RU2563811C1 - Pharmaceutical composition for treating mycotic diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: as an active substance, a formulation according to the invention contains 3-ethoxyxycarbonyl-5-(4-chlorobenzylidene)thiazolidine-2,4-dione 2-5 wt %, and also the pharmaceutical composition is expected to contain carbamide in an amount of 2.5-4.0 wt %, as a keratolytic agent. The ointment also contains a lipophilic base that is petroleum paraffin wax in an amount of 5-7 wt %, stearic acid 2-6.5 wt %, emulsion wax 8-12 wt %, a target additive - benzoic acid 0.1-2 wt % and Vaseline oil up to 100%. The pharmaceutical formulation is produced by fusing the solid ingredients of the base, adding concentrated 3-ethoxyxycarbonyl-5-(4-chlorobenzylidene)thiazolidine-2,4-dione in Vaseline oil and carbamide in Vaseline oil.

EFFECT: producing the pharmaceutical formulation possessing the high chemotherapeutic efficacy and good tolerance, low toxicity that makes it applicable in treating dermatomycosis of different localisation.

2 cl, 3 tbl

Description

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

Fungal skin diseases are widespread in all countries of the world, and, according to the findings of a leading research company (GBI Research, 2012), the growth of fungal diseases despite progress in therapy will continue to progress. Long-term observations have shown that a lasting therapeutic effect cannot be obtained during treatment with only one of the antimycotic drugs. This applies to drugs as a systemic (general) action (griseofulvin, nizoral, lamisil), local action, and their combinations with the use of antifungal and keratolic drugs, pathogenic therapy. This is primarily due to the rapid development of resistance to the drugs used (N.V. Kozhichkina. Journal of the Bulletin of Dermatology and Venereology, No. 1, 2013; IB Shilova et al. Modern medicines for the treatment of dermatomycosis. Chemical farm. Journal, vol. 38, No. 4, 2004). In addition, oral antimycotic drugs are contraindicated in some patients due to hepatotoxicity and other side effects.

Various drugs are known to be used as antifungal agents. In particular, synthetic drugs based on nitrogen-containing heterocyclic compounds, such as ketoconazole, miconazole, clotrimazole, fluconazole (M.D. Mashkovsky. Medicines, ed. 15, Moscow: New Wave, occupy one of the first places in the breadth of the spectrum and therapeutic efficacy). 2005). On their basis, various pharmaceutical compositions have been developed: ointments, creams, gels, etc., the composition of which is selected taking into account the specific properties of the active substances, the peculiarities of their pharmacological action and the breadth of the spectrum of action.

Closest to the proposed invention are a pharmaceutical composition for the treatment of fungal diseases based on the active substance - methyl ester of a thiazolidine-2,4-dione derivative, which is highly effective and low toxic, allowing to expand the arsenal of drugs for the treatment of fungal infections, as well as a method for its preparation (patent RU 2295958, publ. 04.07.2007). The pharmaceutical composition in the form of an ointment for the treatment of fungal diseases includes the following components, wt. %:

3-Ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione 2-5 Emulsion Wax 8-14 Solid paraffin 5-7 Stearic acid 2-6.5 Benzoic acid 0.1-2 Urea 2.5-4.0 Vaseline oil up to 100

A method of obtaining the indicated pharmaceutical composition consists in adding benzoic acid and vaseline oil to the lipophilic base prepared by fusion of stearic acid, solid paraffin, emulsion wax, and after exposure at 75-85 ° C for 30-40 minutes, the previously prepared concentrate of 3-methoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione in vaseline oil.

Used as the active substance in the known composition 3-methoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione is known as a compound that is part of the drug "Mycosidine" with antimicrobial activity (patent SU No. 1417436, publ. April 27, 1996). The patent also describes a process for the preparation of 3-alkoxycarbonyl-5-R-yldentiazolidine-2,4-dione. The drug “Mikozidin, 3% ointment” was not found for commercial use due to the bankruptcy of the manufacturer - FSUE TSHLS-VNIHFI in 2008 and the termination of the patent in 2013.

The composition proposed in patent RU 2295958 was intended for the treatment of fungal lesions of various localization and was illustrated by the example of chemotherapeutic efficacy of 3-methoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione as a 3% ointment on a guinea pig microsporium model, given in table 1.

