RU2791374C1 - Wound healing ointment and method for its production - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine and can be used to produce an ointment with wound healing, antimicrobial, sorption and hemostatic effects, and to treat skin lesions with this ointment. The required technical result is achieved by a wound healing ointment containing a mixture of polyethylene oxide obtained by polymerization ethylene oxide with a consistency in the liquid phase of PEO-400 and in the solid phase of PEO-1500 and PEO-4000, as well as an aqueous suspension of a combination of zinc sulphate and copper sulphate. The process for obtaining the ointment is that the prepared sample of PEO-400 and samples of PEO-1500 and PEO-4000 melted at a temperature of 50-60°C, as well as an aqueous suspension in selected concentrations are mixed until complete homogenization, poured into moulds and quickly cooled at 5°C.

EFFECT: obtaining an ointment the composition of which provides a higher efficiency in the treatment of skin lesions and the expansion on this basis of the arsenal of technical means for obtaining ointments with more effective use in the treatment of skin lesions.

3 cl, 3 ex, 3 tbl, 3 dwg

Description

The invention relates to medicine and can be used to produce an ointment with wound healing, antimicrobial, sorption and hemostatic effects, and to treat skin lesions with this ointment.

A drug is known in the form of an ointment [RU 2712088, C1, A61K 31/60, 01/24/2020], which has a wound healing effect, which contains zinc salicylate as an active ingredient in an amount of 0.1-10 wt. %, which, before being introduced into the ointment base, is subjected to mechanical interaction with starch, taken in a ratio of 1:1 or 1:2 by weight, and contains a mixture of polyethylene glycols as an ointment base, optionally with the addition of other excipients.

The disadvantage of this drug is its relatively low efficiency, and the disadvantage of the method of obtaining it is a relatively narrow scope.

The closest in essence to the composition of the proposed wound healing ointment is a wound healing composition in the form of an ointment [RU 2296571, C1, A61K 33/26, 10.04.2007], which includes the active substance and the base, moreover, it contains iron nanoparticles as the active substance, and in as a base it includes polyethylene glycols (PEG) 400 and 1500 in the following ratio of ingredients, g:

Iron nanoparticles 0.001-1 PEG-400 30-95 PEG-1500 up to 100.

A feature of the composition is that iron nanoparticles have a size of 10-100 nm and it may additionally contain glycerin.

The disadvantage of this composition is the relatively low efficiency of its use for the treatment of skin lesions.

The closest in essence to the proposed method for obtaining a wound healing ointment is a method for obtaining a wound healing composition in the form of an ointment [RU 2296571, C1, A61K 33/26, 10.04.2007], according to which the suspension obtained by ultrasonic dispersion of a mixture of iron nanoparticles with a part of the base is mixed with the rest of the base to a homogeneous state, moreover, the process is carried out at a temperature not exceeding 40°C.

A feature of this method is that a mixture of iron nanoparticles with polyethylene glycol-400 is dispersed, and the amount of polyethylene glycol 400 mixed with iron nanoparticles is 50-75 wt. % of the total amount of polyethylene glycol-400.

The disadvantage of this method is a relatively narrow scope, limited by the possibility of obtaining an ointment with a relatively high efficiency in the treatment of skin lesions.

The objective of the present invention is to develop an ointment composition that provides a higher efficiency of its use for the treatment of skin lesions, as well as to develop a method for producing an ointment with a wider scope, including providing an ointment with a more effective composition for the treatment of skin lesions.

The required technical result consists in obtaining an ointment with a composition that provides a higher efficiency of use in the treatment of skin lesions and, on this basis, expanding the arsenal of technical means for obtaining ointments with more effective use in the treatment of skin lesions.

The problem is solved, and the required technical result regarding the composition of the ointment is achieved by the fact that a wound healing ointment containing a mixture of polyethylene oxide with a consistency in the liquid phase of PEO-400 and in the solid phase of PEO-1500 and PEO-4000, as well as an aqueous suspension of a combination of two to three inorganic and/or organic compounds of zinc, copper, silver, aluminum with a metal content of 10 ^-2 to 10 ^-8 mol/l in the following mass. %:

PEO-400 27…32 PEO-4000 1…15 Aqueous suspension of metal compounds 1…20 PEO-1500 up to 100

In addition, the required technical result regarding the composition is achieved by the fact that inorganic and/or organic compounds of zinc, copper, silver, aluminum are used in the form of cationic and anionic complexes.

The problem is solved, and the required technical result regarding the method of obtaining the ointment is achieved by mixing the prepared PEO-400 sample and the PEO-1500 and PEO-4000 samples melted at a temperature of 50-60 ° C, as well as an aqueous suspension in selected concentrations, mixed in a mortar until complete homogenization, poured into molds and quickly cooled at 5°C.

