RU2654708C1 - Pharmaceutical composition for treatment of dermatomycosis with local use on the basis of thiazolidine-2,4-dione and the method of its production - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and is the pharmaceutical composition for topical administration of dermatomycoses containing the 3-ethoxycarbonyl-5-(4-chlorobenzylidene)thiazolidine-2,4-dione as the active ingredient, the vaseline oil and emulsion wax are used as the auxiliary components, they are characterized by the fact that, as the auxiliary components they comprise the water-soluble chitosan and water.

EFFECT: invention allows to obtain the stable, non-exfoliable medicinal form.

2 cl, 10 tbl, 6 ex

Description

The invention relates to the field of pharmaceuticals and relates to a new pharmaceutical composition in the form of a soft dosage form - a gel for the treatment of fungal diseases of the skin, scalp, nails caused by dermatophytes and / or yeast-like fungi.

The growing incidence of superficial mycoses (fungal diseases) caused by various genera of yeast-like fungi and dermatophytes is an important and still unresolved Health problem in many countries and in Russia, in particular (Uvarova Yu. Antifungal drugs market for the treatment of skin diseases. Remedium 2011, No. 10, pp. 39-41; Antifungals Market to 2017 - Generic Erosion of MajorPolyenes, Azoles, Allylamines and Echinocandins to Slow Value Growth. Reference Code: GBIHC165MR Publication Date: January 2012). All currently used drugs have problems developing resistance, or insufficiency and narrowness of the spectrum of action, or undesirable drug reactions, or the limitations of suitable dosage forms, and quite often a combination of several or all of the above factors. In order to overcome these problems, a search is constantly being made for new molecules that can overcome resistance, and new dosage forms are created to achieve a high therapeutic effect in treatment.

Representatives of a new class of antimycotics from a number of thiazolidine-2,4-dione derivatives compares favorably with most commonly used topical agents (azoles) by an excellent mechanism of action aimed not at inhibiting ergosterol synthesis, but at suppressing the activity of mannosyl transferase protein, which leads to destruction of the cell wall of the fungus ( WO2002017915 A1, 2002; WO2002022612 A1, 2002; WO2003070238 A1, 2003; WO2003070239 A1, 2003; US 6740670 B2, 2004). The 3-alkoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione used as active ingredient are known as chemical compounds with antimicrobial activity (SU 1417436 A, 1996).

Pharmaceutical compositions containing methyl (RU 2295958 C1, 2007) or ethyl (RU 2563811 CI, 2015) hydroxycarbonyl ether 5-para-chlorobenzyl-entiazolidine-2,4-dione with experimentally proven high antifungal activity are patented in the Russian Federation.

The pharmaceutical composition of the drug Mycosidine (RU 2295958 C1, 2007) contains solid petroleum paraffin, stearic acid, petroleum jelly as the lipophilic part of the ointment base. The composition of the pharmaceutical composition was also introduced benzoic acid, which has a transcutaneous and preservative effect. The emulsion wax introduced into the pharmaceutical composition made it close in structure to lycetin and cephalin, which are part of the sebum, which had a softening effect on the skin. Ointment Mycosidine on a lipophilic basis contains 3-methoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione as an active substance, as well as target additives in the following ratio of components, wt. %:

The composition of the lipophilic base and the proposed ratio of the components were optimal and made it possible to ensure the required rate and completeness of release of the active substance and its chemotherapeutic effect at the level of 70%. When using an ointment with a lower concentration of the active substance (up to 2%), the efficiency decreased, and at a concentration above 5% there was a risk of the irritating effect of the drug. The developed pharmaceutical composition on a lipophilic basis made it possible to obtain a good therapeutic effect with the Mycosidine preparation, but it caused complaints from patients due to inconvenience in their use, due to the greasy base.

Closest to the proposed pharmaceutical composition (RU 2563811 C1, 2015) with the active substance 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione contains in addition to the urea supplement, which provides an increase in the percentage of effectiveness in the treatment of fungal skin diseases up to 84-89%, wt. %:

The method of obtaining this pharmaceutical composition is that to the lipophilic base prepared by fusion of stearic acid, solid paraffin, emulsion wax, benzoic acid and liquid paraffin are added, and after exposure at 75-85 ° C for 30-40 minutes, the previously prepared 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione concentrate in vaseline oil, after which urea in vaseline oil is added until a homogeneous mass is obtained (RU 2563811 C1, 2015).

