RU2712088C1 - Medicament exhibiting wound healing action - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: invention refers to medicine and pharmaceutical industry, namely to a medicinal agent in the form of an ointment. Drug contains zinc salicylate as active substance in amount of 0.1–10 wt %, which before introduction into ointment base is subjected to mechanical interaction with starch, taken in ratio 1:1 or 1:2 by weight, and as an ointment base contains a mixture of polyethylene glycols, optionally with addition of other excipients. Proposed drug represents an effective agent for external application in the form of ointment, exhibiting wound healing action.EFFECT: what is presented is a medicament exhibiting wound healing effect.1 cl, 14 dwg, 1 tbl, 1 ex

Description

The invention relates to the field of medicine and the pharmaceutical industry, namely to ointments having a wound healing effect. A medicinal product is described in the form of an ointment, having a wound healing effect, characterized in that zinc salicylate in an amount of 0.1-10 mass is used as the active substance. %, 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 a mixture of polyethylene glycols is used as the ointment base, optionally with the addition of other auxiliary substances.

Treatment of traumatic, infectious, trophic and other violations of the integrity of the skin is relevant and not yet fully resolved to date, a medical problem [1].

One of the most important tasks in the treatment of skin wounds of various origins is the creation of optimal conditions for obtaining the most complete regenerative process. Wound healing is a complex process, the result of which is the restoration of the extracellular matrix and functionally active cover with or without scar formation. Over the past 20 years, numerous studies have been conducted aimed at finding pharmacological agents that purposefully affect the completeness of skin regeneration. Various pharmacological groups of substances have been studied: proteolytic enzymes, anabolic hormones, synthetic antiseptics, adsorbents and other biologically active substances that stimulate metabolic processes [2], [3], [4].

Known drugs for treating wounds containing such active substances as methyluracil, d-panthenol, deproteinized hemoderivative, various plant extracts and some others.

An example is an external gel containing salicylic acid, chitosan and a bioregulator isolated from cattle and water [5]. A significant difference between this pharmaceutical composition and the described one is the presence of water in the composition.

Closest to the described composition is Levomekol ointment, containing chloramphenicol and chloramphenicol and meliluracil (dioxomethyltetrahydropyrimidine) as active substances, and a mixture of polyethylene glycols as an ointment base [6]. An essential feature of this pharmaceutical composition is the absence of water in the composition. However, the use of this drug is associated with a number of significant drawbacks, such as, for example, insufficient clinical efficacy, high incidence of side effects, and a high risk of infections caused by microorganisms resistant to chloramphenicol (7).

Another similar pharmaceutical composition, Methyluracil ointment, did not show sufficient therapeutic efficacy in studying the development of the erythema reaction in response to ultraviolet irradiation of the skin of guinea pigs [8], which indicates a low wound healing efficiency. In addition, this pharmaceutical composition has the significant difference that a lipophilic base consisting of a mixture of petrolatum and lanolin is used as an ointment base, which does not contribute to the outflow of fluid from the wound, and also creates a risk of anaerobic infection.

The common disadvantages of other known pharmaceutical compositions in the form of ointments with wound healing effects also include insufficient clinical efficacy, the risk of adverse reactions, in particular allergic reactions, as well as the complexity of production, scarcity and high cost of raw materials, the inconsistency of the composition of biological preparations.

It is known that zinc compounds have an important biological effect, contribute to the acceleration of tissue regeneration, zinc ion is included as a cofactor in a number of important enzymes involved in key processes of the body. Zinc cation is part of more than 300 enzymes and more than 2000 transcription factors that regulate the metabolism of lipids, proteins, and nucleic acids [9]. However, pharmaceutical compositions in the form of ointments based on a mixture of polyethylene glycols containing zinc salicylate and having a wound healing effect are not known from the state of the art.

The use of certain zinc compounds (oxide, sulfate, gluconate) for the treatment of a number of skin diseases (acne, eczema, ulcers, etc.) is described. For example, the high anti-inflammatory activity of zinc salicylate in the rat formalin test model of acute inflammation has been described [10]. However, in this work, the healing activity was not studied, and the exact characteristics of the studied zinc salicylate (anhydrous or crystalline hydrate) were not indicated, which is essential for the present invention.

