RU2481835C2 - Wound-healing medication for local application - 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 cobalt (II) with metronidasole 0.20-0.50. biocomplex of cobalt (II) with ampicillin 0.20-0.50, trimecaine 3.00-5.00, methyluracyl 1.00-3.00, dimexide 10.00, glycerol 5.00-10.00, hydrophilic base 3.00-7.00, water 77.60-64.00.

EFFECT: extension of assortment of wound-healing medications.

3 tbl, 1 ex

Description

The invention relates to medicine, namely to agents having a multifactorial effect on purulent-inflammatory processes of the skin and used in surgery, dermatology, gynecology, proctology, otorhinolaryngology.

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.

Known tool ointment "Levomekol", FS 42-2922-98, widely used to treat local purulent infections. As an active substance, Levomekol ointment contains chloramphenicol and methyluracil and is prepared on a hydrophilic polyethylene oxide basis. It is used to treat purulent wounds infected with mixed flora, including staphylococci, Pseudomonas aeruginosa and Escherichia coli.

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, edetate disodium, sodium hydroxide, water.

The disadvantages of the Metrogil gel are its intravaginal use and inadmissibility in otorhinolaryngology.

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 lies in the fact that the tool consists of a cobalt biocomplex with metronidazole or a cobalt biocomplex with ampicillin, or a mixture thereof, trimecaine, dimexide, glycerol, methyluracil and a hydrophilic base.

The inventive composition "Metagil" is a non-toxic gel, highly effective in the treatment of skin lesions, not irritating to the 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 "Metagil" is made in the form of a gel and contains a cobalt biocomplex with metronidazole or a cobalt biocomplex with ampicillin, or a mixture thereof, trimecaine, dimexide, glycerol, methyluracil, water, and also a hydrophilic base - water-soluble cellulose cellulose or cellulose cellulose or (cellulose) or , or sodium salt of carboxymethyl cellulose, or hydroxypropyl methyl cellulose) in the following ratio of components in g per 100 g:

Cobalt Biocomplex with Metronidazole 0.2-0.5 Cobalt Biocomplex with Ampicillin 0.2-0.5 Trimecaine 3.0-5.0 Methyluracil 1.0-3.0 Dimexide 10.0-10.0 Glycerol 5.0-10.0 Hydrophilic base 3.0-7.0 Water 77.6-64.0

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, substances that promote skin regeneration, dimexide and glycerin, or a mixture of these substances.

As antimicrobial agents, the gel contains, for example, a cobalt biocomplex with metronidazole or a cobalt biocomplex with ampicillin, or a mixture thereof. As a substance acting on cell regeneration, the gel contains, for example, methyluracil.

Additionally, in order to reduce possible pain, an anesthetic, for example, trimecaine or lidocaine, is included in the composition.

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, p. 301).

Methyluracil (2.4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine). Flavourless white crystalline powder. Slightly soluble in water (up to 0.9% at a temperature of + 20 ° C) and alcohol. Accelerates the processes of cellular regeneration, wound healing, stimulates cellular and humoral defense factors; has an anti-inflammatory effect; possesses anabolic and anti-catabolic activity. Assign with sluggishly healing wounds, burns, bone fractures (Register of medicines).

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 effect. 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).

Glycerin (1,2,3-propanetriol). Colorless, viscous, odorless, sweet liquid. Miscible in any ratio with water, ethanol, methanol, acetone, insoluble in chloroform and ether, soluble in their mixtures with ethanol. It absorbs moisture from the air (up to 40% by weight).

As a hydrophilic base, a water-soluble cellulose derivative is proposed as the most optimal for gel preparation, used to treat local purulent-inflammatory processes and meets all the requirements for this type of base.

The following known substances are taken as water-soluble derivatives of cellulose:

or water-soluble methyl cellulose grade MTs-100, or MTs-400, obtained according to TU-6-55-221-137-93 (Research Institute "Polymersynthesis", Vladimir), carboxymethyl cellulose, reference book "Reagents for biochemistry and research in the field of natural sciences ", SIGMA, 1999, p.22, sodium carboxymethyl cellulose;

or carboxymethyl cellulose - the product of the interaction of cellulose with monochloracetic acid; white solid (Chemistry and technology of cellulose derivatives, edited by L.P. Perepechkin and Yu.L. Pogosov, Vladimir, 1968);

or sodium carboxymethyl cellulose — 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 the cosmetic, perfumery industry, 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. Tenzova, 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 hydroxypropyl methylcellulose. As a result of the non-ionic structure, hydroxypropyl methylcellulose 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 wound healing agent "Metagil" 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 cobalt biocomplex with metronidazole is dissolved in hot distilled water and dimexide, trimecain, glycerin are introduced; the manufacture of a gel base with the introduction of a biocomplex of cobalt with ampicillin and methyluracil 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 cobalt biocomplex with metronidazole dissolves with stirring on a magnetic stirrer. Dimexide, trimecaine, glycerin (composition A) is successively introduced into the resulting solution with stirring.

2nd stage. An aqueous gel or methyl cellulose, or carboxymethyl cellulose, or sodium salt of carboxymethyl cellulose, or hydroxypropyl methyl cellulose is prepared, and the cobalt biocomplex with ampicillin and methyluracil is introduced by trituration (composition B).

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, 0.2 g of the cobalt biocomplex with metronidazole is dissolved with stirring and dimexide (10.0), trimecaine (3.0), glycerin (5.0) are sequentially introduced into the resulting solution (composition A). 3 g of methyl cellulose, or carboxymethyl cellulose, or sodium salt of 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 (27.8 ml) of water is added and thoroughly mixed. The cobalt biocomplex with ampicillin and methyluracil (1.0) are introduced into the gel-like mass by rubbing (composition B).