A disadvantage of the known pharmaceutical composition is the relatively low percentage of therapeutic effectiveness of the ointment (70%).

The objective of the invention is to obtain a highly effective ointment for the treatment of fungal diseases.

The objective of the invention is solved due to the fact that it is proposed to use an ointment for the treatment of fungal diseases containing, as an active substance, an ester of a thiazolidine-2,4-dione derivative, solid petroleum paraffin, stearic acid, liquid paraffin, emulsion wax and benzoic acid is the target additive, and the ointment is characterized in that it contains 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione as the active substance and, additionally, urea as the target additive in the following ratio of components, wt. %:

3-Ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione 2-5 Emulsion Wax 8-12 Solid paraffin 5-7 Stearic acid 2-6.5 Benzoic acid 0.1-2 Urea 2.5-4.0 Vaseline oil up to 100

The problem is also solved by the method of obtaining the above ointment for the treatment of fungal diseases, namely, to the lipophilic base prepared by fusion of stearic acid, solid paraffin, emulsion wax, benzoic acid and liquid paraffin are added and after exposure at 75-85 ° C for 30-40 minutes add pre-prepared concentrate of 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione in vaseline oil, after which urea in vaseline oil is added until a homogeneous mass is obtained .

The technical result of the invention is to increase the therapeutic efficacy of the pharmaceutical composition. The use of ethyl ester of a thiazolidine-2,4-dione derivative instead of methyl and the introduction of the experimentally found optimal amount of urea (2.5-4.0%) into the composition allows to increase the therapeutic efficacy of the proposed drug to 84-89%.

The inclusion of urea in the composition of the medicinal composition is a well-known technique and is used by many researchers to soften or remove the nail plate. This mainly concerns aqueous medicinal compositions with well-known antimycotics: ketoconazole (Bulletin of Dermatology and Venereology, 1987, No. 8, p. 20-25); bifonazole (patent RU 2238092, 2002), fungoterbin (Bulletin of dermatology and venereology, 2009, No. 5, pp. 117-119). Urea concentration ranged from 3.5 to 5%.

So in the patent RU 2238092 (published in 2004) a composition with bifonazole in the form of an aqueous medicinal composition in the following ratio of ingredients in wt. %:

Bifonazole 0.7-1.5 Castor oil 15-25 Cellulose 2.0-3.0 Emulsifier Lanette 3.5-7.0 Twin 80 0.7-1.4 Nipagin 0.1-0.13 Spermaceti 3.0-4.0 Urea 3.5-4.5 Phosphoric acid 0.04-0.06 Purified water the rest is up to 100

The composition is intended to cause onycholysis with urea and painlessly remove the infected nail plate in the focus of mycosis and outside the visible focus of infection. The composition allows you to simultaneously remove the softened nail plate and conduct antimycotic treatment.

As part of the preparation "Mikospor Set", the content of urea in the ointment is 40% (used to completely remove the nail plate), the active substance of bifonazole is 1%.

The use of urea as a keratolytic agent in mono-composition is known: the drug Dardia Lipobalzam, urea concentration 5% (Russian Radar - Encyclopedia of Medicines, No. 22, 2014, p. 373; Bulletin of Dermatology, No. 2, pp. 93-95, 2011), the drug Ureotope, urea concentration of 12%. Moreover, creams with a urea content higher than 5% are preferred. it was found that when the urea content is 2%, only moistening of the skin occurs (Bulletin of Dermatology and Venereology, 2011, No. 2, pp. 93-95).

Thus, the use of urea was limited by moisture-retaining and exfoliating properties (skin), as well as keratolytic effect (nail plate). It was not possible to predict the desired concentration of urea in advance, which would increase the therapeutic efficacy of an ointment containing 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione as an active ingredient.

As studies have shown, the proposed composition of the lipophilic base and the proposed ratio of the components are optimal and can achieve increased therapeutic efficacy up to 84-89%, to provide the required rate and completeness of release of the active substance while maintaining a stable, non-stratified form. The use of ointments with a lower concentration of urea (1.0-2.0%) does not significantly affect the increase in therapeutic efficacy (TE 72-75.5%), and when the urea concentration is above 5% during storage, the color of the composition changes, which indicates to a partial change in the physicochemical properties of the main active substance.

