RU2703295C1 - Anti-burn agent - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an anti-burn agent. Anti-burn agent based on plant extracts, bacteriophages, preserving agents and gelling agents, which contains water extracts of Astragalus vulpinus Willd. herb and Plantago major leaves, polyvalent bacteriophage, active in relation to Staphylococcus aureus, Proteus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, nicotinic acid, riboflavin, biotin, ethylcellulose, carbomer Pemulen, nipagin and distilled water at a certain ratio of components.

EFFECT: above described anti-burn agent is effective, has optimal technological and biopharmaceutical properties.

1 cl, 4 ex

Description

The invention relates to medicine and pharmacy and for the development of integrated tools that activate the processes of post-traumatic repair in damaged skin due to burns and provide anti-infection protection.

According to experts of the World Health Organization, burn injuries of the skin, mucous membranes and burn disease as a whole take third place among other types of injuries. In the etiological plan, thermal burns are the most common, making up more than 90.0% of all burns, and only chemical burns account for up to 5%, electrical trauma burns - up to 2%. It is important to note that approximately 60% of victims of burns with minor and shallow injuries receive assistance on an outpatient basis. It should be noted the significant "complexity" of the burn wound, which is an "unstable" formation with the possibility of increasing the depth of the wound due to local blood flow disorders that cause tissue ischemia.

Based on the above facts, the topical correction of burn lesions plays a significant role in ensuring the uncomplicated course of the wound process. A promising direction is the creation of highly effective anti-burn agents with complex antibacterial, anti-inflammatory, regenerating, immunomodulatory effects, which becomes possible when creating combined preparations. Among the correction tools that have established themselves as effective cytoprotectors, a special place is occupied by preparations of natural and biotechnological origin, characterized by a wide spectrum of pharmacological action, a specific effect, the absence of side effects, and availability according to the criteria for resource supply.

It is known that burns often occur with infection, which requires the use of antimicrobials, which will maintain the microbial cleanliness of the wound. The use of antibiotics is not always justified, since along with the positive characteristics, they have many disadvantages associated with the spreading antibiotic resistance of microorganisms and a significant number of side effects. An analysis of the scientific literature shows that staphylococci, streptococci, Pseudomonas aeruginosa are most often identified in the discharge of burn wounds, and recently enterococci are often found. In this connection, the use of bacteriophages, devoid of antibiotic deficiencies, as part of the local drug is quite justified. The antimicrobial effect of bacteriophage preparations is due to the introduction of the phage genome into the bacterial cell, followed by its multiplication and lysis of the infected cell. Bacteriophages released into the external environment as a result of lysis re-infect and lyse other bacterial cells, acting until the complete destruction of pathogenic bacteria in the focus of inflammation.

The implementation of a comprehensive regenerative, anti-inflammatory and immunomodulatory effects when creating anti-burn agents can be achieved using phytocompositions. Currently, for the correction of defects in damaged skin, products based on plant materials with wound healing ability have been developed (RU 2495671 dated 10/20/2013, RU 2469704 dated 12/20/2012, RU 2325175 dated 05/27/2011, RU 2317098 dated 02.20.2008, KZ 11695 A from 15.07.2007, RU 2240780 from 11.27.2004, RU 2209074 from 07.27.2003, RU 2110272 from 05.10.1998, RU 2070054 from 12.10.1996, RU 2007164 from 02.15.1994, RU 1836096 from 08.23.1993). The disadvantage of such funds is the presence of a large number of phytoextracts from plants of various kinds, which in itself can provoke an irritating effect, initiate an allergic response, which will aggravate the course of the pathological process. Along with this, another drawback should be noted - the presence in their formulation of components that cause side effects. So, for example, the composition made according to RU 2240780 dated 11.27.2004 contains petrolatum and lanolin - well-known allergens that simultaneously increase the stickiness of the composition, which provoke irritation of the skin and mucous membranes, clogging pores and impair skin oxygen supply. The presence in the composition of the dosage form according to document RU 2007164 of 02.15.1994 a large number of chemical components can also cause irritation of the wound surface and the manifestation of allergic reactions. Polyphyte oil, which is part of the dosage form according to document KZ 11695 A of 07.15.2007, has low chemical stability. In addition, vegetable oils require special storage conditions, limit the shelf life and prolonged use of the drug.