In addition, the required technical result regarding the method of obtaining the composition is achieved by the fact that, with rapid cooling, cylindrical forms are used for further use of the ointment in the form of a wound healing pencil.

The illustrative materials show:

in Fig.1. - a planimetric study of the influence of the hydrophilic base of polyethylene oxide on the wound healing process is illustrated;

figure 2 illustrates a planimetric study of the effect of active additives to the hydrophilic base of polyethylene glycol on the wound healing process;

figure 3 - presents photographs of the results of the experiment on the days of observation;

in table 1 - a comparative analysis of the effectiveness of the use of wound healing compositions according to the patent and the drug "Levomikol";

Table 2 presents the results of static processing of experiments without wound treatment and with daily treatment with PEO composition with the addition of copper and zinc compounds.

The proposed wound healing ointment and method for its preparation are implemented as follows.

Characteristics of the components of the ointment.

Polyethylene oxide is obtained by polymerization of ethylene oxide. The consistency depends on the degree of polymerization: liquid PEO-400 and solid PEO-1500, PEO-4000.

Zinc (in the most common and stable form - zinc sulfate hexahydrate) - colorless transparent crystals or fine crystalline powder, astringent taste, odorless. Dissipates in the air. Very easily soluble in water, practically insoluble in ethanol, slowly soluble in glycerin (1:10). Aqueous solutions are acidic. When exposed externally, it causes drying, astringent effects, antimicrobial activity is a consequence of coagulation of microbial proteins. Preliminary dissolution of zinc sulfate in water leads to the absorption of the solution when applied externally and the development of a general toxic effect, therefore its amount in the applied solutions should not exceed 10 ^-4 mol / l. In microquantities, substrate zinc stimulates a number of enzyme systems - alkaline phosphatase, ACE, alcohol dehydrogenase, superoxide dismutase, carbonic anhydrase, etc.

Copper (in the most common and stable form - copper sulfate pentahydrate) - blue crystals or blue crystalline powder, odorless, metallic taste. Slowly dissipates in air. Aqueous solutions are slightly acidic. It has an antiseptic, astringent, cauterizing effect.

Silver (in the most common and stable form - anhydrous silver nitrate) - colorless rhombic crystals, easily soluble in water, in concentrations of 10 ^-7 mol / l and above has a toxic effect. It has an antiseptic, astringent, cauterizing effect.

Aluminum (in the most common and stable form - aluminum chloride hexahydrate) - yellowish-white crystals spreading in air. Let's well dissolve in water. It has an antiseptic, astringent, cauterizing effect.

The method of obtaining wound healing ointment is as follows.

The technology is carried out under aseptic conditions and includes several stages

1. Prepare sample and suspension in the required quantities.

2. A portion of PEO-400 and portions of PEO-1500 and PEO-4000 melted to a liquid state are poured into a mortar together with a suspension.

3. Mix fractions until complete homogenization.

Example 1

1. PEO-400 (30 mass fractions), PEO-1500 (54 mass fractions) and PEO-4000 (15 mass fractions) were melted, an aqueous suspension (1 mass fraction) was introduced, mixed and poured into molds (cylindrical, arbitrary ratio radius and height) and quickly cooled at 5°C.

The advantages of a wound healing ointment with the proposed composition are due to the formation of a dense and, at the same time, plastic-elastic-viscous mass, which is achieved by introducing sufficient amounts of PEO-1500 and PEO 4000. The ointment has a softening effect and its use leads to the formation of a water- and air-permeable smooth up to 1 mm thick film on the wound surface, sorbing (exudate, microbial toxins, tissue decay products), dehydrating (wound edges shrink) and bactericidal (dehydrates the microbial cell) effects, which are enhanced by the introduction of high-molecular solid-phase PEO 4000. Application of mass in the form of a cylinder (wound healing pencil) allows you to comfortably hold it in your hand and, when in contact with the wound, leaves a sufficient, but not excessive layer on it, as when squeezing an ointment from a tube. At the same time, the hands of the person treating the wound remain clean, and the treatment area can be different, which distinguishes the product from napkins and dressings with wound healing fillers. The ointment is consumed in layers and the active surface of the cylinder (wound healing pencil) is constantly updated. The ointment can be stored at room conditions and outdoors without disturbing the geometry and contamination with microorganisms. The product in a small package (0.5-1.0 g) can be used in an individual medicine cabinet. The ointment can be in its original form (cylinder), preferably of adjustable volume, or be packaged in an individual package of an inert material in the form of a wound healing stick. The ointment does not leave greasy marks, has no smell and additional coloring. Example 2

1. Prepare aqueous solutions of compounds of copper zinc metals in the required concentrations of 10 ^-4 mol/l.

2. PEO-400 (30 mass fractions), PEO-1500 (55 mass fractions) and PEO-4000 (5 mass fractions) were melted and mixed with 10 parts of a solution of metal salts.

