RU2403014C1 - Wound healing agent - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine and represents a wound healing agent containing terrilytinum, sodium alginate and water characterised by the fact that in addition, it contains polyguanidine compound - poly-(4,9-dioxadodecanguanidine) chloride, or poly-(4,9-dioxadodecanguanidine) phosphate, or poly-(4,9-dioxadodecanguanidine) succinate, polydon, glycerin, hydroxyethylcellulose, and polyethylene glycol, with the components of the agent being in a certain relation, wt %.

EFFECT: invention provides higher stability of composition, better wound healing properties and accelerated course of a healing process.

1 ex, 2 tbl

Description

The invention relates to medicine, can be used in the manufacture of medicines for the treatment of purulent wounds of varying severity.

In the medical practice of treating wounds of various etiologies and genesis, drug-based hydrogel forms of enzyme-based preparations are of great importance for the effective treatment of infected purulent wounds, rejection of necrotic tissue after burns and frostbite, and acute inflammatory processes after surgical interventions.

The many factors of the pathogenesis of wounds, burns, purulent and inflammatory diseases necessitates the use of effective complex agents with antimicrobial and proteolytic effects, maintaining stability and high activity for a long time, able to affect different parts of the pathogenetic process. However, the use of many drugs containing combinations of drugs to date does not always give a positive effect due to their incompatibility in one drug, which is accompanied by adverse reactions in the form of burning, hyperemia or allergic manifestations. All this limits the use of known means.

A known composition for processing the hands of medical personnel, purulent wounds, injection and surgical fields, set forth in US Pat. RF №2122865, cl. A61L 2/16, Bull. No. 34, 1998

The composition contains an antiseptic agent based on polyguanidine - polyhexamethylene guanidine phosphate (PHMG).

The compounds used retain their antiseptic properties for a long time.

However, hexamethylenediamine used in the production of PHMG phosphate is an allergen, and PHMG transfers these allergenic properties.

Closest to the proposed invention is a composition for covering the wound surface containing sodium alginate, terrilithin, calcium gluconate and water (US Pat. RF No. 2028158, CL A61L 15/38, 1985).

Known drug is highly effective.

However, in this combination, terrilithin is inactivated rather quickly and does not provide the desired therapeutic effect.

When applied to a wound with such a composition, the proteolytic activity of terrilitin decreases.

The technical problem solved by this invention is to increase the stability of the composition, increase the wound healing properties and accelerate the healing process.

To achieve the technical task, a wound treatment product comprising terrilithin, sodium alginate and water additionally contains polyguanidine phosphate or chloride or poly (4,9-dioxadodecanguanidine) succinate, Polydon, hydroxyethyl cellulose glycerin, polyethylene glycol in the following ratio of components in wt.%:

polyguanidine compound 0.2-1.0 terrilitin 15-30 PE sodium alginate 0.1-0.5 polydon 20.0-45.0 glycerol 2.0-5.0 hydroxyethyl cellulose 0.3-1.5 polyethylene glycol 1.0-8.0 water rest

The invention is illustrated as follows.

The highly effective compounds of poly- (4,9-dioxadodecanguanidine) used in the composition for treating wounds have a wide range of biocidal activity with a prolonged effect: antibacterial, fungicidal and virucidal. These compounds have low toxicity and are not allergens.

ECOSEPT poly- (4,9-dioxadodecanguanidine (PDDH) chloride, ECOSEPT poly- (4,9-dioxadodecanguanidine (ECDM) phosphate, and ECOSEPT succinate and PDCG succinate are used as polyguanidine compounds.

These compounds are produced by the Institute of Ecological and Technological Problems (IETP). ECOSEPT trademark belongs to ROO IETP.

The poly- (4,9-dioxadodecanguanidine) succinate (disubstituted) has the following structural formula:

It should be noted that succinic acid, which is part of the PDDG succinate, is a bioactive natural compound. It is present in the human body and therefore a salt of succinic acid is necessary for a person. Succinate PDDH increases the prolonged antiseptic effect of the composition and is most preferred in use.

Terrilitin is introduced into the composition to increase the therapeutic effect of the composition.

The pharmacological effect of terrilithin is the effect on tissue metabolism, the ability to break down necrotic tissue, thin the purulent exudate and blood clots.

Terrylitin is an enzyme preparation of proteolytic action, is a vital product of the mold fungus Aspergillus terricola. Terrylitin is an amorphous powder, white, or white with a yellow tint, or an odorless porous mass, soluble in water, an isotonic sodium chloride solution, or 0.25% novocaine solution, practically insoluble in alcohol.

