RU2846026C1 - Use of aqueous solutions of partial double lithium-copper salt of polyacrylic acid - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention refers to chemistry and pharmaceutics, namely to using 1–5 % aqueous solution of an incomplete double lithium-copper salt of polyacrylic acid of general formula: (-CH₂ CHCOOH-)_n(-CH₂CHCOOLi-)_m(-CH₂CHCOOCu_0.5-)_k, where n=318871–956613, m=96136–288408, k=24573–73718, in which the Li content is 4.43–4.46 % and the Cu content is 3.93–4.10 %, as an external agent stimulating the healing of open wounds, which does not cause antibiotic resistance and prevents the need to use traumatic antiseptic methods.

EFFECT: invention widens the spectrum of pharmacological activity of the incomplete double lithium-copper salt of polyacrylic acid and provides faster healing of open wounds.

1 cl, 2 tbl, 2 ex

Description

The invention relates to pharmacology, pharmaceuticals, the pharmaceutical industry, traumatology, surgery and can be used to accelerate the healing of open wounds.

In recent years, a fairly wide range of materials and medical products based on natural and synthetic materials and antimicrobial agents, antibiotics, antifungal and antiviral drugs in the form of wound dressings, bandages, creams and ointments have been developed in the field of wound healing agents.

Copper, which is also an essential element, is also known for its bactericidal properties.

The wound healing process is complex, multi-stage, and the drugs used to treat wounds affect its different stages and by different mechanisms. There are known ways to accelerate wound healing.

A modified fibrous material is known [US4637820, 1984-03-06, A61F-013/15, A61F-013/20, A61F-013/472, A61F-013/49, A61F-013/53, A61L-015/28, A61L-015/46, D01F-002/24, D06M-011/00, D06M-011/56, D06M-016/00, D06M-101/00, D06M-101/02, D06M-101/06], which contains cellulose fiber that is substituted at its anhydroglucose units with anionic components and coated with copper cations in such a way that the fibers bind from 0.1 to 3 mass % copper based on the mass of the fibers. The degree of substitution of copper atoms in the fibers is preferably from 0.1 to 0.3. Materials obtained using the fibers may include surgical dressings, absorbent cotton wool and various hygienic devices.

The disadvantage of the drug is the low copper content and thus weak antimicrobial properties, which reduces the rate of wound healing of complex wounds.

Known are hygroscopic dressings for absorbing fluid released from a wound [US5977428, 1997-02-03, A61F-013/00, A61L-015/00, A61L-015/16, A61L-015/60, A61L-026/00], which contain a plurality of absorbent hydrogel particles tightly sealed inside a porous container. The porous container does not adhere to the wound and the hydrogel particles remain sealed in the container after absorbing the fluid released from the wound. The particles can be dried polyacrylonitrile hydrogel particles and can contain, release wound healing agents or nutritional elements that promote the healing process, such as copper- and zinc-containing compounds or complexes.

The disadvantage of the drug is its multi-component nature and optional inclusion of metal compounds without specific examples of their effect on wound healing.

A coating is known for treating wounds of various etiologies in the first stage of the wound process [RU2372944, 2009.11.20, A61L 15/44, A61L 15/32, A61K 31/17], which contains a hydrophilic tissue base - a hydrogel layer containing acrylic acid and acrylamide with a cross-linking agent, wherein the hydrogel layer has a pH of 7.0-7.5 and has an absorption capacity of 36-44 g / g, a water-soluble biodegradable polymer containing a mixture of gelatin with poly-N-vinylpyrrolidone, as well as biologically active components: fullerene C60, antimicrobial, necrolytic, antienzymatic and hemostatic, at a certain content of components in the coating. The hydrogel coating has the ability to accelerate wound healing and simultaneously reduce the number of complications during their treatment.

The disadvantages of the wound dressing are the presence of polyvinylpyrrolidone and gelatin, which do not ensure the separation of tissue degradation products and the evacuation of inflammatory components. In addition, the components have potential allergic reactions.

The antimicrobial and wound-healing agent "ultracol" is known [RU2220724, 2004.01.10, A61K 31/4164, A61K 31/513, A61K 35/78, A61K 38/39, A61P 31/00], which contains collagen, methyluracil, metronidazole, sanguiritrin in a certain ratio. The agent has antimicrobial and wound-healing activity, provides a reduction in wound healing time.

The disadvantage of the product is the presence of antimicrobial components, to which resistance may develop.