The resulting mass in terms of external features and physico-chemical characteristics does not differ from that presented in example 1.

Determination of the microbiological activity of the wound healing composition of the ointment.

According to OFS.1.2.4.0010.15 "Determination of antimicrobial activity of antibiotics by agar diffusion method". The test strains were Escherichia coli M17, Staphylococcus aureus P295. Ampicillin was used as a control. The analysis of the results of the experiments was carried out in accordance with GPM.1.1.0014.15 "Statistical processing of the results of determining the specific pharmacological activity of drugs by biological methods", the alignment of the lysis zones was carried out after 24 and 72 hours. The areas of inhibition were determined, the relative change in the zones of lysis of the mineral component was calculated in comparison with the antibacterial effect of ampicillin. The second measurement after 72 hours showed a gradual seeding of the nutrient medium in the zone of action of the antibiotic. At the site of application of the mineral component, there is no secondary growth of the culture, which indicates its stable bactericidal effect and the absence of resistance in microorganisms.

Thus, the proposed wound healing ointment has a high antimicrobial effect against the studied test strains. The zone of growth inhibition in the study of the spectrum of antimicrobial activity is not inferior to the antibiotic ampicillin.

Determination of the activity of individual components of the wound healing ointment.

All manipulations with animals were carried out using general anesthesia, taking into account the provisions for experimental purposes regulated by Appendix No. 8 (“Rules for the Humane Treatment of Laboratory Animals”), “Sanitary Rules for the Arrangement, Equipment and Maintenance of Experimental Biological Clinics (Vivariums)”, Convention on the protection of vertebrate animals used for experimental purposes (Strasbourg, France, 1986) and in accordance with the rules of laboratory practice of the Russian Federation (Order of the Ministry of Health of the Russian Federation No. 267 dated 19.06.2003). The maintenance of animals, their nutrition and care for them was carried out according to the "Sanitary rules for the arrangement, equipment and maintenance of experimental biological clinics (vivariums) of 04/06/1973". Statistical processing of the obtained data was carried out using the Microsoft Excel program, taking into account the correlation coefficient. Significance of differences in mean values was assessed by Student's scores. The wound area was measured using the JMicroVision program.

In the experiment, white laboratory female rats of the Wistar line were used. Animals were divided into groups of 3 individuals - control and experimental. The technique of wound modeling in all groups included the preparation of animals, anesthetic management and actual wound modeling. In the preoperative period, the animals were weighed and examined. On the day of the operation, the rats were in the mode of food and drink deprivation. In all cases, the method of non-inhalation anesthesia with chloral hydrate preparation was used at the rate of 1 ml per 200 g of rat weight intraperitoneally. Effective action was determined by the oppression of consciousness, general behavioral activity. The onset of action of chloral hydrate corresponded to 1-7 minutes, the maximum effect was 20-30 minutes, and the duration was 1.5 hours from the moment of administration. The modeling of wounds was carried out as follows: on the previously depilated skin of the withers of the rat, the contour of two future wounds was applied with a marker using a template: a square of 1 cm ² . The skin was treated twice with 0.05% chlorhexidine bigluconate solution and washed with saline. The scalpel excised the skin and subcutaneous tissue along with the superficial fascia. The rats were kept in individual cages to prevent additional injury to each other. Access to food and water is free.

Experiment results.

A. The control group was not treated. For 1-2 days, the wounds became inflamed, the area could increase, bleeding was often observed. By the 3rd day, the wound area began to decrease, but inflammation and exudation did not disappear. The scab was partially removed, which led to a decrease in the area, on the 9th day the scab came off completely, however, against the background of ongoing inflammation, it re-formed and on the 14th day came down, the wound did not heal (figure 1). Complete healing occurs on the 18-20th day.

B. In the first experimental group, PEO fractions were used in amounts of PEO-400 27÷32, PEO-1500 50÷60, PEO-4000 0÷14, mixed during heating. Homogeneous systems were poured into molds (cylindrical, with an arbitrary ratio of radius and height) and rapidly cooled.

Treatment of the wound with a wax-like mass of PEO, but well applied to the skin wound, leads to a drying effect, which is expressed in the primary decrease in the surface area of the wound. In the group on the 4th-5th day, a full-fledged scab was formed, which, however, increases the area of the wound during a planimetric study. At the same time, the reparation processes under the scab proceed quite effectively, and, unlike untreated wounds, the wounds do not exude, are not mechanically damaged. After the convergence of the scabs on the 8-10th day, the wounds are gradually contracted by primary epithelization and heal by the 16-18th day (figure 1).