However, the inclusion of urea in the pharmaceutical composition, despite a significant increase in the percentage of effectiveness, was not considered satisfactory, since the composition did not withstand the storage stability index. After a year of storage, dark spots appeared in the samples due to the action of urea on the active substance 3-ethoxycarbonyl derivative of thiazolidine-2,4-dione, leading to its destruction and discoloration of the composition.

In addition, in the cited patent TsHLS - VNIHFI (RU 2295958 C, 2007), it was concluded that the preparation of the composition on a hydrophilic-lipophilic basis was limited due to the specific physicochemical properties of the active substance, which required a special selection of components of the lipophilic base.

The technical problem solved by the present invention is to obtain a storage stable pharmaceutical composition with the active substance 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione.

The technical problem is solved by a pharmaceutical composition for the treatment of dermatomycosis in topical application, containing 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione as an active substance, as an auxiliary component, vaseline oil and emulsion wax, which, according to the invention , as auxiliary components also includes water-soluble chitosan and water in the following ratio of components, wt. %:

3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione 2-3 liquid paraffin 7-9 emulsion wax 9-11 water soluble chitosan 0.35-0.45 water up to 100

The technical problem is also solved by the method of obtaining the proposed pharmaceutical composition, which consists in the fact that emulsion wax heated to 60-65 ° C is mixed with a pre-prepared concentrate of 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione in vaseline oil and add to the resulting composition an aqueous solution of chitosan water-soluble, followed by homogenization.

The technical result of the proposed invention is to obtain a stable, non-stratified, dosage form during storage due to the use of water-soluble chitosan widely used in cosmetology and medicine as a part of the composition (DA Slivkin et al. BIOLOGY, PHARMACY, 2011, No. 2, 214-232).

As a result of experimental work, the proposed pharmaceutical composition in the form of a gel corresponding to the requirements for a pharmaceutical product, received the working name Mikolek, was obtained.

The optimal solvent for the chemical substance 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione (hereinafter referred to as the substance) is liquid paraffin. The introduction of an oil solution of the substance into the hydrogel composition involves the creation of an emulsion system that must meet the requirements for diphilic ointments. In this regard, the choice of structure-forming component is made taking into account the thermodynamic state of the dosage form, which is inherent in phase separation and requires stabilization.

The auxiliary ingredients that make up the MIKOLEK gel have various hydrophilic-lipophilic properties and perform a certain functional purpose, which is described in table 1.

Gel Mikolek refers to two-phase emulsion systems.

The quality of preparation of the components of the emulsion having opposite hydrophilic-lipophilic properties determines the uniformity, droplet size of the dispersed phase and, as a result, the stability of the finished gel.

The gel contains components both soluble in water (chitosan) and insoluble in water (liquid paraffin, emulsion wax). The active substance of the gel - the substance Mikolek also practically does not dissolve in water, it is difficult to dissolve in vaseline oil.

During the experiment, critical parameters and the method of preparation of the ingredients that affect the quality of the emulsification of the gel were determined:

- dissolution of the water-soluble component of chitosan in water;

- preparation (melting) of emulsion wax;

- determination of the method of administration of the substance Mikolek and liquid paraffin.

During the development of the Mikolek gel technology, the optimal time and method for dissolving chitosan were studied.

Chitosan has hydrophilic properties, therefore, for its introduction into the gel composition, the method of pre-mixing it with part of the purified water was chosen. As a result, a hydrogel is formed.

Based on the results obtained, it was found that the optimal swelling and dissolution time of 4.0 g of chitosan in 800 g of purified water is 4 hours. When scaling the process, the preparation time of the chitosan solution increases by 20-30%.

Therefore, in addition to controlling the dissolution time, it is necessary, when conducting the technological process, the introduction of a control point - the completeness of dissolution of chitosan, which is determined by the method of visual assessment of the obtained hydrogel.

Emulsion wax is an emulsifying component, therefore its preparation has a primary influence on the quality of the finished product and its stability.

It should be borne in mind that the emulsifier will have the proper emulsifying effect only if the emulsifier, water and oil are taken in strictly defined quantities, wt. %: 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione 2-3; Vaseline oil 7-9; emulsion wax 9-11; water-soluble chitosan 0.35-0.45; water - the rest, up to 100. The following are examples of the composition of the drug, in wt. %

In this regard, the critical parameter of the process is to minimize losses during the preparation and introduction of emulsion wax into the reactor, because It has a high viscosity.

