RU2768705C1 - Acaricidal pharmaceutical composition, agents for treating parasitic diseases caused by scabies, containing said composition (embodiments) - Google Patents

Abstract

FIELD: veterinary science.

SUBSTANCE: group of inventions relates to the field of veterinary science, in particular to a pharmaceutical composition used in parasitic diseases of animal skin caused by scabies mites belonging to the Sarcoptoidea superfamily, and acaricidal agents containing such a composition. Disclosed composition contains, wt. pts.: 5-nitro-4,6-dichlorobenzofuroxane - 9; 4,6-dinitro-5,7-dichlorobenzofuroxane - 1; chlorhexidine - 2. Agents for treating parasitic diseases caused by scabies mites include the above composition and excipients at the following ratios of components, wt. %: said composition 0.05–0.1; polyethylene oxide-400 - 4; polyethylene oxide-1500 - 1; dimethyl sulfoxide - 5; distilled water is balance; or said composition - 0.1; polyethylene oxide-400 - 5; polyethylene oxide-1500 - 1; dimethyl sulfoxide - 5; birch tar - 5; distilled water - balance; or said composition - 0.05; ethyl alcohol 96.3 % - 70; dimethyl sulphoxide - 2; distilled water is balance.

EFFECT: group of inventions provides a high level of antiparasitic, antimicrobial and antifungal activity, therapeutic effectiveness, with reduced toxic effect.

6 cl, 8 tbl, 11 ex

Description

The invention relates to the field of veterinary medicine, in particular to a pharmaceutical composition used in parasitic diseases of the skin of animals caused by scabies mites belonging to the suborder Sarcoptiformes, the superfamily Sarcoptoidea . The invention also relates to acaricides containing the claimed pharmaceutical composition and excipients that (means) can be used to treat animal skin diseases caused by scabies, in particular Psoroptes cuniculi, Psoroptes ovis, Otodectes cynotis, Notoedres cati, as well as methods for obtaining funds .

Further in the text, the applicant gives the terms that are necessary to facilitate an unambiguous understanding of the essence of the claimed materials and to exclude contradictions and / or controversial interpretations when performing an examination on the merits.

The weight part is the part of the component by weight - g, kg, etc.

Invasion - the penetration of parasites into the host organism, that is, infection, [https://ru.wikipedia.org/wiki/Invasion].

Sarcoptoidosis is a disease caused by itch mites of the superfamily Sarcoptoidea, suborder Sarcoptiformes [https://apicenna.ru/bolezni/s/sarkoptoidoz].

The claimed acaricidal pharmaceutical composition contains three active components: chlorhexidine of formula (1), 5-nitro-4,6-dichlorobenzofuroxan of formula (2) and 4,6-dinitro-5,7-dichlorobenzofuroxan of formula (3).

(1) (2) (3)

The invention provides a high level of antiparasitic, antimicrobial and antifungal activity, therapeutic efficacy, reduced toxicity.

Scabies mites, suborder Acariformes, family Sarcoptidae are parasites of domestic and wild animals, can also be in humans, are localized inside or on the skin and cause diseases of sarcoptoidosis. This invasion causes significant economic damage to farm animals, which consists of a decrease in productivity, deterioration in the quality of the skin, and the cost of medical and preventive measures.

The main clinical signs are itching, skin lesions, intoxication of the body and depression of the central nervous system. The fight against such types of diseases caused by mites of the superfamily Sarcoptoidea, such as psoroptosis, sarcoptosis, otodectosis, etc., is technically complicated by the resistance of parasites to the action of many well-known acaricidal agents, and due to their toxicity among animals, there are still cases of deaths. In this regard, the relevance of the task associated with the development and implementation of new effective drugs with low toxicity for the treatment and prevention of sarcoptoidosis seems obvious.

From the level of technology studied by the applicant, technical solutions were identified that coincide with the claimed technical solution for its intended purpose.

Thus, alcohol preparations for the treatment and prevention of sarcoptoidosis based on clofentezin, hexythiazox, thiabendazole, selenotheosin are known [Lashkova V.A. Acaricidal properties of alcohol preparations based on clofentezin, hexythiazox, thiabendazole, selenotheosin / V.A. Lashkova, A.N. Tokarev // Collection of scientific papers: Actual problems of veterinary medicine - No. 150. - St. Petersburg, 2019. - P. 19-20].

In different years, for the treatment of patients with sarcoptoidosis, chemicals from the group of phenols, sulfur, hexachlorane were used [Yatusevich A.I. Parasitology and invasion diseases of animals. Workshop / A.I. Yatusevich, N.F. Karasev, S.I. Stasyukevich, V.A. Patafeev // textbook for university students in the specialties "Veterinary Medicine", "Veterinary Sanitation and Expertise" - Minsk - 2011].

The disadvantages of the known technical solutions is a weak acaricidal effect, and substances from the hexachlorane group are highly toxic substances for animals [Akbaev M.Sh. and other Parasitology and invasion diseases of animals. M.:, "Kolos S" - 2002. - 743 p.].

From the studied state of the art, organophosphate preparations have been identified that have been used for a long time to combat sarcoptoidosis.

Thus, the widespread use of chlorophos (SC ₅₀ = 0.7%) as an acaricide is known [Arkhipov I.A. Anthelmintics: pharmacology and application / I.A. Arkhipov // M., 2009. - 406 p.].

The disadvantage of chlorophos is that it belongs to organophosphorus compounds, which in mammals inhibit the enzyme acetylcholinesterase and disrupt the function of the nervous system.

Known drugs from the group of pyrethroids that destroy ticks that parasitize animals are relatively quickly destroyed in the external environment, which reduces their danger to humans and animals [https://ru.wikipedia.org/wiki/Pyrethroids].

The disadvantages of known drugs from this series of substances is that they all have hepatotoxic, teratogenic, mutagenic, carcinogenic effects [Sokolov V.D. Efficacy and toxicity of acaricides in dogs with demodicosis / V.D. Sokolov, N.P. Andreeva, N.N. Fisenkov // International Veterinary Bulletin. - 2014. - No. 1. - S. 25-28.]. In addition, known drugs, often effective against the tick itself, are ineffective against its eggs.

An invention is known according to the patent of the Russian Federation No. 2067863 "Acaricidal composition for the treatment of scabies of domestic animals", the essence is an acaricidal composition for the treatment of scabies of domestic animals, including the active substance (DV), characterized in that it contains a mixture of 4-nitro- and 6 -nitro-5,7-dichlorobeneofuroxans in a ratio of 70-20: 30-80, respectively, and additionally a surfactant and a diluent in the following ratio, wt. %: a mixture of 4-nitro- and 6-nitro-5,7-dichlorobenzofuroxans - 0.25-1.0; surfactant - 0.50-2.0; diluent - the rest. Composition according to claim 1, characterized in that distilled water or liquid mineral or vegetable oils are used as a diluent.

The known composition is an analogue of the claimed technical solution for its intended purpose, but differs in composition, since its constituent components, namely 6-nitro-5,7-dichlorobenzofuroxan and 4-nitro-5,7-dichlorobenzofuroxan, are different from the components of the claimed composition .

The disadvantage of the known technical solution is the absence of an indication of the effect of the known composition on eggs and a lower acaricidal effect compared to the claimed technical solution.

