RU2573976C2 - Use of benzyl benzoate for new purpose as antimycotic agent, producing and using antimycotic pharmaceutical compositions - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: what is presented is an agent for therapeutic treatment and prevention of fungal diseases of skin and appendages of skin, and extensive and systemic fungal infections of human and animal skin, characterised by the fact that it represents benzyl benzoate and a pharmaceutical composition containing at least 0.1 wt % of this agent High activity of benzyl benzoate on most species of fungal agents and high therapeutic efficacy have been shown.

EFFECT: invention can find application in pharmaceutical industry, medicine, veterinary science, cosmetology and personal hygiene products.

22 cl, 8 ex

Description

The claimed group of inventions relates to the field of medicine and the pharmaceutical industry, in particular to the treatment and prevention of fungal diseases. Fungal diseases of the skin and skin appendages (dermatomycosis), as well as fungal diseases of internal organs (systemic mycoses) account for a large share of infectious diseases in the modern world. In particular, onychomycosis (nail disease) on average occurs in 5-10% of the world's population, and in the age group reaches 30-50%. In industrialized countries, such as the United States, the number of cases of sepsis caused by fungi increases annually by 10%, and in terms of lethal outcome, mycoses are approaching the middle of the top ten among infectious diseases [1]. Mycoses are also widespread among farm and domestic animals. In this regard, the prevention and treatment of fungal diseases is an important task of civil society, the armed forces, industry and agriculture [2, 3].

The emergence of mycoses is facilitated by immunodeficiency due to chronic or severe illnesses, trauma, immunosuppressive therapy, microflora disturbances during long-term treatment with antibiotics, corticosteroids and cytostatics, and their distribution is a consequence of social and professional factors that have been intensified recently by globalization processes. Untreated surface mycoses, in turn, can stimulate the development of extensive and systemic mycoses, affecting the internal organs and tissues of the body, and are a source of infection for others. The need for prevention and effective treatment of infectious and fungal diseases, in particular, will only increase with the deepening global integration processes.

Currently, drugs with direct fungicidal and / or fungistatic action are used to treat mycoses [1, 4, 5]. According to the chemical structure, antimycotics can be divided into groups: polyenes (nystatin, levorin), imidazole derivatives (ketoconazole) and their more advanced analogues - triazoles (itraconazole), a milestone at the end of the 20th century - ekinokandins (caspofungin, micafungin), as well as pyrimidizine derivatives (flucytin ), allylamines (terbinafine, naphthyrin) and other groups. The antimycotic properties of most drugs are associated with a violation at various stages of the synthesis of the main component of the cell membrane of fungi - ergosterol (allylamines, azoles) or binding to ergosterol (polyenes), which leads to a violation of the membrane structure with the final lysis and death of the cell. The mechanism of action of some drugs is more complex, for example, the fungistatic properties of pyrimidine group drugs are due to impaired synthesis in fungi, and nucleic acids, and proteins.

Modern antifungal agents, for example, itraconazole, terbinafine, have a wide spectrum of action and provide a high percentage of cure for patients, while the therapeutic course is from 1-2 months to a year. The need for long-term treatment, coupled with toxicity, side effects (headache, dizziness, impaired digestive and hematopoietic functions, kidneys, liver) and contraindications (for diseases of the blood, liver, kidneys, malignant neoplasms, pregnancy, lactation) limit treatment with antifungal enteric drugs and an injection route of administration.

Antimycotic drugs of local and external use are more widespread. Local treatment is an integral part of the treatment of any fungal disease. External agents make it possible to create high concentrations of active substances on the surface of lesions against pathogens of dermatomycosis, while external therapy has practically no restrictions and contraindications and rarely causes the development of adverse reactions even with prolonged treatment. Antifungal drugs in the form of ointments, creams, liquid sprays, solutions, for example, pevaryl, clotrimazole, econazole, travogen, nizoral, orungal, thermicon, have found the greatest application. Recently, preparations have been proposed for the treatment of onychomycosis in the form of nail polish, for example, batrafen, lotseril. With this method of application, antifungal components penetrate into the nail layer in therapeutically active concentrations [6].

Since the therapeutic course can last up to a year or more, along with the effectiveness of the action, an important selection criterion is the availability (cost) and stability of the drug. For example, the disadvantages of azoles include high cost and lack of stability, limiting the shelf life of drugs [7], as well as low activity in relation to adaptable molds [1]. It should also be borne in mind that the bacterial flora often accompanies fungal and complicates the course of the disease, therefore, topical antimycotic drugs should have not only a wide spectrum of antifungal, but also antimicrobial and anti-inflammatory effects.