To reduce the viscosity, it was proposed to pre-melt emulsion wax. The choice of the optimum melting temperature was carried out experimentally. Optimum results were obtained by melting the wax at a temperature of 60 ± 5 ° C for 15 minutes. This time is sufficient for the complete melting of emulsion wax; the obtained melt consistency allows one to minimize its losses during manipulations at technological stages.

The substance Mikolek has an inhomogeneous lumpy structure, has hydrophobic properties, and practically does not dissolve in water. Therefore, for uniform introduction into the gel, certain difficulties arise.

In the process of pharmaceutical development, it was found that for the uniform distribution of the substance Mikolek the best option is to pre-mix it with liquid paraffin. Based on the data obtained, it was found that the parameters to be controlled when the substance Mikolek with vaseline oil is mixed is a temperature of (40 ± 5) ° C and a time of 10 minutes.

The following sequence of mixing the gel components with each other is established.

часть от расчетного количества воды очищенной, загружают эмульгатор - расплавленный воск эмульсионный, перемешивают до однородного распределения эмульгатора. Далее небольшими порциями вводят гидрофобные компоненты - смесь субстанции Миколек и масла вазелинового. Тщательно перемешивают и добавляют гидрофильный компонент - подготовленный гидрогель хитозана водорастворимого. После перемешивания добавляют оставшуюся

часть воды очищенной.The homogenizer is charged

part of the calculated amount of purified water, the emulsifier is loaded - the emulsion wax is melted, mixed until the emulsifier is uniformly distributed. Next, hydrophobic components are introduced in small portions - a mixture of the substance Mikolek and liquid paraffin. The hydrophilic component is thoroughly mixed and added - the prepared hydrogel of chitosan water-soluble. After stirring, add the remaining

part of the water purified.

Analysis of visual and microscopic data of the gel obtained under various homogenization modes with a rotation speed of 500, 1000, 2000, 4000, 5000 rpm. clearly showed that an increase in the rotational speed of the homogenizer rotor leads to a proven decrease in the particle size of the hydrophobic dispersed phase, and, consequently, to improved stability of the finished dosage form.

Gel Preparation Example

Weighed out 192 g of purified water and 8 g of water-soluble chitosan on the scales and loaded the suspended components into a 400 ml glass beaker.

The contents of the glass were mixed with a glass rod and left for 5 hours at room temperature until a uniform chitosan solution was obtained, periodically mixing the contents of the glass with a glass rod.

Weighed 62.17 g of the substance, 200 g of liquid paraffin, and weighed components were loaded into a glass cup with a capacity of 400 ml.

The glass was placed in a water bath with a temperature of (40 ± 5) ° C; the overhead stirrer was lowered into the glass and the contents of the glass were mixed for 10 minutes at a temperature of (40 ± 5) ° C until a uniform base was obtained.

160.0 g of emulsion wax was weighed on a balance, a weighed quantity was loaded into a glass cup with a capacity of 400 ml, and the contents of the cup were melted in a water bath for 15 minutes at a temperature of 63-65 ° C, periodically stirring with a glass rod. Temperature control is carried out according to the display.

700.0 g of purified water, previously heated to 40 ° C, was weighed on a balance, and a weighed amount of purified water was loaded into a homogenizing reactor. To maintain the temperature in the reactor (40 ± 5) ° C, the heating element located in the jacket of the reactor was periodically turned on.

The molten emulsion wax from the beaker was loaded into the homogenizing reactor. The contents of the reactor were mixed for 20 minutes at a temperature of (40 ± 5) ° C.

The contents of the beaker — a mixture of substance with liquid paraffin — were loaded in small portions into the homogenizing reactor; the homogenizer was turned on and the contents of the homogenizing reactor were stirred at 5000 rpm for 20 minutes at a temperature of (40 ± 5) ° C.

677.83 g of purified water, preheated to 40 ° C, was weighed on the scales, the weighed amount of purified water was loaded into the homogenizing reactor in small portions and the contents of the homogenizing reactor were mixed at 5000 rpm for 20 minutes at a temperature of (40 ± 5) ° C.

The contents of the chitosan hydrogel beaker were loaded into the homogenizing reactor, the homogenizer was turned on, and the contents of the homogenizing reactor were stirred at 5000 rpm for 20 minutes.

Produced visual control of the uniformity of the gel. If necessary, stirring was continued at 5000 rpm with the reactor homogenizer turned on for 15 minutes.