Currently, the effective use of zinc compounds for the treatment of skin diseases and injuries is hindered by properties such as extremely low solubility (zinc oxide), or, conversely, high solubility and the associated easy penetration into the systemic circulation, which increases the risk of systemic toxic effects (sulfate zinc). In addition, since zinc hydroxide is an extremely weak base, soluble zinc salts are characterized by susceptibility to hydrolysis even under physiological conditions, which leads to an increase in the acidity of the medium at the injection site, a decrease in pharmacological activity, and a local irritant effect.

At the same time, the use of salicylic acid to obtain zinc salts has several advantages, since salicylate anion has its own pharmacological activity (analgesic, anti-inflammatory, antiseptic, keratolytic). In addition, due to the spatially closely located carboxyl and hydroxyl groups in the salicylic acid molecule, complexation processes occur during the formation of salts with zinc ions, which also favorably affects the spectrum of pharmacological activity of the obtained salts.

Salicylic acid (o-hydroxybenzoic acid) is the simplest aromatic hydroxy acid, which is colorless crystals, poorly soluble in water and highly soluble in organic solvents; widely distributed in nature, mainly in the form of a glycoside of its methyl ester (methyl salicylate). In industry, it is usually obtained by carboxylation of phenol. Salicylic acid has weak antiseptic, irritating and keratolytic (in high concentrations) properties. Applied externally in ointments, pastes, powders and solutions in the treatment of skin diseases; the sodium salt of salicylic acid (sodium salicylate), its amide (salicylamide) and acetylsalicylic acid (aspirin) are used as antipyretic, anti-rheumatic, anti-inflammatory and painkillers; due to its antiseptic effect, it is used in food preservation. Salicylic acid is toxic in large doses; for humans, the estimated LD ₅₀ is 1.75 g / kg [5].

Hydrated and anhydrous complexes of zinc with salicylic acid Zn (Sal) ₂ ⋅ 2H ₂ O and Zn (Sal) ₂ , as well as zinc monosalicylate Zn (Sal) have been described [11].

The literature describes the medical use of zinc salicylate, but most sources do not specify the composition (anhydrous salt of Zn (Sal) ₂ , or crystalline hydrate Zn (Sal) ₂ ⋅ 2H ₂ O, which is essential for the described drug). Presently known methods for producing zinc salicylates suggest an exchange reaction in an aqueous solution between a soluble zinc salt (sulfate, chloride, nitrate) and a soluble salicylate (sodium, potassium), which has a number of disadvantages, such as the possibility of partial hydrolysis of the obtained product, inconstancy of composition, impurities of the starting reagents and other reaction products [12], [13].

A pharmaceutical composition containing zinc salicylate is described, which is hydrophilic and hydrophobic creams to prevent skin irritation [14]. A significant difference from the described invention is the use of the dosage form of hydrophilic and hydrophobic cream, which is a water-glycerin emulsion used to prevent irritation of intact skin. The presence of water in the composition of these compositions creates the conditions for the hydrolysis of zinc salicylate and a decrease in pharmacological activity. The wound healing effect of these compositions is not described.

Thus, the technical problem is that the pharmaceutical composition containing zinc salicylate should not contribute to its hydrolysis. Lipophilic ointment bases are known in the art, for example, petroleum jelly - a mixture of liquid and solid saturated hydrocarbons. However, for a number of reasons, such compositions are not the optimal choice for treating wounds, since, firstly, they interfere with free gas exchange, creating conditions for anaerobic infection, and secondly, they reduce the bioavailability of hydrophilic active substances (including zinc salicylate).

In this case, to ensure the wound healing effect of the pharmaceutical composition, polyethylene glycols (PEG) can be components of the ointment base known from the prior art. In addition, these ointment bases do not require the introduction of water into the composition of the composition, and, therefore, do not create conditions for the hydrolysis of zinc salicylate. Medicines in the form of ointments having a healing effect, containing zinc salicylate as the active substance, and a mixture of polyethylene glycols as an active substance (ointment base), are not currently described, therefore, the disclosed invention has the sign of "novelty."

Polyethylene glycols (PEGs) are water-soluble non-ionic polymers prepared by ring opening polymerization of ethylene oxide. Depending on the average molecular weight, they are viscous liquids or solids. PEG mixtures in various ratios are widely used as ointment bases. Ointment bases containing PEG mixtures have several advantages: they are odorless, mix well with water, are insoluble in oils, do not dissociate in the aquatic environment, do not change in the presence of electrolytes; they are well applied to the skin and evenly distributed over it, without interfering with gas exchange and without disrupting the activity of the skin glands, they have some own bactericidal effect, are osmotically active, which is essential in the treatment of infected wounds [15] [16].

