UA52120A - Remedy for prevention and treatment of mycoses - Google Patents

Abstract

The remedy for prevention and treatment of the mycoses contains the antimycotic myconasol and the auxiliary components – dimethylsulfoxide (dimexide) and ethanol.

Description

Description of the invention

The invention relates to medicine, as in medicines used in dermatology for the prevention and treatment of fungal and bacterial lesions of the skin, hair, nails, mucous membranes, genitals, etc.

There are about 100,000 species of fungi in the world around humans, a large part of which, under certain conditions, can cause fungal diseases of a local or systemic type. If earlier fungal infections were traditionally dealt with by dermatologists, now, in connection with the significant spread of localization and diversity of 70 clinical manifestations, mycoses attract the close attention of doctors of various specialties (1). In general, the problem of mycoses has gone far beyond the boundaries of the dermatological clinic (2 - 41. The incidence of fungal infections has been increasing in recent decades. The spectrum of pathogens of dermatomycoses is changing, the emergence of resistant forms is more often noted, the problem of treating "deep" visceral lesions with pathological fungi and concomitant infection is becoming more and more urgent. . An analysis of the incidence of fungal infections caused by dermatophytes shows that 12 years ago, such a massive infection as favus has almost been eliminated, and the number of cases of trichophytosis has decreased. At the same time, hundreds of thousands of patients with microsporia (especially among children) are registered annually, millions people are affected by mycoses of the feet and onychomycoses (nail lesions). Moreover, if the main cause of mycoses of the feet in the 30s - 50s was Eridegptorpuiyup Kashytap-UMoii, today there is a continuous increase in diseases caused by Tgisporpuiyup gigbut, even the name of a new nosological form appears - rubrophytia g, Bi.

The beginning of antibiotic therapy of fungal infections was laid in 1951 with the discovery of the antidermatophytic drug griseofulvin and the polyene antibiotic nystatin. Until recently, the most widely used fungistatic agents were Nystatin (tablets, suppositories), Levorin (ordinary, buccal and vaginal tablets, ointment, powders for preparing suspensions, inhalations), Griseofulvin (tablets, suspensions, liniments), Amphotericin B (intravenous injections, ointment) , Amphoglucamine (tablets), Mycoheptin (tablets) (b). "

Nowadays, antifungal agents are prescribed not only for local therapy, but are also used for systemic administration. The first group includes solutions for external use, ointments, creams, gels, sprays, vaginal tablets and suppositories, powders in the form of powders, antifungal nail polishes (7). Intravenous solutions, tablets, capsules, dragees, oral suspensions, solutions for internal use, etc. are used for the treatment of systemic mycoses.

Medicines of various chemical origins are used for the prevention and treatment of fungal diseases: --

Polyene antibiotics: nystatin, levorin, natamycin (pimafucin), amphotericin B and its liposomal su form - ambisome; 3o - Pyrimidine derivatives: flucytosine (Ancotil); o - Azoles: a) imidazoles - ketoconazole (Nizoral); miconazole (klion-D, miconazole-Darnytsia, mikogel-KMP), oxiconazole (mifungar), econazole (ekalin); "b) triazoles - fluconazole (Diflucan, Mycosyst), itraconazole (Orungal), tioconazole (Trozid), sertaconazole Z 50 (Zalain); c - Allylamines: terbinafine (lamizil);

From" - Other derivatives - undecylenic acid (cinkundan, undecin, mycoseptin), carboxylic acid (octycil), chloro-nitrophenols (nitrofungin), bisquaternary ammonium bases (decamine), decamethoxine (antifungin).

The currently used drugs have significant drawbacks that reduce their therapeutic value. Such disadvantages are: i-th - complete or partial insolubility in water and difficulties in preparing medicinal (pharmaceutical) forms for local use; - in most cases, the use of soft medicinal forms (ointments, creams, gels), which makes it difficult for them to - penetrate the folds of the skin and mucous membranes; ka 20 - undesirable cosmetic effect on clothing (greasy stains, quick soiling of underwear, stockings, hats, etc., skin and clothing coloring); c - insufficient concentration causes rapid development of resistant forms; - the development of resistant forms leads to the ineffectiveness of treatment and the discrediting of the drug, which is currently observed in 30 - 4095 medicinal products |8); 29 - due to the low effectiveness of drugs in the form of soft dosage forms (ointments, creams, gels) sharply in the duration of treatment increases, which increases the cost of treatment, the risk of the emergence of resistant forms, an increase in the frequency of side effects and poisoning; - if necessary, the impossibility of creating an increased concentration of the drug in the case of using soft dosage forms (ointments, creams, gels) due to their low fluidity, in contrast to the use of a liquid dosage form (solution); - impossibility or considerable difficulty in filling deep caverns and sinuses with soft medicinal forms (ointments, creams, gels), and, comparable to this, easier penetration when using a liquid medicinal form (solution) of an antimycotic.

