RU2481834C2 - Antimicrobial composition for treatment of wounds and burns - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel medication for treatment of purulent-inflammatory processes of skin and mucous membranes of different etiology. Medication is made in form of gel and contains the following ingredients with the following ratio of components in g per 100 g: biocomplex of metronidazole with zinc 0.5-2.0, biocomplex of furacilinum with copper 0.1-0.2, trimecaine 3.0-5.0, vitamins (vitamin A, vitamin E, vitamin PP, vitamin C or their mixture) 0.1-1.0, dimexide 10.0, hydrogel of methylsiliconic acid 1.0-5.0, hydrophilic base 3.0-7.0, water 82.3-69.8.

EFFECT: extension of assortment of wound-healing medications.

2 tbl, 1 ex

Description

The invention relates to medicine, namely to the production of medicines for external use.

Known means the gel "Metrogil Dent", which as the active substance contains metronidazole and chlorhexidine. Excipients: disodium edetate, menthol, sodium saccharin, propylene glycol, carbomer-940, purified water.

The disadvantages of the Metrogil Dent gel are its use only for the treatment and prevention of infectious and inflammatory diseases of the oral cavity.

The closest is the gel "Metrogil", approved by the Pharmacological Committee of the Ministry of Health of the Russian Federation on March 1, 2004, pr. No. 56, registration number: П№011666 / 04. As an active substance, the Metrogil gel contains metronidazole and excipients: propyl hydroxybenzoate, propylene glycol, carbomer-940, disodium edetate, sodium hydroxide, water.

The disadvantages of the Metrogil gel include its only intravaginal use and the inadmissibility of use in otorhinolaryngology, the absence of anesthetic effect.

The objective of the invention is to increase the non-invasiveness of wound treatment, the creation of a highly effective drug from the point of view of bioavailability, having a multidirectional therapeutic effect on purulent-inflammatory processes and improving its regenerative effect.

The invention consists in the fact that the product consists of a zinc biocomplex with metronidazole and a copper biocomplex with furacilin, or a mixture thereof, vitamins selected from the group: vitamin E, vitamin C, vitamin PP, vitamin A, or a mixture thereof, anesthetic (trimecain, lidocaine ), dimexide, methylsilicic acid hydrogel (Enterosgel) and hydrophilic base.

The inventive composition "Nifugil" is a non-toxic gel, highly effective in the treatment of skin lesions, non-irritating wound surface, hydrophilic and easily absorbed, followed by resorption and effect on the wound process.

The task is achieved in the following way.

The inventive wound healing agent "Nifugil" is made in the form of a gel and contains a zinc biocomplex with metronidazole and a copper biocomplex with furacilin, or a mixture of them, vitamins selected from the group: vitamin E, vitamin C, vitamin PP, vitamin A, or a mixture thereof; anesthetic (trimecaine, lidocaine), dimexide, hydrosilicon methylsilicic acid, water, as well as a hydrophilic base - modified cellulose derivatives (or methyl cellulose or carboxymethyl cellulose or sodium carboxymethyl cellulose or hydroxypropyl methyl cellulose) in the following ratio of 100 components:

Zinc biocomplex with metronidazole 0.5-2.0 Biocomplex of copper with furacilin 0.1-0.2 Trimecaine 3.0-5.0 Vitamins (Vitamin A, E, C, PP) 0.1-1.0 Dimexide 10.0-10.0 Methylsilicic Acid Hydrogel (Enterosgel) 1.0-5.0 Hydrophilic base 3.0-7.0 Water 82.3-69.8

The invention allows to prolong the action of drugs and, thereby, increase the non-invasiveness of treatment, especially burn and extensive trophic skin lesions, mucosal lesions.

The gel contains drugs in amounts that provide their therapeutic effect.

As a medicine, the gel contains at least one component selected from the group comprising antimicrobial agents, anesthetics, vitamins, skin regeneration promoting substances, dimexide or a mixture of these substances.