Known anti-burn agent, which is a composition of substances of plant origin based on oil extracts from Hypericum perforatum, sea buckthorn, chamomile, a series of dioecious nettle and having a combined pronounced bactericidal and wound healing effect (RU 1836096 from 08.23.93). A disadvantage of the known means is the complexity of the technological process of preparation, including the processing of part of the components first with alcohol and then with vegetable oil.

An anti-burn agent containing unrefined sunflower oil, burdock root and chamomile flowers, and a method for preparing it by infusing dried plant material for a month on unrefined vegetable oil are considered (RU 2159628 from 11.27.2000). The tool has analgesic and wound healing activity, prevents the formation of keloid scars and helps restore the skin. The disadvantage is the length of the technological process of its manufacture, as well as a limited range of extracted biologically active substances: during oil extraction; only fat-soluble substances pass into the extractant, while tannins and glycosides, which have a pronounced anti-inflammatory effect, are not subject to extraction.

There is a natural product for external use that has anti-inflammatory, antiparasitic, antifungal and anti-burn effects, containing vegetable, or linseed, or cedar oil, 10-20% alcohol tincture of propolis and fir oil (RU 2192273 dated 10.11.2002). The disadvantage of using alcohol tincture is the ability to expand coagulation necrosis in a burn wound.

Known agent for treating wounds, burns and infectious and inflammatory diseases of the skin, skin appendages and mucous membranes containing betulin or its derivative, an antimicrobial agent selected from catamine AB, miramistin, sulfanilamide, trimethoprim, triclosan, metronidazole or a mixture thereof, as well as an anesthetic , excipients, thickener and water (RU 2452475 dated June 10, 2012). The disadvantage of this tool is the possibility of side effects mediated by the influence of potent synthetic substances with antimicrobial and antifungal properties, which reduce local immunity and, ultimately, slow down the regeneration processes.

Known pharmaceutical composition for the treatment of burns, including xymedon and base-forming agents, which are sodium salts of biopolymers, water-retaining agent glycerin, stabilizer, preservative and distilled water (RU 2317811 from 02.27.2008). This composition includes a synthetic compound with regenerative activity, but does not have anti-inflammatory effects.

There is an antibacterial agent containing a concentrate of bacteriophages, a gelling agent in the form of a nonionic or anionic high molecular weight compound, a nonionic surfactant (surfactant), a preservative, a pH regulator and water (RU 2480239 from 04/27/2013). This product is intended for disinfectant use only.

Also considered is an antibacterial agent of selective action, including a bacteriophage concentrate, plant extract, a stabilizing additive, essential oil, an antioxidant, a preservative and the prebiotics necessary for the development of normoflora - amino acid and sugar, as well as a sorbent and proteolytic enzyme (RU 2366436 from 09/10/2009). The tool is proposed for the prevention of dental diseases. Its use is recommended for the destruction of pathogenic bacteria by bacteriophages and stimulation of normal flora with prebiotics.

The closest in technical essence to the present invention is a gel dosage form of a complex preparation with bacteriophages, containing as active components one or more varieties of bacteriophage concentrates distributed in a medium with preservatives, plant extracts, essential oils and stabilizing additives (RU 2156133 from 09/20/2000 ) The disadvantage of the prototype is the absence in the preparation of factors that create optimal conditions for phagolysis and preserve the virulent properties of bacteriophages.

The technical result of the present invention is the development of a comprehensive anti-burn agent that stimulates the processes of post-traumatic repair in damaged skin and exhibits anti-infection protection in case of burn injury. The technical result of the invention is also to obtain an effective anti-burn agent with optimal technological and biopharmaceutical properties, namely thixotropy, uniformity, good spreadability, colloidal stability, optimal hydrogen index; subject to the conditions determining the phagolysis and preservation of the virulent properties of bacteriophages throughout the entire period of storage and use.

As a result of using the present invention, it becomes possible to expand the range of environmentally friendly highly effective complex anti-burn agents by combining the bactericidal action of bacteriophages and phytopreparations with a stimulating repair effect.