At the same time, a disadvantage of ointment bases containing PEG mixtures known from the prior art is incompatibility with salicylates and salts of heavy metals [16]. Thus, a drug containing zinc salicylate as an active ingredient in the ointment base, consisting of a mixture of polyethylene glycols, is not obvious to a person skilled in the art, and therefore has the sign of "inventive step".

Thus, from the prior art, ointments based on polyethylene glycols as antimicrobial agents that do not contain zinc salicylate are known, and creams with zinc salicylate as agents for the prevention of skin irritation are also known, but ointments based on polyethylene glycols containing zinc salicylate having wound healing are not known. action, therefore, there is a sign of novelty. The person skilled in the art is not aware of the wound healing properties of zinc salicylate, but it is known that polyethylene glycols are not compatible with salicylates, therefore, the composition containing zinc salicylate and a mixture of polyethylene glycols is neither new nor obvious. It is not known about the inclusion of anhydrous zinc salicylate in the composition of ointments after mechanical interaction with starch. For a person skilled in the art, the stability of the resulting composition is not obvious.

The present invention is the creation of a new effective, safe and stable medicinal product for external use in the form of an ointment with a wound healing effect.

To solve this problem, a drug was developed in the form of an ointment containing zinc salicylate as an active ingredient, which is previously subjected to mechanical interaction with starch, and as an ointment base, a mixture of polyethylene glycols, not necessarily with the addition of known auxiliary substances (propylene glycol, benzyl and isopropyl alcohols and other).

Technical result

The drug in the form of an ointment contains as an active substance from 0.1% to 10 mass. % (optimally 1 wt.%) of zinc salicylate, which before mechanical composition is subjected to mechanical interaction with starch in a ratio of 1: 1 or 1: 2 by weight, and as an ointment base, a mixture of polyethylene glycols, optionally with the addition of other known from the prior art excipients that do not interact with zinc salicylate.

The study of the kinetics of absorption of the active substance (zinc salicylate) was carried out on a diffusion model in an agar gel with an indicator of iron (III) chloride. We studied 2 compounds (composition No. 1 and composition No. 2), differing in the method of introducing zinc salicylate into the composition of the ointment base. Composition No. 1 (with starch) was prepared by adding, with stirring, to a molten mixture of PEG1500, PEG400 and isopropyl alcohol a mixture of zinc salicylate with starch, previously subjected to mechanical action (grinding) for 10 minutes. Stirring was continued for 15 minutes and then the resulting ointment was cooled. Composition No. 2 was prepared by adding a solution of zinc salicylate in isopropyl alcohol to the molten mixture of PEG1500 and PEG400 with stirring. Stirring was continued for 15 minutes and then the resulting ointment was cooled.

A study of the diffusion of zinc salicylate from ointments of various compositions into an agar gel with iron (III) chloride showed that preliminary grinding of zinc salicylate with starch before introduction into the composition of the ointment base does not interfere with the release of the active substance, but at the same time promotes a longer release, slowing down absorption into the systemic circulation. This ensures a longer presence of the active substance directly in the area of damage. In addition, this helps to improve the safety of treatment, reducing the risk of locally irritating effects and manifestations of systemic toxic reactions.

Thus, the technical result in this case will be to optimize the release profile of the active substance and increase the safety of treatment.

The study of the mechanisms of wound healing action of zinc salicylate was carried out during studies of metabolic, migration and proliferative activity, as well as biochemical indicators of mechanical damage during cultivation in the presence of zinc salicylate solution in rat fibroblast culture. The study included the following series of experiments:

1) Carrying out the MTS test on a fibroblast culture with solutions of zinc salicylate (ZS), zinc acetate (ZA), methyluracil (MU) and sodium salicylate (NS) in 3 concentrations.

2) Testing the migratory and proliferative activity of fibroblasts by scarification of the cell monolayer by co-culturing cells with solutions of zinc salicylate (ZS), zinc acetate (ZA), methyluracil (MU) and sodium salicylate (NS) in 3 concentrations.

3) Conducting a biochemical analysis of the degree of damage and restoration of the protein structure after testing for the migration activity of fibroblasts by scarification of the cell monolayer by co-culturing cells with solutions of zinc salicylate (ZS), zinc acetate (ZA), methyluracil (MU) and sodium salicylate (NS) .

