RU2445083C1 - Agent for treating pyoinflammatory processes of soft tissues and mucous membranes - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and is applied in surgery, dermatology, obstetrics, gynaecology and otorhinolaryngology for treating pyoinflammatory processes of soft tissues and mucous membranes. An agent contains the following components, mass fractions: as a base - enterosgel (60.0-80.0), as therapeutic components, an antiseptic - 0.05% chlorhexidine bigluconate (20.0-40.0), and a regeneration stimulator - methyluracil (2.0-4.0).

EFFECT: invention provides the therapeutic agent possessing antiseptic, wound-healing and sorption functions.

4 tbl, 2 ex

Description

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

Among topical drugs for the treatment of purulent-inflammatory processes of soft tissues, ointments and gels on the bases that do not injure the damaged surface when applied to the wound are widely used, provide drainage of the wounds, and the medicinal substances that make up their composition provide the necessary therapeutic effect. Most ointments and gels of this use contain antibiotics. However, at present, interest has increased in antiseptics, which have a much smaller range of side effects, they are less likely to develop microbial resistance, they practically do not cause allergic reactions, and at the same time they have a wide spectrum of antimicrobial effects, and retain their activity for a long time.

The prototype of the invention was the drug "Imosgent" manufactured by ZAO "EOF" KREOMA-PHARM "(Ukraine) (Secret developments serve medicine /www.apteka.ua/ No. 239 (18) from 05/10/2000), which consists of enterosgel and immobilized on its surface is the antibiotic gentamicin sulfate. However, the antibiotic gentamicin sulfate is rather obsolete and has a wide range of side effects (nephrotoxicity, neurotoxicity, ototoxicity, elevated serum levels of liver transaminases, bulirubina, urea and creatinine, cylinduria, proteinuria, anemia, granulocytopenia, fever, skin rash, pruritus, rash, nausea vomiting, headache, drowsiness).

The objective of the invention is the creation of a medicinal product with antiseptic, wound healing and sorption functions.

This object is achieved in that the agent consists of enterosgel and a solution of chlorhexidine bigluconate (0.05%) and a regeneration stimulator - methyluracil immobilized on its surface by simple physical immobilization in the following ratio of components, mass fractions:

Methyluracil 2.0-4.0

(FS 42-0256-07)

A solution of chlorhexidine bigluconate (0.05%) 20.0-40.0

(TU 9158-002-76922630-2005)

Enterosgel 60.0-80.0

(FSP 42-0533540704)

Feature Description

Methyluracil. 2,4-dioxo-6-methyl-1,2,3,4-tetrahydro-pyrimidine. Synonym: Metacil. Flavourless white crystalline powder. Slightly soluble in water (up to 0.9% at a temperature of + 20 ° C) and alcohol. By the chemical structure, methyluracil is a pyrimidine derivative. According to experimental data, a number of drugs of this group have anabolic and anti-catabolic activity, accelerate cell regeneration processes; accelerate wound healing, stimulate cellular and humoral defense factors. They also have anti-inflammatory effects. A characteristic feature of compounds of this series is the stimulation of erythro- and especially leukopoiesis, in connection with which they are usually assigned to the group of leukopoiesis stimulants. Medicines containing methyluracil: levomecol (chloramphenicol + methyluracil), levosin (chloramphenicol + methyluracil + sulfadimethoxine + trimecaine), methyluracil ointment 10%, waxed (dressing with methyluracil ointment 10%), wax dressing (with beeswax and wax) . Ointments containing methyluracil are used for: nonspecific vulvitis, colpitis, cervical erosion, proctitis, condition after operations on the rectum and perineum, erosive and ulcerative lesions of the oral mucosa and periodontium; burns (II-III century), with sluggish healing wounds, bone fractures. Contraindications: hypersensitivity, excessive granulation at the site of application of the drug.

Chlorhexidine bigluconate. It is one of the most active local antiseptic agents. Chemically, it is a dichloro-containing derivative of biguanide. Chlorhexidine has a fast and strong bactericidal effect on gram-positive and gram-negative bacteria. Not valid for viruses and spores. The drug is stable and after treating it with the skin, it remains on it in a certain amount, which continues to give a bactericidal effect. The drug remains active in the presence of blood, pus. Chlorhexidine is also effective against pathogens of sexually transmitted diseases. To disinfect wounds, burns, use a 0.5% aqueous solution; for hand disinfection - 0.5% alcohol solution or 1% aqueous solution. Release form: 20% aqueous solution in bottles. For the individual prevention of sexually transmitted diseases, it is available in the form of a 0.05% solution in a special plastic package of 100 ml.