Known source [L.M. Yusupova, S.Yu. Garmonov, I.M. Zakharov, A.R. Bykov, T.V. Garipov, I. F. Falyakhov // Means of biological protection for multipurpose purposes based on chlorine derivatives of nitrobenzofuroxan // Bulletin of the Kazan Technological University. - 2004. - No. 1. - S. 103 -111.]. The essence is a mixture of biologically active substances 5-nitro-4,6-dichlorobenzofuroxan, 4,6-dinitro-5,7-dichlorobenzofuroxan, which has fungicidal and acaricidal activity. As a criterion for evaluating the acaricidal activity of a mixture of 5-nitro-4,6-dichlorobenzofuroxan, 4,6-dinitro-5,7-dichlorobenzofuroxan, the value of SC ₅₀ determined on ticks Psoroptes cuniculi is presented: SC ₅₀ = 0.069%.

The disadvantage of the known technical solution is the lower acaricidal and bactericidal activity compared to the claimed technical solution and the lack of action on the eggs of mites.

A source [https://ru.wikipedia.org/wiki/Chlorhexidine] was identified from the studied state of the art, the essence is chlorhexidine - a drug, an antiseptic, effective against gram-positive and gram-negative bacteria (Treponema spp., Neisseria gonorrhoeoae, Ureaplasma spp., Bacteroides fragilis, Chlamydia spp.), protozoa (Trichomonas vaginalis), viruses and fungi. It is stable, after treatment of the skin it remains on it in a certain amount sufficient for the manifestation of a bactericidal effect.

The well-known drug chlorhexidine is used by the applicant as an antibacterial component of the claimed pharmaceutical composition.

From the studied state of the art, analogues of the claimed technical solution have been identified on the methods of obtaining acaricidal preparations.

So, the invention is known according to the patent of the Russian Federation No. 2497508 "Acaricidal pharmaceutical composition based on a salt of Quaternary phosphonium, substituted dinitrobenzofuraxan and xymedone hydrochloride", the essence in relation to the method is that in a porcelain mortar they mix and grind in weight ratios (0.1:1:10) -0.1 g of a quaternary salt of phosphonium - n-hexadecyltriphenylphosphonium bromide of the formula (1), 1 g of 5,7-bis-(m-nitroanilino)-4,6-dinitrobenzofuraxan (2) and 10 g of xymedone hydrochloride (3) until a homogeneous red powder. Then, 100 ml of dimexide (solvent) are added in portions with thorough stirring and stirred until a homogeneous liquid is obtained. The liquid is a dosage form of the pharmaceutical composition "Dehelm KD" for the treatment of animals infected with scabies mites, which is used in the form of a spray.

In this case, the known sequence of actions differs from the claimed sequence, selected taking into account the properties of the components of the claimed means.

From the studied prior art, no technical solutions similar to the claimed technical solution in terms of composition and method of preparation have been identified, therefore, independent claims are made without a distinctive part.

At the same time, the applicant believes that the claimed technical solution is not a summation of known technical solutions, since the composition of active ingredients (DI) of the composition and means selected by the applicant using these AI for the treatment of animal diseases caused by ticks Psoroptes cuniculi (composition A), Psoroptes ovis (composition B), Otodectes cynotis (composition C), Notoedres cati (composition C), the ratio of their components, as well as methods for their preparation is not obvious to a person skilled in the art. From the studied level of technology, the Applicant has not identified compositions and means in which the claimed components would be used simultaneously in the claimed ratio and for the stated purpose, namely, for parasitic diseases of the skin of animals caused by scabies mites. The ratio of the components was selected by the applicant empirically. From the studied prior art, methods of obtaining with the claimed sequence of actions have not been identified either.

The objective and technical result of the claimed technical solution is the development of an acaricidal pharmaceutical composition, as well as agents containing the specified composition for a complex effect on scabies mites of the Sarcoptidae family Psoroptes cuniculi, Psoroptes ovis, Otodectes cynotis, Notoedres cati, as well as methods for obtaining these agents, which expands the arsenal of known means of the specified purpose and eliminates the shortcomings of known analogues, while the claimed composition and the claimed funds obtained by the claimed method:

- have a complex acaricidal effect both on the imago of the tick and on its eggs,

- have fungicidal activity due to the presence of components (2) and (3) with known fungicidal activity,

- have antibacterial activity due to the presence of component (1) with known antibacterial activity, which (component (1)) additionally promotes the transport of components (2) and (3) through the cuticle of the tick and destroys it,

- have a synergistic effect of the biological action of the components (2) and (3) due to their complex effect.

Thus, the active components included in the composition have acaricidal, fungicidal and antibacterial effects, activate regeneration processes in tissues and have a reduced toxic effect.

The need to create products with a complex acaricidal, fungicidal and antibacterial action is due to the fact that mites enter into a symbiotic interaction with staphylococci and fungi, as a result of which the affected skin becomes a breeding ground for bacteria and fungi.

At the same time, due to the rapid habituation of parasites and microorganisms to single-component substances, it is preferable to develop multi-component substances.

The essence of the claimed technical solution is acaricidal pharmaceutical composition, characterized in that it contains the following ratio of components, parts by weight: 5-nitro-4,6-dichlorobenzofuroxan - 9; 4,6-dinitro-5,7-dichlorobenzofuroxan - 1; chlorhexidine - 2. Means of composition A for the treatment of parasitic diseases caused by scabies mites Psoroptes cuniculi, characterized in that it contains the following ratio of components, wt. %: composition according to claim 1 - 0.05-0.1; polyethylene oxide-400 - 4; polyethylene oxide-1500 - 1; dimethyl sulfoxide - 5; distilled water - the rest. Means composition B for the treatment of parasitic diseases caused by scabies mites Psoroptes ovis, characterized in that it contains the following ratio of components, wt. %: composition according to claim 1 - 0.1; polyethylene oxide-400 - 5; dimethyl sulfoxide - 5; birch tar - 5; distilled water - the rest. Means of composition B for the treatment of parasitic diseases caused by scabies mites Otodectes cynotis and Notoedres cati, characterized in that it contains the following ratio of components, wt. %: composition according to claim 1 - 0.05; ethyl alcohol 96.3% - 70; dimethyl sulfoxide - 2; distilled water - the rest. Means according to claim 4, characterized in that it is made in the form of ear drops. Means according to claim 4, characterized in that it is made in the form of a spray. The method of obtaining funds of composition A according to claim 2, which consists in taking 0.038 - 0.076 wt. % 5-nitro-4,6-dichlorobenzofuroxan and 0.004-0.008 wt. % 4,6-dinitro-5,7-dichlorobenzofuroxan, then add 4 wt. % polyethylene oxide-400 and stirred until completely dissolved at a temperature of 60°C, then add 1 wt. % polyethylene oxide-1500 and stirred until complete dissolution, add with stirring 0.008-0.016 wt. % chlorhexidine; then add with stirring 5 wt. % dimethyl sulfoxide, distilled water up to 100 wt. % and stirred at room temperature until a homogeneous gel is obtained; the resulting agent of composition A is filtered and packaged in vials. The method of obtaining means of composition B according to claim 3, which consists in taking 0.076 wt. % 5-nitro-4,6-dichlorobenzofuroxan and 0.008 wt. % 4,6-dinitro-5,7-dichlorobenzo-furoxan, then add 5 wt. % polyethylene oxide-400 and stirred until completely dissolved at a temperature of 60°C, then add 1 wt. % polyethylene oxide-1500 and stirred until complete dissolution, then add with stirring 0.016 wt. % chlorhexidine; then add with stirring 5 wt. % dimethyl sulfoxide, 5 wt. % birch tar, distilled water up to 100 wt. % and stirred at room temperature until a homogeneous gel is obtained; the resulting agent of composition B is filtered and packaged in vials. The method of obtaining means of composition B according to claim 4, which consists in taking 0.038 wt. % 5-nitro-4,6-dichlorobenzofuroxan and 0.004 wt. % 4,6-dinitro-5,7-dichlorobenzofuroxan, then add 70 wt. % 96.3% ethyl alcohol and stirred until completely dissolved at a temperature of 60°C, add with stirring 0.008 wt. % chlorhexidine; then add with stirring 2 wt. % dimethyl sulfoxide, distilled water up to 100 wt. % and stirred at room temperature until a homogeneous liquid is obtained; the resulting agent of composition B is filtered and packaged in vials. A method for obtaining a composition B agent according to claim 9, characterized in that the vials are provided with a dropper dispenser. A method for obtaining a means of composition B according to claim 9, characterized in that the vials are equipped with a pump and a pressure device with a folding cannula.

