RU2404751C2 - Wound healing agent - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the field of medicine, namely to wound healing agents. As antiseptic component the agent contains chloride of poly-(4,9-dioxadodecaneguanidine) (PDDG), or phosphate (PDDG), or succinate (PDDG). Agent contains hydroxyethylcellulose, polyvinylpyrrolidone (Polydone), glycerin, sodium alginate and water at a certain ratio of components.

EFFECT: invention makes it possible to reduce toxicity and allergenicity.

2 tbl, 3 ex

Description

The invention relates to medicine, namely to means, including polymeric materials used in surgery for the treatment of wounds, burns, skin lesions of varying severity.

Local treatment of wounds of various etiologies, including those infected and purulent, remains an urgent problem in modern medicine.

As antibacterial drugs for the treatment of wounds, antibiotics are used (RF patent No. 2034572, class A61L 15/31, publ. 05/10/95), enzymes (RF patent No. 2085218, class A61L 15/00, publ. 07.27.97; RF patent No. 2074709, class A61K 9/06) or anti-inflammatory pharmacological substances, for example, sea buckthorn oil, alfalfa (AS RF No. 602185, class A61L 15/01, RF patent No. 2143925, A61L 15/32).

The many factors of the pathogenesis of wounds, ulcers and abscesses (especially those infected with a sluggish healing process), their anatomy, determine the need for a wide arsenal of drugs and the multi-stage treatment. Therefore, the use of complex drugs, including drug substances acting on different parts of the pathogenetic process, is justified. 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.

Known agent for the treatment of wounds containing the natural dye shikonin with antimicrobial action (RF patent No. 2071788, CL A61L 15/32, publ. 01.20.97, Bull. No. 2).

The disadvantage of this tool is the limited therapeutic effect on the wound process, due only to its antiseptic properties, as well as the absence of a prolonged effect,

The closest in essence and the achieved effect to the proposed invention is a composition for treating 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.

The technical problem solved by the invention is to reduce the toxicity and allergenicity of the drug, in addition, the scope of the drug is expanding.

The technical problem is solved due to the fact that in a wound healing agent including a polyguanidine compound and water, poly- (4,9-dioxadodecanguanidine) chloride, or poly- (4,9-dioxadodecanguanidine) phosphate, or poly- (4,9-dioxadodecanguanidine) and optionally hydroxyethyl cellulose, Polydon, glycerin and sodium alginate in the following ratio of components in wt.%:

polyguanidine compound 0.2-1.0 hydroxyethyl cellulose 0.5-1.5 Polydon 20.0-30.0 glycerol 2.0-5.0 sodium alginate 0.1-0.5 water rest

The invention is illustrated as follows.

The highly effective poly- (4,9-dioxadodecanguanidine) compounds used in the wound healing agent 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.

Most preferred is the use of PDDG succinate.

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

It should be noted that succinic acid, which is part of 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.

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

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.

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.

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, Polydon (modifications A or B-1) with a viscosity of 3000-25000 cps is used. 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 wound healing agent.

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

The quantitative content of the components of the wound healing agent is optimal and is selected on the basis of numerous experiments.

Table 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 1.

The process of preparing a wound healing agent has the following stages. The first stage is dispersed in a weighed amount of water glycerin, hydroxyethyl cellulose, sodium alginate for 30 minutes at a temperature of 35-40 ° C with periodic stirring of the mass. The mixing mode and design features of the reactor should prevent foaming.

The second stage - the residual amount of water, Polydon 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 wound healing agent is Packed in individual sealed packaging, sterilized by the radiation method with a dose of 2.0 ± 0.5 Mrad.

In specific examples, the content of the components of the wound healing agent is presented in wt.%.

Example No. 1

PDDG chloride 0.2 hydroxyethyl cellulose 1,0 Polydon 20,0 glycerol 5,0 sodium alginate 0.3 water rest

The resulting composition stimulates the regeneration processes, contributes to the elimination of wound and microflora, accelerating the healing of lesions. It is used to treat infected wounds, including acute and chronic.

Example No. 2

PDH phosphate 1,0 hydroxyethyl cellulose 1,5 Polydon 23.0 glycerol 3.0 sodium alginate 0.1 water rest

The resulting composition can be used to treat purulent wounds, pressure sores, ulcers of trophic, venous and ulcerative defects in diabetic foot syndrome. Wound healing agent stimulates the development of reparative processes, helps to cleanse and quickly epithelize wounds.

For example, in the treatment of pressure sores, the treatment of which takes a long time with repeated necrotomies, drug changes, a large number of antibiotics, such a case is noted. Patient R., 26 years old, was in the department of City Clinical Hospital №20 in Moscow for 7 months after a serious injury, developed sepsis and with multiple bedsores. After treating the wounds with tampons with the proposed wound healing agent, 3 weeks later the wounds were healed, and it would seem that the hopeless patient was discharged in satisfactory condition.

Example No. 3.

pdg succinate 0.6 hydroxyethyl cellulose 0.5 Polydon 30,0 glycerol 2.0 sodium alginate 0.5 water rest

The resulting composition can be used to treat burns, has a plasticizing effect on the burn wound, creates a moist environment on the wound, optimal for the course of regeneration processes, accelerates epithelization, prevents the penetration of microbes.