Enterosgel. The enterosorbent, created on the basis of a hydrogel of methyl silicic acid, which, having high sorption activity (more than 4.5 μmol / g), also exhibits high selectivity - it sorbs only medium molecular toxic metabolites and substances with a lower molecular weight (metal ions, mineral salts) ) and high molecular weight (common proteins, immunoglobulins) sorption are not exposed. Enterosgel also shows selectivity for sorption of microorganisms. It actively sorbes pathogenic and pathogenic microflora on its surface, destroying its membrane and sorbing cellular contents. The antimicrobial effect of the drug is quite intense: 1 g of enterosgel absorbs more than 10 ⁴ pathogenic bacteria on its surface.

The method is carried out as follows.

The manufacture of a medicine includes two stages:

first stage: the calculated amount of a 0.05% solution of chlorhexidine bigluconate is added to the corresponding sample of enterosgel and mixed until a homogeneous mass is obtained;

second stage: to the pre-ground weighed sample of methyluracil, the obtained enterosgel gel with a 0.05% solution of chlorhexidine bigluconate is added in parts and mixed until a homogeneous mass is obtained.

EXAMPLE ON THE METHOD FOR PRODUCING

To 70.0 mass fractions of enterosgel, 30.0 mass fractions of a 0.05% solution of chlorhexidine bigluconate are added, mixed until a homogeneous mass is obtained, then to obtained 2.0 mass fractions of methyluracil, the resulting enterosgel gel with chlorhexidine bigluconate solution is added in portions and mixed until a homogeneous masses.

DETERMINATION OF THE MICROBIOLOGICAL AND OSMOTIC ACTIVITY OF THE IMMOBILIZED FORM OF CHLORGEXIDINE BIGLUCONATE AND METHYLURACIL

The antimicrobial spectrum of the developed ointment was studied by agar diffusion for St.aureus ATCC 6538-P, Bac.subtilis ATCC 6633, Bac.cereus ATCC 10702, E.coli ATCC 25922, Proteus vulgaris and Pseudomonas aeruginosa ATCC 9027, Candida albicans ATCC strains 885-653. The results of determining the spectrum of antimicrobial activity are presented in table 1.

From the data presented in table 1, it follows that the developed ointment has a biocidal effect in relation to all studied test strains. The growth retardation zone when studying the spectrum of antimicrobial activity of the developed ointment is most pronounced in relation to the test strains St.aureus ATCC 6538-P, E.coli ATCC 25922, which is 1.6-1.8 times more than the growth retardation zone in study 0 , 05% solution of chlorhexidine bigluconate.

The osmotic activity of the developed ointment was determined according to the method of V.G. Gunko in comparison with a 10% hypertonic sodium solution

chloride and 70% aqueous enterosgel gel. The results of determining the osmotic activity of the developed ointment are presented in table.2.

table 2 The results of determining the osmotic activity of the developed ointment (M ± m) Test sample Time h Osmotic activity,% immobilized form of chlorhexidine bigluconate and methyluracil 5 42.2 ± 2.5 * 70% aqueous enterosgel gel 5 37.4 ± 2.8 * 10% sodium chloride solution 5 11.9 ± 1.2 Note: the significance of differences in average values was determined between 70% aqueous enterosgel gel and the immobilized form of chlorhexidine bigluconate and methyluracil in relation to a 10% sodium chloride solution. Index * marks the values of p <0.05.

The data presented in table 2 allow us to conclude that the osmotic activity of 70% aqueous enterosgel gel and the immobilized form of chlorhexidine bigluconate and methyluracil exceed the hypertonic solution by more than 3 times. Thus, enterosgel provides the developed ointment with a high dehydrating effect and will contribute to the removal of purulent exudate from the wounds.

EXAMPLE OF EXPERIMENTAL APPLICATION

The study of the wound healing activity of the developed ointment was carried out in an experiment on male Wistar rats weighing 180-200 g, in which a purulent wound was modeled according to the method of P. I. Tolstoy (1976). The experimental animals were divided into three series, 30 animals each.