Further, the applicant provides a description of the claimed technical solution.

The task and the claimed technical result are solved by the development of the claimed composition, the claimed agents for the treatment of animal diseases such as psoroptosis, otodectosis and notoedrosis caused by scabies mites belonging to the suborder Sarcoptiformes, the superfamily Sarcoptoidea, in particular Psoroptes cuniculi, Psoroptes ovis, Otodectes cynotis, Notoedres cati, as well as ways to obtain these funds.

In this case, the claimed composition contains active ingredients (hereinafter referred to as AI) from a combination of three components (1), (2) and (3), and the claimed funds contain, in addition to the claimed composition, excipients.

Further, the Applicant provides a brief description of the action of each component of the claimed composition and the claimed means.

5-nitro-4,6-dichlorobenzofuroxan (2) and 4,6-dinitro-5,7-dichlorobenzofuroxan (3) have acaricidal activity against scabies mites and at the same time fungicidal action.

Chlorhexidine (1) is a broad-spectrum antiseptic, pharmacological action - antibacterial, bactericidal, antiseptic. Destroys bacterial cell membranes [State Register of Medicines (May 26, 2016)].

Dimethyl sulfoxide is a solvent, and also has an anti-inflammatory and analgesic analgesic effect on the applied affected area of the animal's skin, enhances the penetration of a number of medicinal substances through the skin due to the ability to penetrate biological membranes, including skin barriers.

Birch tar has antiseptic, keratolytic, anti-inflammatory, insecticidal, antiparasitic and disinfectant effects, improves tissue blood supply, stimulates the regeneration of the epidermis of damaged tissues, enhances the process of keratinization, dries wounds and accelerates their healing. After a short exposure, it kills many bacteria and, in particular, tubercle bacillus and anthrax spores. In low concentrations, it activates the growth of granulation, in strong concentrations (above 10%) it sharply weakens.

Polyethylene oxide-400 and polyethylene oxide-1500 are solvents for AD (2) and (3) and, at the same time, prolongators of the therapeutic effect of AD. They are also gelling agents.

Ethyl alcohol is a solvent, preservative and antiseptic.

Distilled water is a solvent.

Further, the applicant describes the preparation of the individual components of the claimed pharmaceutical composition and the claimed funds.

5-Nitro-4,6-dichlorobenzofuroxan of formula (2) is obtained by a known method described, for example, in [Mukhametsina A.M., Yusupova L.M., Khuziakhmetova A.N. / Optimization of the synthesis of 5-nitro-4,6-dichlorobenzofuroxan with quality control of feedstock, intermediate and final reaction products // Kazan National Research Technological University, June 11, 2016] [https://izron.ru/articles/problemy- meditsiny-v-sovremennykh-usloviyakh-sbornik-nauchnykh-trudov-po-itogam-mezhdunarodnoy-nauch/sektsiya-52-farmatsevticheskaya-khimiya-farmakognoziya-spetsialnost-14-04-02/optimizat-siya-sinteza-5-nitro- 4-6-dikhlorbenzofuroksana-s-kontrolem-kachestva-iskhodnogo-syrya-prome/].

4,6-Dinitro-5,7-dichlorobenzofuroxan of formula (3) is obtained according to a known method described, for example, in [Yusupova L. M., Spatlova L. / Optimization of the synthesis of 5,7-dichloro-4,6-dinitrobenzofuroxan / / Bulletin of Kazan Technological University, 2011, p. 49-56].

Chlorhexidine of formula (1) is a white crystalline powder, soluble in water, for example, [https://shop.evalar.ru/encyclopedia/item/chlorgeksidin/].

Dimethyl sulfoxide is a commercial product (for example, according to THE 2635-114-44493179-08).

Polyethylene oxide-400 is a commercial product (for example, according to TU 2483-167-05757587-2000).

Polyethylene oxide-1500 is a commercial product (for example, according to TU 2483-167-05757587-2000 as amended)

Birch tar is a marketable product (for example, registration number in GRLS - Reg. No. FS-001672).

Ethyl alcohol is a commercial product (for example, according to GOST 5962-2013).

Distilled water is obtained by distillation.

Development of the claimed composition consisting of components (1), (2), (3), which has a complex acaricidal, bactericidal, fungicidal action.

In one aspect, the invention relates to an acaricidal pharmaceutical composition having a complex acaricidal, bactericidal, fungicidal action against scabies mites belonging to the suborder Sarcoptiformes, superfamily Sarcoptoidea.

When developing the claimed composition, the applicant studied the acaricidal activity of the active substances (1), (2) and (3), taken at various ratios in mass percent in order to select the optimal ratio.

The evaluation was carried out by determining the mean lethal concentration of CK ₅₀ determined on the example of adult ticks Psoroptes cuniculi _.

For testing, aqueous emulsions of compositions No. 1-No. 9 (Table 1), 100 ml each, with concentrations, wt. %: 1.0; 0.1; 0.05; 0.025; 0.005.

In Petri dishes, on filter paper 10 cm in diameter impregnated with compositions No. 1-No. 9 of the indicated concentrations, 20 active and not injured adults of Psoroptes cuniculi mites were planted. Then the Petri dishes were closed with a lid and placed in a thermostat at a temperature of 27-29°C and a humidity of 95%.

In the control, filter paper was soaked in saline.

Accounting for the results of the acaricidal action of various concentrations of the studied compositions No. 1-No. 9 was carried out by observing under an MBS-1 microscope and a BM-51-2 binocular magnifier through 1, 2, 3, 6, 9, 12, 18, 24, 36, 48, 60 and 72 hours. At the same time, the criterion for the death of ticks was considered to be their lack of motor activity and reaction to touching with light stroking them with a thin needle. With each concentration of the drug, the experiment was carried out in triplicate. The assessment of the acaricidal activity of the compositions (average lethal concentration of SK ₅₀ ) was carried out according to the results of the state of ticks according to the formula of G. Kerber [https://dommedika.com/farmakology/587.html]. The results are presented in Table 1.