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

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

The study of the specific activity of the proposed gel compositions (table 1) was carried out in experiments in vitro and in vivo.

The study of the antimicrobial activity of the proposed drug 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 obtained results made it possible to establish an increase in antimicrobial activity due to the co-presence of a cobalt biocomplex with metronidazole and a cobalt biocomplex with ampicillin, trimecaine, methyluracil, dimexide, glycerol and a base - a water-soluble derivative of cellulose (or methyl cellulose or carboxymethyl cellulose or carboxymethyl cellulose or carboxymethyl cellulose cellulose or carboxymethyl cellulose) table 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 a rabbit eye when a test sample is applied to it, which is expressed in response to an irritant in the form of an eyelid closure.

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 at 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.

Table 2 The results of the study of antimicrobial activity of gels No. p / p Objects of research Growth inhibition zones, mm Staphylococcus aureus ATCC 6538-P Escherichia coli ATCC 25922 Bacillus subtillis ATCC 6633 one. Gel "Metrogil" 17.1 ± 0.3 15.2 ± 0.2 18.9 ± 0.3 2. Composition No. 1 19.4 ± 0.3 18.6 ± 0.2 20.2 ± 0.2 3. Composition No. 2 16.6 ± 0.2 12.5 ± 0.3 15.0 ± 0.3 four. Composition No. 3 25.7 ± 0.2 24.5 ± 0.3 27.2 ± 0.2 5. Composition No. 4 23.0 ± 0.3 22.4 ± 0.2 20.5 ± 0.3 6. Composition No. 5 33.4 ± 0.2 31.2 ± 0.3 32.6 ± 0.3

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

The relative strength of the anesthetic effect was calculated according to the Rainier index, summing up the number of irritations in 13 measurements, starting from the 8th minute, within an hour.

The indicator of complete anesthesia was considered the absence of a blinking reflex for 1 min at 100 contacts of calibrated hairs with the cornea of the eye.

The duration of general anesthesia was characterized by the time from the start of anesthesia to the complete restoration of sensitivity.

The results obtained were processed by the method of variation statistics (GF XI, M., 1987, v. 1, p. 199), are presented in table 3.

The high values of the Rainier index, the duration of general anesthesia for the proposed multicomponent gel formulations (as compared with the control) indicate not only the synergistic effects of trimecaine and the metronidazole biocomplex with cobalt, trimecaine and the ampicillin biocomplex with cobalt or their mixture, 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 we used sexually mature Wistar male rats weighing 100-120 g. The animals were divided into groups: control (untreated), comparisons: treatment with the official 0.2% Levomekol ointment; treatment with a gel containing metronidazole (composition 1, table 1) and experimental, i.e. treatment with the developed agent (composition 5, table 1).

The total percentage reduction in the area of the wound in the dynamics in the experimental group by the 13th day of the experiment was 90.66%, in the comparison groups - 63.57% and 62.46% and in the control group - 45.37%.

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.

Table 3 Local anesthetic activity according to the Rainier method Objects of research Anesthesia indicators The time of onset of anesthesia, min Duration of anesthesia, min Rainier Index Cond 3% solution of trimecaine (control) 1,0 ± 0,0 8.5 ± 1.5 424.4 ± 9.4 3% solution of trimecaine on a 3% Na-CMC gel 1,0 ± 0,0 20.4 ± 3.1 600.4 ± 3.9 3% solution of trimecaine on a 3% Na-CMC gel containing metronidazole (0.5%) 1,0 ± 0,0 88.1 ± 2.2 1100.4 ± 5.6 3% solution of trimecaine on a 3% Na-CMC gel containing ampicillin (0.5%) 1,0 ± 0,0 89.2 ± 1.9 1200.2 ± 4.3 3% solution of trimecaine on a 3% Na-CMC gel containing metronidazole biocomplex with cobalt (0.5%) 1,0 ± 0,0 100.2 ± 2.8 1300.0 ± 2.0 3% solution of trimecaine on a 3% Na-CMC gel containing ampicillin biocomplex with cobalt (0.5%) 1,0 ± 0,0 99.5 ± 4.0 1300.0 ± 1.5 3% solution of trimecaine on a 3% Na-CMC gel containing biocomplexes: metronidazole with cobalt (0.5%) and ampicillin with cobalt (0.5%) 1,0 ± 0,0 105.5 ± 3.1 1300.0 ± 2.4

Thus, the proposed wound healing agent "Metagil" in comparison with the prototype has a higher antimicrobial activity, a strong local anesthetic effect and effective wound healing properties, which are due to a combination of antimicrobial agents, local anesthetic, dimexide, methyluracil, glycerol and a base containing water-soluble cellulose-derivative , and potentiate the action of 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 combined gels 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 "Metagil" 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)

An agent 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 cobalt biocomplex with metronidazole and a cobalt biocomplex with ampicillin, trimecaine, dimexide, glycerin, methyluracil, water, as well as a hydrophilic base the following ratio of components in g per 100 g:
Cobalt (II) Biocomplex with Metronidazole 0.20-0.50 Cobalt (II) Biocomplex with ampicillin 0.20-0.50 Trimecaine 3.00-5.00 Methyluracil 1.00-3.00 Dimexide 10.00-10.00 Glycerol 5.00-10.00 Hydrophilic base 3.00-7.00 Water 77.60-64.00