RU2706115C1 - Antifungal and antimicrobial agent of complex action - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and aims at preventing and treating fungal and other infectious-inflammatory skin diseases. Antifungal and antimicrobial agent of complex action contains terbinafine hydrochloride, benzalkonium chloride, alcohol, mint oil and purified water. Components are used in claimed amounts. Also provided is a medicinal preparation in the form of a spray obtained from said agent.

EFFECT: using the group of inventions enables improving local antimycotic and antimicrobial effectiveness with respect to such strains as Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Proteus vulgaris ATCC 4636, Pseudomonas aeruginosa ATCC 27853, Basillus subtilis ATCC 6633 and Candida aibicans ATCC 653/885, Aspergillus niger ATCC 16404, Epidermophyton floccosum ATCC 15694, Microsporum gypsum ATCC 24102, wherein anti-inflammatory, deodorant and antipruritic action is achieved.

4 cl, 3 tbl, 6 ex

Description

The claimed invention relates to therapeutic, cosmetic, medical preparations and is an antifungal and antimicrobial agent of local complex action, which has antifungal and antibacterial activity, exhibits anti-inflammatory, deodorizing and antipruritic effects.

The inventive antifungal agent of complex action can be used for the prevention and treatment of fungal and other infectious and inflammatory skin diseases. Also, the claimed tool can be used to deodorize feet and shoes. In addition, the claimed agent can be used to inhibit the growth activity of the strains: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Proteus vulgaris ATCC 4636, Pseudomonas aeruginosa ATCC 27853, Basillus subtilis ATCC 6633, and Candida aibicans ATCC 163/88 ATCCper / 653/88 ATCCper / 653/88 ATCCper / 6538888 , Epidermophyton floccosum ATCC 15694, Microsporum gypsum ATCC 24102.

The closest in combination of features to the claimed object is the selected as a prototype antifungal drug in the form of vaginal suppositories "TERBENIOL", described in the patent of Ukraine for utility model No. 33021, published on 10.06.2008, which contains benzalkonium chloride, terbinafine hydrochloride in one suppository, nimesulide, tween-80, and as a base - polyethylene oxide-400 and polyethylene oxide-1500 in the following ratio of components, mass. %:

terbinafine hydrochloride - 0.09-0.011

benzalkonium chloride - 0.013-0.017

nimesulide - 0.09-0.11

TBiH-80 - 0.02-0.04.

Polyethylene oxide-400 and polyethylene oxide-1500 (in the ratio of 5:95) - up to 3.0.

The disadvantages of this technical solution is the possibility of using it only in the form of vaginal suppositories, and not the ability to use for the prevention and treatment of fungal and other infectious and inflammatory skin diseases. Also, the invention does not have a deodorizing and antipruritic effect, cannot be used for feet and shoes. In addition, the use of nimisulide, a synthetic anti-inflammatory drug, can cause an allergic reaction.

The basis of the invention is the task of creating an antifungal agent of complex action suitable for topical application, which has antifungal and antibacterial activity, exhibits anti-inflammatory, deodorizing and antipruritic effect.

The problem is solved by obtaining a product containing terbinafine hydrochloride and benzalkonium chloride, and a drug based on it used in the form of a spray. A distinctive feature is that the claimed tool additionally contains alcohols, peppermint oil and purified water in the following ratio of components, mass. %:

terbinafine hydrochloride - 0.3-1

benzalkonium chloride - 0.03-0.1

alcohols - 10-80,99

peppermint oil - 0.03-0.1

purified water - the rest.

Alcohols according to the invention are any pharmaceutically acceptable monohydroxy or polyhydric alcohol, or mixtures thereof. Preferably, the alcohols are either an individual alcohol selected from the group consisting of propylene glycol, glycerol, 96% ethyl alcohol, or mixtures thereof consisting of two or three alcohols.

The presence of alcohols improves the solubility of the active substances and has an antipruritic effect. Peppermint oil due to the cooling and distracting effect together with alcohol creates an antipruritic effect. In this case, alcohol and peppermint oil are involved in the destruction of bacteria and fungi, which are the cause of itching, enhancing the action of the active substances of the drug.