Nowadays, from the pharmaceutical forms for the treatment of mycoses, medicinal products for external use are used, which include one or more ingredients (9, 10). Among them, the ointment "Clotrimazole" (RoHa, Poland), "Mikospor" (Waueg, Germany), Miconazole-Darnytsia (Darnytsia,

Ukraine), "Candybene" (I tsdm/d Megkie, Germany), "Diflucan" (Riigeg, SILA), "Pimafucin" (Matapiosnpi Eigore,

Japan), solutions - "Antifungin" bottles 0.196 of 25 ml (JSC "Monfarm"), "Naftifin" bottles of 1095 of 1 Oml, "Nitrofungin" (2-chloro-4-nitrophenol and triethylene glycol and ethyl alcohol 5095) bottles of 25 ml. Most of them contain one active component, which is unable to meet all the requirements for such devices.

Other medicines for the treatment of skin diseases are aimed at stopping or completely eliminating inflammatory processes. So, for example, "Algofin", "Analgol", "Analgolan" ointments cause only an analgesic effect, which is also quite weak, but they have almost no antifungal, antiseptic and 7/0 M local anesthetic effect. Ointments "Calendula", "Bonafton" and "Bom-Benge" have antiseptic and distracting properties, but they are very weak in terms of antimycotic, analgesic and anti-inflammatory properties and, practically, they almost do not act as antimicrobial drugs. Combined ointments "Prednikarb", "Oflokain", "Indomethacin ointment" have an anti-inflammatory effect, but do not have a fungistatic, antiseptic and local anesthetic effect. On the contrary, the latter, given in the example of ointments used for inflammation of the skin /5 and mucous membranes during self-treatment of fungal lesions, can cause the expansion of the affected surfaces and the spread of infection even before the development of septic conditions.

Close to the claimed drug is "Mikospor" from the company "Bayer" (Germany) (9, 101. It includes:

Bifonazole 1 g

a-isopropyl myristate 52.6 g

Ethyl alcohol up to 100 ml

Disadvantages of this drug are: - very high price, which makes it difficult to use the drug by wide strata of the population; - inclusion of patent-protected compounds in the composition of the drug; 29 - the absence of auxiliary substances in the composition of the drug that could increase the penetration of the main active compound - bifonazole into fungal cells, folds of the skin and mucous membranes, damaged areas of nails, etc.; - the impossibility of strengthening the effect upon repeated application to the same affected area.

Along with this, the imported drug "Nitrofungin" ("SaIepa" is also used in liquid form in Ukraine

Czech Republic). Nitrofungin contains chloronitrophenol (2-chloro-4-nitrophenol). Available in 25ml bottles (9, 10). This solution has a clear but extremely weak antifungal effect and, in addition, has a number of other disadvantages: - it has insufficient antimicrobial, analgesic and local anesthetic effects; - - insufficient antiseptic effect of the drug, which is very important for combined lesions with the presence of Ge! already infected cells, or with the threat of such an infection, which is usually observed in the long course of fungal lesions |5, 61; o - the use of "Nitrofungin" has a cosmetic drawback, since the drug has a yellow "caustic" and rather persistent color that contaminates clothes and shoes when it is used on areas where the skin must be covered by clothes or shoes (onychomycosis of the nails, mycosis of the skin of the hands and legs, neck, vagina, perineum, etc.); « du - the absence of excipients in the composition of the drug capable of transporting chloronitrophenol-o (2-chloro-4-nitrophenol) into fungal cells, skin folds and mucous membranes, damaged areas of nails, etc.; c - a large number of resistant forms of fungi to existing antifungal agents; :z" - almost complete absence of local anesthetic and analgesic action; - insufficient antimicrobial, anti-inflammatory and antiseptic effectiveness of "Nitrofungin" and "Mycospor" drugs; p 15 The closest analog (prototype) of the claimed medicinal product is an antifungal drug

Miconazole-Darnytsia (Darnytsia, Ukraine), cream 295 in tubes of 15g (10). Domestically produced drug, the main active substance of which is miconazole (9, 10). It includes: - Miconazole 0.2g