4) Biochemical analysis of the degree of damage and restoration of the lipid structure after testing for the fibroblast migration activity by scarification of the cell monolayer by co-culturing cells with solutions of zinc salicylate (ZS), zinc acetate (ZA), methyluracil (MU) and sodium salicylate (NS) .

5) Evaluation of the adaptive capabilities of cells by the dynamics of changes in protein SH-groups after testing for the fibroblast migration activity by scarification of the cell monolayer by co-culturing cells with solutions of zinc salicylate (ZS), zinc acetate (ZA), methyluracil (MU) and sodium salicylate ( NS).

To study the mechanisms of wound healing action of zinc salicylate (ZS), the following series of experiments were performed on a fibroblast culture:

1) MTS test: colorimetric test to assess the metabolic activity of cells.

2) Scratch test: determination of the migration activity of cells by scarification of the cell monolayer with subsequent fixation of images at fixed time intervals.

3) Determination of total protein concentration by the Lowry method in:

- a control group of cells without a scratch test and without the addition of test compounds;

- in a group of cells after a scratch test, cultivation without test compounds;

- in the group of cells after a scratch test, cultivation with the studied compounds ZS, ZA, MU and NS, each in 3 concentrations.

4) Determination of the concentration of carbonyl derivatives of proteins in the following groups:

- in the control group of cells without scratch test and without the addition of test compounds;

- in the group of cells after a scratch test, cultivation without the addition of test compounds;

- in the group of cells after the scratch test, cultivation with the addition of the studied compounds ZS, ZA, MU and NS, each in 3 concentrations.

5) Determination of the concentration of thiobarbiturate (TBA) -sensitive products:

- a control group of cells, cells without a scratch test and without the addition of test compounds;

- in the group of cells after a scratch test, cultivation without the addition of test compounds;

- in the group of cells after a scratch test, cultivation with the addition of the studied compounds ZS, ZA, MU and NS, each in three concentrations.

6) Evaluation of the content of SH-groups by the photometric method using Ellman's reagent in:

- a control group of cells, cells without a scratch test and without the addition of test compounds;

- in the group of cells after a scratch test, cultivation without the addition of test compounds;

- in the group of cells after the scratch test, cultivation with the addition of the studied compounds ZS, ZA, MU and NS, each in 3 concentrations.

The results of the study showed that the tested substances ZS, ZA, MU and NS statistically significantly increase metabolic and proliferative activity at concentrations of 0.5; 2.5 and 10.0 μmol / L for 24 hours. The highest activity in this type of study was demonstrated by the studied substances ZA and ZS. When assessing migration activity, it was noted that in the first 12 hours of the study, it was higher in fibroblasts cultivated with the studied substance ZS at a concentration of 0.5 μmol / L.

When studying the degree of damage to proteins after scarification damage, it was found that the restoration of SH-groups of proteins from damage occurred most effectively under the influence of ZS at a concentration of 0.5 μmol / L. In addition, ZS, unlike NS, did not cause an increase in lipid damage [18].

Thus, it has been shown that zinc salicylate (ZS) increases the metabolic and proliferative activity of fibroblasts comparable to zinc acetate (ZA). But, at the same time, zinc salicylate (ZS) at a concentration of 0.5 μmol / L has a greater effect on the migration activity of fibroblasts in the first 12 hours after causing scarification damage compared to zinc acetate (ZA). In the case of methyluracil (MU) and sodium salicylate (NS), in contrast, a decrease in the migration activity of fibroblasts was observed.

Thus, the technical result of the use of zinc salicylate as a wound healing substance is realized in increasing metabolic and proliferative activity, as well as in increasing the migration activity of fibroblasts (in contrast to zinc acetate and methyluracil) and in protecting cellular lipids from damage (in contrast to sodium salicylate).

Preclinical study of the wound healing pharmacological activity of an ointment containing 1 mass. % of zinc salicylate, previously subjected to mechanical interaction with starch, and the mixture of polyethylene glycols was used as the basis, studying the effect of the ointment on the course of the wound (uninfected) process under conditions of modeling a linear skin wound in 12 male rats. The animals were divided into 4 groups of 3 individuals (group No. 1: control — without treatment; group No. 2: ointment base without zinc salicylate; group No. 3: composition with zinc salicylate; and group No. 4: comparison drug — Levomekol ointment) . All preparations were applied daily for 8 days in an amount of 0.5 g / animal. Pathology was induced by applying to the dorsal surface under general anesthesia according to the template with a wound scalpel to a length of 50 ± 0.2 mm to the own fascia.