The combination of the active components of terbinafine hydrochloride and benzalkonium chloride in a topical agent suppresses the growth activity of the strains: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Proteus vulgaris ATCC 4636, Pseudomonas aeruginosa ATCC 27853, Basillus ATTCCCC 6533 ATIBIB 6533 , Aspergillus niger ATCC 16404, Epidermophyton floccosum ATCC 15694, Microsporum gypsum ATCC 24102. The use of peppermint oil in a topical agent provides anti-inflammatory, deodorizing and antipruritic effects.

The inventive preparation contains in one dose of terbinafine 0.0003-0.001 g and benzalkonium chloride 0.00003-0.0001 g. The amount of the substance in one dose of the spray of the claimed preparation was calculated as follows.

X ₁ = ratio of the amount of substance in 100 g of the drug to the number of doses in 100 g

The number of doses of spray in 100 g of the claimed sample is 1000 doses, since one sprayed dose of the drug is 0.1 g.

The decrease in the concentration of terbinafine in the inventive tool compared with the prototype is from 11 to 300 times, and benzalkonium chloride from 170 to 400 times. In this case, the inventive mixture is highly active in relation to the above strains, as demonstrated by the examples below. Based on examples, the strength of the claimed drug is at least an order of magnitude higher than previously known, which proves the presence of a synergistic effect that manifests itself in the interaction of a mixture of the effects of the claimed funds.

The inventive antifungal and antimicrobial agent of complex action contains the following components, mass. %:

terbinafine hydrochloride 0.3-1

benzalkonium chloride 0.03-0.1

alcohols 10-80,99

peppermint oil 0.03-0.1

purified water 18.65-89.64.

The drug in the form of a spray obtained from the above means contains in 100 g of the drug:

terbinafine hydrochloride 0.3-1 g

benzalkonium chloride 0.03-0.1 g

alcohols 10-80.99 g

peppermint oil 0.03-0.1 g

purified water 18.65-89.64 g.

The inventive antifungal complex action is made as follows.

Alcohols, peppermint oil, terbinafine hydrochloride, benzalkonium chloride are loaded into the reactor, excluding the ingress of powders onto the walls of the reactor. Add purified water. Turn on the stirrer. Mix the contents of the reactor for 30 minutes.

Examples of the compositions of the inventive antifungal agent of complex action, in which the content of the components corresponds to the optimal value and the boundary values given in the claims, as well as values that go beyond the boundary values, are given in the table below.

To study the properties of the inventive antifungal complex-acting agents, a microbial suspension of strains (microorganisms) was prepared using a Densi-La-Meter device (manufactured by PLIVA-Lachema, Czech Republic; wavelength 540 nm).

A microbial suspension of the strains was prepared by washing with a physiological solution of a pure bacterial culture. The culture of strains was synchronized using low temperature (4 ° C). The microbial load was 10 ⁷ microbial cells per 1 ml of medium and was established according to the McFarland standard. An 18-24 hour culture of microorganism strains was taken into the work. Müller-hinton agar was used for research (Production India “HIMediaLaboratorles Pvt. Ltd India”, the shelf life of the medium is Xi.2018). Saburo agar was used for Candidaalbicans (Production - India, “HIMediaLaboratorles Pvt. Ltd India”, the expiration date of the medium is Xi.2018p.).

To compare the results, we took the control drug Lamikon spray 1% 25 grams, which was manufactured by PAT "Farmak", Ukraine, of the following composition: 1 g of the solution contains terbinafine hydrochloride in terms of 100% anhydrous substance 10 mg (1%). Excipients - benzoic acid, polyethylene glycol (macrogol) 20 cetostearyl ether, propylene glycol, poloxamer 407, sodium edetate, water for injection.