As antimicrobial agents, the gel contains, for example, a biocomplex of metronidazole with zinc and a biocomplex of furatsilin with copper or a mixture thereof.

As vitamins, the gel may contain, for example, retinol, ascorbic acid, alpha-tocopherol, nicotinic acid.

Additionally, in order to reduce possible pain, the composition includes, as an anesthetic, for example, trimecaine, or lidocaine, or a mixture thereof.

Trimecaine (α-diethylamino-2,4,6-trimethylacetanilinide hydrochloride) is a crystalline powder, white or white with a slight yellowish tint, very easily soluble in water, easily soluble in alcohol; has high activity in all types of anesthesia, especially superficial (FS 42-2390-92 "Trimekain"; Pryanishnikova NT. Clinical use of trimekain. // Surgery. - 1966. - N8. - P.51-55; Mashkovsky M. D. Medicines. -Kharkiv: Torsing, 1997. - T.1, S.301).

Dimexide (Dimethyl sulfoxide). Colorless transparent liquid or colorless crystals, melting at a temperature of 18.5 ° C, with a specific odor. Hygroscopic. Miscible in all proportions with water and alcohol. It has a local anesthetic, local anti-inflammatory, antimicrobial (antiseptic) and fibrinolytic effects. It penetrates quickly and well through biological membranes, incl. through the skin and mucous membranes, increases their permeability to other drugs. Changes the sensitivity of antibiotic-resistant microflora. It is used in combination with other medicinal substances for better and deeper penetration into tissues (Register of Medicines).

Hydrogel of methylsilicic acid (enterosgel) is an enterosorbing, enveloping, antidiarrheal, detoxification drug based on organic silicon, designed to remove toxic substances from the body and the gastrointestinal tract. Enterosgel selectively sorbes from the blood medium molecular endogenous and exogenous toxic substances of various nature: bacterial toxins, allergens, antigens, viruses, drugs and poisons. Adsorb some metabolic products. Does not adsorb trace elements. It stops the manifestations of dysbiosis, helps to normalize the function of the hematopoietic and immune systems. As a result of selective adhesion, enterosgel destroys pathogenic microorganisms and removes their particles containing endo- and exotoxins. It has anti-inflammatory and regenerative effects on the mucous membrane of the stomach and intestines, prevents the occurrence of erosive damage, is non-toxic and harmless, has an organic surface and is fully compatible with tissues and substrates of the body, is chemically inert in the body. It is used for intoxications of various origins: poisoning, alcohol intoxication, intestinal infections, foodborne diseases, dysbiosis, food and drug allergies, toxicoinfectious liver damage, purulent-septic processes, burn disease in the intoxication phase, etc.

As substances that stimulate reparative processes in a wound, there may be:

or nicotinic acid is a vitamin and lipid-lowering agent. In the body, it turns into nicotinamide, which binds to coenzymes of type I and II codehydroginases (NAD and NADP) that transfer hydrogen, is involved in the metabolism of fats, proteins, amino acids, purines, tissue respiration, glycogenolysis, and the synthetic process. Replenishes the deficiency of vitamin PP, normalizes the concentration of blood lipoproteins, dilates small vessels, improves microcirculation, exerting a weak antigoagulant effect. It is used for hypo- and vitamin deficiency PP, chronic infections, non-healing wounds and trophic ulcers;

or ascorbic acid (L-Ascorbic acid) is a white organic powder with an acidic taste. Easily soluble in water, soluble in alcohol; possesses pronounced antioxidant properties, participates in the formation of terahydrofolic acid and tissue regeneration, the synthesis of steroid hormones, collagen, procollagen (Register of medicines);

or retinol (vitamin A) exists naturally in the form of retinol and beta-carotene. Designed for antioxidant function. Vitamin A deficiency leads to dry skin, an unhealthy grayish tint, dissection and brittle hair, fragility and slow growth of nails. Vitamin A slows down the aging of the body and helps to keep the skin smooth and supple for a long time;

or tocopherol (vitamin E) - provides normal oxygen uptake and inhibits the oxidation processes in the body, necessary for the body to properly absorb the vitamins of all other groups. It is important for the course of metabolic processes especially in muscle tissue, as well as for maintaining energy balance, and reduces the risk of a number of chronic diseases.