Currently, benzyl benzoate is used externally in the form of 10% and 20% ointments, creams and water-soap emulsions for scabies and pediculosis [8]. It is known that with external use, benzyl benzoate penetrates the upper layers of the epidermis, but is not absorbed into the systemic circulation, practically has no side effects and contraindications. Recently, it was proposed to use benzyl benzoate for demodicosis [9], as a disinfectant based on ethanol as an active additive along with menthol [10, 11], and also as a component of the carrier base for the parenteral painkiller composition for parenteral administration [12].

Closest to the claimed solution are the listed benzyl benzoate-based products used for scabies, pediculosis, demodecosis [8, 9], and also as disinfectant solutions for the same purposes [10, 11]. Examples of pharmaceutical and parapharmaceutical compositions containing benzyl benzoate for the prophylaxis and treatment of fungal diseases are not known in the world scientific and patent literature, and the new function and proposed purpose do not follow clearly from its structural formula, accepted purpose, or, as a consequence, previously known properties.

The technical task of the group of inventions related by a single inventive concept is to create an effective tool and pharmaceutical composition and expand the arsenal of tools and pharmaceutical compositions for therapeutic treatment and prevention of fungal diseases.

The technical result, which provides a solution to the problem using the claimed group of inventions, is to reduce side effects, increase the effectiveness of treatment and reduce costs by using benzyl benzoate and pharmaceutical compositions based on it for the treatment of fungal infections of the skin and skin appendages, as well as systemic mycoses of humans and animals.

The essence of the invention in terms of funds is that the tool for therapeutic treatment and prevention of fungal diseases of the skin and skin appendages, extensive and systemic mycoses of the skin of humans and animals is benzyl benzoate.

The essence of the invention in terms of the pharmaceutical composition is that the pharmaceutical composition for the therapeutic treatment and prevention of fungal diseases of the skin and skin appendages, extensive and systemic mycoses of human and animal skin contains a means for the therapeutic treatment and prevention of fungal diseases of the skin and skin appendages, extensive and systemic mycoses of human and animal skin, which is benzyl benzoate, in an amount of not less than 0.1 wt.%.

In special cases of implementation, the composition is made in the form of an ointment containing the following ingredients (in wt.%): From 10 to 50% benzyl benzoate, from 10 to 20% glycerol, from 15 to 50% sorbitol, from 3 to 10% vegetable oil, the rest up to 100% - distilled water.

In special cases of implementation, the composition is made in the form of nail polish containing the following ingredients (in wt.%): From 30 to 50% benzyl benzoate, 5% glycerol, 1% urea, from 5 to 15% carboxymethyl cellulose, from 30 to 50% ethyl acetate , 5% ethanol, the rest up to 100% is distilled water.

In particular cases of implementation, the composition is made in the form of a solution for intramuscular injection containing the following ingredients (in wt.%): From 1 to 70.% benzyl benzoate, from 30 to 85% ethyl oleic acid and not more than 10% benzyl alcohol.

In particular cases of implementation, the composition contains one or more enzyme preparations. In particular cases of implementation, the composition contains one or more compounds from among keratolytic and keratoplastic agents. In particular cases of implementation, the composition contains one or more irreplaceable and non-essential amino acid compounds, peptides and pentidomimetics. In special cases of implementation, the composition contains one or more compounds from among vitamins and vitamin-like compounds. In particular cases of implementation, the composition contains one or more compounds from among the means stimulating receptors of the skin and subcutaneous tissues. In special cases of implementation, the composition contains one or more compounds from among the means stimulating metabolic processes. In particular cases of implementation, the composition contains one or more surface-active compounds. In particular cases of implementation, the composition contains one or more sulfur-containing compounds and mucolytic agents. In particular cases of implementation, the composition contains one or more antioxidant compounds. In particular cases of implementation, the composition contains one or more compounds from among emollients. In particular cases of implementation, the composition comprises one or more complexing agents.

In particular cases of implementation, the composition contains at least one auxiliary substance from the group of systemic and local antifungal agents, antibiotics, antiseptics, analgesic or anti-inflammatory drugs, enzyme preparations, keratolytic or keratoplastic agents, amino acids, peptides, peptidomimetics, vitamins, vitamin-like compounds, agents stimulating the receptors of the skin and subcutaneous tissues, agents stimulating the metabolic processes, surface-active compounds, serosoder aschih compounds, mucolytics, anti-oxidants, emollients, complexing agents, compounds for correction of acid-base status, the ionic equilibrium and the ionic strength of the composition, stabilizers.

In special cases of implementation, the composition is made in a form selected from the group: solution, emulsion, ointment, cream, gel, suspension, paste, aerosol, powder, foam, including capsules, suppositories, tablets, solution for infusion, solution for intramuscular injections, nail polish, shampoo, soap, lotion, deodorant, and also made in the form of an impregnated patch, sponge, napkin, towel.