The remaining examples are summarized in table 1.

Clinical trials of the proposed wound healing agents were carried out in the Podolsk city clinical hospital, department of purulent surgery GKB number 15 named. O.M. Filatova, Moscow, at the Department of Hospital Surgery No. 1 of the Russian State Medical University of Moscow.

The study included 243 patients, including 195 patients with infectious and inflammatory diseases of the skin and soft tissues: acute, chronic, postoperative (festering) wounds, pressure sores, ulcers (trophic, venous, SDS), as well as 48 patients with burns to the body and limbs.

The area of wound defects ranged from 2.0 to 100 cm. ² Wounds were in stages I-III of the wound process.

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

Processing was carried out daily in the presence of inflammation in the wound area.

When perifocal inflammation subsided, exudation decreased and marginal epithelialization appeared, the wound was treated with a wound healing agent at least once every 2 days.

The experimental group consisted of 122 patients, in the complex of therapy of which the proposed wound healing agent was used, and 121 patients who made up the control group received standard therapy.

All patients aged 19 to 67 years. Control patients were comparable with the experimental groups by the nature of the pathology and age.

Clinical trials have shown that due to the medicinal properties of the composition, the proposed wound healing agent provides a plasticizing effect on wound tissues, stimulates autolysis and allows you to quickly clean the wound of necrotic masses, fibrinous plaque and cellular detritus, accelerating the granulation process. The positive dynamics during the wound process, which was characterized by an accelerated rate of cleansing the wound from necrosis, the growth of granulation tissue and marginal epithelization, made it possible to shorten the hospitalization of patients.

Biomedical tests conducted at the Testing Laboratory of the Research Institute of Transplantology and Artificial Organs of the Russian Medical Technologies showed the absence of cytotoxicity in the suspension short-term culture of mobile cells (cattle seed) and on the mouse fibroblast culture of the L-929 line. Tests in vivo in animals have shown that the proposed wound healing agent does not cause an allergic, sensitizing effect, not toxic.

Tests to determine the antimicrobial activity of the drug were carried out in two ways. The first method was used to determine the zones of suppression of microorganisms during diffusion of the test substance into a solid nutrient medium (Fedorov Yu.A., Koren V.N. “Microbiological methods for the study of dental hygiene products” in the book “Fundamentals of oral hygiene.” L., “Medicine ", 1973, s.3-215).

For this, 1 ml of a 24-hour microbial suspension of test microorganisms with a concentration of 5 × 10 ⁵ CFU / ml was applied to the surface of a solid nutrient medium in a Petri dish (20 ml). It was dried for 30 minutes, and then wells with a diameter of 6 mm were made in a nutrient medium into which samples of the proposed wound healing agent were placed. The number of holes did not exceed 6 per Petri dish. For 30 minutes, Petri dishes were kept at room temperature (20 ° C), then they were placed in a thermostat for 24-48 hours at a temperature of 37 ° C and, after this period, the zones of inhibition of microbial growth, including the diameter of the wells, were taken into account. The size of the zones of oppression was judged on the antimicrobial effect of the investigated composition. It should be borne in mind that the diffusion rate of polymer antiseptic agents is lower than the diffusion rate of low polymer antiseptic agents.

To obtain reliable results, all experiments were performed in triplicate, the testing time was 48 hours. The experimental data were processed statistically.

Table 2 presents the test results of the antimicrobial activity of the samples of the wound healing agent according to examples 1, 2 and 3, as well as to compare the sample of the agent made according to the composition of the prototype (1% aqueous solution of PHMG).

The proposed wound healing agents formed growth retardation zones from 20 to 40 mm, which corresponds to a sufficiently high antimicrobial activity, while the agent made using polyhexamethylene guanidine phosphate (according to the prototype) showed growth retardation zones from 18 to 24 mm.

The second way to test antimicrobial activity is to determine 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 wound healing agents, performed according to examples 1, 2 and 3, showed that after 2 minutes of contact, no microflora was found in any case after contamination of the nutrient medium with Escherichia coli.

The results of antimicrobial activity tests showed that the proposed wound healing along with stimulating regeneration action has a high antimicrobial effect, which contributes to a significant reduction in the level of bacterial infection, which is important in the treatment of infected wounds and the prevention of suppuration after damage to the skin.

table 2 Wound healing samples Microorganism growth inhibition zones, mm S. aureus E. coli Ps. aeruginosa Example 1 28 22 24 Example 2 40 27 26 Example 3 33 25 twenty Prototype Example 24 twenty eighteen

Claims (1)

A wound healing agent comprising a polyguanidine compound and water, characterized in that poly- (4,9-dioxadodecanguanidine) chloride, or poly- (4,9-dioxadodecanguanidine) phosphate, or poly- (4,9- dioxadodecanguanidine) and additionally contains hydroxyethyl cellulose, polydone, glycerin and sodium alginate in the following ratio, wt.%:
polyguanidine compound 0.2-1.0 hydroxyethyl cellulose 0.5-1.5 polydon 20.0-30.0 glycerol 2.0-5.0 sodium alginate 0.1-0.5 water rest