Additional stimulation of repair processes in the wound in the proposed pharmacological agent can be applied both in the form of a monocomponent (one of the vitamins), and a mixture of components (vitamins) with a different mechanism and spectrum of action.

As a hydrophilic base (water-soluble cellulose derivatives), the following known substances may be:

or water-soluble methyl cellulose grade MTs-100 or MTs-400, obtained according to TU-6-55-221-137-93 (Research Institute "Polymersynthesis", Vladimir);

or carboxymethyl cellulose, reference book "Reagents for biochemistry and research in the field of natural sciences", SIGMA, 1999, p.22 - the product of the interaction of cellulose with monochloracetic acid; white solid (Chemistry and technology of cellulose derivatives. / Ed. by L.P. Perepechkin and Yu.L. Pogosov. Vladimir, 1968.);

or carboxymethyl cellulose sodium salt — the sodium salt of cellulose ether and glycolic acid. White or slightly yellowish powder, or odorless fibrous product, soluble in cold and hot water. It forms highly viscous solutions. Not carcinogenic. It is widely used in cosmetic, perfumery industries, in medicine and pharmacy as an auxiliary substance in eye drops, emulsions, suspensions, ointments, as part of toothpastes, tablets, etc. (Registration number 68/333/16; State Register of Medicines. M., 2000. - 1203 p .; Polymers in the pharmacy. / Edited by A.I. Tentsova, M.T. Alyushina. - M. Medicine, 1985.-256 p.);

or hydroxypropyl methylcellulose - a product of non-animal origin with high microbiological and chemical stability. White powder without taste or smell; inert to most active and auxiliary substances, the powder has good fluidity and does not form dust in the air; soluble in water in any proportion with the formation of a transparent liquid of various viscosities, depending on the type of hydroxymethyl cellulose. As a result of the non-ionic structure, hydroxymethyl cellulose solutions are stable to various pH values and tolerant to salts. In combination with other film-forming agents, it can be used to create soluble film coatings; it is a good gelling agent. High viscosity types can be used to create highly transparent thick ophthalmic preparations.

The use of hydrophilic bases (modified cellulose derivatives) in the proposed pharmacological agent provides fast delivery of active substances to both microbial cells and tissue cells, which increases the therapeutic activity of the proposed drug. In addition, dehydration with a hydrophilic base of cells of non-positive microorganisms reduces their resistance, which also increases the therapeutic activity of the proposed drug. The use of dimexide additionally improves microcirculation in wound tissues due to their dehydrating effect, and also has an additional anti-inflammatory effect due to the absorption of fluid and reduction of edema of wound tissues.

Nifugil wound healing agent is atraumatic and is intended for the treatment of skin and mucosal lesions.

For the proposed composition of a multicomponent gel, taking into account the nature and properties of its constituent ingredients, a preparation technology has been developed that includes three stages.

A wound healing agent is prepared as follows: at the beginning, the zinc biocomplex with metronidazole is dissolved in hot distilled water and one of the proposed vitamins or their mixture, local anesthetic (or trimecaine, or lidocaine), dimexide is successively introduced; the manufacture of a gel base, followed by the introduction of a copper biocomplex with furacilin and an organosilicon compound by grinding; mixing the gel base and the dissolved remaining components to obtain a homogeneous homogeneous mass.

1st stage. In hot distilled water (70 ° C), the zinc biocomplex with metronidazole dissolves with stirring on a magnetic stirrer. Dimexide, one of the vitamins or their mixture, anesthetic (composition A), is successively introduced into the resulting solution with stirring.