The method of diffusion of the drug into agar was carried out by "wells". Determination of the activity of antibacterial drugs was carried out on two layers of a dense nutrient medium spilled in Petri dishes. In the lower layer, “hungry” non-seeded media (agar-agar, water, salts) were used. The bottom layer is a lining of 10 ml of “hungry agar” on which 3-6 thin-walled stainless steel cylinders with a diameter of 8 mm and a height of 10 mm are installed horizontally horizontally. A top layer, which consists of a nutrient agar medium, molten and cooled to 40 ° C to which the corresponding standard of the daily culture of test strains was introduced. Previously, the upper layer was well mixed until a homogeneous mass was formed. After transition to a gelatinous state, the cylinders were pulled with sterile tweezers. The tested drugs were placed in the wells that formed: Lamikon spray 1% 25 grams, which was manufactured by PAT "Farmak", Ukraine, and a sample of the inventive complex-acting agent 0.3 ml.

The volume of medium for the upper layer ranged from 14 to 16 ml. The cups were dried for 30-40 minutes at room temperature and placed in a thermostat for 18-24 hours.

When evaluating the antimicrobial and antifungal properties of the drugs, the following criteria were used:

- the absence of zones of growth inhibition of the strains around the well, as well as zones of delay of up to 10 mm, indicates that the strains are not sensitive to the studied local drug introduced into the well;

- growth retardation zones with a diameter of 10-15 mm indicate a low sensitivity of the strains to a topical preparation;

- growth retardation zones with a diameter of 15-25 mm are regarded as an indicator of the sensitivity of the strains to a topical preparation; - growth inhibition zones, the diameter of which exceeds 25 mm, indicates a high sensitivity of the strains to the drug local action.

To obtain reliable data to draw a conclusion regarding the effectiveness of the drugs, three independent trials were made (number of repetitions of studies). Test data on the antibacterial activity of the drugs are shown in table N2.

Test data antifungal activity of the drugs are shown in table No. 3.

The data in Table N2 indicate that, in contrast to the known drug (which does not have an antibacterial effect), the claimed drug even actively dilutes 1: 6 and actively suppresses the growth of strains: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Basillus subtilis ATCC 663333 It also has an antifungal effect more than the comparison drug Lamikon (PAT. Farmak, Ukraine), as can be seen from the data in Table N3, there is an active suppression of the growth of Candida aibicans ATCC 653/885, Aspergillus niger ATCC 16404, Epidermophyton floccosum fungi ATCC 15694, Mi crosporum gypsum ATCC 24102, it should be noted that the claimed drug diluted 3 times (the concentration of the active substance is 3 times less than the comparison drug) has a comparable strength with the comparison drug. That is, the claimed topical agent obtained on the basis of a biologically active substance has a very strong antimicrobial and antifungal action.

It should be noted in addition that the use of peppermint oil additionally provides anti-inflammatory, deodorizing and anti-itching effects.

From the above data from Table N2 and N3, it can be seen that at 1% concentration of a biologically active substance in a local preparation, the effectiveness of this active biological substance is manifested, which indicates that the local drug can be effectively used for the prevention, treatment of fungal and other infectious and inflammatory skin diseases.

The use of the composition N1, in which the components are taken in ratios that go beyond the lower boundary values, is inappropriate, because this composition will not show high sensitivity to the studied strains, will show an insufficient pharmacological effect.

The use of composition N4, in which the components are taken in ratios that go beyond the upper boundary values, is impractical because there will be no dissolution of the active components and a local irritant effect will be manifested.

The optimal ratio of components corresponds to the composition of N2 and No. 3.

The inventive therapeutic and prophylactic drug can be used as an antifungal agent of local complex action, which has antifungal and antibacterial activity, exhibits anti-inflammatory, deodorizing and antipruritic effects.

The invention is presented using the following examples, which do not limit the scope of the claimed claims.

Example 1. Spray for topical use.

