 g of the drug should contain at least 500 units. Collagenase has proteolytic activity; influencing mainly collagen fibers, it contributes to the melting of scabs and necrotic tissues. Used to accelerate the rejection of scabs and necrotic tissue after burns and frostbite; with trophic ulcers for purification from purulent-necrotic deposits. Release form: in hermetically closed bottles on 65ED (0,13 g) or 1625ED (3,25 g) of drug. Storage: in a dry, dark place at a temperature of no higher than + 10 ° C (http://dic.academic.ru/dic.nsf/meditem/912).

Collagenases are native enzymes that can convert native, insoluble fibrous collagen into soluble by cleaving peptide bonds under physiological conditions at a certain pH and temperature, which leads to the conversion of collagen into gelatin, which is destroyed by most proteases.

Collagenase properties: pH 7.2-7.6; highest activity at body temperature; bred on isotonic sodium chloride solution without antiseptics and soap solutions.

In the process of industrial production of collagenase, “concomitant” peptidases (amidase, esterase) with a non-specific proteolytic effect are mixed with it.

Along with necrolysis in the collagenase wound, dissolving the wound exudate enveloping the microbial cell facilitates access to it of various antibacterial drugs, for example, antibiotics with which collagenase is well compatible. ("Theory and practice of local treatment of purulent wounds", edited by prof. B.M. Datsenko, 1995, publishing house "Health", p. 169).

Antiseptics, heavy metals, detergents, soaps weaken collagenase activity. It should not be combined with tetracyclines, thyrotricin, gramicidin. Currently, several types of collagenases are produced in Russia: collagenase from the pancreas of cattle; Collagenase-K from Kamcha crab; Collagenase-kk (composition: clostridiopeptidase A, amidase, esterase) isolated from Clostridium histolyticum (part of the Iruxol ointment); Polycollagenase-K from hydrobionites (Enzyme preparations. Http://www.rusmedserver.ru/ojogi/36.html).

Collagenase-kk is available as a lyophilisate substance in bottles or plastic bags. Registration No. P N00200 / 01 (http://www.rusmedserv.com/lekarstva/kollagenaza-kk.html).

Collagenase KK 259ED - lyophilized hygroscopic powder or porous mass, compressed in the form of a tablet of gray-brown color.

Collagenase KK 250ED is obtained from the liver and pancreas of commercial species of crabs. Proteolytic enzyme with collagenolytic (expressed to a greater extent), elastolytic, trypsin and chemotrypsin activity. It helps to cleanse purulent wounds, the early appearance of granulations and epithelization, prevents the development of rough scars, maintains the elasticity of the skin and soft tissues. The drug is available in the form of a lyophilized powder for the preparation of a solution for external use, containing collagenase 250 IU (0.5 g) in ampoules with a capacity of 5 ml (http://www.rlsnet.ru/tn_index_id_11365.htm).

In a preferred embodiment, the proposed composition contains from 0.5 to 6.0% collagenase by weight, more preferably from 1.0 to 4.0% by weight.

The composition of the proposed pharmaceutical composition together with fluoroquinolones uses a complex of bacteriolytic and proteolytic enzymes that lyse gram-positive microorganisms, primarily staphylococci, resistant to antibiotics (patents RU 1549227, C12N 9/00, publ. 20.12.1995; RU 2193063, C12N 9/00 , published on November 20, 2002). This complex is used in medicine under the name lysoamidase, and in veterinary medicine - lysomast.

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; muramoylalaninamidase - 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.

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

It should be noted 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, hygroscopic, the pH of lysoamidase is from 3.5 to 5.5, it is sparingly soluble in water. Soluble in 0.01 M sodium phosphate buffer, pH 8.0. 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 LE. 1 mg of the substance contains at least 12 LE. Lizoamidase is thermophilic. It is allowed to heat no higher than + 37 ° C. Lysoamidase is stored in a dry, dark place at a temperature of no higher than + 10 ° C.

On the basis of this complex, a pharmacological preparation was developed, produced in the form of lyophilized powder, packaged in 10 ml bottles of 50 PE, 100 PE with hermetically sealed rubber stoppers. At the same time, the delivery kit 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.

The solution with lysoamidase promotes a faster reduction in the area of wounds and earlier (by 2 days compared to wounds treated with chymopsin, and by 4 days compared to wounds treated with lysozyme) wound closure. Moreover, the use of lysoamidase in vivo at doses 15 times less than the commonly used doses of lysozyme, causes a similar effect with respect to gram-positive coccal microflora. When applied to a wound, a solution of lysoamidase even in low concentrations (a 0.01% solution was used, while a 0.5-1% solution is acceptable) has a more pronounced wound healing effect than solutions of chymopsin and lysozyme in commonly used concentrations exceeding protein concentration of lysoamidase is 300 times and 15 times, respectively. Moreover, lysozyme has only bactericidal properties, and chymopsin has only proteolytic properties.

The drug is most active in relation to the group of staphylococci: complete cell lysis, determined by optical density, was observed after 1-30 minutes for various strains. The strains of bacteria Staphylococcus aureus, which are the most pathogenic for humans, had the greatest sensitivity - a decrease in optical density to 0 in 5 minutes. Lizoamidase has a strong antistaphylococcal effect - 100 μg of the drug lyses 10 ⁹ microbial cells of staphylococcus in 5-10 minutes.

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 with the help of 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, 1995, publishing house " Health ”, p. 139, 143), as well as surface-active substances (surfactants) when used together in one pharmaceutical combination composition.