A wound treatment agent is known [RU2194535, 2002.12.20 A61L 15/28, A61L 15/30], containing, by weight %: a water-soluble cellulose derivative 1.0-15.0, alginic acid 0.1-15.0. The sum of the water-soluble cellulose derivative and the water-soluble polysaccharide of plant origin that forms polyanions in solution is 1.0-17.0 and at least one component selected from the group consisting of carrageenan, pectin, fucoidin, zosterin, gum arabic, xanthan gum, tragacanth, and water is the balance. The wound treatment agent may additionally contain at least one component selected from the group consisting of antibiotics and antiseptic substances. The agent contains, for example, lincomycin or gentamicin as an antibiotic. As an antiseptic, the product contains, for example, miramistin, or chlorhexidine, or dioxidine, or colloidal silver, or silver salt. The product contains medicinal components in an amount of up to 10 wt.%. The product forms an elastic vapor-permeable coating directly on the wound, which does not require additional fixation.

The disadvantage of the product is its multi-component nature, the antibiotic in the product, which can cause antibiotic resistance. The presence of silver in the composition is unknown, optional and no examples of its use are given.

A healing agent is known for closing and treating purulent-necrotic and infected wounds, burns, trophic ulcers [RU2271814, 2006.03.20, A61K 31/722, A61K 31/785, A61K 31/136, A61K 31/375, A61K 38/43, A61P 17/02] using in a composition in a given ratio water-soluble chitosan of natural origin, polyalkylene guanides phosphopag and biopag, proteolytic enzymes from the pepsin or collagenase series, ascorbic acid and an anesthetic. The agent has combined wound healing, bacteriostatic and immunostimulating properties, stimulating regenerative-reparative processes and accelerating the growth of healthy wound cells.

The disadvantage of the product is that it is a gel-like suspension in aerosol form, which greatly limits its shelf life.

A hemostatic antiseptic and wound-healing sponge is known [RU 2226406 2004.04.10, A61L 15/32, A61L 15/34], containing gelatin as a base, kanamycin sulfate as an active component and furacilin, characterized in that it additionally contains methyluracil. It is used in the form of films and sponges based on collagen or gelatin, which makes it possible to quickly stop bleeding, protect the wound from secondary infection, reduce pain and stimulate wound healing.

The disadvantage of the product is the potential allergic reactions of its components and the use of an antibiotic.

A remedy is known [RU 2485938 2017.06.27, A61K 9/06, A61K 41/00, A61K 47/30] that has the ability to accelerate wound healing, reduce the number of purulent complications during their treatment, and also have an antiseptic and anti-inflammatory effect. Modified sparsely cross-linked acrylic polymers (RAP) or suspensions based on them were used as a gelling component, subjected to electrophysical action of an electrical nonlinearly distorted signal with two homogeneity intervals, while the concentration of modified RAP in the hydrogel should correspond to 0.2-0.6 mass %, the viscosity should be 45-85 Poise, and the pH value = 7.2 ± 0.2. The formulation also includes antiseptics and/or antimicrobial components and/or antioxidants and/or antihypoxants and/or anti-inflammatory components.

The disadvantage is its multi-component nature and the unknown ratio of the contribution of each component.

A known agent [RU2744545, 2021.03.11, A61K 41/00, A61P 17/02] provides increased efficiency in the treatment of wounds, burns and infectious and inflammatory skin diseases, in the form of a gel based on an aqueous solution of RAP. The gel as an acrylic polymer containing carbopols (carbomers), in the presence of particles of foamed graphite, anesthetic, antimicrobial agent and water, is exposed to an electric field with a variable frequency-modulated frequency, which affects the gel through an electrode.

The disadvantages are the difficulty of obtaining the gel, its multicomponent nature, and the possibility of developing antibiotic resistance.

Of great importance is the creation of reparative drugs with multifunctional properties - hemostatic and antimicrobial, since wound healing is often complicated by bleeding, infectious infections, and the therapeutic effect of antibiotics due to the potential resistance of pathogenic microflora to them is very weak. In the case of complex wounds, wound infection and purulent-necrotic process often develop. In this case, traumatic methods of antisepsis are often used, such as mechanical physical and surgical, which leads to extensive tissue defects with the formation of coarse scars.

A hemostatic agent based on a double lithium-copper salt of polyacrylic acid [RU2585366, 2016.05.27, A61K 9/08, A61K 31/78, A61K 31/30, A61K 31/315, A61P 17/02], which has hemostatic and antimicrobial properties, was selected as a prototype.

Well-known information that one of the leading initial factors of the wound healing process is hemostasis, as well as maintaining asepsis for the proliferation of healthy cells, allowed us to hypothesize that licupril from the RAP class, in addition to the already known hemostatic and antimicrobial action, can also have a stimulating effect on the healing of open wounds. Likupril forms a coating, which is a film with a high degree of adhesion and cohesion, which easily models the wound relief, providing strong contact with the surface of wounds of different nature, closes, potentially protects wounds from possible infection, and promotes favorable wound healing.

The aim of the present invention is to expand the range of effective means for treating open wounds without antibiotics in the composition, without the need to use traumatic methods of antisepsis.

The task is to create an effective antibiotic-free product for external use to treat open wounds. A non-antibiotic product based on an incomplete double lithium-copper salt of polyacrylic acid that stimulates regenerative and reparative processes.