Ethyl alcohol 77.9%, glycerol 1.0%, peppermint oil 0.05%, raspberry extract 0.01%, terbinafine hydrochloride 1.0%, benzalkonium chloride 0.1% citric acid 0.001%, excluding ingestion, are loaded into the reactor powders on the walls of the reactor. Add purified water 19.939%. Turn on the stirrer. Mix the contents of the reactor for 30 minutes. The resulting solution is poured into vials with a dispensing device by a nebulizer.

Example 2. Drops for topical application.

Ethyl alcohol of 77.9%, glycerol 1.0%, peppermint oil 0.05%, eucalyptus extract 0.01%, terbinafine hydrochloride 1.0%, benzalkonium chloride 0.1% citric acid 0.001 ^% , excluding ingestion, are loaded into the reactor powders on the walls of the reactor. Add purified water 19.939%. Turn on the stirrer. Mix the contents of the reactor for 30 minutes. The resulting solution is poured into vials with a dropper dosing device.

Example 3. Topical gel balm.

Download 22.0% in propylene glycol, PEG-40 hydrogenated castor oil 2%, peppermint oil 0.05%, terbinafine hydrochloride 1.0%, benzalkonium chloride 0.1%, hydroxyethyl cellulose 0.75%, citric acid 0.01% , excluding the ingress of powders on the walls of the reactor. Add purified water 79.09%. Turn on the stirrer. Mix the contents of the reactor for 30 minutes. The resulting solution is poured into vials.

Example 4. Spray-U.

Ethyl alcohol 77.75%, glycerol 1.0%, peppermint oil 0.05%, raspberry extract 0.01%, terbinafine hydrochloride 1.0%, urotropin 0.15%, benzalkonium chloride 0.1% acid are loaded into the reactor lemon 0.001% excluding the ingress of powders on the walls of the reactor. Add purified water 19.939%. Turn on the stirrer. Mix the contents of the reactor for 30 minutes. The resulting solution is poured into vials with a dispensing device spray.

Example 5. Drops-U.

Ethyl alcohol 77.75%, glycerol 1.0%, peppermint oil 0.06%, eucalyptus extract 0.01%, terbinafine hydrochloride 1.0%, urotropin 0.15%, benzalkonium chloride 0.1% acid are charged into the reactor lemon 0.001% excluding the ingress of powders on the walls of the reactor. Add purified water 19.939%. Turn on the stirrer. The contents of the reactor are stirred for 30 minutes. The resulting solution is poured into bottles with a dropper dosing device.

Example 6. Gel-balm for topical application.

Download 22.0% in propylene glycol, PEG-40 hydrogenated castor oil 2%, peppermint oil 0.05%, terbinafine hydrochloride 1.0%, urotropine 0.15%, benzalkonium chloride 0.1%, hydroxyethyl cellulose 0.75%, citric acid, excluding the ingress of powders on the walls of the reactor. Added purified water 78.94%. Turn on the stirrer. Mix the contents of the reactor for 30 minutes. The resulting solution is poured into vials.

Claims (6)

1. Antifungal and antimicrobial agent of complex action, which contains terbinafine hydrochloride, benzalkonium chloride, characterized in that it contains alcohol, peppermint oil and purified water in the following ratio of components, mass. %: terbinafine hydrochloride 0.3-1 benzalkonium chloride 0.03-0.1 alcohols 10-80,99 peppermint oil 0.03-0.1 purified water 18.65-89.64 2. The antifungal and antimicrobial agent of complex action according to claim 1, characterized in that the alcohols are selected from the group consisting of propylene glycol, glycerin, ethyl alcohol 96%, or mixtures thereof, consisting of two or three alcohols. 3. The drug in the form of a spray, obtained from the product according to claim 1, containing in 100 g of the drug: terbinafine hydrochloride 0.3-1 g benzalkonium chloride 0.03-0.1 g alcohols 10-80.99 g peppermint oil 0.03-0.1 g purified water 18.65-89.64 g 4. The drug in the form of a spray according to claim 3, characterized in that the alcohols are selected from the group consisting of propylene glycol, glycerin, ethyl alcohol 96%, or mixtures thereof, consisting of two or three alcohols.