On the 8th day, the animals were euthanized under ether anesthesia, a piece of the wound surface of the skin was cut 7 cm high and 4 cm wide (2 cm on both sides of the scar) and using an electronic dynamometer with an accuracy of 5 grams, the tensile strength of the scar was determined , gradually increasing the load on the edges of the wound.

In a preclinical study of the wound healing pharmacological activity of a medicament obtained in the described manner in the form of an ointment in an experimental model of a linear aseptic skin wound in rats, it was shown that when using an ointment containing 1 mass. % of zinc salicylate obtained by the described method, at a dose of 0.5 g / animal, not only a statistically significant increase in the effort required to break the suture (2916.6 ± 236.2 g) was observed, relative to animals of other groups (1961 , 2 ± 405.3 gr. - ointment base without zinc salicylate; 1280.6 ± 343.0 gr. - Levomekol ointment; 836.6 ± 65.6 gr. - without treatment), but also the presence of pronounced regenerative properties . In animals, inflammatory processes were not revealed during visual examination, the wound is clean, healing without granulation. The absence of granulomas and a purulent inflammatory process allows us to conclude that wounds are healed by primary intention. In all the studied parameters, the composition obtained by the described method significantly exceeded both the ointment base (a mixture of polyethylene glycols without zinc salicylate) and the comparison drug (Levomekol ointment - a combination of methyluracil and chloramphenicol in a mixture of polyethylene glycols) [17].

In another preclinical study of pharmacological activity in an experimental model of linear aseptic skin wounds in rats, two ointment compositions were compared, differing in the method of introducing zinc salicylate into the ointment base. Composition No. 1 (with starch) was prepared by adding, with stirring, to a molten mixture of PEG1500, PEG400 and isopropyl alcohol a mixture of zinc salicylate with starch, previously subjected to mechanical action (grinding) for 10 minutes. Stirring was continued for 15 minutes and then the resulting ointment was cooled. Composition No. 2 was prepared by adding a solution of zinc salicylate in isopropyl alcohol to the molten mixture of PEG1500 and PEG400 with stirring. Stirring was continued for 15 minutes and then the resulting ointment was cooled.

On the 5th day of treatment with composition No. 1 (with starch), the linear wound size decreased on average from 5.0 cm to 3.9 cm, and in the group of animals receiving composition No. 2 (without starch) from 5.0 cm to 4 5 cm (the difference was statistically significant, p <0.05).

The technical result obtained (higher treatment efficiency) can be explained by a more optimal release profile of the active substance (zinc salicylate) and, accordingly, a longer presence of the active substance in the wound area. The results obtained are completely consistent with experimental data on the release profile of the active substance (zinc salicylate) from two ointment formulations by diffusion into an agar gel with an indicator - iron (III) chloride.

Thus, the described invention meets the sign of "industrial applicability".

The essence of the invention can be illustrated by the following example, which includes but is not limited to various variants of a specific technical implementation (qualitative characteristics of the starting components, composition and ratio of excipients of the ointment base, order of mixing of the components, temperature and duration of mixing, etc.).

Example

Getting zinc salicylate

The starting compounds are zinc sulfate, analytical grade. ZnSO ₄ ⋅ 7H ₂ O and sodium carbonate, ppm. Na ₂ CO ₃ ⋅ 10H ₂ O was recrystallized from distilled water. To obtain zinc carbonate, a portion of zinc sulfate heptahydrate (2.927 g, 10.18 mmol) was dissolved in 10 ml of distilled water; a portion of sodium carbonate of decahydrate (2.871 g, 10.03 mmol) was also dissolved separately in 10 ml of distilled water. To the zinc sulfate solution, with vigorous stirring, a sodium carbonate solution was gradually slowly slowly added in small portions at room temperature. After adding the entire sodium carbonate solution, stirring was continued for another 15 to 30 minutes. Then the mixer was turned off and the reaction mixture was left at room temperature for 1-3 hours. Then the stirrer was turned on again and with vigorous stirring, the volume of the mixture was adjusted with distilled water to 50 ml. Stirring was continued for 10-15 minutes. Then the mixer was turned off and the mixture was left at room temperature for 3-6 hours until complete sedimentation. A white granular precipitate of zinc carbonate was filtered off (white ribbon filter) and washed with 5-10 ml portions of distilled water (80-100 ml in total) until the washings were neutral with phenolphthalein. Excess water was removed between sheets of filter paper. The product was not completely dried. Obtained 1,401 g of precipitate (11.24 mmol in terms of 100% ZnCO ₃ ).