A new pharmaceutical composition is obtained by fusion of the solid components of the base, followed by the addition of a concentrate of 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione in vaseline oil and urea in vaseline oil. It is preferable to use micronized urea, as it mixes better with liquid paraffin and other components. An ointment is obtained that meets the requirements for a pharmaceutical agent.

Example 1. Obtaining a pharmaceutical composition

5.0 g of stearic acid are charged into a container with a stirrer and heated to 60-70 ° C. 6.0 g of solid petroleum paraffin, 10.0 g of emulsion wax, 0.2 g of benzoic acid and 62.0 g of liquid paraffin are sequentially loaded into the same container. The resulting mass is stirred for 30-40 minutes, maintaining a temperature of 75-85 ° C. After exposure, the temperature of the mixture is reduced to 60 ° C and partly loaded into it is a pre-prepared concentrate of 3.0 g of 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione in 5 g of vaseline oil and then the mass is mixed with 4 , 0 g of urea in 10.0 g of liquid paraffin to obtain a homogeneous mass.

Get 100 g of the pharmaceutical composition in the form of a 3% homogeneous mass that meets the requirements of the Global Fund XI, issue. 2, p. 145, in appearance, microbiological purity, stable during storage

Table 2 shows the experimental results.

Example 2. Obtaining a pharmaceutical composition

Analogously to example 1, a mass containing 3.0 g of active ingredient is loaded and mixed with 5.0 urea in 10.0 g of liquid paraffin until a homogeneous mass is obtained. After 2 months, during control storage, point changes in the color of the composition (yellowing) were noted.

Example 3. Obtaining a pharmaceutical composition

Analogously to example 1, a mass containing 3.0 g of active ingredient is loaded and mixed with 2.0 g of salicylic acid in 12.0 g of liquid paraffin. The mass exfoliated when standing.

Evidence of antifungal activity

Example 4. The study of the pharmaceutical composition for antifungal activity in vivo in the model of microsporia of guinea pigs

In vivo antifungal activity was studied on the model of experimental microsporia of albino guinea pigs (males weighing 200-300 g). The animals were infected with a zoopathogenic strain of Microsporum canis. For vaccination, a fragment of a 10-12-day-old culture of the pathogen was taken along with Saburo agar and affected hair. After thorough grinding in a sterile mortar, the culture was applied to the epilated and scarified surface of the back skin area 2-3 cm in size.

Treatment of experimental animals began 7 days after infection and was carried out for 21 days. The drugs were rubbed into the affected area of the skin of the pigs daily in an amount of 1-1.5 g, as the reference drugs used ointment "Mycosidine" and "Nizoral" (ketoconazole).

The severity of the infectious process was recorded 1 time in 7 days according to the area or area of the lesion and the type of lesion (desquamation, papules, ulceration). The indicators were expressed in points (0, 1, 2, 3, 4). The chemotherapeutic efficacy score was calculated as a percentage of the difference in scores in the control and the experimental groups, divided by the total score in the control. The following parameters were evaluated: 1) the specific glow of the lesions in the rays of a Wood fluorescent lamp (if there is a pathogen); 2) microscopic examination of material taken from lesions; 3) the time of restoration of the coat; 4) the local irritant effect of drugs. On the 29th day, after 21 days of treatment and 7 days of observation, the final results were recorded.

As a result of studies on the chemotherapeutic efficacy of the claimed pharmaceutical composition based on 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione with the addition of urea in the composition of guinea pig microsporia, its high chemotherapeutic effectiveness was established. In this group of animals, the infectious process was less intense, the affected lesions quickly cleared of ulcerated skin in the lesion foci. The day of complete recovery was considered the first day from the start of treatment, when no hairs affected by the fungus were found in the outbreak, and there was no erosion and crust. Uniform restoration of the coat was noted from the 12th day of treatment. The chemotherapeutic efficacy rate was 84-89%.

The described dosage form in terms of chemotherapeutic efficacy exceeded the drug - the closest analogue (RU 2295958) (TE 70%), as well as the comparison drugs "Mycosidine" and "Nizoral" (TE 70.5% and 42.5%, respectively). The generalized data of the described studies are shown in table 3.