Technical result:

- acceleration of healing of open wounds;

- a simple, easy-to-use, atraumatic dosage form that fits well even on wounds with complex relief, with the potential to avoid mechanical, physical and surgical methods of antisepsis;

- expansion of the spectrum of pharmacological activity of the incomplete double lithium-copper salt of polyacrylic acid.

It is proposed to use a 1-5% aqueous solution of an incomplete double lithium-copper salt of polyacrylic acid (licupril), corresponding to the general formula: (–CH ₂ CHCOOH–) _n (–CH 2 CHCOOLi–) _m (–CH ₂ CHCOOCu _0.5 –) _k , where n = 318871-956613, m = 96136-288408, k = 24573-73718, the Li content is 4.43-4.46%, Cu – 3.93-4.10 _% , the molecular weight varies from 1,000,000 to 3,000,000.

According to the invention, The product does not contain antibiotics.

According to the invention, the wound surface can be re-treated to speed up healing without the need for traumatic antiseptic methods.

Previously, such studies of licupril have not been conducted, despite the relevance of the problems of stimulating proliferative-reparative processes in open wounds, scratches, as well as those resulting from surgical intervention or injuries.

Accordingly, the positive result obtained allows the use of the specified substance for a new purpose – to accelerate the treatment of open wounds without the risk of developing antibiotic resistance.

The study of the possibility of using licupril to stimulate proliferative-reparative processes in open wounds is carried out as follows.

Experiments are conducted on white mongrel rats weighing 180-200 g. Animals are kept in accordance with the rules of laboratory practice in the Russian Federation [Order of the Ministry of Health of the Russian Federation No. 267 of 19.06.2003] and the rules of the European Convention for the Protection of Vertebrate Animals used for experimental and other scientific purposes [ETS No. 123 of 18.03.1986]. At the end of the experiment, the animals are euthanized by cervical dislocation of the 5th vertebra, observing the rules of the convention.

Likupril is prepared by mixing the drug obtained by a known method with official distilled water until completely dissolved [RU2585366, 2016.05.27, A61K 9/08, A61K 31/78, A61K 31/30, A61K 31/315, A61P 17/02].

Data obtained using the official 0.9% sodium chloride solution are accepted as placebo control.

An open wound model is used. First, the hair is cut off from the back in the area between the shoulder blades and disinfected. Then, under general gas (ether) anesthesia, a 1 ^cm2 area of skin is removed from the animal. After this, the condition of the animals is monitored for 9 days and the area of damage in ^cm2 is measured every other day.

Animals are grouped into 10-head groups as follows:

1) placebo group – control, in which the wound is washed daily with saline solution (0.9% sodium chloride);

2) an experimental group in which a solution of licupril is applied to the wound daily.

Licupril solution, which is a gel, closes a wound of any shape when applied.

The results obtained are characterized by the following examples, which provide data showing the dose effects of the use of licupril.

Example 1.

In this series of experiments, a 1% solution of licupril is used. The results are described in Table 1.

Table 1. Relative (in %) changes in wound area in rats (M±m) under conditions of using 1% licupril solution.

Days Licupril
1% aqueous solution Control
(0.9% NaCl) 1 100 100 3 79.9±1.5* 90.1±1.8 5 41.1±1.1* 75.4±1.7 7 16.7±0.8* 58.2±1.2 9 0 46.1±1.1

* differences with control are significant (p≤0.05)

By the 9th day, treatment of the wound with a 1% solution of licupril leads to complete wound healing, while in the control only a twofold reduction in the wound size is achieved.

Example 2.

In this series of experiments, 5% aqueous solutions of licupril and 0.9% NaCl are used. The results are characterized in Table 2.

Table 2. Relative (in %) changes in wound area in rats (M±m) under conditions of using a 5% solution of licupril.

Days Licupril,
5% aqueous solution Control,
(0.9% NaCl) 1 100 100 3 61.8±1.2* 90.1±1.8 5 26.2±1.1* 75.4±1.7 7 0 58.2±1.2 9 46.1±1.1

* differences with control are significant (p≤0.05)

In this example, after treating the wound with a 5% solution of licupril, complete healing of the wound is achieved by the 7th day of the experiment, in contrast to the control, where the wound area by this time is still more than 50%.

Claims (1)

The use of 1-5% aqueous solution of incomplete double lithium-copper salt of polyacrylic acid, having the general formula: (-CH ₂ CHCOOH-) _n (-CH ₂ CHCOOLi-) _m (-CH ₂ CHCOOCu _0.5 -) _k , where n = 318871-956613, m = 96136-288408, k = 24573-73718, in which the Li content is 4.43-4.46%, Cu - 3.93-4.10%, as an external agent that stimulates the healing of open wounds, does not cause antibiotic resistance and prevents the need for traumatic antiseptic methods.