Manufacturer - Federal State Unitary Enterprise "St. Petersburg Research Institute of Vaccines and Serums and the Enterprise for the Production of Bacterial Preparations" FMBA of Russia (FS 42-2245-98).

Sodium alginate (VFS 42-1680-87) is a fine white powder, refers to polysaccharides, is readily soluble in water, hygroscopic. Sodium alginate effectively stimulates cell regeneration, helps to stop bleeding, eliminate inflammation and accelerate healing processes, and also has sorbing properties, which is especially important in the wound process. The combination of sodium alginate with the polymer components of the composition of the wound healing agent provides the formation of an additional polymer layer, which makes the wound micro-impermeable.

The combination of sodium alginate with terrilitin helps to increase the activity and stability of terrilithin.

Polydon - is a water-polymer composition of high molecular weight polyvinylpyrrolidone in the form of a transparent gel. Polydon is produced by LLC Orgpolymersynthesis SPb, St. Petersburg in accordance with TU 9365-002-46270704-2001, using polydon (modifications A or B-1) with a viscosity of 3000-25000 cP. Polydon in combination with a polyguanidine compound forms complexes with reduced toxicity, and also helps to increase the stability and homogeneity of the composition of the means for treating wounds.

Glycerin is an enveloping and astringent component. Glycerin (GOST 6259-75) is a transparent viscous liquid with a basic substance content of at least 99 wt.%. Glycerin promotes the penetration of active substances into the affected area of the skin, and also has a softening and astringent effect.

Hydroxyethyl cellulose is a water-soluble cellulose derivative and is used as a gelling component in wound care products. This is a white powder with a content of the main component of at least 97 wt.% (TU 6-05-1857-87).

Polyethylene glycol is a transparent, viscous, colorless or almost colorless hygroscopic liquid, used as a thickener and stabilizer of the hydrogel composition of the product. Polyethylene glycol with a molecular weight of 285-630 g / mol (PEG 300 - PEG 600) is most preferred as a structure-forming component for this composition. Manufacturer - Merck KGaA (Germany) with the marking of PEG 300, PEG 400, PEG 600.

The high effectiveness of the claimed funds for the treatment of wounds is achieved due to the combined action of terrilithin and polyguanidine compounds. This combination contributes to the stability of the therapeutic effect of terrilithin and the biocidal effect of the polyguanidine compound, which leads to increased protective properties of the skin, regeneration of affected skin areas, accelerates epithelization and restoration of the affected area.

The hydrogel base, on which the mixture is prepared, provides easy and quick penetration of the substance into the tissue, and also protects the terrilithin enzyme from destruction. To a large extent, this is facilitated by the mutual interaction of terrilithin and the guanidine compound.

Water is used as a base according to GOST 6709-72 (distilled).

The quantitative content of the components of the means for treating wounds is optimal and is selected on the basis of numerous experiments.

Table No. 1 presents data confirming the optimality of the declared limits.

Alternative features of claim 1 of the claims provide the same technical result as shown in table No. 1.

The preparation process has the following stages.

The first stage - in the reactor at a temperature of 35-40 ° C with periodic mixing of the mass, glycerin, hydroxyethyl cellulose, sodium alginate are dispersed in a weighed amount of water.

The design features of the reactor and the mixing mode should prevent foaming.

The second stage - the residual amount of water, polydone, polyethylene glycol, terrilithin and the polyguanidine compound are successively introduced into the resulting dispersion with stirring. Then the mixture is stirred at a temperature of 25-30 ° C for 1-2 hours until a homogeneous viscous solution is obtained.

The resulting product is Packed in individual sealed packaging, sterilized by the radiation method with a dose of 2.0 ± 0.5 Mrad.

The resulting agent for the treatment of wounds is a homogeneous translucent hydrogel, easily applied to diseased areas of the skin. The tool is highly stable.

Example No. 1.

In the reactor at a temperature of 35 ° C with stirring in a weighed amount of water, dispersed in wt.%: Glycerol - 3.0, hydroxyethyl cellulose - 1.0, sodium alginate - 0.1.

A homogeneous dispersion is obtained in the form of a gel. The rest of the water is introduced sequentially with stirring and in wt.%: Polydone - 20.0, polyethylene glycol (PEG-300) - 1.0, terrilithin - 15 PE and polyguanidine compound - PDDG chloride - 0.2.

The resulting agent in the form of a hydrogel is applied to the affected area. The hydrogel is easily modeled in various parts of the body, and adheres well to the wound surface. Other examples are summarized in table No. 1.

The successful use of the agent for the treatment of purulent wounds was discovered (combustiology, purulent surgery, podiatry, phlebology).