Table 1. Evaluation of the acaricidal activity of active substances (1), (2) and (3), determined on Psoroptes cuniculi mites

composition number Ratio
[(2) : (3)] Ratio
[(2) : (3)] : (1) SK _50,
% one 9:1 [9 : 1] : 1 0.007 2 9:1 [9 : 1] : 2 0.007 3 9:1 [9 : 1] : 3 0.008 4 8:2 [8 : 2] : 1 0.009 five 8:2 [8 : 2] : 2 0.009 6 8:2 [8 : 2] : 3 0.01 7 7:3 [7 : 3] : 1 0.02 8 7:3 [7 : 3] : 2 0.02

nine 7:3 [7 : 3] : 3 0.03 Control (saline) - - 0

From the results presented in Table 1, it can be seen that for the ratio (2) : (3) = 9 : 1, the value of SC ₅₀ has the smallest value, equal to 0.007-0.008%.

For ratios (2) : (3) = 8 : 2 the value of SC ₅₀ was 0.009-0.01%, and for ratio (2) : (3) = 7 : 3 the value was 0.03-0.04%, which more than 0.007-0.008%, therefore, in the future, the applicant did not consider these ratios.

For the ratio [(2) : (3)] : (1) = [9 : 1] : 1 and [9 : 1] : 2, the value of SC ₅₀ was 0.007%, and for the ratio [(2) : (3)] : (1) = [9 : 1] : 3-0.008%.

Thus, from the results of the experiment, the applicant concludes that the most preferred ratio of the components of the claimed composition is [(2) : (3)] : (1) = [9 : 1] : 2 in parts by weight.

At the same time, from the data given in Table 1, one can draw a logical conclusion about the synergistic effect of the biological action of components (1), (2) and (3). Thus, it is known that for a mixture of components (2) and (3) SC_fifty = 0.069% [L. M. Yusupova, S. Yu. Garmonov, I. M. Zakharov, A. R. Bykov, T.V. Garipov, I.F. Falyakhov // Means of biological protection of multi-purpose based on chlorine derivatives of nitrobenzofuroxan // Bulletin of the Kazan Technological University. - 2004. - No. 1. - S. 103-111.], And in a composition containing simultaneously (1), (2) and (3), depending on the ratio of components (Table 1), acaricidal activity is: SC_fifty \u003d 0.007% -0.03%, while in the stated ratio (2) : (3) \u003d 9 : 1 SC_fifty = 0.007%, which is an order of magnitude less than SC_fiftymixtures (2) and (3).

The claimed composition is obtained in the following way:

Example 1. Obtaining the claimed composition containing active ingredients in the ratio [(2) : (3)] : (1) = [9 : 1] : 2.

Actually the claimed composition in order to study its effectiveness is obtained as follows.

Take 9 parts by weight of 5-nitro-4,6-dichlorobenzofuroxan of formula (2), for example 9 g, add 1 part by weight of 4,6-dinitro-5,7-dichlorobenzofuroxan of formula (3), for example 1 g, triturate, for example , in a porcelain mortar, until a homogeneous powder is obtained.

Add 2 parts by weight of chlorhexidine of formula (1), for example 2 g, mix at room temperature until a homogeneous powder is obtained.

The claimed composition is obtained in the weight ratio [(2) : (3)] : (1) = [9 : 1] : 2.

To obtain the claimed compositions A, B and C, the components of the claimed composition (2) and (3) are taken in a ratio of 9: 1 parts by weight, dissolved in various solvents depending on the composition obtained (for compositions A and B - in PEG-400 and PEG-1500, for composition B - in ethanol), then add 2 parts by weight of component (1).

Then auxiliary substances are added and the sequence of actions is carried out according to Examples 2-5.

The acaricidal activity of the claimed composition is shown in Table 1.

At the same time, according to the applicant, the claimed composition has a bactericidal and fungicidal effect due to the known fungicidal activity of compounds (2) and (3) and the known bactericidal activity of compound (1).

Development of claimed agents for the treatment of parasitic diseases caused by scabies mites.

In another aspect, the invention relates to agents for the treatment of parasitic diseases of animals caused by scabies, such as:

- psoroptosis (Table 2, formulations A, B),

- otodectosis (Table 2, composition B),

- notoedrosis (Table 2, composition B).

The composition of the claimed funds as an active substance (AI) includes the claimed acaricidal pharmaceutical composition of three active components (1), (2) and (3) at a mass ratio of [(2) : (3)] : (1) = [9 : 1] : 2, as well as an acceptable solvent and excipients for creating a dosage form.

The compositions and forms of the claimed funds are designed in such a way as to carry out the treatment most effectively:

- for the treatment of psoroptosis (mites parasitize on the surface of the skin), formulations A and B have been developed in the form of a gel, which allows the formulations not to drain from the skin surface;

- for the treatment of otodectosis (mites parasitize in the ears), composition B has been developed in the form of ear drops;

- for the treatment of notoedrosis (ticks parasitize under the epidermal layer of the skin), composition B has been developed in the form of a spray, which allows you to quickly and least costly treat animals.

The compositions of the declared funds are given in Table 2.

Table 2. Compositions of the claimed agents for the treatment of parasitic diseases caused by scabies mites

Composition of the product, form Disease, type of tick Composition components Content, wt. % Composition A, gel Psoroptosis,
Psoroptes cuniculi claimed composition
[(2) : (3)] : (1) = [9 : 1] : 2 0.05-0.1 polyethylene oxide-400 (PEG-400) 4 polyethylene oxide-1500 (PEG-1500) one dimethyl sulfoxide five distilled water rest Composition B, gel Psoroptosis, Psoroptes ovis claimed composition
[(2) : (3)] : (1) = [9 : 1] : 2 0.1 polyethylene oxide-400 (PEG-400) five polyethylene oxide-1500 (PEG-1500) one dimethyl sulfoxide five Birch tar five distilled water rest Composition B, drops, Composition B, spray Otodectosis, Otodectes cynotis Notoedrosis,
Notoedres cati claimed composition
[(2) : (3)] : (1) = [9 : 1] : 2 0.05 ethyl alcohol 96.3% 70 dimethyl sulfoxide 2 distilled water rest

Further, the applicant provides the claimed method for obtaining the claimed acaricidal pharmaceuticals in general:

- first, a solution of the claimed composition is prepared, for which components (2) and (3) are taken, taken in a weight ratio of 9: 1, mixed with each other, dissolved either in PEG-400 and PEG-1500 (compositions A, B), or in ethyl alcohol (composition B) at a temperature of 60°C, component (1) is added to the resulting solution with stirring,

- then dimethyl sulfoxide is added sequentially with stirring, then birch tar (composition B), then distilled water to 100%, everything is stirred at room temperature until a homogeneous composition is obtained.

The resulting composition is filtered and packaged in vials.

Further, the applicant gives examples of the claimed methods for obtaining the claimed funds in more detail.

Example 2. Obtaining composition And with the content of active ingredients (1), (2) and (3) 0.05 wt. %.

With a total content of active ingredients (1), (2) and (3) equal to 0.05 wt. % at their ratio [(2) : (3)] : (1) = [9 : 1] : 2, the content of individual substances in composition A is: (1) = 0.008 wt. %, (2) = 0.038 wt. %, (3) = 0.004 wt. %.

To obtain a product in the form of a gel (composition A with an active ingredient content of 0.05 wt.%), the following sequence of actions is performed.