In particular cases of implementation, the composition contains auxiliary components that are mixed with benzyl benzoate in an inert atmosphere. In special cases of the implementation of the composition after mixing benzyl benzoate with auxiliary components, it is filtered through a membrane with a pore diameter of 0.22 μm. In special cases of implementation, the composition is made with the possibility of treating surfaces and objects for therapeutic treatment and prevention of fungal diseases of the skin and skin appendages, extensive and systemic mycoses of humans and animals. In particular cases of implementation, the composition is adapted to be used individually or in combination with antimicrobial therapy in the treatment and prevention of infectious diseases of humans and animals.

The feasibility of using benzyl benzoate as a means for the therapeutic treatment and prevention of fungal diseases of the skin and skin appendages, extensive and systemic mycoses of the skin of humans and animals has been established as a result of a study of its antifungal properties. As a result, it was confirmed that benzyl benzoate exhibits high antimycotic activity, penetrates well into the layers of the nail and hair, is rapidly absorbed, distributed into the bloodstream by injection methods of administration and can be used as a treatment for fungal infections of the skin and skin appendages, as well as in complex therapy of systemic mycoses.

For example, as an additional component to improve the therapeutic and prophylactic properties of the compositions of the invention, various natural and synthetic compounds of organic and inorganic nature can be used to complement and enhance the therapeutic and prophylactic effect. It is preferable to include in the composition according to the invention one or more of the following auxiliary agents suitable for modifying the action and improving the condition of the patient and / or the treated surfaces:

- antifungal agents, for example, from systemic and local antimycotics, for example, nystatin, levorin, ketoconazole, itraconazole, caspofungin, micafungin, flucytosine, tebinafine, naphthyrin;

- antibiotics acting on gram-positive and gram-negative bacteria, for example, azithromycin, lomefloxacin, erythromycin, oleandomycin, midecamycin, spiramycin, leukomycin, josamycin, doxycycline, glycocycline, morphocycline, oletetrin, minocyclic amincincin, amincicin, amincicin, amicamycin amycin, amicamycin amycin

- antiseptics that act on the microflora indiscriminately, to which bacteria, fungi, protozoa, viruses, in particular, iodine, potassium iodide, potassium permanganate, salicylic, benzoic, boric acid, resorcinol, fucorcin, parabens, phonols are sensitive;

- analgesic and anti-inflammatory drugs, for example, from among pyrazolone derivatives, in particular, antipyrine, amidopyrine, analgin; among para-aminophenol derivatives, in particular phenacetin, paracetamol; from the group of salicylates, in particular acetylsalicylic acid, acecelisine, sodium salicylate, salicylamide, methyl salicylate, mesazalazine; among pyrazolone derivatives, in particular, butadione, tribuzon; from the derivatives of phenylpropionic, phenylacetic, indoline acetic and anthranilic acids, in particular, ibuprofen, orthophene, indomethacin, naproxen, piroxicam, ketoprofen; as well as sulindac, mefenamic acid, niflumic and dioxibenzoic acid, diflunisal, chlotazole, dimethyl sulfoxide, nimesulide;

- enzyme preparations, for example, proteolytic enzymes, in particular trypsin, chymotrypsin, collagenase, terrilithin, ribonuclease, deoxyribonuclease, asperase, lysoamidase, profesim, caripazin, lecozyme, hyaluronidase, which increase tissue permeability and, in particular, for tissue repair, ronidase;

- keratolytic and keratoplastic agents, for example, salicylic, acetic, benzoic acid, urea, dimethyl sulfoxide, ammonium sulfite, esters;

- amino acids irreplaceable and interchangeable, peptides and peptidomimetics exhibiting antimicrobial, antiviral, surface-active, stimulating, anti-inflammatory and other physiological properties [13];

- vitamins and vitamin-like compounds, for example, retinol, dehydroretinol, alpha-tocopherol, panthenol, peridoxin, biotin, inositol, levocarnitine, orotic acid, ascorbic acid, omega-3 and omega-6 fatty acid triglycerides, methionine, S-methylmethionide, S-methylmethionide;

- agents stimulating the receptors of the skin and subcutaneous tissues, for example, of plant origin, containing essential oils, in particular menthol, validol, turpentine oil, ant alcohol; containing bitterness, in particular, plantain juice, wormwood herb, bitter tincture; synthetic agents, in particular chloroform, chlorobutanol hydrate, ammonia solution; bee venom;

- agents that stimulate metabolic processes, for example, derivatives of pyrimidine, thiazolidine, uracil, adenosine, hypoxanthine; biogenic stimulants, in particular, aloe extract, humisole, amniocene and other biogenic preparations;

- surface-active agents, for example, fatty acids and alcohols, macromolecular compounds, in particular polyvinylpyrrolidone, polyvinyl alcohol, twins, bentonites;