The proposed tool for the treatment of wounds promotes enzymatic cleansing of the wound, stimulates the lysis of necrotic tissue, creates favorable conditions in the wound to suppress wound infection and the development of reparative processes and epithelization of wounds.

Clinical trials of the proposed wound healing agents were carried out in 574 hospital of the Moscow military district, purulent surgery department of Clinical hospital №15 named after O.M. Filatova, Moscow, Department of Hospital Surgery No. 1 of the Russian State Medical University, Moscow.

The study included 146 patients, of which 120 patients with infectious and purulent-inflammatory diseases of the skin and soft tissues; chronic purulent, postoperative (festering) wounds, pressure sores, trophic ulcers, venous ulcers, diabetic foot syndrome, as well as 46 patients with an infected burned surface of the body.

The area of wound defects ranged from 2.0 to 100 cm.

Before applying the product, the wound was treated with saline and thoroughly dried.

Processing was carried out daily in the presence of a purulent-inflammatory process in the wound area.

An agent for treating wounds was used until the stage of cleansing the wound from necrotic tissue and the absence of purulent discharge.

The experimental group consisted of 75 patients, in the complex of therapy of which the proposed agent for the treatment of wounds was used, and 71 patients who made up the control group received standard therapy.

All examined patients were aged 19 to 65 years. Control patients were comparable with the experimental groups by the nature of the pathology and age.

Clinical trials have shown that the proposed tool for the treatment of wounds provides easy simulated hydrogel coating of the wound, contributes to the rapid cleansing of wounds from necrotic masses due to the healing properties of the composition, which accelerates granulation and positive dynamics of the course of the wound process. In addition, the proposed tool for the treatment of wounds has an antimicrobial effect, preventing secondary infection of the wound, which is also one of the conditions for the speedy healing of the wound. The absence of an allergic and local irritating effect of the proposed means for treating wounds is shown.

The proteolytic activity of the agent was determined by the Kunitz method. The modification method using casein substrate is based on determining the rate of the enzymatic reaction of substrate hydrolysis under the action of the studied proteolytic enzymes. A 2% casein solution in 0.2 M phosphate buffer solution at pH 8.0 was used as a substrate. The substrate was stirred on a magnetic stirrer until completely dissolved at room temperature. Casein solution was stored at a temperature of 5-7 ° C for no more than 10 days in the dark. Before analysis, the pH of the casein solution was adjusted to pH 8.0 with a concentrated sodium hydroxide solution on a pH meter.

Phosphate buffer pH 8.0 was poured onto the samples (experimental and control) and placed on a shaker in a thermostat at a temperature of 37 ° C. After 10 minutes, 2% casein solution was rapidly poured into the tubes. First, a predetermined volume of 10% trichloroacetic acid solution and then casein solution were poured into a control tube. The contents of the tubes were mixed and placed for 60 minutes on a shaker in a thermostat. The reaction was stopped by adding to each tube a predetermined amount of 10% trichloroacetic acid solution. After 10-15 minutes (after sedimentation), the resulting suspension was filtered through a paper filter. Then, the optical density was measured on a spectrophotometer at 280 nm.

The value of proteolytic activity was calculated by the formula:

;

;

Dop - the optical density of the experimental sample;

Dk is the optical density of the control sample;

P is the dilution;

CT is the tyrosine coefficient;

t is the incubation time in minutes;

g - sample, mg.

Table No. 2 presents the data on the relative proteolytic activity of terrilithin (the initial activity of terrilithin was taken as the activity of samples of the drug before irradiation) in the proposed tool for treating wounds after radiation sterilization.

From table No. 2 it follows that the components of the composition of the proposed means for the treatment of wounds have a stabilizing effect on the proteolytic activity of terrilithin in the sterilization process. High levels of terrilitin activity after exposure to ionizing radiation are stored in the hydrogel composition of the product without the use of freezing and freeze drying.

Samples of the proposed funds and the prototype sample were tested for antimicrobial activity, which consists in determining the minimum time required to completely suppress the growth and development of test microorganisms.

A suspension of test microorganisms was added to the test substance in an amount of 10 ⁵ CFU / ml; for this, 1 ml of the test substance was poured into test tubes. The tubes were shaken and, at intervals of 2-5-10 and 30 minutes, were sown on solid nutrient media. Petri dishes were placed for 24-48 hours in a thermostat at 37 ° C. After this period, the number of colonies grown was counted and the bactericidal activity of the test substance was judged by this indicator.