Due to the presence of protease and bacteriolytic enzymes in lysoamidase, which also have proteolytic activity, the drug cleans wounds from necrotic masses well. Lizoamidase in the form of a solution accelerates the process of cleansing wounds from necrotic masses by 4-6 days, in addition, the use of the drug in the early stages after surgery causes more rapid (5-7 days) wound healing.

Fragments of destroyed cells with the necrolytic effect of lysoamidase have an immunostimulating effect. In the treatment of purulent wounds of soft tissues, it accelerates the course of the wound process compared to other traditional and non-traditional means. The microflora content decreases faster, the cytogram normalizes faster, the rejection of necrotic masses is faster, and granulation and even epithelization of tissues occurs.

The terms of treatment of patients with purulent wounds of soft tissues were reduced in many cases by 2 times. Lysoamidase stimulates reparative processes, exerting, in addition to the non-proliferative and bacteriolytic effects, the course of the 2nd phase of inflammation, not only due to the reduction of the 1st phase, but also due to the directly stimulating effect on the cells of granulation tissue, acting directly on proliferate cells.

In a preferred embodiment, the composition contains from 0.01 to 2.0 wt. % lysoamidase, more preferably from 0.05 to 1.2 wt. %

In the proposed composition, fluoroquinolones are used with lysoamidase for the treatment of wounds with polyvalent microflora, which includes gram-positive and gram-negative microorganisms. Since some strains of gram-positive bacteria - staphylococci (MRSA), streptococci (CNS) (see table 1) are resistant to certain fluoroquinolones (ofloxacin, ciprofloxacin, levofloxacin), and bacteriolytic enzymes that are part of lysoamidase lyse gram-positive pathogenic microorganisms such as microorganisms and streptococci, the combined use of lysoamidase and some fluoroquinolones in one combined composition expands its therapeutic activity compared to single drugs used separately.

To compensate for the reduced activity of certain fluoroquinolones (ofloxacin, levofloxacin, moxifloxacin) to Pseudomonas aeruginosa strains, Trilon B or surfactants (decamethoxin, miramistin), or the above aminoglycosides, were introduced into the pharmaceutical composition of these fluoroquinolones with lysoamidase.

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

To ensure the proteolytic properties of the proposed pharmaceutical composition with fluoroquinolones, enzyme complexes with the proteolytic effect of imosimase or ultralysine (which also has a collagenolytic effect) are added to it.

Imosimase is an enzyme preparation obtained by immobilizing bacterial proteases on polyethylene oxide. It has a proteolytic effect. The drug is used for acute and chronic purulent-necrotic processes (processes with tissue necrosis).

Imosimase is available in the form of a liquid or dry porous mass in 10 ml bottles, 1 ml of liquid in a bottle has 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. The enzyme preparation is stored at a temperature of +4 - + 8 ° C.

The method of preparation preparation is based on radiation modification (pegelation) of bacterial proteases with polyethylene oxide. Imosimase is an enzyme obtained by immobilizing bacterial proteases (proteinases) from Bacillus subtilis (hay bacillus) on a chemically inert water-soluble polymer - polyethylene oxide 1500, with an activity of (100 ± 30) PE / cm ³ . It is a clear, light liquid (opalescence is acceptable), 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, it is thermostable in the presence of a substrate (up to + 80 ° C), resistant to endogenous proteolysis inhibitors, hydrolyzes denatured proteins with various amino acid sequences with high speed, including fibrin and collagen, it has anti-inflammatory activity, does not cause allergic reactions (http://www.bionet.nsc.ru/booklet/Rus/RusApplied/RazrabotkiImozimazaRus.html).

The imosimase concentrate is mixed with the basis of the proposed composition in the required volume (weight).

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 purulent detritus is accelerated, inflammation is stopped by enzymatic lysis of peptide inflammatory mediators, pain, swelling and hyperemia pass. The detoxification effect is due to enzymatic lysis and inactivation of toxins secreted by most pathogenic microorganisms, as well as toxins formed during tissue breakdown.

As a result of the use of imosimase, an 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.

Imosimase is incompatible with tetracycline antibiotics, alcohols, chloramine, solutions of iodine, potassium permanganate, hydrogen peroxide, copper and silver salts, calcium salts. There are no contraindications to the use of the drug (http://www.biopark-moscow.ru/catalog/more/imo/).

Imosimase is used for purulent-necrotic processes of various etiologies and localizations: suppuration of postoperative wounds, purulent wounds after opening abscesses, phlegmon, infected wounds, burns, frostbite, non-healing wounds, trophic and radiation ulcers, osteomyelitis, preparation of purulent wounds for plastic surgery dr .. (http://www.bionet.nsc.ru/booklet/Rus/RusApplied/RazrabotkiImozimazaRus.html)

The consumption of the drug during use 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. %, more preferably from 1.0 to 5.0 wt. % dry concentrate imosimase.

As part of the proposed pharmaceutical combination composition, together with fluoroquinolones, an ultralizine complex is used, which contains collagenase and protease enzymes.

Ultralizine is part of Streptolaven ointment (http://www.webapteka.ru/drugbase/name18566.html) and Lavender ointment according to patent RU 2484811, A61K 9/06, 06/20/2013. It has proteolytic activity. Influencing mainly on collagen fibers, it contributes to the melting of scabs (hardened blood layer and / or dead tissue covering the skin defect) and necrotic tissue. Ultralizin (patent RU 2340371, А61Р 17/00, 12/10/2008) - a substance for the production of medicines, cosmetic creams. It selectively acts on soft tissues and skin integuments.