A mixture of components (2) and (3) is prepared in the ratio (2): (3) = 9:1, for which they take 0.038 wt. % (for example, 0.038 g) of 5-nitro-4,6-dichlorobenzofuroxan of formula (2) and 0.004 wt. % (for example, 0.004 g) of 4,6-dinitro-5,7-dichlorobenzofuroxan of formula (3), then add 4 wt. % PEG-400 (for example, 4 g), the mixture is stirred at a temperature of 60°C, for example, in a porcelain glass, until completely dissolved, add 1 wt. % PEG-1500 (for example, 1 g) and stirred until complete dissolution. Add with stirring 0.008 wt. % chlorhexidine of formula (1) (for example, 0.008 g).

Then add with stirring 5 wt. % dimethyl sulfoxide (DMSO) (for example, 5 g), then distilled water to 100 wt. %, (for example, 89.95 g), and stirred at room temperature, for example, using a magnetic stirrer, until a homogeneous gel is obtained.

The resulting product in the form of a gel (composition A with an active ingredient content of 0.05 wt. %) is filtered and packaged in vials. Vials can be, for example, plastic or glass, followed by an investment in a cardboard box.

Applied by application to the affected area of the skin of the animal by application, for example, using a swab.

The resulting agent in the form of a gel (composition A with an active ingredient content of 0.05 wt. %) is an agent for the treatment of animals infected with scabies mites Psoroptes cuniculi from psoroptosis.

Example 3. Obtaining composition And with the content of active ingredients (1), (2) and (3) 0.1 wt. %.

With a total content of active ingredients (1), (2) and (3) equal to 0.1 wt. % at their ratio [(2) : (3)] : (1) = [9 : 1] : 2, the content of individual substances in composition (A) is: (1) = 0.016 wt. %, (2) = 0.076 wt. %, (3) = 0.008 wt. %.

To obtain a product in the form of a gel (composition A with an active ingredient content of 0.1 wt.%), the following sequence of actions is performed.

A mixture of components (2) and (3) is prepared in the ratio (2) : (3) = 9 : 1, for which 0.076 wt. % (for example, 0.076 g) of 5-nitro-4,6-dichlorobenzofuroxan of formula (2) and 0.008 wt. %. (for example, 0.008 g) 4,6-dinitro-5,7-dichlorobenzofuroxan of formula (3), the mixture is dissolved in 4 wt. % PEG-400 (for example, 4 g) at a temperature of 60°C, for example, in a porcelain glass, add 1 wt. % PEG-1500 (for example, 1 g) and stirred until it is completely dissolved. Add with stirring 0.016 wt. % chlorhexidine of formula (1) (for example, 0.016 g).

Then add with stirring 5 wt. % dimethyl sulfoxide (DMSO) (for example, 5 g), then distilled water to 100 wt. %, (for example, 89.90 g), and stirred at room temperature, for example, using a magnetic stirrer, until a homogeneous gel is obtained.

The resulting product in the form of a gel (composition A with an active ingredient content of 0.1 wt. %) is filtered and packaged in vials. Vials can be, for example, plastic or glass, followed by an investment in a cardboard box.

Applied by application to the affected area of the skin of the animal by application, for example, using a swab.

The resulting agent in the form of a gel (composition A with an active ingredient content of 0.1 wt. %) is an agent for the treatment of animals infected with scabies mites Psoroptes cuniculi from psoroptosis.

Example 4 Preparation of Composition B

With a total content of active ingredients (1), (2) and (3) equal to 0.1 wt. % at their ratio [(2) : (3)] : (1) = [9 : 1] : 2, the content of individual substances in composition B is: (1) = 0.016 wt. %, (2) = 0.076 wt. %, (3) = 0.008 wt. %.

To obtain a product in the form of a gel (composition B), the following sequence of actions is performed.

A mixture of components (2) and (3) is prepared in the ratio (2) : (3) = 9:1, for which they take 0.076 wt. % (for example, 0.076 g) of 5-nitro-4,6-dichlorobenzofuroxan of formula (2) and 0.008 wt. %. (for example, 0.008 g) 4,6-dinitro-5,7-dichlorobenzofuroxan of formula (3), add 5 wt. % PEG-400 (for example, 5 g) at a temperature of 60°C, for example, in a porcelain glass, add 1 wt. % PEG-1500 (for example, 1 g) and stirred until it is completely dissolved. Add with stirring 0.016 wt. % chlorhexidine of formula (1) (for example, 0.016 g).

Then add with stirring 5 wt. % DMSO (for example, 5 g), then 5 wt. % birch tar (for example, 5 g), then distilled water to 100 wt. %, (for example, 83.90 g), and stirred at room temperature, for example, using a magnetic stirrer, until a homogeneous yellow gel is obtained.

The resulting product in the form of a gel (composition B) is filtered and packaged in vials. Vials can be, for example, plastic or glass, followed by an investment in a cardboard box.

Applied by application to the affected area of the skin of the animal by application, for example, using a swab.

The obtained agent in the form of a gel (composition B) is an agent for the treatment of animals infected with scabies mites Psoroptes ovis from psoroptosis.

Example 5 Preparation of Composition B

With a total content of active ingredients (1), (2) and (3) equal to 0.05 wt. % at their ratio [(2) : (3)] : (1) = [9 : 1] : 2, the content of individual substances in composition B is: (1) = 0.008 wt. %, (2) = 0.038 wt. %, (3) = 0.004 wt. %.

To obtain funds (composition B), the following sequence of actions is performed.

A mixture of components (2) and (3) is prepared in the ratio (2) : (3) = 9:1, for which 0.038 wt. % (for example, 0.038 g) of 5-nitro-4,6-dichlorobenzofuroxan of formula (2) and 0.004 wt. % (for example, 0.004 g) of 4,6-dinitro-5,7-dichlorobenzofuroxan of formula (3), the mixture is dissolved in 70 wt. % (for example, 70 g) of 96.3% ethyl alcohol with a density of 0.7893 g/cm ³ at a temperature of 60°C, for example, in a porcelain glass, and stirred until completely dissolved. Add with stirring 0.008 wt. % chlorhexidine of formula (1) (for example, 0.008 g).

Then add with stirring 2 wt. % DMSO (for example, 2 g), then distilled water to 100 wt. %, (for example, 27.95 g), and stirred at room temperature, for example, using a magnetic stirrer, until a homogeneous liquid is obtained.

The resulting product in the form of a liquid (composition B) can be used as follows:

- in the form of ear drops for the treatment of animals infected with scabies mites Otodectes cynotis, from otodectosis, for which composition B is filtered and packaged in vials, which are pre-equipped with a dropper dispenser. Vials can be, for example, plastic or glass, followed by an investment in a cardboard box.

Applied by application to the ears of the animal in the form of ear drops. It can be applied to the affected area of the skin of the ears, for example, with a swab.

- in the form of a spray for the treatment of animals infected with scabies mites Notoedres cati, from notoedrosis, for which composition B is filtered and packaged in vials, which are pre-equipped with a pump and a pressure device with a folding cannula. Vials can be, for example, plastic or glass, followed by an investment in a cardboard box.

Apply by applying to the affected area of the skin of animals in the form of a spray.

Further, the applicant gives examples of studying the effectiveness of the claimed means of compositions A, B, C.

Example 6 Study of the effectiveness of a gel formulation (composition A) against isolated Psoroptes cuniculi mites.