As the richest source of biologically active compounds, which has a multifunctional effect on the basic regulatory systems of the body under the influence of damaging traumatic factors, the plant Astragalus fox (Astragalus vulpinus Willd) is of scientific interest. A wide range of physiological activity of the Astragalus fox herb extract is determined by the uniqueness of the chemical composition of the herbaceous part of the plant: the presence of alkaloids, flavonoids (campferol, quercetin, isoramnetin, astragaloside), triterpene saponins (dasiantosides), nitrogen-containing compounds, including glycine, phenol and amino acids, their esters, coumarins, higher fatty acids, polysaccharides, B, C, E, PP vitamins, glycyrrhizic acid salts, trace elements, tannins, essential oils, Amedi. The literature shows the neuroregulatory, immunomodulating, antioxidant, sedative effects of Astragalus fox [Sergalieva M.U., Mazhitova M.V., Samotrueva M.A. The biological activity of plant extracts of the genus Astragalus [Electronic resource] // Modern problems of science and education. - URL: http://www.science-education.ru/128-21809 (accessed September 28, 2015; Sergalieva M.U., Yasenyavskaya A.L. Study of the effect of Astragalus fox herb extract on rat behavior under conditions of immune stress // Scientific forum: Medicine, Biology and Chemistry: collection of articles on the materials of the III international scientific and practical conference - No. 1 (3) - M., Publishing House "ICNO", 2017. - P. 19 -23]. There is evidence of anti-inflammatory and regenerative effects of Astragalus fox herb extract (RU 2681851 dated 03/13/2019), which emphasizes the relevance of the use of Astragalus extract in compositions with various antimicrobial components with the aim of potentiation of the pharmacological action in burn lesions.

Proven pharmacological properties possesses a large plantain. Phytochemical studies of Psyllium leaves proved the presence of pectic acid, galactan, flavonoids (luteopolin, apigenin, quercetin, scutellarein, hispidulin, baikalein, luteolin and their derivatives), iridoids, saponins, coumarin esculetin, bitter, tannic, steroid; organic acids (benzoic, salicylic, lilac, etc.), hydroxycinnamic acids (chlorogenic, cinnamon, para-coumaric, ferulic, coffee, lilac, vanilla, etc.), macro- and microelements. Pharmacological and clinical studies have shown that extracts from the leaves of Psyllium greater accelerate the healing of infected wound surfaces, reduce the amount of purulent discharge, stimulate the growth of granulations and epithelization, and also have a pronounced anti-inflammatory effect and promote the regeneration of the skin and mucous membranes.

The introduction of a polyvalent bacteriophage into the anti-burn agent provides a complex antimicrobial effect against Staphylococcus, Streptococcus, Proteus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and prevents the development of possible complications of classical antibiotic therapy, namely, inhibition of immunity to bacterial cultures and antibiotic resistance.

The presence of aqueous extracts of Astragalus fox herb and plantain leaves in the claimed agent explains their positive effect on the recovery of damaged skin as a result of a wide range of pharmacological activity. The composition of the basic components of the claimed tool allows you to maintain its stability and technological properties, as well as to ensure the completeness and speed of release of active substances in pathologically altered tissues throughout the shelf life.

To achieve the objective of the invention, the composition of the drug was introduced as the main active ingredients - water extracts of Astragalus fox herb and leaves of the Great plantain; as gelling components, ethyl cellulose and Pemulen carbomer, nipagin as a preservative ingredient, and nicotinic acid, riboflavin, biotin as components that improve the stable and lysing properties of bacteriophages.

The soft dosage form in the form of a gel has several advantages, due to its base with high osmotic activity, which prevents excessive moisture loss by tissues, and helps to completely remove excess tissue infiltrate formed in burned tissues. Applying a gel form in the form of a dressing on a damaged area of the skin provides a painless and atraumatic removal of them during dressings.

The use of a combination of gel-forming components contributes to the achievement of positive technological characteristics and the pharmacological synergy of all ingredients used in the composition of the product, both biologically active and auxiliary.

Gelling agents ethyl cellulose and carbomer of the Pemulen type provide, when applied to wound and burn surfaces, the formation of a finest smooth protective film, are well distributed over a pathologically altered surface, provide a prolonged action, complete and uniform release of active substances, while not interacting with other components and with the skin ; does not have toxic and carcinogenic properties; It is not absorbed into the systemic circulation and does not accumulate in the tissues.

Metabolic components, in particular, nicotinic acid, riboflavin and biotin, which are important as components of a nutrient medium for bacteriophages, are considered as factors determining the optimal conditions for phagolysis and preservation of the virulent properties of bacteriophages throughout the entire storage and use period. Along with these properties, these vitamins play an important role in the metabolic processes of the skin and mucous membranes, helping to reduce oxygen starvation, improving blood flow by acting on the capillaries, restoring the structure of neural fibers, and, ultimately, accelerating the regeneration processes.

The preservative nipagin provides a wide range of protection against a wide range of microorganisms that violate the quality and reduce the shelf life of the drug. Nipagin is safe, does not irritate the skin, does not have toxicity and oncogenicity, and is approved for use in medical practice. The introduction of this preservative in soft dosage forms, including gel, does not affect the consistency of the product, does not exfoliate and does not reduce the viscosity.