A biologically active substance containing collagenase and protease is an ultrafiltrate isolated from the culture fluid of the Streptomyces Ivendulae strain VPKM S-910 with collagenolytic activity of 1800-2500 KEA / ml and proteolytic activity of 120-200 PE / ml.

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

Ultralizine provides the proteolytic and collagenolytic properties of the proposed pharmaceutical composition with fluoroquinolones.

The healing of wound infections is often delayed, which is associated with the suppression of the immune reactivity of tissues. It is known that patients with severe signs of immune dysfunction during microbial infection are shown synthetic immunomodulators, such as tiloron, polyoxidonium and (http://uhonos.ru/infekcii/stafilokokk/), cycloferon, etc. In order to increase the granular immune response tissue and speedy wound epithelization in the composition of the proposed pharmaceutical composition additionally introduced immunomodulators: tiloron, cycloferon, polyoxidonium.

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.

Tiloron increases the body's resistance to infections caused by bacteria, fungi, and protozoa. The immunomodulatory activity of tilorone is especially pronounced against the background of immunosuppressive conditions caused by various reasons, including surgical interventions. Tiloron has 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, 04/27/2009; RU 2348400, A61K 31/06, 10.03 .2009).

Studies have shown 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 (article "Study of the therapeutic activity of tilorone in various forms in pathological conditions skin "," Cytokines and inflammation ", Volume 10, No. 3,2011, p. 98-101, patent RU 2423971, A61K 31/06, 07/20/2011).

These studies show that for traumatic wounds associated with impaired innervation and blood supply to tissues, a pharmaceutical combination composition containing tilorone can be used to heal them.

In a preferred embodiment, the composition comprises from 0.05 to 10% (mass) of tilorone, more preferably from 0.5 to 5%.

In the proposed combined pharmaceutical composition, tilorone is used with fluoroquinolone in one 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.

A low molecular weight inducer of endogenous interferon - meglumine acridone acetate (trade name is cycloferon) (patent RU 2036198). Meglumine acridone acetate is prepared 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). It is a chemically stable hygroscopic crystalline substance, readily soluble in water and most organic solvents. In some cases, N-methylglucamine enhances the therapeutic effect of drugs, for example, painkillers, sedatives, hypnotics, and muscle relaxants, and has an antiplatelet effect due to normalization of calcium metabolism in platelets. It also selectively affects the potassium / sodium pump and the release of intracellular calcium (acridonoacetic acid is the active ingredient in N-methyl-glucamine preparations, 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, embryo-toxic and carcinogenic effects.

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

It is used in the form of 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.

Cycloferon is also used in the form of a liquid ointment - 5% of the liniment of cycloferon containing 0.05 g of acrid acetic 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 up to 100% (CYCLOFERON® http://www.e-apteka.ru/doc/Vidal_docs/drug_info24196.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 composition contains from 2 to 15% (mass) of cycloferon, more preferably from 5 to 12.5%, 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 fluoroquinolone in one 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.

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 of 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 antibodies of the IgG and IgM class, which protect against infections, but not IgE antibodies, which are responsible for allergic reactions (Polyoxidonium. Www.mtu-net.ru/doctor99/5nklassifik1polioxidoniy2905.htm).

Polyoxidonium is a water-soluble polymer having in its polymer chain a large number of lightly 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 cytoxic 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 in the blood is achieved 1 hour after administration, the 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, with interferons and their inducers. Its use in complex therapy can increase efficiency 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 used for chronic recurrent inflammatory diseases of any etiology, rheumatoid arthritis, acute and chronic viral and bacterial infections, various forms of tuberculosis, acute and chronic allergic diseases, during and after chemo-and radiation therapy of tumors, to reduce the nephro- and hepatotoxic effects of drug preparations for activation of regenerative processes, in the correction of immunodeficiency states of various origins and autoimmune diseases, as well as for section of secondary immunodeficiencies resulting from aging, for the rehabilitation of often and long-term sick people.

The drug is available in the form of 0.012 g tablets, an injection solution of 3-4% and 6-8%, as well as suppositories weighing 1.3 g, containing 0.006 g and 0.012 g of polyoxidonium. Rectally applied once a day for the first three days daily, and then - with an interval of 48 hours. Course - 10 suppositories (http://polioxidonii.lek-va.ru/).

In a preferred embodiment, the composition comprises from 0.4 to 10% (wt.) Polyoxidonium, more preferably from 5 to 10%.

In sources known to the authors, the use of fluoroquinolones in any pharmaceutical composition for external and local use together with polyoxidonium was not found.

In the proposed combined pharmaceutical composition, polyoxidonium is used with fluoroquinolones in one composition for the treatment of purulent wounds with polyvalent microflora as an immunomodulator of local (local) action with detoxification activity, accelerating wound healing in phase II of the wound process.

In the proposed composition, as one of a number of auxiliary components, a reparative stimulant is used, if necessary, in the form of at least one of the following substances: xymedon, methyluracil, etaden, or a physiologically acceptable mixture thereof, but not limited to.

Xymedon - N- (β-hydroxyethyl) -4,6-dimethyldihydropyrimedone-2, a pyrimidine derivative of the 3rd generation with high regenerative activity (SU 1685454, publ. 1991). The preparation is a crystalline powder of white or pink tint, odorless, bitter taste, with a melting point of 139-143 ° C, easily soluble in water, alcohol, physiological saline. The standard therapeutic dosage is 100 mg / kg; for humans, the daily dose is usually 30 mg / kg.