A sample is taken in an amount of 2.0 g per analysis. The analysis is considered positive if the gel is homogeneous, white and the quantitative content of the substance is in the range from 2.7 to 3.3%.

The stability of the obtained Mikolek gel was determined by the appearance indicator during storage of the gel. For 3 months, the gel remained uniform and white.

Additional advantages of the Mikolek gel are provided by creating an emulsion base such as oil in water: ease of production of an emulsion base, good affinity for skin, pH value neutral to tissues, regenerative effect, organoleptic properties, consumer qualities, etc. In addition, chitosan provides plasticity water emulsion system.

In vivo antifungal activity - the results of a study of the antifungal activity of the Mikolek dosage form in two concentrations of 3% and 2%.

The antifungal activity of the substance 3-ethoxycarbonyl-5 (4-chlorobenzidylene) thiazolidine-2,4-dione and dosage forms based on it (gel 2% and 3%) in relation to pathogens of dermatophytosis was evaluated on the model of trichophytosis and microsporia in guinea pigs and skin candidiasis in laboratory mice. The effect of the drug was evaluated in comparison with commercial antifungal drugs - Exoderil® and Nizoral®.

Microorganisms.

The strain Trichophyton mentagrophytes 18 VGNKI clinical isolate isolated from patients with dermatophytosis of guinea pig in 1977, is used to control the immunogenicity of vaccines against dermatophytosis. The strain has high virulence; it is used to reproduce trichophytosis in laboratory animal models.

Strain Trichophyton rubrum 2902 VGNKI clinical isolate, isolated in 2010 from a patient with human rubromycosis. The strain has high virulence; it is used to reproduce trichophytosis in laboratory animal models.

Strain Microsporum canis c.20 VGNKI clinical isolate isolated from a diseased white mouse. The strain has high virulence; it is used to reproduce microsporia on models of laboratory animals.

Strain Candida albicans ATCC 24443. The strain is obtained from the American collection of reference cultures (ATCC), sensitive to fluconazole and voriconazole.

Animals.

To reproduce the model of experimental dermatophytosis, guinea pigs weighing 200-250 g were used.

To reproduce a model of cutaneous candidiasis, laboratory white mice of the BALB line weighing 18-26 g were used.

To exclude the influence of gender on the experimental results, only females were used.

The experiment consisted in infecting guinea pigs with virulent strains of Trichophyton mentagrophytes, Trichophyton rubrum and Microsporum canis. After the development of the clinical picture of dermatophytosis, the animals underwent pharmacological therapy according to the scheme below (table 2). During the experiment, the intensity of the disease was evaluated, the assessment was confirmed by a cultural study of clinical material.

The results of determining the specific antifungal effectiveness of the Mikolek preparations (Mikolek 2%, Mikolek 3%) and the gel base * of the Mikolek preparation for the Trichophyton mentagrophytes pathogen in the guinea pig trichophytosis model are presented in Tables 3, 4 (2% and 3% are the substance content in the preparation, wt.%) (Gel base - composition without active substance).

t _p - a biometric indicator used for statistical calculations (Student's t test); t _crit - a critical biometric indicator.

Analyzing the data shown in table 3, we can conclude that the therapeutic efficacy of the drug "Mikolek 3%" is higher. So, on the 6th day of therapy, the TE indicator for the Mikolek 3% preparation reaches 27%, while the TE of the Mikolek 2% preparation is 8.1%. However, these differences were not statistically significant (t _p. Is 0.65 and 0.16, respectively). From 12 days from the start of treatment with TE, the preparations “Mikolek 2%” and “Mikolek 3%” become equal, which is confirmed by statistical analysis (t _p is 2.00 and 2.84, respectively).

In general, the effectiveness of the drugs “Mikolek 2%” and “Mikolek 3%” can be considered the same, since significant differences between the lesion index (PI) in the control group and the experimental groups are found only on days 12-13, which correspond to equal therapeutic effectiveness.

The study of clinical material selected from animals from these groups confirmed the fact that the animals fully recovered in the Mikolek 2% and Mikolek 3% groups. The causative agent of trichophytosis was not found in the material taken from these animals on the 13th day of treatment. In the material selected on the 10th day of therapy, the pathogen was also not found. From the material selected from animals of the control group on the 13th day of therapy, the pathogen is excreted.

For comparison, the TE of the drug Nizoral on day 13 is 57.7%, t _p 1.75; TE of the drug Exoderil on day 13 is 76.9%, t _p 1.76.