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

In the 2nd series (control), they were treated with imosgent ointment.

In the 3rd series (experimental), they were treated with an ointment consisting of a 0.05% solution of chlorhexidine bigluconate and methyluracil immobilized on enterosgel.

Dressings were carried out daily. The course of the wound process in experimental animals was evaluated by clinical (by the external condition of the wound), planimetric (method by L.I. Popova), microbiological, histological methods, the results of the studies were processed statistically (calculated average values, reliability criteria). Animals were withdrawn from the experiment by an overdose of ether anesthesia on days 1, 3, 7, 10, 15.

After modeling on the 1st day in all series, the wounds looked as follows: there was hyperemia, swelling of the surrounding tissues and edges of the wounds, their bottom was covered with plaque of fibrin with patches of necrosis, and abundant purulent discharge was observed.

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

When using the ointment we developed, compared with the control (ointment and imosgent), the time was reduced: the disappearance of perifocal edema was 1.4 times (5.4 ± 0.2 days and 7.8 ± 0.2 days, respectively), the wound cleansed in 1, 3 times (6.9 ± 0.2 days and 8.8 ± 0.2 days, respectively), the appearance of granulations 2.0 times (4.1 ± 0.2 days and 8.3 ± 0.2 days, respectively) , the beginning of marginal epithelization by 2.3 times (4.2 ± 0.2 days and 9.8 ± 0.2 days, respectively). The results of the assessment of the course of the wound healing process are presented in Table 3.

Table 3 The results of the study of the clinical course of the wound process (M ± m) Series Clinical signs (day) The disappearance of perifocal edema Wound cleansing The appearance of granulations Beginning of marginal epithelization Model 8.1 ± 0.2 9.2 ± 0.3 8.5 ± 0.2 10.6 ± 0.2 The control 7.8 ± 0.2 8.8 ± 0.2 8.3 ± 0.2 9.8 ± 0.2 Experienced 5.4 ± 0.2 * 6.9 ± 0.2 * 4.1 ± 0.2 * 4.2 ± 0.2 * Note: the significance of differences in average values was determined in the experimental series - in relation to the control series. Index * marks the values of p <0.05.

Thus, the use of the developed ointment contributed to the reduction of the main phases of the wound healing process by 1.3-2.3 times, in comparison with the treatment with imosgent ointment, which confirms its high efficiency in the treatment of purulent wounds.

The results of a planimetric study indicate a more rapid decrease in the area of wounds in the treatment of developed ointment compared to an untreated wound and a wound treated with an imaging agent. So, by the 7th day, the area of wounds decreased: in the 1st series - by 27.7%, in the 2nd series - by 32.0%, in the 3rd series - by 49.3%, respectively. The results of a planimetric study are presented in table 4.

Table 4 Results of a planimetric study (M ± m) Series The percentage reduction in the area of wounds (%) 3 days 7 days 10 days 15 days Model 12.8 ± 6.1 27.7 ± 9.7 46.1 ± 13.8 78.1 ± 18.5 The control 14.1 ± 6.4 32.0 ± 10.2 48.9 ± 13.9 82.5 ± 17.0 Experienced 20.9 ± 7.4 * 49.3 ± 10.9 * 82.1 ± 10.6 * 99.7 ± 2.6 * Note: The significance of differences in average values was determined in the experimental series - in relation to the control series. Index * marks the values of p <0.05.

Thus, the obtained data of a planimetric study confirm the high efficiency of the developed ointment in the treatment of purulent wounds. It helps to reduce the area of wounds by 99.7 ± 2.6% on the 15th day, increases the healing rate by 1.5-2.1 (1.7 ± 0.1) times in comparison with imosgent ointment.

Data from a microbiological study showed that the 3rd series (treatment with an ointment consisting of a 0.05% solution of chlorhexidine bigluconate and methyluracil immobilized on enterosgel) microbial contamination of wounds was significantly less than in the 2nd series (treatment with an ointment ointment), starting with 3 days and throughout the observation period. In the 3rd series, on the 5th day, the microbial contamination of wounds is 7.4 times less than in the 2nd series (10.9 ± 2.2 × 10 ⁵ and 8.1 ± 2.1 × 10 ⁶ CFU / g, respectively), on the 10th day - 21.3 times less than in the 2nd series (28.7 ± 1.1 × 10 ³ and 6.1 ± 1.5 × 10 ⁵ CFU / g, respectively) , on the 15th day in the 3rd series, the growth of the microbial culture was not observed, and in the 2nd series the microbial seeding was 11.2 ± 0.7 × 10 ⁴ CFU / g. Thus, it was found that the immobilized form of chlorhexidine bigluconate and methyluracil reduces the microbial contamination of wounds by 7.4-21.3 times compared with imosgent ointment.