- sulfur-containing compounds and mucolytic agents, for example, thiols, in particular, N- (2-amino-3,5-dibromobenzyl) -N-methylcyclohexylamine hydrochloride, trans-4 - [(2-amino-3,5-dibromobenzyl) amino ] cyclohexanol hydrochloride, N-acetylcysteine, unitiol; thiosulfates, in particular sodium thiosulfate;

- antioxidants, in particular alpha tocopherol, ascorbyl palmiate, butyl hydroxyanisole, butyl hydroxytoluene, propyl gallate, emoxypine, ubiquinone, ascorbic acid, thiourea, sulfites and hydrosulfites;

- emollients, in particular glycerin, propylene glycol;

- complexing agents, in particular ethylenediaminetetraacetic acid, ferrocin;

- means for correcting the acid-base state, ionic equilibrium and ionic strength, for example, acids, in particular salicylic, citric, acetic, benzoic acid, hydrochloric, sulfuric, nitric, phosphoric, boric acid, phenol, sulfonic acids; bases, in particular, ammonium hydroxide, potassium, sodium, magnesium, calcium; salts, in particular reduced acids and bases;

The compositions of the invention may also contain components for stabilizing the compositions and improving their consumer properties:

- film-forming bases, for example, a water-insoluble film-forming agent, in particular methyl cellulose, nitrate cellulose, polyvinyl acetate, (co) polymers of acrylic, methacrylic, ethyl acrylic, trimethylaminoethyl methacrylic, vinyl, maleic, crotonic acid, N-vinylpyridridyl, nitride, pyrrolidone, , esters, in particular, containing quaternary ammonium groups, short chain and fatty alcohols;

- plasticizers, for example, based on phthalates or camphor, in particular dialkyl phthalates; oils containing fatty hydroxy acids, in particular castor oil, silicone oils;

- film modifiers to improve the application of varnish and its curing after evaporation of the solvent, for example, acrylic, polyamide, sulfamide, arylsulfonamide formaldehyde resins, cellulose derivatives, cellulose derivatives;

- dyes and coloring pigments, pearlescent products, for example, crystalline violet, fuchsin, brilliant green, brilliant blue, siena, eosin, iron oxide pigments yellow and red, titanium dioxide, fucorcin;

- sedimentation inhibitors, for example, tween-80, polyvinyl, aerosil, cellulose ethers, bentonites, detergents;

- perfumes, for example, cinnamaldehyde, ethyl propionate, limonene, ethyl maltol, methyl salicylate, allyl hexanoate :;

- solvents, preferably physiologically acceptable, for example, hydrocarbons, alcohols, ethers and esters used in medicine and cosmetics, ketones, in particular esters of acetic acid and monohydric alcohols, such as ethyl, propyl and butyl acetate, if necessary, in a mixture with aromatic hydrocarbons, such as toluene, and / or alcohols, such as ethanol, propanol, butanol, phenol.

In particular, the combination of solvents is crucial for the drying time of the nail polish, the ability to distribute and other properties of the varnish and varnish film. In this case, the combination of solvents preferably consists of a mixture of low boiling (with a boiling point up to 100 ° C) and medium boiling (with a boiling point up to 200 ° C) solvents.

The antifungal compositions according to the invention, containing benzyl benzoate as the active substance, can be made in the form of solutions, emulsions (ointment, cream, gel), suspensions (paste), aerosols, solid sols (powders), foam, including capsules , suppository, tablets, solutions for enteral and / or parenteral administration, nail polishes, shampoos, gels, soaps, lotions, deodorants, and also made in the form of plasters, sponges, napkins, towels. In particular, antifungal compositions for treating smooth skin are preferably in the form of a cream or ointment, for treating scalp and hair, preferably in the form of a solution, aerosol or gel, for treating onychomycosis, preferably in the form of an ointment or nail polish, for wiping and processing surfaces and objects, hands, affected areas - preferably in the form of a solution, aerosol, soaked sponges and napkins; for the treatment of systemic mycoses, preferably in the form of solutions for infusion and intramuscular injection.

The content of benzyl benzoate in the compositions according to the invention can be from 0.1 to 100 wt.%, Preferably from 5 to 60 wt.%, In particular 5, 10, 20 or 50% for therapeutic use. The content of benzyl benzoate in the compositions according to the invention for prophylactic purposes is preferably from 0.1 to 5 wt.%. The content of other additional components in the compositions according to the invention depends on the structure of each compound and, therefore, on its properties, in particular physiological and physico-chemical properties (physiological effect, ability to penetrate the nail, skin, solubility, etc.).