In the available sources of scientific, technical and patent literature, information on a comprehensive anti-burn agent that stimulates the reparative ability of damaged skin containing aqueous extracts of Astragalus fox herb and plantain leaves in combination with ethyl cellulose, Pemulen carbomer, nipagin and a vitamin complex consisting of nicotinic acid, riboflavin and biotin not detected. Thus, the claimed invention meets the criterion of "novelty."

When checking the patentability of the claimed invention, it was established that it meets the conditions of industrial applicability, since the high quality and effectiveness of the funds obtained is achieved. It was also established that the invention meets the conditions of an inventive step, since the claimed tool differs from the analogue (RU 2156133 from 09/20/2000) by introducing, as the main active ingredients, aqueous extracts of Astragalus fox herb and plantain leaves, as gelling components like ethyl cellulose and arbomer type Pemulen, nipagin as a preservative, nicotinic acid, riboflavin, biotin as components that improve the stable and lysing properties of bacteriophages.

Under the conditions of the experiment, a comprehensive anti-burn agent was developed and tested with optimal thixotropy, uniformity, good spreadability, optimal conditional viscosity, colloidal stability, and an optimal hydrogen index.

The claimed agent can be obtained as follows: aqueous extracts of Astragalus fox and Psyllium grass obtained by vortex extraction in a ratio of 1: 1 are mixed in equal amounts with ethyl cellulose and Pemulen carbomer to uniformity; after swelling of the latter, after 20 minutes, a mixture of purified filtrates of bacterial phagolysates Staphylococcus, Streptococcus, Proteus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli with nicotinic acid, riboflavin and biotin dissolved in it (in a ratio of 1: 0.1: 1); upon reaching the desired consistency nipagin is added.

In an experiment on laboratory animals, the effectiveness of the claimed drug in the treatment of burn wounds has been proved. Daily applications of a comprehensive anti-burn gel gel resulted in normalization of the functional potential of damaged skin, correction of destructive transformations in it, stimulation of reparative processes and acceleration of the healing time of affected tissues. The claimed tool has a high specific physiological activity in the treatment of experimental burn wounds in all phases of the wound process, contributing to wound healing in a short time.

The essence of the invention is illustrated by the following examples showing the achievement of a technical result.

Example 1. Received a comprehensive anti-burn agent in the form of a gel, where: aqueous extract of Astragalus fox herb 3.0 wt. %; water extract of the leaves of Plantain large 3.0 wt. %; polyvalent bacteriophage 0.5 wt. %; nicotinic acid 0.01 wt. %; riboflavin 0.001 wt. %; Biotin 0.01 wt. %; ethyl cellulose 1.0 wt. %; Pemulen carbomer 1.0 wt. %; nipagin 0.05 wt. %; distilled water - the rest.

The resulting product was a viscous homogeneous mass with good spreadability (shear rate 199 s ^-1 ); a hydrogen index in the range of 6.8; conditional viscosity 6356 cps; colloid stable (no signs of separation) and thixotropic (the presence of a hysteresis loop).

Example 2. Received a comprehensive anti-burn agent in the form of a gel, where: aqueous extract of Astragalus fox herb 5.0 wt. %; water extract of the leaves of Plantain large 5.0 wt. %; polyvalent bacteriophage 1.0 wt. %; nicotinic acid 0.02 wt. %; riboflavin 0.002 wt. %; Biotin 0.02 wt. %; ethyl cellulose 2.0 wt. %; Pemulen carbomer 2.0 wt. %; nipagin 0.1 wt. %; distilled water - the rest.

The resulting product was a viscous homogeneous mass with good spreadability (shear rate of 202 s ^-1 ); a hydrogen index in the range of 6.9; conditional viscosity 6368 cps; colloid stable (no signs of separation) and thixotropic (the presence of a hysteresis loop).

Example 3. Experimentally proved the effectiveness of the proposed tool, including aqueous extracts of grass Astragalus fox and plantain leaves of a large, polyvalent bacteriophage, using auxiliary components (ethyl cellulose; Pemulen carbomer, nipagin, nicotinic acid, riboflavin, biotin), made in the form of a gel, in treatment of thermal skin burns in laboratory animals. Evaluation of the effectiveness of the application was carried out on the basis of the following criteria: reduction of the area of the burn defect, acceleration of the recovery and epithelization of burn skin wounds; reduction of treatment time.