2nd stage. An aqueous gel or methyl cellulose or carboxymethyl cellulose or sodium carboxymethyl cellulose or hydroxypropyl methyl cellulose is prepared. By grinding, a biocomplex of copper with furacilin and an organosilicon compound (composition B) are introduced.

3rd stage. The components of composition A are added in small portions to the composition B with thorough mixing until a uniform viscous system is obtained.

An example of a method for producing a gel

In 10.0 ml of hot distilled water, 0.5 g of the zinc biocomplex with metronidazole is dissolved with stirring and dimexide (10.0), one of the vitamins, for example, ascorbic acid (0.1), an anesthetic, for example, is sequentially introduced into the resulting solution. trimecaine (3.0) (composition A). 3 g of either methyl cellulose or carboxymethyl cellulose or sodium carboxymethyl cellulose or hydroxypropyl methyl cellulose are placed in 40.0 ml of warm distilled water and left to swell for 40-60 minutes, then the remaining amount (32.4 ml) of water is added and mixed thoroughly. A copper biocomplex with furatsilin and an organosilicon compound (1.0) (composition B) are introduced into the gel mass by grinding.

Composition A containing an antimicrobial preparation (zinc biocomplex with metronidazole), dimexide, trimecain, ascorbic acid is introduced into the gel obtained with stirring.

In appearance, the prepared gel is a homogeneous yellowish mass of a gel-like consistency, a slightly bitter taste that causes numbness of the tip of the tongue.

The composition of the gels are presented in table 1.

Table 1 The composition of the gels No. p / p Component Name No. of ointment composition one 2 3 four 5 one Antimicrobial drug: 0.5 - - - Metronidazole
Furatsilin 0.1 - - - - Zinc biocomplex with metronidazole 0.5 0.5 - copper biocomplex with furatsilin 0.1 0.1 2 Trimecaine 3.0 3.0 3.0 3.0 3.0 3 Dimexide 10.0 10.0 10.0 10.0 10.0 four Vitamins or a mixture thereof 0.1 0.1 0.1 0.1 0.1 5 Organosilicon compound 1,0 1,0 1,0 1,0 1,0 6 Sodium salt of carboxymethyl cellulose (or methyl cellulose, or carboxymethyl cellulose, or hydroxypropyl methyl cellulose) 3.0 3.0 3.0 3.0 3.0 7 Water 82,4 82.8 82,4 82.8 82.3

The study of the antimicrobial activity of the proposed compositions was carried out by diffusion in agar on solid nutrient media by analyzing zones of growth inhibition of test microorganisms used to determine the antimicrobial effect of drugs. Studies were carried out for the following standard strains of microorganisms: Staphylococcus aureus ATCC 6538-P, Escherichia coli ATCC 25922, Bacillus subtillis ATCC 6633. It was found that the antimicrobial effect is actively manifested in relation to all of the above test cultures.

The results obtained made it possible to establish an increase in antimicrobial activity due to the combined presence of a zinc biocomplex with metronidazole and a copper biocomplex with furacilin, trimecaine, an organosilicon compound, vitamins, dimexide, and a base - a water-soluble cellulose derivative (or methyl cellulose, or carboxymethyl cellulose, sodium or carboxymethyl cellulose, or ) (table 2).

table 2 The results of a study of the antimicrobial activity of ointments No. p / p Objects of research Growth inhibition zones, mm Staphylococcus aureus ATCC 6538-P Escherichia coli ATCC25922 Bacillus subtillis ATCC 6633 one Gel "Metrogil" 17.1 ± 0.3 15.2 ± 0.2 18.9 ± 0.3 2 Composition 1 19.4 ± 0.3 18.6 ± 0.2 20.2 ± 0.2 3 Composition 2 20.1 ± 0.3 15.4 ± 0.2 19.1 ± 0.2 four Composition 3 27.0 ± 0.3 26.6 ± 0.2 28.2 ± 0.3 5 Composition 4 26.4 ± 0.4 21.7 ± 0.3 24.3 ± 0.4 6 Composition 5 35.2 ± 0.3 34.6 ± 0.3 33.9 ± 0.2

The local anesthetic activity of the developed gels was studied in vivo by the Rainier-Valet method, which is based on the change in the sensitivity of the cornea of the rabbit eye when a test sample is applied to it, which is expressed in response to an irritant in the form of a closure of the eyelid.