The Applicant studied the effectiveness against isolated mites Psoroptes cuniculi means in the form of a gel (composition A) at the stated concentrations of AI = 0.05; 0.1 wt. % (Table 3, formulations 3 and 4). At the same time, to confirm the correctness of the choice of the indicated concentrations, the compositions with concentrations of AI = 0.005; 0.025; 1.0 wt. % (Table 3, formulations 1, 2 and 5).

The studies were carried out under in vitro conditions on isolated P.cuniculi ticks taken from spontaneously infested rabbits according to the method of Ilyashchenko V.I. (Ilyashchenko V.I. Sarcoptoid mites, improvement of methods for diagnosing and combating them.: Abstract of the thesis. doctoral biologist, sciences. S. - P., 1993. - 36 p.).

In Petri dishes with a diameter of 10 cm, filter paper impregnated with aqueous emulsions of compositions of 1-5 studied concentrations was placed and 20 selected active and not injured adult ticks were planted. Then the Petri dishes were closed with a lid and placed in a thermostat at a temperature of 27-29°C and a humidity of 95%.

In the control, filter paper was soaked in saline.

Accounting for the results of the acaricidal action of various concentrations (compositions 1-5) was carried out by observation under the microscope MBS-1 and binocular magnifier BM-51-2 after 1, 24 and 72 hours. At the same time, the criterion for the death of ticks was considered to be their lack of motor activity and reaction to touching with light stroking them with a thin needle. With each concentration of the drug, the experiment was performed in triplicate.

The results obtained are shown in Table 3.

Table 3. Study of the effectiveness of the agent in the form of a gel on isolated mites Psoroptes cuniculi (in vitro)

composition number
wa Σ DW [(2) : (3)] : (1) = [9 : 1] : 2, wt. % Number of ticks in the experiment Tick condition 1 hour 24 hours 72 hours alive dead % dead alive dead % dead alive dead % dead one 0.005 twenty 8 12 60 2 eighteen 90 - twenty one hundred 2 0.01 twenty 7 13 65 2 eighteen 90 - twenty one hundred 3 0.05 twenty - twenty one hundred - twenty one hundred - twenty one hundred 4 0.1 twenty - twenty one hundred - twenty one hundred - twenty one hundred five 1.0 twenty - twenty one hundred - twenty one hundred - twenty one hundred Control - twenty twenty - 0 twenty - 0 twenty - 0

From the data shown in Table 3, it can be seen that 1 hour after the application of composition 1, 12 mites out of 20 (60%) were dead, composition 2-13 mites out of 20 (65%). Under the action of formulations 3, 4, 5, no live ticks were detected after 1 hour. The study of samples 24 and 72 hours after application of compositions 3, 4, 5 showed 100% acaricidal effect.

In the control, using only water, ticks remained alive throughout the study period. At the same time, it was found that the concentration of components corresponding to composition 4 is sufficient to achieve the claimed technical result, while there is no need to further increase the concentration of active components corresponding to composition 5.

Thus, the results obtained confirmed that the optimal concentrations of the agent in the form of a gel are the total concentration of active ingredients (1), (2) and (3) = 0.05-0.1% at their ratio [(2) : (3)] : (1) = [9 : 1] : 2 (composition A).

Example 7. Study of the effectiveness of the agent in the form of a gel (composition A) in the disease of rabbits caused by Psoroptes cuniculi mites (in vivo).

Experiments to study the effectiveness of the claimed agent (composition A) in the form of a gel in rabbit psoroptosis were carried out on rabbits naturally infected with psoroptosis with an average degree of damage. The animals were kept in the personal subsidiary farm of Shangaraev R.I.

As a result of acarological studies of skin scrapings, acariform mites Psoroptes cuniculi were isolated. Animals showed the following clinical signs: anxiety, itching, wounds, foci with the formation of thick crusts, inflammation, decreased appetite in the area of damaged skin.

The rabbits were divided into 6 groups (3 rabbits in each), the affected areas of the skin were treated with a product of composition A with a declared concentration of active ingredient of 0.05-0.1% (groups 3, 4). At the same time, to confirm the correctness of the choice of the indicated concentrations, the compositions with concentrations of AI = 0.005; 0.01; 1.0% (groups 1, 2, 5). The treatment was carried out twice with an interval of 7 days:

- 1 group was treated with a composition with an active ingredient concentration of 0.005%;

- group 2 was treated with a composition with an active ingredient concentration of 0.01%;

- group 3 was treated with the claimed agent with a concentration of active ingredient of 0.05%;

- group 4 was treated with the claimed agent with a concentration of active ingredient of 0.1%;

- group 5 was treated with a composition with a concentration of active ingredient 1%;

- in group 6, no treatment was performed (control).

Laboratory diagnostics in rabbits was carried out by examining, taking and examining scrapings from the inner surface of the auricles and examining the presence of eggs and live mites.

The results were taken into account after 6, 10, 15, 20 and 30 days.

The research results are presented in Table 4.

Table 4. Study of the effectiveness of agents in the form of a gel in rabbit psoroptosis caused by Psoroptes cuniculi mites

No. gr. II* before treatment AI by day 6 days 10 days 15 days 20 days 30 days eggs adult mite eggs adult mite eggs adult mite eggs adult mite eggs adult mite eggs adult mite one +++ +++ + - + + + + + + + + 2 +++ +++ + - - - - - - - - - 3 +++ +++ - - - - - - - - - - 4 +++ +++ - - - - - - - - - - five +++ +++ - - - - - - - - - - 6 +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++

* AI - invasion intensity

+ - single eggs and adults of mites

+++ - high degree of invasion.

From the data given in Table 4, it can be seen that before treatment, in scrapings from the skin in all groups of both experimental and control animals, an infective onset (eggs and adults of the acariform tick) was detected.

In rabbits of the 1st group, no mites were found on the 6th day of treatment, however, there were eggs in the scrapings. On days 10, 15, 20, and 30, eggs and adults of ticks in different stages of development were found in these groups.

In rabbits of the 2nd group on the 6th day after the treatment of adults, mites were not found, however, there were eggs in the scrapings. On the 10th, 15th, 20th and 30th days in these groups, the infective onset was not detected - eggs and adults of the tick were absent.

In rabbits of the 3rd, 4th and 5th groups on the 6th day after treatment, no mites were found in scrapings of adults and eggs.

Rabbits of group 6 (control) were infected with psoroptosis during all periods of the study.

Thus, from the results obtained, it can be concluded that the claimed compositions 3, 4 and composition 5 are the most effective in the treatment of rabbit psoroptosis. the claimed agent in the form of a gel with a concentration of AI = 0.05-0.1 wt. % at a ratio of components [(2) : (3)] : (1) = [9 : 1] : 2.

Example 8. Study of the effectiveness of the claimed agent (composition B) in the form of a gel in sheep psoroptosis in vivo.

The therapeutic efficacy of the agent (composition B) in the form was studied on sheep naturally infested with Psoroptes ovis ticks.

Animals were kept at the sheep farm KP "Tan" Cheremshansky district of the Republic of Tatarstan. Sick animals from the flock were identified by clinical signs that were mild (sometimes slight hair loss, reddening of the skin).

In the experiment, 20 sheep were used, aged from 6 to 8 months, which were divided into 4 groups (5 animals each).

- 1 group was treated with the claimed composition B in the form of a gel.

- Group 2 was treated with a 0.0125% solution of the known antiparasitic drug "Ciperil" (comparison group).

- Group 3 was treated with a 0.1% solution of the known antiparasitic drug "Butox 50" (comparison group).