The resulting zinc carbonate was gradually added in small portions with vigorous stirring to 69 ml of a 2% solution of salicylic acid in 70% ethyl alcohol (the drug “Solution of salicylic alcohol 2% acid”) containing 1.38 g (10 mmol) of salicylic acid. Stirring of the resulting milky white suspension was continued for 2-3 hours. Then the stirrer was turned off and the reaction mixture was left at room temperature for 4-6 hours to settle. After that, the zinc salicylate solution was filtered (white ribbon filter). Excess unreacted zinc carbonate (0.646 g, 5.168 mmol) indicates the formation of a salt of the composition Zn (Sal) ₂ . Thus, the reaction can be described by the equation:

(where SalH is salicylic acid)

The solvent was removed from the alcoholic solution of zinc salicylate by any suitable method without heating above 50 ° C. Obtained 1.751 g (5.165 mmol) of zinc salicylate, corresponding to the formula Zn (Sal) ₂ , with a yield in terms of the total amount of zinc carbonate 91.9%, in terms of the amount of reacted zinc carbonate 99.94%.

The obtained product was identified by conducting qualitative reactions to zinc ions and salicylate ions, as well as by UV and IR spectroscopy.

In addition, the resulting zinc salicylate can be identified by known quality chemical reactions. An aqueous solution of zinc salicylate obtained by the described method gives a qualitative reaction to Zn ^{2+ ions} with potassium hexacyanoferrate (II) (yellow blood salt) K ₄ [Fe (CN) ₆ ] - the formation of a white zinc hexacyanoferrate (II) precipitate, as well as a qualitative reaction to salicylate ion with a solution of iron (III) chloride FeCl ₃ - the appearance of intense red-violet staining of the solution.

Description of the composition of medicinal compositions with zinc salicylate

Medicinal compositions with the zinc salicylate obtained by the described method can include ointments based on a mixture of polyethylene glycols with different molecular weights in various ratios, containing, in addition, starch, propylene glycol, benzyl alcohol, isopropyl alcohol, vinylin and others not containing water and not containing as auxiliary substances interacting with zinc salicylate components.

The content of the active substance (zinc salicylate) can be from 0.1% to 10%. The starch content may correspond to the amount of zinc salicylate, or a two- or three-fold excess of starch may be used.

The table below presents the composition of the studied variants of the composition (g).

Obtaining a medicinal composition in the form of an ointment with zinc salicylate

Option number 1

Composition:

Zinc salicylate - 0.1 g

Polyethylene glycol-1500 (PEG-1500) - 7 g

Polyethylene glycol-400 (PEG-400) - 2.88 ml

Propylene glycol - 0.06 ml

Benzyl alcohol - 0.06 ml

Starch - 0.1 g

Production technology: PEG-1500 is melted in a water bath with vigorous stirring. Separately, triturated in a mortar 0.1 g of starch, add 0.1 g of zinc salicylate. Rubbing is continued for 5-10 minutes. A pre-prepared solution of PEG-400 with propylene glycol and benzyl alcohol is added to the molten PEG-1500. Stirred for 2-3 minutes. A carefully ground mixture of zinc salicylate with starch is then added. Stirring is continued for 30-60 minutes when heated in a water bath at 50-80 ° C. Then the mixer is turned off and the ointment is hot packed in plastic jars with a screw-on plastic cover. Cool at a temperature of 0-4 ° C.

Option number 2

Composition:

Zinc salicylate - 0.1 g

Polyethylene glycol-1500 (PEG-1500) - 5 g

Polyethylene glycol-400 (PEG-400) - 2.88 ml

Propylene glycol - 0.06 ml

Benzyl alcohol - 0.06 ml

Starch - 0.1 g

Isopropyl alcohol - 2 ml

Production technology: PEG-1500 is melted in a water bath with vigorous stirring. Separately, triturated in a mortar 0.1 g of starch, add 0.1 g of zinc salicylate. Rubbing is continued for 5-10 minutes. A pre-prepared solution of PEG-400 with propylene glycol, benzyl alcohol and isopropyl alcohol is added to the molten PEG-1500. Stirred for 2-3 minutes. A carefully ground mixture of zinc salicylate with starch is then added. Stirring is continued for 30-60 minutes when heated in a water bath at 50-80 ° C. Then the mixer is turned off and the ointment is hot packed in plastic jars with a screw-on plastic cover. Cool at a temperature of 0-4 ° C.