0.1 g of the test gel was injected into the conjunctival sac of the rabbit's eye using a syringe. Using calibrated hairs, rhythmic irritations were applied to the cornea with a frequency of 100 beats per minute after 1, 2, 5, 8, 10, 12, 15 minutes and then every 5 minutes until the eyelids closed.

The time between the injection of the gel sample and the onset of the pharmacological effect was taken as the rate of local anesthesia.

High values of the Rainier index (more than 1300 ± 2.5 srvc), the duration of general anesthesia (more than 100.2 ± 3.4 min) for the proposed multicomponent gel formulations (compared with the control (424.4 ± 9.4 srvc. units)) indicate not only the synergistic effects of trimecaine and biocomplexes of zinc with metronidazole and copper with furatsilin, but also the prolongation of the anesthetic effect.

A study of the wound healing activity of a multicomponent gel was carried out on a model of a full-layer purulent wound in an experiment on laboratory animals. In the experiment, sexually mature Wistar male rats weighing 100-120 g were used. The animals were divided into groups: control (untreated), comparisons (treatment with official 0.2% Levomekol ointment, and treatment with a gel containing metronidazole (composition 1, table 1 )) and experimental (treatment with the developed tool (composition 5, table 1)).

The total percentage reduction in wound area in dynamics in the experimental group by 11 days of the experiment was 92.3%, in the comparison groups - 59.4% and 63.5% and in the control group - 40.2%, respectively

According to the dynamics of changes in the area of wounds, clinical, microbiological and histological indicators, a pronounced therapeutic effect of the developed agent was established in comparison with the official ointment “Levomekol” and composition 1 containing metronidazole.

Thus, the proposed wound healing agent "Nifugil" in comparison with the prototype has a higher antimicrobial activity, a strong local anesthetic effect and effective wound healing effect, which are due to the combination of antimicrobial agents (zinc and metronidazole biocomplexes and copper with furacilin), local anesthetic vitamin D organosilicon compounds and bases containing water-soluble derivatives of cellulose, and potentiating each other. An optimal method for the preparation of the proposed gel formulations has been developed, at which maximum therapeutic effectiveness is achieved.

The proposed composition of the combined gel allows you to expand the range of available drugs used to treat local purulent-inflammatory processes of the skin and mucous membranes of various etiologies.

The invention provides a multidirectional therapeutic effect on purulent-inflammatory processes, the wound healing agent "Nifugil" is highly effective in terms of bioavailability.

The invention provides a reduction in treatment time by reducing the time required to restore skin integrity.

Claims (1)

A remedy for the treatment of purulent-inflammatory processes of the skin and mucous membranes of various etiologies, characterized in that it is made in the form of a gel and contains a biocomplex of metronidazole with zinc, a biocomplex of furacilin with copper, trimecain, dimexide, vitamins selected from the group (vitamin E, vitamin C , vitamin PP, vitamin A), an organosilicon compound, water, as well as a hydrophilic base in the following ratio of components in g per 100 g:
Metronidazole Zinc Biocomplex 0.5-2.0 Biocomplex furatsilina with copper 0.1-0.2 Trimecaine 3.0-5.0 Vitamins (vitamin A, vitamin E, vitamin PP, vitamin C, or a mixture thereof) 0.1-1.0 Dimexide 10.0-10.0 Methylsilicic acid hydrogel 1.0-5.0 Hydrophilic base 3.0-7.0 Water 82.3-69.8