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. It was found that the stimulating effect of Xymedon is most fully manifested in the first 5-7 days, wound healing occurs much faster than in the control group (methyluracil), the forming scar ripens faster, granulation tissue growth is less pronounced, the process of collagenogenesis starts earlier. Xymedon in reparative activity surpasses the methods of medication and physiotherapy known to date. However, he does not change the normal course of wound healing: the same phases of the wound healing process are observed, but with a significant shortening of them. 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. It is morphologically proved that 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.

The immunostimulating effect of Xymedon has been proven in experiments performed in in vitro and in vivo systems, and is also fully confirmed in the clinic. 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 has bactericidal activity. Other dosage forms of xymedon (powder, ointment) also have antibacterial properties.

The antioxidant effect of xymedon is expressed in a membrane-stabilizing effect (http://www.medicum.nnov.ru/nmj/2002/3/18.php).

In a preferred embodiment, the composition contains from 1.0 to 10.5 wt. % xymedon, more preferably from 4.0 to 10.0 wt. %

Methyluracil, being a pyrimidine derivative, has anabolic and anti-catabolic activity. The substance has no 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; stimulates erythro- and leukopoiesis.

In a preferred embodiment, the proposed composition contains from 1.0 to 10.5 wt. % methyluracil, more preferably from 4.0 to 10.0 wt. %

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 developed composition contains from 0.5 to 2.0 wt. % etaden.

In the proposed composition, as one of a number of auxiliary components, an anesthetic is used, if necessary, in the form of at least one of the following substances: lidocaine or trimecain, but not limited to.

Lidocaine - (2-diethylamino) -N- (2,6-dimethylphenyl) acetamide, usually used in the form of hydrochloride. This white or almost white crystalline powder is poorly soluble in water. Often used is its hydrochloric salt, which is readily soluble in water. Lidocaine has a lower toxicity than trimecaine (patent RU 2283088, A61K 9/06, 09/10/2006).

Trimecaine - 2- (diethylamino) -N- (2,4,6-trimethylphenyl) acetamide is used as the hydrochloride. It is a crystalline powder, white or yellowish tinted, which is soluble in water and alcohol. Possessing sufficient lipophilicity, it penetrates the nerve fiber membrane, binds to receptors and disrupts the processes of depolarization, 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 6.5 wt. % However, the most optimal use of anesthetics in the proposed composition is in the range from 1.0 to 3.0 wt. %

In the proposed composition, as one of a number of auxiliary components, a preservative is used, if necessary, in the form of at least one of the following substances: Trilon B, nipagin, nipazole or their physiologically acceptable mixture, but not limited to.

Nipagin or methyl paraben (methyl parahydroxybenzoate) - methyl ester of paraoxybenzoic acid actively inhibits the growth of gram-positive bacteria, less active against gram-negative bacteria and molds. Better than other esters of para-hydroxybenzoic acid, it dissolves in water, but is less effective for antibacterial purposes. It is mainly used in combination with other preservatives (for example, phenoxyethanol, imidazolidine urea and others). 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 it in the form of a 0.07% solution.

These preservatives are compatible with almost all medicines, with the exception of sodium bicarbonate, sodium tetraborate and silver nitrate.

The mixture may contain nipagin and nipazole, in particular in a ratio of 1: 3.

The low toxicity of parabens makes it possible to use them in local topical preparations - suspensions, liniments, solutions, suppositories of gelatin capsules, etc. (S.I. Marchenko, “Lecture notes on the course of technology for dosage forms and galenic preparations”, lecture No. 6 t, www .opu.odessa.ua / konsp / KI.229.doc).

In the proposed composition, as one of a number of auxiliary components, a detergent is used, if necessary, in the form of at least one of the following substances: tween-80 or tween-20, but not limited to.

Non-inogenic detergents with high surface activity, which do not create ions in aqueous solutions, have a dissolving and disinfecting effect. Non-inogenic detergents make it possible to expose protein preparations to shear and surface overloads without causing protein denaturation.

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).

In the proposed composition, as one of a number of auxiliary components, a stabilizer is used, if necessary, in the form of at least one of the following substances: ethonium, citric acid, miramistin, or a physiologically acceptable mixture thereof, but not limited to.

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 the properties of a chelating agent.

From the microbiological point of view, 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, the hydrophilic bases of pharmaceutical compositions are more preferable, since they serve as drug conductors into the microbial cell.

Hydrophilic bases that can be used in the proposed 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, and 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, liquid paraffin, lanolin, waxes (these bases are usually 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 (PEO) - water-soluble products of 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 microbes 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, not irritate the mucous membranes, have a long shelf life, high physiological indifference, which contributes to their use in liquid, ointment-like and formable 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 various molecular weights are registered: PEO-400, PEO-1000, PEO-1500, PEO-2000 and PEO-4000. When mixing PEO-400 solvent with PEO-1500 polymer, the latter acts as a thickener, which, depending on its 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 (HLB) 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 be 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, as well as excessive dehydration of tissue cells, osmotic shock, leading to their death.