TE of the comparison drug Exoderil is also confirmed by a mycological culture test (negative, selection on day 13). From the clinical material selected on day 13 from animals from the Nizoral group, it was possible to identify the causative agent of trichophytosis.

The data shown in table 3 indicate the therapeutic efficacy of the gel base of the drug "Mikolek", which is 73.07% on day 13. These data are not random, as they are statistically confirmed. Perhaps this effect is associated with the softening effect of the gel base, which contributes to a visual decrease in PI. However, animal recovery does not occur, as evidenced by a cultural study of the material (13 days, a positive result of the study). The results of determining the specific antifungal effectiveness of the Mikolek preparations (Mikolek 2%, Mikolek 3%) and the gel base of the Mikolek preparation with respect to Trichophyton rubrum trichophytosis pathogen in the guinea pig trichophytosis model are presented in Tables 5, 6.

Analyzing the data shown in table 5, we can conclude that the slightly higher TE of the drug "Mikolek 3%" compared with the drug "Mikolek 2%". Starting from the 12th day of treatment, both drugs show 100% therapeutic efficacy in relation to Trichophyton rubrum infection, which is confirmed by the results of statistical analysis (tp. Values significantly exceed critical values, see table 6)

The results of the cultural mycological study confirm the complete mycological recovery of animals from the groups “Mikolek 2%” and “Mikolek 3%” (selection of material on day 13, the result is negative). The result of the study of material from animals from the groups “Control without therapy” and “Gel base” is positive (selection on day 13).

The therapeutic effect observed in the Gel Foundation group (62.96% on day 13, t _p 1.75) is due to the softening effect of the gel base, visually reducing the severity of clinical signs. No animal recovery is observed (positive study of clinical material)

For comparison, the TE of the drug Nizoral on day 13 is 66.6%, t _p 1.85; TE of the drug Exoderil on day 13 is 77.7%, t _p 1.86.

The study of clinical material showed the following: the Nizoral group, 13 days - a positive result; Exoderil group, 13 days - negative result.

The results of determining the specific antifungal effectiveness of the Mikolek preparations (Mikolek 2%, Mikolek 3%) and the gel base of the Mikolek preparation in relation to the microsporium pathogen Microsporum canis in the guinea pig microsporium model are presented in Tables 7, 8.

Analyzing the data shown in table 7, we can conclude that approximately the same effectiveness of drugs "Mikolek" with a concentration of active substance of 2 wt. % and 3 wt. % The maximum TE is achieved on the 13th day from the day the treatment is started, it is 82.6%. The dynamics of the increase in TE in both drugs is approximately the same; TE is also confirmed by the negative result of the culture study (selection on 10 days, selection on 13 days). The result of the study of the material from the animals of the control group is positive (selection on 10 and 13 days)

The therapeutic efficacy of the gel base is not confirmed by cultural research, nor is it statistically confirmed.

The value of TE of the drugs Mikolek 2% ”and“ Mikolek 3% ”is statistically confirmed only on the 13th day from the day the treatment was started.

It is worth saying that the dynamics of changes in PI allows us to make an assumption about the possible 100% effectiveness of the Mikolek preparations in relation to Microsporum canis on the 15-16th day from the day the treatment was started. This concerns mainly the complete disappearance of clinical signs of complete recovery (absence of pathogen in the clinical sample) occurred in the group "Mikolek% 3" on day 10 after start of treatment (TE 46,66%, t _p 1,005). In the “Mikolek 2%” group, full recovery occurred only on the 13th day (negative value of the culture study).

For comparison, the TE of the drug Nizoral on day 13 is 56.6%, t _p 1.85. A culture study showed a positive result (13 days). TE of the drug Exoderil on day 13 is 69.6%, t _p 1.76. Cultural research showed a negative result (13 days). The results of determining the specific antifungal effectiveness of the Mikolek preparations (Mikolek 2%, Mikolek 3%) and the gel base of the Mikolek preparation against Candida albicans candidiasis causative agent in laboratory mouse skin candidiasis models are presented in Tables 9, 10.

From the data of table 9, we can conclude about the effectiveness of the drugs "Mikolek" in relation to Candida albicans. The maximum statistically confirmed effectiveness is achieved on day 13 and is equal to 92.8% and 100% for a drug with 2% of the active substance and 3%, respectively.