* With an increase in the concentration of the active substance to 5%, TE reached the highest values - 93%, however, the clinical picture of the course of the infection process in the foci on the skin of animals was characterized by the presence of hyperemia, which may indicate the presence of an insignificant but irritating effect of the drug used at higher concentrations

Example 5. Electron microscopic examination

Electron microscopic examination of the skin showed that in groups of animals treated with the proposed medicinal ointment containing urea, all layers of the skin in the area of infection were within normal limits. Dermis and hair follicles have not been changed. In the group of animals treated with Mycosidine ointment 3% (RU 2295958), insignificant intercellular edema remained in the deep layers of the skin. In the control group of animals, 2 months after infection, all the symptoms of the inflammatory reaction were recorded on the skin: exudation, edema, slight erosion. In the primordial and styloid layers of the skin, the phenomena of vacuolar dystrophy were expressed, the dermis was infiltrated by dense inflammatory exudate.

Example 6. The study of the local irritant effect

Visual observation throughout the experiment did not reveal any pathological abnormalities in the behavior of experimental animals in comparison with the control. The appearance of the animals was neat: the coat was smooth, shiny; no hair loss was noted; eyes are not inflamed; ears and limbs are without features. The dynamics of body mass had a positive trend: experimental animals by weight did not lag behind the control.

Functional changes were not identified. Breathing is free, not difficult; urination is not difficult; The excreta is framed.

Hematological studies did not reveal differences in peripheral blood indices between experimental and control animals.

Example 7. The study of subchronic toxicity of the composition in rabbits

In a subchronic experiment on rabbits, a study was made of the general toxic properties of the ointment of the claimed composition.

The ointment was applied to rabbits on an epilated scarified area of skin on the back for 2 months at a dose of 1 g / kg; the indicated dose exceeds the recommended therapeutic daily dose for a person by about 15 times.

It has been shown that ointment applications in the indicated dose for 2 months do not lead to the death of animals and do not affect their general condition and behavior.

Visual observation throughout the experiment did not reveal any pathological abnormalities in the behavior of experimental animals in comparison with the control. The appearance of the animals was neat: the coat was smooth, shiny; no hair loss was noted; eyes are not inflamed; ears and limbs are without features. The dynamics of body mass had a positive trend: experimental animals by weight did not lag behind the control.

Functional changes were not identified. Breathing is free, not difficult; urination is not difficult; The excreta is framed.

Hematological studies did not reveal differences in peripheral blood indices between experimental and control animals.

Pathomorphological examination did not reveal traces of the damaging effect of the drug on the structure of internal organs, except for mildly expressed protein dystrophy in the liver; signs of local irritation were absent.

Thus, as a result of the experiments, it was found that the proposed pharmaceutical composition with the inclusion of urea in the pharmaceutical composition in the form of an ointment is well applied to the skin, promotes better penetration of the active substance deep into the skin, does not have a local irritant effect and has high bioavailability and chemotherapeutic efficacy equal to 84-89%.

Claims (2)

1. The pharmaceutical composition in the form of an ointment for the treatment of fungal diseases, containing as an active substance an ester of a thiazolidine-2,4-dione derivative, solid paraffin as a lipophilic base, stearic acid, liquid paraffin, emulsion wax and benzoic acid as a target additive , characterized in that as the active substance it contains 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione and, in addition, urea in the following ratio of components, wt. %:
3-Ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione 2-5 Emulsion Wax 8-12 Solid paraffin 5-7 Stearic acid 2-6.5 Benzoic acid 0.1-2 Urea 2.5-4.0 Vaseline oil up to 100 2. A method of obtaining a pharmaceutical composition in the form of an ointment for the treatment of fungal diseases according to claim 1, which consists in adding benzoic acid and vaseline oil to the lipophilic base prepared by fusing stearic acid, solid paraffin, emulsion wax and after exposure to 75 -85 ° C for 30-40 minutes add pre-prepared concentrate of 3-ethoxycarbonyl-5- (4-chlorobenzylidene) thiazolidine-2,4-dione in vaseline oil, after which urea in vaseline oil is added until a homogeneous oil is obtained. sy.