Studies have shown that 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 eliminate these drawbacks, bases have been developed that have the mildest cytotoxic effect on tissue cells. These bases 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 ratio between 1,2-propylene glycol and PEO-400 in a hydrophilic basis is considered an important biopharmaceutical factor that 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 tissue 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. Dotsenko. 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 number 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. Indeed, carbonyl groups were detected in a polyethylene oxide gel by reaction with dinitrophenylhydrazine. 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, pp. 217, 218, www.golkom.ru/book/48_1.htm,)

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 in pharmacology are actively used conjugated with a carrier - immobilized pharmacological agents. It is known that hydrophilic polymers such as PEG, hydroxyethylene starch, polyvinylpyrrolidone and others can be associated with biologically active substances by adsorption on their surface or 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, an increase in the half-life, a decrease in toxicity, and an increase in the selectivity of action due to qualitative changes in the 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. At the same time, 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, the 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 technology for processing a solution of polyethylene oxide 1500 in water with accelerated electrons, a gel is obtained that contains from 1 to 4% polyethylene oxide. Such a gel is the "Geco" hydrogel - a colorless gel-like 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 that has a cellular structure - cells of type A, which determine the hydrophilicity of the system, and type B, they 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 1500 gel, which is a mixture of water and large molecules of crosslinked or cross-linked polyethylene oxide in a fairly 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 gel structure makes it possible to attribute the polyethylene oxide gel to moisturizing cream bases. Hydrogel "Geko" has a widely varying structural viscosity, prone to thinning 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%. Its physico-chemical properties: 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.

Hydrogel "Gecko" is used in the proposed pharmaceutical combination composition as a basis with the dissolution of active components and target additives in it in the manufacture of an ointment (or gel) for the treatment of wounds in the second phase of the wound process.

Silicon is an essential element. In the human body, it is found in almost all tissues. It has been established that silicon compounds are necessary for the normal development and formation of epithelial and connective tissue, they contribute to collagen biosynthesis and bone formation, and play a significant role in metabolic processes.

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 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, this 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. Gels based on hyaluronic acid are used to treat local and general purulent-inflammatory processes, thermal and chemical burns, trophic ulcers in chronic venous insufficiency, radiation injuries of the skin, cracks, abrasions, as well as for the treatment of long-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 is a complete analogue of hyaluronic acid, promotes tissue regeneration without scarring, and has the ability to stimulate cell migration and proliferation. Used in concentrations ranging from 0.01 to 0.5%.

In the proposed pharmaceutical combination composition, hyaluronic acid or sodium hyaluronate is 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 the detoxification blood substitute fluid, which binds toxic substances of various structures and excretes their body. (Blood-replacing 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 made it possible to select the above bases with hyperosmolar properties for the proposed pharmaceutical composition.

Using these bases for liquid, soft and soft formulated dosage forms, as well as fluoroquinolones, antibiotics, synthetic antibacterial agents, antimycotics, enzymes or their complexes, immunomodulators and, if necessary, auxiliary components in the form of stimulants of the reparative process, anesthetics, preservatives, detergents stabilizers are offered pharmaceutical combined compositions of hydrophilic liquid preparations, ointments, creams, gels, capsules and suppositories for rectal and vaginal application, as well as aerosols and sprays.

The type of dosage form of the proposed pharmacological preparation depends on the molecular weight of the hyperosmolar substances used, their ratio in the composition of the mixture, as well as the quantitative ratio of the hyperosmolar base with other components of the pharmacological preparation. Based on these quantitative ratios, the dosage form of the proposed pharmacological preparation can 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 water-glycol solvents of higher fatty alcohols or acids, stabilized by hydrophilic surfactants. Creams are two- 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, tragacanth, 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 gelling agents can additionally fulfill 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 drugs from environmental factors and has advantages over suppositories, since substances in the form of an ointment, liniment, cream, gel, emulsion, suspension, etc. can be encapsulated. The release of a drug is faster and easier than with suppositories since under the influence of a weakly alkaline medium (pH 7.3-7.6) the contents of the rectum, the gelatinous membranes swell, and in this state, even a slight remoteness of the rectal wall is sufficient to rupture and release it waiting for 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;

- accurate dosage is ensured when using metering devices;

- leads to a 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 maintain sterility 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, V.I. Chueshov et al., Kharkov, 2002, p. 640).

Medications in the form of a spray are used for topical, external, intranasal use. The main advantages of the dosage form sing the following:

- a drug in the form of a spray leads to a quick therapeutic effect;

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

- the small size of the particles determines a high degree of their penetration into the folds, pockets, cavity of the wound or mucous membrane and in other hard-to-reach places;

- there is no danger of contamination of the drug from the outside, as the cylinder is hermetically sealed. It also prevents the drug 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.

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

Some fluoroquinolones in the proposed pharmaceutical combination composition are active against gram-negative and, to a lesser extent, gram-positive microorganisms, moderately

sensitive to most anaerobes, are active against atypical bacteria: chlamydia, mycoplasmas, legionella. Fluoroquinolones are not active against fungi, mold and protozoa, do not have analgesic, anti-inflammatory, proteolytic and reparative effects.

To compensate for the shortcomings of fluoroquinolones in the proposed pharmaceutical composition, special target additives have been introduced: antibiotics and synthetic antibacterial substances, including microorganism resistance inhibitors, active against strains resistant to fluoroquinolones, as well as fungi, molds and protozoa; bacteriolytic, proteolytic or collagenolytic enzymes or their complexes; antimycotics; immunomodulators and, if necessary, stimulants of the reparative process, anesthetics and other excipients.