- in group 4, no treatment was performed (control).

Before treatment with drugs, the sheep were sheared. Application of drugs was carried out twice with an interval of 7 days by spraying the entire surface of the body.

The diagnosis of psoroptosis was confirmed by acarological examination of sheep skin scrapings 3, 7, 14, 21, 28, 35, 45 days after drug treatment and according to clinical signs.

The effectiveness of the investigated claimed composition B in sheep psoroptosis is presented in Table 5.

Table 5. Study of the effectiveness of various acaricidal agents for in vivo sheep psoroptosis caused by Psoroptes ovis mites

No. gr. II* before treatment AI by day 3
days 7
days 14 days 21 days 28 days 35 days 45
days Eggs Ticks in different stages of development Eggs Ticks Eggs Ticks Eggs Ticks Eggs Ticks Eggs Ticks Eggs Ticks Eggs Ticks one +++ +++ - - - - - - - - - - - - - - 2 +++ +++ + - - - - - - - - - - - - - 3 +++ +++ + - + - + + + + + + + + +++ +++ 4 +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++

* AI - intensity of invasion.

+ - single eggs and adults of mites.

+++ - high degree of invasion.

Studies have shown that itching and scratching of the affected areas in the sheep of the experimental groups appeared up to seven days, and in the control group of animals, signs of dermatitis of parasitic etiology were observed throughout the experiment.

From the data given in Table 5, it can be seen that before the treatment of sheep with acaricidal preparations, both Psoroptes ovis mites and their eggs were found in skin scrapings from sick sheep.

In sheep of the 1st group, treated with the claimed composition B, on the 3rd day after the start of treatment, no mites and eggs were found in scrapings of the skin of sheep during acarological examination. A rapid recovery of the affected areas of the skin, their overgrowth with new hair was noted.

In sheep of the 2nd group, treated with "Ciperil", on the 3rd day only eggs of the causative agent of psoroptosis were found, in the following days neither eggs nor mites were found in scrapings.

In sheep of the 3rd group, treated with Butox 50, on days 3 and 7 after treatment, eggs of psoroptosis pathogens were detected, on day 14 and in subsequent periods of the study, live ticks were found, from day 28 eggs appeared, as well as new lesions.

In sheep of the 4th group (control), both ticks and their eggs were found throughout the entire experimental period, and the clinical signs of psoroptosis became more pronounced.

Thus, it can be concluded that the claimed agent of composition B, with a double treatment of sheep naturally infected with the pathogen Psoroptes ovis, has a pronounced acaricidal effect. At the same time, the sheep treated with the claimed agent did not become re-infected for 45 days.

Example 9. Study of the acaricidal efficacy of the claimed agent (composition B in the form of ear drops) in rat otodectosis caused by Otodectes cynotis mites (in vivo).

The test of therapeutic acaricidal efficacy of the claimed agent of composition B was carried out on 20 rats, weighing 180-200 grams, naturally infected with otodectosis.

The animals were kept in the vivarium of the Department of Epizootology and Parasitology of the FGBOU VO KSAVM. Initially, they were noted to have stunted growth and dull hair color. Then the animals periodically showed anxiety attacks, they squealed, ran quickly in the cage, shook their heads. Some animals were noted to have lopsidedness.

Laboratory diagnostics in rats was carried out by taking and examining scrapings from the auricles. All drugs were used in the form of ear drops twice with an interval of 7 days.

After the diagnosis was established, the rats were divided into 5 groups:

- 1 group was treated with the declared means of composition B.

- group 2 was treated with a 0.01% solution of hexidine in a 70% alcohol-water solution;

- group 3 was treated with a 0.05% solution of a mixture of 5-nitro-4,6-dichlorobenzofuroxan of formula (2) and 4,6-dinitro-5,7-dichlorobenzofuroxan of formula (3) in a ratio of 9: 1 in 70% alcohol-water solution;

- Group 4 was treated with a mixture of excipients: 2 g of dimethyl sulfoxide, 68 g of ethyl alcohol 96.3%, the rest was water up to 100 g.

- in group 5, no treatment was performed (control group).

The studies were carried out on eggs and adults of the mite Otodectes cynotis. All drugs were applied to the affected area of rats in the form of ear drops twice with an interval of 7 days.

Laboratory diagnostics in rats was performed by examining, taking and examining scrapings from the inner surface of the auricles and examining the presence of eggs and live mites.

The results were taken into account after 6, 12, 18 and 24 days.

The research results are presented in Table 6.

Table 6. The study of the effectiveness of the claimed means of composition B in the form of ear drops in the disease caused by Otodectes cynotis mites.

No. gr. II* before treatment AI by day 6 days 12 days 18 days 28 days eggs adult mite eggs adult mite eggs adult mite eggs adult mite eggs adult mite one +++ +++ - - - - - - - - 2 +++ +++ ++ ++ ++ ++ + + + + 3 +++ +++ + - + - + - - - 4 +++ +++ +++ +++ +++ +++ ++ ++ + + five +++ +++ +++ +++ +++ +++ +++ +++ +++ +++

* AI - intensity of invasion.

+ - single eggs and adults of mites;

++ - moderate degree of invasion;

+++ - high degree of invasion.

The data in Table 6 shows that:

- in the 1st group of rats, the claimed agent of composition B in the form of ear drops has an acaricidal effect already on the 6th day after treatment. At the same time, it was found that the claimed agent has a detrimental effect both on the eggs of the pathogen and on the imago of ticks. This is evidenced by the negative results obtained in the study of scrapings taken on 6 and 12, as well as in subsequent periods of treatment;

- in the 2nd group of rats, it was found that the intensity of invasion became less, but during the entire period of the study, eggs and adults of the mite Otodectes cynotis were found in the scrapings;

- in the 3rd group of rats, it has an acaricidal effect on ticks, but within 18 days of the study, eggs of the tick Otodectes cynotis were found in scrapings;

- in the 4th group of rats, the intensity of invasion became less, but during the entire period of the study, eggs and adults of the mite Otodectes cynotis were found in scrapings.

- in the 5th group of rats throughout the entire experimental period, during acarological studies of skin scrapings from the ears, both eggs and adults of ticks at different stages of development were found in the field of view of the microscope.

From the results of the studies described in Example 10, it can be concluded that the claimed agent of composition B, taken, for example, in the form of ear drops, has an acaricidal effect against the mite Otodectes cynotis.

Example 10. Study of the effectiveness of the claimed agent (composition B in the form of a spray) for the treatment of feline notoedrosis caused by the pathogen Notoedres cati.

Experiments to study the effectiveness of the claimed agent in the form of a spray (composition B) were carried out on patients with cat notoedrosis caused by the Notoedres cati pathogen parasitizing on the scalp. Before use, the claimed means of composition B in the form of a spray was heated to 30-35°C. The treatment was carried out by aerosol spraying into the affected areas of the head, where pathogens are localized.

The cats were divided into 3 groups (3 cats each). The treatment was carried out 2 times with an interval of 6 days.

- 1 group was treated with composition B of the claimed agent in the form of a spray.

- Group 2 was treated with the drug "Ivermek Spray" (comparison group).

- in group 3, no treatment was performed (control).

The study results were taken into account by examining the treated skin surface and examining scrapings for the presence of an invasive onset 7, 15 and 30 days after treatment.

The results are shown in Table 7.