The study was conducted on sexually mature outbred male rats. Animals were divided into groups: 1) control, including animals with thermal burn (wounds regenerated naturally); 2) experimental, including animals with thermal burns, the treatment of wounds of which was carried out by the method of applications of a comprehensive anti-burn agent, made in the form of a gel (2 times a day for 10 days).

The effectiveness of the use of the proposed drug was evaluated visually by the borders of the wound, the nature of the reparative process, the rate of epithelialization of wounds on the days of measuring the area of the wounds of a burn defect.

In the post-traumatic period, within 5 days after the burn exposure, in the control group of animals in the interscapular region of the back, a thermal skin injury was observed, covered with a yellow-brown scab with signs of pathological destructive processes. In the control group of animals, the absence of inflammatory ulcerations and necrotic formations was observed only by the 9th day of the experiment.

In the experimental group of animals already on the 3rd day of treatment with applications of the claimed funds, early scab rejection, contraction of the wound edges and, as a result, reduction of its size were noted. In 60% of animals of the same group, on the 5th day, the scab was completely torn away, and the beginnings of granulation tissue appeared. By the 6th day, the skin of the animals of the experimental group was characterized by the complete absence of a scab, reduced by 1.5 times the area of the burn wound.

External use by the application method of the inventive agent has led to the stimulation of post-traumatic repair processes in damaged skin, which consists in stopping pathological processes in the wound, in correcting destructive transformations in the skin, in reducing the area of burn wounds, in accelerating the healing time of affected skin and, as a result, shortening the time treatment.

Example 4. Experimentally proved the effectiveness of the proposed tool, including aqueous extracts of grass Astragalus fox and plantain leaves of a large, polyvalent bacteriophage, using auxiliary components (ethyl cellulose; Pemulen carbomer, nipagin, nicotinic acid, riboflavin, biotin), made in the form of a gel. Evaluation of the effectiveness of the application was carried out on the basis of the absence of a characteristic growth of microorganism strains on a solid nutrient medium. To determine the antibacterial effect of the gel, the agar diffusion method was used according to the methodological recommendations for studying the specific activity of antimicrobial drugs. Microorganism cultures were grown at a temperature of 37 ° C for 24 hours. For testing, they were diluted 1: 1000 with a sterile 0.9% sodium chloride solution. 1 ml of suspension of the test strains of Staphylococcus aureus, Proteus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli was applied to the agarized surface of the nutrient medium. The cups were dried and holes were made with a special punch with a diameter of 10 mm. The test gel was added to the wells. Analysis was performed after 24 hours by measuring the growth inhibition zone around the well.

The following results were obtained: 24 hours after the introduction of gel samples into the wells, a decrease in the zone of characteristic growth of microorganisms by 75% was observed for Staphylococcus aureus and Escherichia coli; 70% relative to Proteus, Klebsiella pneumoniae and Pseudomonas aeruginosa.

Thus, an achievement of the present invention is to provide an agent comprising aqueous extracts of Astragalus fox herb and the leaves of Psyllium large, polyvalent bacteriophage, using auxiliary components (ethyl cellulose; Pemulen carbomer, nipagin, nicotinic acid, riboflavin, biotin), made in the form of a gel, for treatment of thermal burns of the skin, characterized by optimal technological and biopharmaceutical characteristics that determine the phagolysis and preservation of the virulent properties of bacte iofagov throughout the storage and use of the term.

Claims (2)

An anti-burn agent based on extracts of plants, bacteriophages, preservatives and gelling agents, characterized in that it contains aqueous extracts of the herb Astragalus fox and the leaves of Plantain major, a multivalent bacteriophage active against Staphylococcus aureus, Proteus, Pseudomonas aeruginosa, Klebsiella pneumoniai, nicherichota acid, nicherichicin, Escherichina , riboflavin, biotin, ethyl cellulose, Pemulen carbomer, nipagin and distilled water in the following ratio, wt.%: Astragalus fox aquatic herb extract             3.0-5.0 Plantain Large Aquatic Leaf Extract 3.0-5.0 Polyvalent bacteriophage active against Staphylococcus aureus, Proteus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli                         0.5-1.0 A nicotinic acid                                             0.01-0.02 Riboflavin                                                                 0.001-0.002 Biotin                                                                     0.01-0.02 Ethyl cellulose                                                             1.0-2.0 Carbomer Pemulen                                                             1.0-2.0 Nipagin                                                                       0.05-0.1 Distilled water                                           rest