The above acids can be included both in free form and in the form of physiologically acceptable salts with organic or inorganic bases. Appropriate compounds can be used as the active component and additional components, regardless of the preparation method, while meeting the requirements of chemical purity. Water can be used distilled, or drinking softened, or drinking, meeting the requirements of SanPiN 2.1.4.1074-01.

The stage of preparation of the compositions according to the invention can be carried out at a temperature of from -5 to 200 ° C, in particular at 10-50 ° C, preferably at 10-20 ° C. The steps of adding compounds capable of oxidizing are preferably carried out in an inert atmosphere, for example nitrogen, argon at a reduced temperature. At various stages of preparation, the mixture can be filtered through a membrane, for example, with a pore diameter of 0.22 μm. In some cases, various components, including benzyl benzoate, can be mixed, dissolved or diluted immediately before use. It should be noted that benzyl benzoate and some compounds from among the additional components are sensitive to the acidity of the medium - they hydrolyze / degrade in alkaline and acidic environments. Therefore, for water-based compositions containing benzyl benzoate and other pH sensitive additional components, a pH of 5-6 is preferred, in particular a pH of 3 to 8, less preferably a pH of 2 to 11. Other conditions, as well as the order in which the components are mixed in the preparation appropriate compositions are selected based on the physicochemical properties of the individual components of the mixture, as well as the general mixture based on scientific feasibility and economic feasibility, without prejudice to therapeutic, preventive, consumer x properties of the pharmaceutical composition.

Some examples of antifungal compositions of the invention

The antifungal composition in the form of an ointment contains in weight percent the following components: benzyl benzoate - 10-50%, glycerin - 10-20%, sorbitol 15-50%, cetostearyl alcohol 3-10%, distilled water - up to 100%.

The antifungal composition in the form of nail polish contains in weight percent the following components: benzyl benzoate - 30-50%, lomiflaxacin - 0-20%, glycerin - 5%, urea - 1%, carboxymethyl cellulose - 5-15%, ethyl acetate - 30-50 %, ethanol - 5%, distilled water - up to 100%.

The antifungal composition in the form of a solution for intramuscular injection contains in weight percent the following components: benzyl benzoate - 1-70%, benzyl alcohol - 0-10%, oleic acid ethyl ester - 30-90%.

The antifungal composition in the form of a gel contains the following components in weight percent: benzyl benzoate - 2-30%, propylene glycol - 2-5%, carbomer 910 - 2-4%, N-acetyl-cysteine - 0-2%, nystatin - 0-1 %, chloramphenicol - 0-1%, menthol - 0-0.2%, methyl paraben - 0.1-0.2%, alpha-tocopherol - 0.01-0.05%, limonene - 0.01-0, 05%, water up to 100%.

The antifungal composition in the form of an emulsion contains in weight percent the following components: benzyl benzoate - 2-30%, polyethylene glycol cetyl stearyl ether - 1-5%, sodium stearate - 5-10%, aloe extract - 0-1%, chymotrypsin 0-0.1 %, sodium ethylenediaminetetraacetate - 0.01-0.05%, water up to 100%.

The antifungal composition in the form of a paste contains the following components in weight percent: benzyl benzoate - 2-50%, dimethyl sulfoxide - 0-10%, salicylic acid - 0.1-0.5%, titanium dioxide - 1-5%, starch 10-20 %, medical vaseline up to 100%.

The antifungal composition in the form of soap contains in weight percent the following components: benzyl benzoate - 2-50%, methyl salicylate - 0.1-0.5%, triethanol amine - 0.1-0.2%, sodium stearate - 40-72%, sodium carbonate - 1-2%.

The antifungal composition in the form of a spray contains the following components in weight percent: benzyl benzoate - 2-50%, peppermint essential oil 0.1-0.2%, ethyl alcohol up to 100%.

The antifungal composition in the form of a spray contains (in wt.%) 0.1-50% benzyl benzoate, 5% distilled water, up to 100% ethyl alcohol).

The antifungal composition in the form of a soft gelatin capsule contains 0.1-0.5 g of benzyl benzoate, 0.2-0.4 g of lomiflaxacin. The capsule shell contains in weight percent the following components: gelatin - 45-50%, glycerin - 10-12%, water up to 100%.

The antifungal composition in the form of a solution contains the following ingredients (in wt.%): From 2 to 50% benzyl benzoate, from 0 to 30% dimethyl sulfoxide, from 0 to 30% vitamin A, from 0 to 30% vitamin E, the rest up to 100% - oil of organic (rapeseed, corn, linseed, sunflower, olive, peach, rosehip, fir, burdock, castor) or mineral (silicone) origin.

An antifungal composition in the form of a solution for the impregnation of sanitary napkins containing the following ingredients (in wt.%): From 2 to 60% benzyl benzoate, from 0 to 50% dimethyl sulfoxide, the rest up to 100% - distilled water.