Table 7. Study of the effectiveness of various acaricidal agents in feline disease caused by ticks Notoedres cati

No. gr. II* before treatment AI by day 7 days 15 days 30 days eggs adult mite eggs adult mite eggs adult mite eggs adult mite one +++ +++ - - - - - 2 +++ +++ - + - - - - 3 +++ +++ +++ +++ +++ +++ +++ +++

* AI - intensity of invasion.

+ - single eggs and adults of mites

+++ - high degree of invasion.

From the data given in Table 7, it can be seen that before treatment, both adults of Notoedres cati mites and eggs were found in skin scrapings of sick animals. In the acarological study of animals of group 1 (composition B) 7, 15 and 30 days after treatment, adults and tick eggs were not found.

In cats of the 2nd group, 7 days after the start of treatment, mite eggs were found in scrapings from the skin. In subsequent periods of research, the results of acarological studies were negative. Animals of the control group were infected with notoedrosis during all periods of the study.

Thus, in the treatment of feline notoedrosis, the claimed agent of composition B, for example, in the form of a spray, is the most effective.

Example 11. Determination of acute toxicity of the claimed three-component acaricidal pharmaceutical composition.

It is known from the prior art that 5-nitro-4,6-dinitrobenzofuroxan (2) belongs to the 3rd hazard class (LD50=380 mg/kg) [Yusupova, L.M. Fungicidal and toxicological properties of functionally substituted nitrobenzofuroxans / L.M. Yusupova, S.Yu. Garmonov, I.M. Zakharov, A.R. Bykov, I.F. Falyakhov, T.V. Garipov // Chemical Pharmaceutical Journal. - 2008. - T. 42. - No. 4. - S. 27-29].

When assessing the acute toxicity of the claimed acaricidal pharmaceutical composition, the Guidelines for Experimental (Preclinical) Study of the Toxicity of New Pharmacological Substances were used (edited by R.U. Khabriev, 2005). The claimed composition was dissolved in sunflower oil.

In the experiment, 49 white rats were used, weighing 200-220 g.

According to the principle of analogues, the animals were divided into 7 groups of 7 animals each.

6 groups served as experimental, one - control.

1-6 experimental groups were administered the claimed acaricidal pharmaceutical composition intragastrically using a probe in the form of a solution in sunflower oil at doses of 500, 700, 900, 1100, 2300 and 1500 mg/kg, respectively.

Rats of the control group were injected with sunflower oil at a dose of 5 ml.

Rats were allowed to water and feed 4 hours after the introduction of the claimed composition. Observation was carried out for 14 days. Attention was paid to mobility, mental status, the presence of food excitability, the condition of the skin and visible mucous membranes. The dead animals were subjected to post-mortem autopsy.

The mean lethal dose LD50 was calculated using the formula:

LD50 = LD100 - Σ ⋅(Z ⋅D)/n,

where:

LD100 - absolute lethal dose;

Z is the arithmetic mean of two values of the number of test objects that showed a positive effect when exposed to each of two adjacent doses;

D is the interval between doses (mg/kg);

n is the number of animals in the group.

The results of determining the acute toxicity of the claimed acaricidal pharmaceutical composition in the form of a spray are presented in Table 8.

Table 8. Study of acute toxicity of the claimed acaricidal pharmaceutical composition in the form of a spray for intragastric administration

Investigated doses, mg/kg 500 700 900 1100 1300 1500 Number of animals in a group, n 7 7 7 7 7 7 Number of surviving animals in each group 7 7 7 five 2 0 Number of dead animals in each group 0 0 0 2 five 7 Z 0 0 0 one 35 6 D, mg/kg 200 200 200 200 200 200 Z⋅D 0 0 0 200 700 1200

Based on the results of the data shown in Table 8, the LD50 of the claimed acaricidal pharmaceutical composition was calculated:

LD50 = 1500 - (200 + 700 + 900) / 7 = 1500 - 2100 / 7 = 1500 - 300 = 1200 mg/kg.

Thus, the average lethal dose of the claimed composition in the form of a spray for intragastric administration was 1200 mg/kg, which corresponds to hazard class 4 (low-hazard substances) in accordance with GOST 12.1.007-76 "System of labor safety standards (SSBT). Harmful substances. Classification and general safety requirements”.

Thus, from the above, we can conclude that the applicant has achieved the claimed technical result, namely: an acaricidal pharmaceutical composition and agents containing it have been developed for a complex effect on scabies mites of the Sarcoptidae family Psoroptes cuniculi, Psoroptes ovis, Otodectes cynotis, Notoedres cati, as well as methods for obtaining these funds, which expands the arsenal of known funds for the specified purpose and eliminates the shortcomings of known analogues, while the claimed composition and the claimed funds obtained by the claimed method:

- have a complex acaricidal effect both on the imago of the tick and on its eggs,

- have fungicidal activity due to the presence of components (2) and (3) with known fungicidal activity,

- have antibacterial activity due to the presence of component (1) with known antibacterial activity, which (component (1)) additionally promotes the transport of components (2) and (3) through the cuticle of the tick and destroys it,

- have a synergistic effect of the biological action of the components (2) and (3) due to their complex effect.

Thus, the active components included in the composition have acaricidal, fungicidal and antibacterial effects, activate regeneration processes in tissues and have a reduced toxic effect.

The claimed technical solution complies with the "novelty" patentability condition for inventions, since at the date of submission of the application materials by the applicant from the studied prior art, no sources have been identified that have a set of features identical to the set of features of the claimed technical solution.

The claimed technical solution complies with the "inventive step" patentability requirement for inventions, since the totality of the claimed features provides technical results that are not obvious to a specialist, exceeding the technical result of the prototype. From the studied state of the art, the Applicant has not identified compositions in which the claimed components would be used simultaneously in the claimed ratio and in the claimed purpose, namely, as part of a pharmaceutical composition for the treatment of parasitic diseases of the skin of animals. The ratio of the components was selected by the applicant empirically.

The claimed technical solution complies with the patentability condition "industrial applicability" for inventions, because the claimed composition can be obtained by using known components using standard equipment and known techniques.

Claims (10)

1. Acaricidal pharmaceutical composition, characterized in that it contains the following ratio of components, parts by weight: 5-nitro-4,6-dichlorobenzofuroxan
4,6-dinitro-5,7-dichlorobenzofuroxan nine
one chlorhexidine 2 2. An agent for the treatment of parasitic diseases caused by scabies mites of the Sarcoptoidea superfamily, characterized in that it contains the following ratio of components, wt. %: composition according to claim 1 0.05 - 0.1 polyethylene oxide-400 4 polyethylene oxide-1500 one dimethyl sulfoxide five distilled water rest 3. An agent for the treatment of parasitic diseases caused by scabies mites of the Sarcoptoidea superfamily, characterized in that it contains the following ratio of components, wt. %: composition according to claim 1 0.1 polyethylene oxide-400 five polyethylene oxide-1500 one dimethyl sulfoxide five birch tar five distilled water rest 4. An agent for the treatment of parasitic diseases caused by scabies mites of the Sarcoptoidea superfamily, characterized in that it contains the following ratio of components, wt. %: composition according to claim 1 0.05 ethyl alcohol 96.3% 70 dimethyl sulfoxide 2 distilled water rest 5. Means according to claim 4, characterized in that it is made in the form of ear drops. 6. Means according to claim 4, characterized in that it is made in the form of a spray.