The results of the study of samples of funds for the treatment of wounds, performed according to examples 1, 2 and 3, showed that after 2 minutes of contact in no case was live microflora detected after contamination of the nutrient medium with Escherichia coli, while the prototype sample showed the absence of antimicrobial activity.

Thus, the high effectiveness of the claimed funds for the treatment of wounds is confirmed by the preservation of the high proteolytic activity of the agent after sterilization. The use of a sterile hydrogel agent promotes the rapid cleansing of wounds from necrotic masses, a significant reduction in the level of bacterial infection due to the high antimicrobial activity, which is important in the treatment of infected wounds and the prevention of secondary infection.

Table 1 No. p / p The connection polyguanidine, wt.% Terry Litin, PE Sodium alginate, wt.% Polydon, wt.% Glin rin, wt.% Hydroxy ethyl cellulose, wt.% PEG, wt.% Water Note one 2 3 four 5 6 7 8 one PDDG chloride - 0.2 fifteen 0.1 20,0 3.0 1,0 1.0 (PEG300) rest A homogeneous transparent wound treatment with a prolonged biocidal and wound healing effect. 2 PDDH phosphate - 1.0 thirty 0.3 30,0 5,0 1,5 5.0 (PEG400) rest 3 PDG succinate - 0.6 twenty 0.5 45.0 2.0 0.3 8.0 (PEG600) rest four PDDG chloride - 0.15 * twenty 0.5 30,0 3.0 1,0 5.0 (PEG400) rest Decrease in biocidal effect and prolonged action. 5 PDDG chloride - 1.05 * twenty 0.5 30,0 3.0 1,0 5.0 (PEG400) rest Technically impractical. 6 PDDG chloride - 0.6 fourteen* 0.5 30,0 3.0 1,0 5.0 (PEG400) rest Decrease in wound healing effect. 7 PDDG chloride - 0.6 31 * 0.5 30,0 3.0 1,0 5.0 (PEG400) rest Limit the scope of the tool. 8 PDDG chloride - 0.6 twenty 0.05 * 30,0 3.0 1,0 5.0 (PEG400) rest Decrease in therapeutic effect. 9 PDDG chloride - 0.6 twenty 0.55 * 30,0 3.0 1,0 5.0 (PEG400) rest Deterioration of technological characteristics. 10 PDDG chloride - 0.6 twenty 0.5 18.0 * 3.0 1,0 5.0 (PEG400) rest Promotes thinning of the composition. eleven PDDG chloride - 0.6 twenty 0.5 47.0 * 3.0 1,0 5.0 (PEG400) rest Increasing the viscosity of the composition. 12 PDDG chloride - 0.6 twenty 0.5 30,0 1.9 * 1,0 5.0 (PEG400) rest Deterioration in performance. 13 PDDG chloride - 0.6 twenty 0.5 30,0 5.1 * 1,0 5.0 (PEG400) rest Promotes thinning of the composition. fourteen PDDG chloride - 0.6 twenty 0.5 30,0  3.0 0.2 * 5.0 (PEG400) rest Liquefying the composition. fifteen PDDG chloride - 0.6 twenty 0.5 30,0  3.0 1.6 * 5.0 (PEG400) rest Unwanted thickening of the composition. 16 PDDG chloride - 0.6 twenty 0.5 30,0  3.0 1,0 0.9 * (PEG400) rest Deterioration of the structural characteristics of the product. 17 PDDG chloride - 0.6 twenty 0.5 30,0  3.0 1,0 8.1 * (PEG400) rest Decrease in wound healing effect. Note: * - the content of the component is beyond the stated limits.

table 2 Wound Treatment Samples Dose, kGy fifteen twenty 25 thirty 35 Example 1 97.4 97.2 96.7 94.2 91.4 Example 2 98.3 98.1 97.8 96.4 92.2 Example 3 96.8 96.6 96.5 94.1 89.2 Prototype Example 98.3 98.0 96.3 92.1 88.9

Claims (1)

An agent for treating wounds, including terrilithin, sodium alginate and water, characterized in that it further comprises a polyguanidine compound - poly- (4,9-dioxadodecanguanidine) chloride, or poly- (4,9-dioxadodecanguanidine) phosphate, or poly- ( 4,9-dioxadodecanguanidine), polydone, glycerin, hydroxyethyl cellulose and polyethylene glycol in the following ratio, wt.%:
polyguanidine compound 0.2-1.0 terrilitin 15-30 PE sodium alginate 0.1-0.5 polydon 20.0-45.0 glycerol 2.0-5.0 hydroxyethyl cellulose 0.3-1.5 polyethylene glycol 1.0-8.0 water rest