The dynamics of the increase in the TE of the Mikolek preparations with respect to the causative agent of candidiasis looks unstable: a gradual increase to 10% (2-7 days, then a decrease to 4% (8 days), an increase to 14% (9 days), a smooth increase to 25% ( 9-11 days). Then follows a sharp jump in TE from 25 to 42% (11-12 days), then another one, from 42% to 100% (12-13 days). The drug "Mikolek 2%" shows similar results, but the changes in FC are not so drastic.

Cultural research (10 days, 13 days) shows negative results for both experimental groups.

The drug Nizoral reaches 100% therapeutic efficacy already on the 10th day from the day the treatment was started, the value of TE is confirmed statistically (comparison with the control group that did not receive therapeutic drugs). TE is also confirmed by cultural research (10 days, 13 days)

TE of the drug Exoderil is not statistically confirmed, a cultural study is positive on days 10 and 13, which allows us to conclude that this drug is ineffective for the causative agent of skin candidiasis.

In relation to the causative agent of trichophytosis Trichophyton mentagrophytes, the preparations "Mikolek 3%" and "Mikolek 2%" show absolute therapeutic efficacy, while Nizoral and Exoderil - 57.7 and 76.9%, respectively. Moreover, complete recovery on day 13 occurred in the groups “Mikolek 2%”, “Mikolek 3%”, Exoderil, which is confirmed by cultural mycological study of clinical material. The material selected from animals from these groups on the 13th day after the start of treatment is free from the causative agent of trichophytosis. When analyzing material from animals from the “Control without therapy” and “Nizoral®” groups, selected 13 days after the start of treatment, the causative agent of trichophytosis (Trichophyton mentagrophytes) was isolated. The isolated strain is identical in morphological and biochemical characteristics to the strain T. mentagrophytes 18.

In relation to another causative agent of trichophytosis - Trichophyton rubrum - the preparations "Mikolek 2%" and "Mikolek 3%" also showed absolute effectiveness. The Nizoral® and Exoderil® preparations used for comparison showed a lower therapeutic efficacy of 66.6 and 77.7%, respectively. The rest of the picture is similar to that obtained on the previous model of trichophytosis (pathogen - T. mentagrophytes). The effectiveness of therapy was confirmed by a cultural study of clinical material in the groups “Mikolek 2%”, “Mikolek 3%” and “Exoderil” (negative result on day 13) and not confirmed for the group “Nizoral” (positive result on 13 day). The strain isolated from animals from the group “Control without therapy” is identical to strain T. rubrum 2902.

Based on these data, it can be concluded that Mikolek is more effective for treating trichophytosis compared to Exoderil® existing on the market.

In relation to Microsporum canis, the causative agent of microsporia, the preparations "Mikolek 2%" and "Mikolek 3%" showed the same effectiveness, equal to only 82.6% on the 13th day of treatment. However, a cultural mycological study showed complete recovery of animals from these groups (in the Mikolek 3% group, the pathogen did not stand out from the material selected on the 10th day of treatment). The drug "Mikolek" showed better therapeutic efficacy than the existing exoderil drug on the market. The effectiveness of the drug Nizoral® is not confirmed by a cultural study (positive result on day 13)

In relation to the causative agent of skin candidiasis - Candida albicans - Mikolek preparations showed unequal therapeutic efficacy. So, “Mikolek 2%” is slightly inferior to the drug “Mikolek 3%”: their effectiveness is 92.9 and 100%, respectively, on the 13th day after the start of treatment, respectively. The drug Nizoral® available on the market showed 100% effectiveness already on the 10th day from the day the treatment was started. The effectiveness of the drug Exoderil is not statistically confirmed, a culture study showed a positive result. In cases with the preparations "Mikolek 2%", "Mikolek 3%" and Nizoral®, a culture study showed a negative result.

Claims (3)

1. A pharmaceutical composition for the treatment of dermatomycosis in topical application, containing 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione as an active substance, as an auxiliary component, vaseline oil and emulsion wax, characterized in that as auxiliary components includes water-soluble chitosan and water in the following ratio of components, wt. %: 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione 2-3 liquid paraffin 7-9 emulsion wax 9-11 water soluble chitosan 0.35-0.45 water up to 100 2. A method of obtaining a pharmaceutical composition according to claim 1, which consists in the fact that emulsion wax heated to 60-65 ° C is mixed with a pre-prepared concentrate of 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione in oil vaseline and add to the resulting composition an aqueous solution of chitosan water-soluble, followed by homogenization.