The method of using benzyl benzoate for a new purpose and the antifungal compositions of the invention containing benzyl benzoate can be either independent or in combination with direct-action antifungal therapy in the treatment of fungal diseases, or in combination with other agents when, for one reason or another, there is a risk of fungal infection. In particular, the preparation and compositions of the invention can be used individually or in combination with antimicrobial therapy in the treatment of various infectious diseases of humans and animals, in particular in the treatment of antibiotics, corticosteroids and cytostatics, when there is a risk of complication of the main therapeutic course of treatment with a fungal infection. The method of application can also be combined with technical methods and approaches, for example, treatment with an antifungal agent is preceded by the removal of the affected area of the nail mechanically or using keratolytic plasters.

Technical result of the present invention: Benzyl benzoate is highly active against most types of pathogens of mycoses, and its concentration created on the surface of the lesion far exceeds the minimum inhibitory concentration of fungal growth. Benzyl benzoate preparations and compositions of the invention containing benzyl benzoate can be easily formulated as topical and topical agents, as well as injection, are stable, the content of the active ingredient is high, and have a low cost. The treatment with the proposed compositions of the invention has the following advantages: effective treatment of fungal diseases of the skin and appendages of human and animal skin, accessibility for outpatient treatment, low cost (about an order of magnitude lower than commercial drugs), the use of drugs in combination with systemic therapy with direct-acting antifungal drugs pronounced / severe mycoses superior in effect to monotherapy with systemic drugs.

The achievement of the above technical result is ensured by the fact that in the treatment of fungal lesions of the skin and skin appendages, a benzyl benzoate preparation or a composition according to the invention with a benzyl benzoate content of 0.1 to 100% by weight is applied to the surface of the affected area. The product is preferably rubbed into clean and dry skin of the affected area (after thorough washing with soap and warm water). In the treatment of onychomycosis, the composition according to the invention, for example, in the form of nail polish is preferably applied 3-5 times a week to all nails of the hands and feet. In the treatment of extensive mycoses, the composition is preferably applied after thorough washing in the shower, while the product is rubbed into the skin of the hands, trunk, legs, including soles and fingers, nails, and hairy parts of the body. In the treatment of extensive and systemic mycoses, pharmaceutical compositions in the form of solutions for infusion and intramuscular injection containing benzyl benzoate from 0.1 to 100 wt.%, Preferably from 5 to 20 wt.%, In particular 10 wt.%, Should also be used.

The suitability of the invention for the prevention and treatment of fungal lesions of the skin and its appendages is confirmed by the following examples.

Example 1. A cow, 8 years old. The diagnosis is hoof fungus. Objectively: the lesion focus is pinkish in the front hoof, bloating, initial signs of hoof exfoliation. Treatment: The preparation of benzyl benzoate, ointment 20%, was applied evenly to the affected areas of the hoof 2-3 times a day and 1 time per day on the other limbs. After 3 months, a complete cure was noted.

Example 2. Sick volunteer, 35 years old. The diagnosis is rubromycosis of the feet. Objectively: several lesions of pinkish-cyanotic color with clear boundaries. Treatment: outpatient. The pharmaceutical composition in the form of an ointment (composition in wt.%: 20% benzyl benzoate, 20% salicylic acid, 10% glycerol, 2% soap) was applied with a thin even layer on the affected areas of the skin 3-5 times a day and lightly rubbed. After 1 month, a complete cure was noted.

Example 3. A sick volunteer of 45 years. Diagnosis: onychomycosis of the hands. Objectively: 2 nails with varying degrees of yellowish lesion, thickened. Treatment: outpatient. The pharmaceutical composition in the form of nail polish of the following composition (wt.%): 30% benzyl benzoate, 5% glycerol, 1% urea, 5% carboxymethyl cellulose, 30% ethyl acetate, 5% ethanol, distilled water up to 100%, applied 3-5 times per week on all nails of the hands and feet. After 5 months, a complete cure was noted.

Example 4. A patient is 65 years old. Diagnosis: onychomycosis of the feet. Objectively: 2 nails with varying degrees of yellowish lesion, thickened. Treatment: outpatient. The pure substance of benzyl benzoate was applied in a thin layer twice a day on all nails of the hands and feet. After 7 months, a complete cure was noted.