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

On the 1st day after modeling, the microscopic picture in all series is as follows. The entire surface of the wound is covered with a massive fibrinous-leukocyte layer. Most white blood cells are in a state of decay. The connective tissue under the leukocyte scab is sharply swollen, infiltrated by segmented leukocytes and single macrophages. The underlying connective tissue fiber is loosened, its fibroblasts are polymorphic, have a basophilic cytoplasm and swollen, loosened nuclei. The blood vessels are dilated. There are foci of hemorrhage of diapedetic nature. Edematous phenomena spread to the edges of the skin. The epithelium is dystrophic, vacuolated, its edge is flattened.

On the 3rd day in the group of animals, when treated with ointment imosgent, the surface of the wound is covered with a scab. Under the scab are the rudiments of granulation tissue, infiltrated by polymorphic nuclear leukocytes. On the 7th day on the surface of the wound - a leukocyte-necrotic scab is partially present. The bottom of the wound is made by a full-fledged granulation tissue rich in blood vessels. Fibroblasts of the connective tissue of various process forms are located in cords surrounding the blood vessels. Signs of regional epithelization are noted. On the 10th day, the epithelial shaft was formed at the border of the wound defect. Granulation tissue is clearly delimited from the intact dermis and is infiltrated by polymorphonuclear leukocytes. On the 15th day, the wound defect was completely performed by bundles of immature collagen fibers. The surface of the wound defect is covered by the epidermis, in which the stratum corneum was absent.

On the 3rd day in the treatment using the developed ointment, a sharp boundary of granulation and intact skin is expressed. Moderate infiltration by polymorphonuclear leukocytes of newly formed granulations is noted. On the 7th day, the wound defect is completely filled with granulation tissue and covered with the epidermis. Single subepidermal hemorrhages of intravital origin. Moderate infiltration of granulation by polymorphonuclear leukocytes is noted. On the 10th day there is a “blurring” of the boundaries of the focus of the regenerated reticular dermis and a decrease in the volume of young collagen due to scar remodeling. The skin is restored in the area of the angle of the wound defect. On the 15th day, a complete restoration of the reticular layer of the skin was observed with the exception of derivatives: hair follicles and sebaceous glands.

Thus, in the series where the treatment was carried out with the developed ointment, there is a more rapid cleansing of the wound surface from leukocyte-necrotic masses (by the 3rd day) and more active growth of granulation tissue. The beginning of the growth of the epithelium along the edges of the wound occurs from 3 days. By the 7-10th day, a significant part of the wound or its entire surface is epithelized.

The use of the ointment we developed in the treatment of purulent wounds in the I and II phases of the wound process increases the healing rate by 1.5-2.1 (1.7 ± 0.1) times, helps to reduce the main stages of the course of the wound process by 1.3-2 , 3 (1.8 ± 0.2) times, 7.4-21.3 times reduces the microbial contamination of wounds, accelerates the formation and maturation of granulation tissue, promotes early and rapid epithelization of the wound surface compared to treatment with imosgent ointment.

We give examples:

1) Methyluracil 2.0

A solution of chlorhexidine bigluconate (0.05%) 30.0

Enterosgel 70.0

2) Methyluracil 3.0

A solution of chlorhexidine bigluconate (0.05%) 40.0

Enterosgel 60.0

3) Methyluracil 4.0

A solution of chlorhexidine bigluconate (0.05%) 20.0

Enterosgel 80.0

Claims (1)

An agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes containing sorbent Enterosgel as a base, characterized in that it contains a 0.05% solution of chlorhexidine bigluconate antiseptic and a methyluracil regeneration stimulator in the following mass fractions:
Methyluracil 2.0-4.0 A solution of chlorhexidine bigluconate (0.05%) 20,0-40,0 Enterosgel 60.0-80.0