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

The combined use of fluoroquinolones 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 preparation together with fluoroquinolones provides the 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 is to improve microcirculation in wound tissues by reducing histamine activity, reducing secondary tissue necrosis in the wound circumference, reducing the degree of edematous reaction with exudative inflammation, further improving cleaning of the wound surface and stimulating the tissue repair process.

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

The use of anesthetics in the proposed pharmaceutical combination composition suppresses pain in the treatment of wounds and burns.

To provide additional stimulation of the repair processes in the wound, the proposed composition is applied, both in the form of a mono component and as a mixture of components, substances that stimulate the healing process in the wound. 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.

Preservatives, stabilizers, non-inogenic detergents provide long-term storage of the pharmaceutical composition while maintaining its activity in case the active substances of the composition and its target additives, including the base, are subject to degradation or the action of microorganisms. Nonionic detergents and solubilizers provide the dissolution of poorly soluble substances in the base.

The use of a hydrophilic base consisting of a mixture of polyethylene oxides and proxanol in the proposed pharmaceutical composition provides fast delivery of active substances to both microbial cells and tissue cells, which increases the therapeutic activity of the proposed pharmaceutical composition. In addition, the dehydrogenation of the hydrophilic base of the 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.

The above set of properties of the proposed pharmaceutical combination composition was not previously known, which indicates a significant novelty of the proposed solution.

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 implementation of the invention is illustrated by the following examples, but is not limited to.

Examples 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 use No. 1.

Example 10

Ointment for external use No. 2.

Example 11

Ointment for external use No. 3.

Example 12

Ointment for external use No. 4.

Example 13

Ointment for external use No. 5.

Example 14

Ointment for external and local use No. 6.

Example 15

Ointment for external and local use No. 7.

Example 16

Ointment for external and local use No. 8.

Example 17

Ointment for external and local use No. 9.

Example No. 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 use 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 use No. 16.

Example 25

Ointment for external and local application No. 17.

Example 26

Ointment for external and local application No. 18.

Example 27

Ointment for external and local application No. 19.

Example 28

Ointment for external and local application No. 20.

Example 29

Ointment for external and local application No. 21.

Example 30

Ointment for external and local application No. 22.

Example 31

Ointment for external and local application No. 23.

Example 32

Ointment for external and local application No. 24

Example 33

Ointment for external and local application No. 25.

Examples for phase II wound healing

Example 34

Ointment for external and local application No. 26.

Example 35

Ointment for external and local application No. 27.

Example 36

Gel for external and local application No. 28.

Example 37

Gel for external and local application No. 29.

Example 38

Gel for external and local application No. 30.

Example 39

Gel for external and local application No. 31.

Example 40

Gel for external and local application No. 32.

Example 41

Gel for external and local application No. 33.

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

Example 42

Composition for the preparation of suppositories No. 1.

100 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm, 32 mm long, and a weight of 2.7 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 corresponds to GF XI requirements (Art. Suppositories, p. 151-153).

Example 43

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 2.75 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 44

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 2.6 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) ° C, which meets the requirements GF XI (Art. Suppositories, p. 151-153).

Example 5

Composition for the preparation of suppositories No. 4.

100 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm, 32 mm long, and a weight of 2.71 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 corresponds to GF XI requirements (Art. Suppositories, p. 151-153).

Example 46

Composition for the preparation of suppositories No. 5.

100 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm, 32 mm long, and a weight of 2.58 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 corresponds to GF XI requirements (Art. Suppositories, p. 151-153).

Example 47

The ointment from example 9 (ointment for external and local use No. 1 with ofloxacin) was filled in 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).

Example 48

The ointment from example 14 (ointment for external and local use No. 6 with ciprofloxacin) was filled in 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).

Example 49

The ointment from example 19 (ointment for external and local use No. 11 with levofloxacin) 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).

Example 50

The ointment from example 25 (ointment for external and local use No. 17 with sparfloxacin) 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).

Example 51

The ointment from example 29 (ointment for external and local use No. 21 with moxifloxacin) 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 compositions for filling aerosol cans.

Example 52

Pharmaceutical combination aerosol composition No. 1.

Example 53

Pharmaceutical combination aerosol composition No. 2.

Example 54

Pharmaceutical combination aerosol composition No. 3.

Example 55

Pharmaceutical combination aerosol composition No. 4.

Example 56

Pharmaceutical combination aerosol composition No. 5.

Examples of a pharmaceutical combination composition used in the form of a spray.

Example 57

Pharmaceutical combination composition for spray No. 1.

Example 58

Pharmaceutical combination composition for spray No. 2.

Example 59

Pharmaceutical combination composition for spray No. 3.

Example 60

Pharmaceutical combination composition for spray No. 4.

Example 61

Pharmaceutical combination composition for spray No. 5.

The antimicrobial activity of ointments based on some of the proposed pharmaceutical combined compositions was studied according to the “Guidelines 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 using the 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 hole, as well as the growth retardation zone of up to 10 mm, were considered as lack of sensitivity to the drug;

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

- growth inhibition 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 table 2 shows the results of experimental verification of antimicrobial activity against hospital strains of known ointments in comparison with some combined hydrophilic ointment compositions according to the proposed invention.

From the data of this table it can be 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.

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 formed, as well as aerosols and sprays containing fluoroquinolones and targeted additives.