Blueprints

Figures 1-7 are IR spectra of zinc salicylate and salicylic acid.

Figure 8 is a UV spectrum of zinc salicylate and salicylic acid.

Figures 9-10 are micrographs of zinc salicylate crystals.

Figures 11-14 are photographs of the wound surface on the 8th day of treatment, respectively, ointment base without zinc salicylate, ointment with 1% zinc salicylate, ointment "levomekol" and the control group of animals without treatment.

List of references

1. Wayne K. Stadelmann, MD, Alexander G. Digenis, MD, Gordon R. Tobin, MD, Physiology and Healing Dynamics of Chronic Cutaneous Wounds // Am J Surg. 1998; 176 (Suppl 2A): 26S-38S

2. Brailovskaya T.V. Morphological characteristics of the course of the wound process during experimental modeling of cut and torn-bruised skin wounds / T.V. Brailovskaya, T.A. Fedorina // Biomedicine. - 2009. - Vol. No. 1. - S. 68-74.

3. Volodina T.A. Study of the reparative properties of phytogel containing extracts of thyme and licorice / T.A. Volodina, N.A. Penyevskaya, S.I. Viktorov, M.A. Ohai, A.V. Mayorova // Basic Research, 2012. - Issue. No. 11 -2. - S. 472-477.

4. Grabarskaya EA The study of wound healing activity of a new multicomponent ointment / E.A. Grabarskaya, N.V. Danilevskaya, A.A. Deltsov, A.A. True // RVZh MJ. - 2015. - Issue. No. 3. - S. 48-50.

5. Yamskov IA, et al. RF patent No. 2468814. Wound healing gel. 2011.

6. Mrinal Gupta, Vikram K. Mahajan, Karaninder S. Mehta, and Pushpinder S. Chauhan, Zinc Therapy in Dermatology: A Review // Dermatology Research and Practice Volume 2014, Article ID 709152, http://dx.doi.Org /10.1155/2014/709152

7. Yakovchuk T.B., Katyushina O.B., Khusainov D.R., Korenyuk I.I., Gamma T.V., Cheretaev I.V., Kolotilova O.I. Anti-inflammatory activity of salts of salicylic and acetylsalicylic acids // Scientific notes of Taurida National University. IN AND. Vernadsky Series "Biology, Chemistry". Volume 24 (63). 2011. No2. S. 332-338.

8. Tuyebakhova ZK Vibrational spectra of salicylic acid and salicylates of cobalt (II), nickel (II), manganese (II), zinc and cadmium. Diss. Ph.D. M .: 1984.

9. Pascale Lemoine, Bernard Viossat, Nguyen Huy Dung, Alain Tomas, Georges Morgantc, Frederick T. Greenaway, John R.J. Sorenson, Synthesis, crystal structures, and anti-convulsant activities of ternary [ZnII (3,5-diisopropylsalicylate) 2], [ZnII (salicylate) 2] and [ZnII (aspirinate) 2] complexes // Journal of Inorganic Biochemistry 98 ( 2004) 1734-1749

10. T.B. Koksharova, S.V. Curando, I.V. Stoyanova, S.E. Sambursky. Coordination compounds of 3d-metal salicylates with 4-phenylthiosemicarbazide // Visnik ONU, Volume 15, issue 2, 2010, pp. 23-28.

11. Report on the contract No. б / н dated 03/13/2019 “Preclinical study of the wound healing effect of ointment compositions PEG / ZS and PEG / PG”, FSBEI HE Ryazan State Medical University, Ryazan, 2019.

Claims (1)

A medicinal product in the form of an ointment, having a wound healing effect, characterized in that it contains zinc salicylate in an amount of 0.1-10 wt.%, Which is subjected to mechanical interaction with starch taken in a ratio of 1: 1 before being introduced into the ointment base or 1: 2 by weight, and as an ointment base contains a mixture of polyethylene glycols, optionally with the addition of other excipients.

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