Example 5. A study was made of the prophylactic effectiveness of the composition according to the invention in the form of a gel relative to the placebo composition in two groups of employees of public baths, in each group of five men and five women. The participants of the first group, before starting work and after finishing work, applied an even layer to the open parts of the hands and feet in the form of a gel of the following composition (wt.%): 30% benzyl benzoate, 3% propylene glycol, 3% carbomer 910, 1% N-acetyl cysteine, 0.1% menthol, 0.1% methylparaben, 0.01% alpha-tocopherol, 0.01% limonene, distilled water to 100%. Participants in the second group (control) similarly used a placebo gel composition of the following composition: 3% propylene glycol, 3% carbomer 910, 1% N-acetyl cysteine, 0.1% menthol, 0% methyl paraben, 0.01% alpha tocopherol, 0.01% limonene, distilled water up to 100%. During the tests, participants in both groups did not use other means, including special means for the prevention of fungal diseases. After six months of observation, a four-fold decrease in the incidence of fungal lesions of the skin and its appendages was noted in the first group relative to the control group.

Example 6. The study of the preventive effectiveness of the composition in the form of a spray, which was used to process the inner surface of the personal shoes of two groups of military personnel, in each group of ten military personnel. The inner surface of the shoes of the participants of the first group was treated with a spray (composition in weight percent: 20% benzyl benzoate, 5% distilled water, 100% ethyl alcohol) once a week. Shoes of the participants of the second group (control) were treated in the same way with a placebo spray (composition in wt.%: 5% distilled water, ethyl alcohol up to 100%). The inner surface of the shoes of both groups was not processed by other means, including special means for the prevention of fungal diseases. Participants in the two groups did not use other means, including special means for the prevention of fungal diseases. After six months of observation, there was a seven-fold decrease in the incidence of fungal lesions of the skin of the feet and its appendages in the first group relative to the control group.

Example 7. Patient 37 years old. Diagnosis: onychomycosis of the feet, duration of the disease: 10 years. He previously underwent treatment with fluconazole-based drugs in the form of 15 mg capsules and terbinafine in the form of 200 mg tablets. However, treatment was discontinued due to the detection of side effects of fluconazole and terbinafine. On examination: the nail plate of the big toe has strips of yellow, yellow with gray in color at the edges and in the central part, along the growth line. The stained areas of the nail plate are thickened due to horny masses (moderate subungual hyperkeratosis). The free edge of the plate is loosened. On the skin of the feet there are small affected areas of the interdigital folds and soles with pronounced redness and peeling.

Outpatient treatment. In the first procedure, the surface of the nail was ground with a cosmetic file, removing the material of the nail with a moistened cotton swab. A few drops of a solution were applied to the prepared nail surface, containing (in wt.%) 50% benzyl benzoate, 20% peach oil and 30% dimethyl sulfoxide, using a dry cotton swab, the solution was evenly distributed over the surface of the plate, capturing small near-nail sections of the skin. The application procedure was repeated 2 times a week for 6 months. After the end of treatment, by appearance, the unchanged nail plates grew to 2/3 of the nail bed.

A gel containing (in wt.%) 20% benzyl benzoate, 1% arerespol, triethanolamine (up to pH 6.0), 0.2% nipagin, 0.1% nipazole, 0.1% tween-80 was applied to the affected areas of the skin distilled water up to 100%. The gel application procedure was repeated 2 times a day. After the first application of the gel, the disappearance of a sensation of dryness, burning and itching in the area of the affected skin was recorded. On the third day, the skin had a natural shade, peeling stopped. The treatment was continued for another 7 days until the full restoration of the affected skin areas.

Example 8. The study of the preventive effectiveness of the composition according to the invention in the form of sanitary napkins impregnated with a solution containing (in wt.%): 20% benzyl benzoate, 40% dimethyl sulfoxide and distilled water up to 100%, relative to the placebo composition in two groups of employees of public baths , in each group there are four men and five women. Participants of the first group every two hours wiped open areas of their hands and feet with sanitary napkins soaked in a solution of the above composition. Participants in the second group (control) similarly used commercially available sanitary napkins. During the tests, participants in both groups did not use other means, including special means for the prevention of fungal diseases. After six months of observation, a six-fold decrease in the incidence of fungal lesions of the skin and its appendages was noted in the first group relative to the control group.

These formulations of antifungal pharmaceutical compositions and methods for their use are not exhaustive. The present invention can be implemented in many other ways in accordance with its essence within the scope of the claimed claims, therefore, it should be understood that the description is merely illustrative and in no way limits the present invention.

Information sources

1. Diagnosis and treatment of human mycoses. Eds. Hospenthal D.R. and Rinaldi M.G. Humana Press. Totowa, New Jersey. 2008.

2. Pokrovsky V.I., Lobzin Yu.V. Therapeutic Archive. 2005, 11, 5-7.

3. Sergeev Yu.V. Medical mycology. 2007, 1, 305-312.

4. A practical guide to anti-infectious chemotherapy. Ed. Strachunsky L.S., Belousova Yu.B., Kozlova S.N. Ed. 2nd. M .: Borges, 2002.