The proposed pharmaceutical combination compositions based on fluoroquinolones with the above target additives destroys both gram-positive and gram-negative microorganisms, including those resistant to antibiotics, as well as fungi and protozoa. They have high therapeutic activity, improve usability, reduce the consumption of the active substance, help cleanse wounds from purulent necrotic masses, give an anesthetic effect, additionally stimulate reparative processes in the wound, improve microcirculation, reduce secondary tissue necrosis in the wound circumference associated with excess free radical oxidation, reduce the likelihood of resistant strains to the antimicrobial complex of the composition, have a local immunomodulating effect.

The search for information did not reveal identical and similar technical solutions. From the sources studied, it is known that fluoroquinolones can be combined with aminoglycosides, metronidazole, dioxidine and some other antibacterial drugs, and an additive or synergistic effect is observed. However, in known sources, the authors have not found the combined use of one or two fluoroquinolones in one pharmaceutical composition for the treatment of purulent wounds together with antibiotics that are not fluoroquinolones, synthetic antibacterial agents, including those that reduce the resistance of microorganisms, antimycotics, immunomodulators. An unexpected effect of the proposed solutions is to increase the activity and expand the therapeutic effect of the composition containing fluoroquinolones and the listed target additives on a hydrophilic basis.

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

The set of essential features of the claimed pharmaceutical combined compositions for external use based on fluoroquinolone 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 combined compositions does not follow obviously from the existing level of technology, since it was not previously known that some active target additives indicated in the considered technical solution retain their activity when used together with fluoroquinolones in one composition on hydrophilic basis.

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

Therefore, the applicant believes that the claimed pharmaceutical combination of the composition for local and external use based on fluoroquinolones and target additives according to the proposed solution meets the criterion of "novelty" and has an inventive step.

The inventive pharmaceutical combination compositions based on fluoroquinolones 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. ), in the treatment of patients with extensive atherosclerotic and venous trophic ulcers, with diabetic foot syndrome complicated by the infection caused by vysokorez tent gram-positive and gram-negative aerobic and anaerobic microorganisms, fungi, resistant to the vast majority of systemic antimicrobial and antifungal drugs.

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

The proposed pharmaceutical combination compositions for local and external use on the basis of fluoroquinolones and target additives can be used for industrial serial production of liquid dosage forms, for example, such as solutions, liniment, suspensions, but not limited to, oily soft forms, for example, such as ointments, gels, but not limited to them, as well as for industrial production of formed soft dosage forms (suppositories and gelatin capsules for rectal administration), and gaseous aerosols olei and sprays.

IPC 90 fluoroquinolones presented in the proposed pharmaceutical combination composition

Claims (34)