B. For other experimental groups, dense cylindrical masses were prepared according to the previous recipe, adding aqueous solutions of zinc or copper compounds or their mixtures with a metal concentration of 0.065 g/l at the homogenization stage in an amount up to 2% of the total mass, sequentially mixing them into the PEO system . The viscosity and plastic-elastic properties of the mass, as well as its adhesion, do not change.

Different concentrations of injected solutions of metal compounds change the rate of eschar formation, eschar stiffness, fragility and additional tissue damage in and around the wound. At the optimum concentration of zinc and copper salts, wound healing occurs on day 12-14 (see figure 2).

Example 3

Animals - white laboratory female rats of the Wistar line - were divided into control and experimental groups and comparisons. The composition applied as a test was prepared according to the recipe of example 2 and contained PEO in a ratio sufficient to obtain a plastic-elastic-viscous mass in the form of a cylinder and solutions of copper and zinc salts with a concentration of 10 ^-4 mol/l. Levomikol ointment of composition methyluracil, chloramphenicol, PEO (macrogol) was used as a reference drug. The technique of wound modeling in all groups included the preparation of animals, anesthetic management and actual wound modeling. In the preoperative period, the animals were weighed and examined. On the day of the operation, the rats were in the mode of food and drink deprivation. In all cases, the method of non-inhalation anesthesia with chloral hydrate preparation was used at the rate of 1 ml per 200 g of rat weight intraperitoneally. The rats were kept in individual cages to prevent additional injury to each other. Access to food and water is free.

Processing of the received data was carried out using a set of standard statistical programs Excel; the main statistical characteristics were determined.

The photographs (figure 3) presents the results of the experiment on the days of observation. When using the wound-healing composition according to the patent, a scab is formed already on the first day, it is dry, clean, tissues are being restored around the wound with complete regeneration of functions, in contrast to the control and reference drug. On the 6th-8th day of the experiment, the animals of the comparison group showed an inflammatory process in the tissues adjacent to the wound. The woolly cover in the wound area is completely restored when using the wound-healing compositions according to the patent, when using the Levomikol preparation, complete regeneration of damaged tissues does not occur (the difference between the clipped and not clipped areas persists for 3 weeks). Based on the special instructions for the use of Levomikol, when applied to large areas of the skin and long-term courses of treatment, a clinical blood test is required, which indirectly indicates the possibility of Levomikol affecting the blood formula.

The effectiveness of the use of wound healing compositions according to the patent and the drug "Levomikol" was evaluated according to the indicators presented in table 1, the statistical indicators of the planimetric study for the control experiment and the experiment with the wound healing composition according to the patent are presented in table 2, which presents the results of static processing of experiments without wound treatment and with daily treatment with a composition of PEO with the addition of copper and zinc compounds. U criterion Mann-Whitney (1 group PEO with metals N=7); (group 2 control N=11) Marked * criteria are significant at p<.05000.

Thus, thanks to the introduced improvements, the required technical result is achieved, which consists in obtaining an ointment with a composition that provides a higher efficiency of use in the treatment of skin lesions and, on this basis, expanding the arsenal of technical means for obtaining ointments with more effective use in the treatment of skin lesions.

The wound healing properties of the proposed ointment are improved due to the enhancement of their own metabolic processes with the introduction of metal compounds proposed from the sample through the formation of active organometallic complexes with enzymatic tissue systems, as well as due to the formation of a colorless transparent dense water- and air-permeable coating adhering to the wound when mixing the indicated amounts of PEO- ov 400, 1500, 4000, which also has antimicrobial activity, which greatly expands the possibilities of using the ointment.

Claims (4)

1. Wound healing ointment containing a mixture of polyethylene oxide obtained by polymerization of ethylene oxide with a consistency in the liquid phase of PEO-400 and in the solid phase of PEO-1500 and PEO-4000, as well as an aqueous solution of a combination of zinc sulfate and copper sulfate with a metal content of 10 ^-2 up to 10 ^-8 mol/l in the following wt.%: PEO-400 27…32 PEO-4000 1…15 Aqueous solution of metal compounds 1…20 PEO-1500 up to 100 2. The method of obtaining a wound healing ointment according to claim 1, which consists in the fact that the prepared sample of PEO-400 and the samples of PEO-1500 and PEO-4000 melted at a temperature of 50-60 ° C, as well as an aqueous solution of a combination of zinc sulfate and copper sulfate with metal content from 10 ^-2 to 10 ^-8 mol/l in selected concentrations mixed until complete homogenization, poured into molds and quickly cooled at 5°C. 3. The method according to p. 2, characterized in that during rapid cooling, cylindrical forms are used for further use of the ointment in the form of a wound healing pencil.

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