5. Mashkovsky M.D. Medicines Ed. 12th M .: Medicine, v.2, 1993

6. RU 2261701 C2, 02.28.2001.

7. US 6040307, 2000-03-21.

8. The register of medicines of Russia. Encyclopedia of drugs. Ed. 14th M., 2007

9. RU 2210365 C1, 12/17/2001.

10. RU 02261089 C1, 08/12/2004.

11. RU 2104696 C1, 05/12/1997.

12. RU 2141845 C1, 07.24.96.

13. Mikhalkin A.P. Obtaining, properties and application of N-acylamino acids. The success of chemistry. 1995, 64, 275-292.

Claims (22)

1. The tool for therapeutic treatment and prevention of fungal diseases of the skin and skin appendages, extensive and systemic mycoses of the skin of humans and animals, characterized in that it is benzyl benzoate. 2. A pharmaceutical composition for the therapeutic treatment and prevention of fungal diseases of the skin and skin appendages, extensive and systemic mycoses of human and animal skin, characterized in that it contains the agent according to claim 1 in an amount of at least 0.1 wt.%. 3. The composition according to claim 2, characterized in that it is in the form of an ointment containing the following ingredients (in wt.%): From 10 to 50% benzyl benzoate, from 10 to 20% glycerol, from 15 to 50% sorbitol, from 3 to 10% vegetable oil, the rest up to 100% - distilled water. 4. The composition according to claim 2, characterized in that it is in the form of nail polish containing the following ingredients (in wt.%): From 30 to 50% benzyl benzoate, 5% glycerol, 1% urea, from 5 to 15% carboxymethyl cellulose, from 30 to 50% ethyl acetate, 5% ethanol, the rest up to 100% is distilled water. 5. The composition according to claim 2, characterized in that it is made in the form of a solution for intramuscular injection containing the following ingredients (in wt.%): From 1 to 70.% benzyl benzoate, from 30 to 85% ethyl oleic acid and not more than 10% benzyl alcohol. 6. The composition according to claim 2, characterized in that it contains one or more enzyme preparations. 7. The composition according to claim 2, characterized in that it contains one or more compounds from among keratolytic and keratoplastic agents. 8. The composition according to claim 2, characterized in that it contains one or more essential amino acids, peptides and pentidomimetics. 9. The composition according to claim 2, characterized in that it contains one or more compounds from among the vitamins and vitamin-like compounds. 10. The composition according to claim 2, characterized in that it contains one or more compounds from among the means stimulating the receptors of the skin and subcutaneous tissues. 11. The composition according to claim 2, characterized in that it contains one or more compounds from among the means that stimulate metabolic processes. 12. The composition according to claim 2, characterized in that it contains one or more surface-active compounds. 13. The composition according to claim 2, characterized in that it contains one or more sulfur-containing compounds and mucolytic agents. 14. The composition according to claim 2, characterized in that it contains one or more antioxidant compounds. 15. The composition according to claim 2, characterized in that it contains one or more compounds from among emollients. 16. The composition according to claim 2, characterized in that it contains one or more compounds from among the complexing agents. 17. The composition according to claim 2, characterized in that it contains at least one auxiliary substance from the group of systemic and local antifungal agents, antibiotics, antiseptics, analgesic or anti-inflammatory drugs, enzyme preparations, keratolytic or keratoplastic agents, amino acids, peptides , peptidomimetics, vitamins, vitamin-like compounds, agents stimulating the receptors of the skin and subcutaneous tissues, agents stimulating the metabolic processes, surface-active compounds, seros -containing compounds, mucolytics, anti-oxidants, emollients, complexing agents, compounds for correction of acid-base status, the ionic equilibrium and the ionic strength of the composition, stabilizers. 18. The composition according to any one of paragraphs.2, 17, characterized in that it is made in a form selected from the group: solution, emulsion, ointment, cream, gel, suspension, paste, aerosol, powder, foam, including in the form capsules, suppository, tablets, solution for infusion, solution for intramuscular injection, nail polish, shampoo, soap, lotion, deodorant, and also made in the form of an impregnated patch, sponge, napkin, towel. 19. The composition according to any one of paragraphs.2, 17, characterized in that it contains auxiliary components that are mixed with benzyl benzoate in an inert atmosphere. 20. The composition according to any one of paragraphs.2, 17, characterized in that after mixing benzyl benzoate with auxiliary components, it is filtered through a membrane with a pore diameter of 0.22 μm. 21. The composition according to any one of paragraphs.2, 17, characterized in that it is made with the possibility of treating surfaces and objects for therapeutic treatment and prevention of fungal diseases of the skin and skin appendages, extensive and systemic mycoses of humans and animals. 22. The composition according to any one of paragraphs.2, 17, characterized in that it is made with the possibility of using individually or in combination with antimicrobial therapy in the treatment and prevention of infectious diseases of humans and animals.