1. A pharmaceutical composition for treating purulent wounds, comprising an antibiotic from the fluoroquinolone class, an anesthetic and a base, characterized in that it contains at least one substance selected from the series: antibiotic - aminoglycoside selected from the group of netilmicin, amikacin and sisomycin, dioxidine and / or a synthetic antibacterial agent that reduces the resistance of microorganisms, an enzyme or complex of enzymes with proteolytic and / or bacteriolytic activity, a synthetic immunomodulator or their physiologically acceptable w mixture with the following ratio of components, wt.%: fluoroquinolone class antibiotic                                     0.05-5.00 anesthetic                                                                                         0.5-6.0 antibiotic - aminoglycoside selected from the group netilmicin, amikacin and sisomycin                              0.5-5.5 dioxidine and / or synthetic antibacterial agent microbial resistance                             0.01-5.0 an enzyme or complex of enzymes with proteolytic and / or bacteriolytic activity 0.05-16.00 synthetic immunomodulator                                                 0.05-12.50 the basis                                                                                                 rest, however, an antibiotic from the fluoroquinolone class is limited to one substance selected from the series: ciprofloxacin, levofloxacin, sparfloxacin, moxifloxacin, or a combination of the two. 2. The pharmaceutical composition according to claim 1, characterized in that it contains lidocaine or trimecaine as an anesthetic. 3. The pharmaceutical composition according to claim 1, characterized in that it contains dioxidine, preferably in an amount of 0.1-5.0 wt.%. 4. The pharmaceutical composition according to claim 1, characterized in that as a synthetic antibacterial agent that reduces the resistance of microorganisms, it contains at least one substance selected from the series: Trilon B, trimethoprim, dimexide, surface-active antiseptic, or a mixture thereof. 5. The pharmaceutical composition according to claim 4, characterized in that as a surface-active antiseptic, it contains at least one substance selected from the series: miramistin, decamethoxin, sodium lauryl sulfate, or a mixture thereof. 6. The pharmaceutical composition according to claim 1, characterized in that the enzyme or complex of enzymes with proteolytic and / or bacteriolytic activity for the treatment of purulent wounds is limited to only one substance selected from the range: lidase, asperase, protease, collagenase, lysoamidase, imosimase, ultralizin . 7. The pharmaceutical composition according to claim 1, characterized in that the synthetic immunomodulator is limited to only one substance selected from the range: tilorone, cycloferon, polyoxidonium. 8. The pharmaceutical composition according to claim 1, characterized in that it also includes a reparative process stimulator, limited to only one substance selected from the series: xymedon, methyluracil, ethaden, in an amount of from 0.5 to 10.0 wt.% . 9. The pharmaceutical composition according to claim 1 or 8, characterized in that it additionally includes an antimycotic - clotrimazole or cyclopiroxolamine - in an amount of from 0.2 to 3.5 wt.%. 10. The pharmaceutical composition according to claim 1, characterized in that it contains at least one hydrophilic substance selected from the series: proxanol (emuxole), polyethylene oxide, propylene glycol, polyvinylpyrrolidone, polyethylene oxide gel 1500, glycerohydrogel based on silicon glycerates, calcium or magnesium alginate, acrylic acid copolymer, sodium carboxymethyl cellulose, oxidized cellulose, methyl cellulose, glycerin or a physiologically acceptable mixture thereof in various combinations providing rheological requirements depending on the dosage form of the pharmaceutical combination composition and, if necessary, in a mixture with at least one substance from the series: phosphate buffer solution, purified water, alcohol of higher fat synthetic fractions, vinylin, emulsifier, solubilizer, stabilizer, detergent , preservative, or a mixture thereof. 11. The pharmaceutical composition according to p. 1, or 8, or 9, characterized in that it is made in the following dosage forms: liquid, soft, solid, gaseous. 12. The pharmaceutical composition according to p. 11, characterized in that it is made in the form of a liquid dosage form: solution, suspension. 13. The pharmaceutical composition according to p. 11, characterized in that it is made in the form of a soft dosage form: liniment, ointment, gel, cream, suppositories. 14. The pharmaceutical composition according to claim 11, characterized in that it is made in the form of a solid dosage form - capsules for rectal or vaginal use. 15. The pharmaceutical composition according to p. 11, characterized in that it is made in the form of a gaseous dosage form: aerosol or spray. 16. A pharmaceutical composition for the treatment of purulent wounds containing ofloxacin, anesthetic and a base, characterized in that it contains at least one substance selected from the series: sparfloxacin, antibiotic aminoglycoside, dioxidine and / or synthetic antibacterial agent that reduces the resistance of microorganisms, an enzyme or complex of enzymes with proteolytic and / or bacteriolytic activity, a synthetic immunomodulator or their physiologically acceptable mixture in the following ratio of components, wt.%: ofloxacin                                                                              0.05-5.00 sparfloxacin                                                                  0.05-5.00 anesthetic                                                                                  0.5-6.0 antibiotic - aminoglycoside                                              0.5-5.5 dioxidine and / or synthetic antibacterial microorganism resistance agent        0.01-5.0 enzyme or proteolytic enzyme complex and / or bacteriolytic activity                            0.05-16.00 synthetic immunomodulator                                        0.05-12.50 the basis                                                                                        rest, while the antibiotic - aminoglycoside is selected from the group comprising netilmicin, amikacin and sisomycin. 17. The pharmaceutical composition according to claim 16, characterized in that it contains lidocaine or trimecaine as an anesthetic. 18. The pharmaceutical composition according to p. 16, characterized in that it contains dioxidine, preferably in an amount of 0.1-5.0 wt.%. 19. The pharmaceutical composition according to p. 16, characterized in that as a synthetic antibacterial agent that reduces the resistance of microorganisms, it contains at least one substance selected from the series: Trilon B, trimethoprim, dimexide, surface-active antiseptic or a mixture thereof. 20. The pharmaceutical composition according to p. 19, characterized in that as a surface-active antiseptic, it contains at least one substance selected from the series: miramistin, decamethoxin, sodium lauryl sulfate, or a mixture thereof. 21. The pharmaceutical composition according to claim 16, wherein the enzyme or complex of enzymes with proteolytic and / or bacteriolytic activity is limited to one substance selected from the range: lidase, asperase, protease, collagenase, lysoamidase, imosimase, ultralysin. 22. The pharmaceutical composition according to p. 16, characterized in that the synthetic immunomodulator is limited to one substance selected from the range: tiloron, cycloferon, polyoxidonium. 23. The pharmaceutical composition according to claim 16, characterized in that it further comprises a reparative process stimulator limited to one substance selected from the series: xymedon, methyluracil, ethaden, in an amount of from 0.5 to 10.0 wt.%. 24. The pharmaceutical composition according to p. 16 or 23, characterized in that it additionally includes an antimycotic - clotrimazole or cyclopiroxolamine in an amount of from 0.2 to 3.5 wt.%. 25. The pharmaceutical composition according to p. 16, characterized in that it contains at least one hydrophilic substance selected from the series: proxanol (emuxol), polyethylene oxide, propylene glycol, polyvinylpyrrolidone, gel of polyethylene oxide 1500, glycerohydrogel based on silicon glycerates, calcium or magnesium alginate, acrylic acid copolymer, sodium carboxymethyl cellulose, oxidized cellulose, methyl cellulose, glycerin or their physiologically acceptable mixture in various combinations providing rheological requirements depending on the dosage form of the pharmaceutical combination composition and, if necessary, in a mixture with at least one substance from the series: phosphate buffer solution, purified water, alcohol of higher fatty synthetic fractions, vinylin, emulsifier, solubilizer, stabilizer, detergent , preservative, or combinations thereof. 26. The pharmaceutical composition according to p. 16, or 23, or 24, characterized in that it is made in the following dosage forms: liquid, soft, solid, gaseous. 27. The pharmaceutical composition according to p. 26, characterized in that it is made in the form of a liquid dosage form: solution or suspension. 28. The pharmaceutical composition according to p. 26, characterized in that it is made in the form of a soft dosage form: liniment, ointment, cream, gel, suppository. 29. The pharmaceutical composition according to p. 26, characterized in that it is made in the form of a solid dosage form - capsules for rectal or vaginal use. 30. The pharmaceutical composition according to p. 26, characterized in that it is made in the form of a gaseous dosage form: aerosol or spray.