Kk 20 Hydrophilic cream base up to 100 g. "2 It is quite an effective tool, but it is inferior to the proposed "Composition" in terms of effectiveness. In addition, it has almost no analgesic and local anesthetic effect. It has a very weak antimicrobial effect, which is extremely important in the presence of concomitant inflammation and the development of an already pronounced pain syndrome. Along with this, this drug has a number of disadvantages, in particular: p - the composition includes one active substance, miconazole; - the composition of Miconazole-Darnytsia (Darnytsia, Ukraine) includes as a base - a hydrophilic cream base that does not have its own antifungal and antimicrobial effect; - the composition of Miconazole-Darnytsia (Darnytsia, Ukraine) does not include substances that could increase the permeability of 60 the main active substance - miconazole into fungal cells, skin folds, mucous membranes, etc.

The basis of our invention is to solve the set task - to create a highly effective combined drug for external use in the form of a liquid (solution) for application to the affected areas in the treatment and prevention of mycosis, complicated by inflammation of the skin, mucous membranes and damage to nails and hair caused by contamination with microorganisms (staphylococci, streptococci, fecal pathogens, 65 eumycetes, etc.).

The task is achieved by selecting ingredients compatible with each other in the composition of the combined drug, which have antimycotic, antimicrobial, anesthetic, anti-inflammatory and antiseptic effects with the following ratio of components in grams:

Miconazole 0.5 - 10g (2g) 9 Dimethyl sulfoxide 10 - 100g (6Og)

Ethyl alcohol up to 100ml (4Oml)

The drug is prepared as follows. 2 g of the active substance miconazole nitrate is weighed and poured into a 100 ml volumetric flask. Add 100 ml of dimethylsulfoxide and mix thoroughly. Ethyl alcohol is added to the resulting solution up to the mark of 100 ml, mixed thoroughly.

The ratio of components in the claimed medicinal product, within the specified limits, contributes to a complex surface and deep local and partially resorptive effect on pathogenic fungi and concomitant infection in the underlying layers of the skin and other tissues. At the same time, an antimycotic, antimicrobial, analgesic and anti-inflammatory effect on the affected tissues is revealed, and a high level of therapeutic effect is ensured. t The advantages of the properties of the proposed medicinal combination are given below.

Unlike the existing domestic drug Miconazole-Darnytsia (Darnytsia, Ukraine) and imported "Mycospor" and "Nitrofungin", the medicine called "Composition" has a number of advantages that were discovered in the process of studying its pharmacological properties. The advantages of the proposed composition, in comparison with the prototype: 1. Technologically simple and cheap economic preparation of the dosage form; 2. Does not cause contamination of the treated surface;

C. Easy application at any age, which does not require special medical education and can be used by patients for self-treatment; 4. Easy dosage for any area of damage; 29 5. The possibility of wetting to achieve penetration of the drug due to the capillary effect to any "affected areas of the skin, mucous membranes, nails, hair, etc.; 6. The possibility of inconspicuous (aesthetic) long-term treatment of open affected areas, especially hair, nails, skin, inguinal areas; 7. The possibility of repeated application of a large amount in order to achieve a local (local) increase in the concentration of active active substances, thanks to the evaporation (drying) of solvents and the increase in the local concentration of the active active component; 8. A wide range of therapeutic effect: along with antimycotic - antimicrobial, anti-inflammatory, - local anesthetic, analgesic; Gee! 9. The finished medicinal form costs 3 - 5 times cheaper compared to foreign analogues, which gives a high positive pharmacoeconomic effect; at 10. Thanks to the complex action, there is almost a complete absence of the appearance of resistant forms of fungi.

The method of application is as follows: the liquid is applied to the affected areas in drops with a small reserve for its gradual penetration and absorption into adjacent areas and hard-to-reach layers, folds, nail beds, subcutaneous tissues. -at

The antimycotic and anti-inflammatory effect develops after 30-40 minutes. The duration of action of the medicinal product with one application is at least 5-7 hours. If necessary, the procedure is repeated 2-3 or more times a day. It is especially important to apply the liquid at night, while you can cover the affected areas with polyethylene film for a longer retention of miconazole nitrate, dimethyl sulfoxide and ethyl alcohol on the infected areas. The duration of the treatment course is determined depending on the positive therapeutic effect and the course of the disease.

We came to the use of the composition, which is claimed as a medicinal product, as a result of studying its specific pharmacological properties, such as antimycotic, antimicrobial, anti-inflammatory, anesthetic and antiseptic in comparison with the prototype and similar medicinal products.

The results of some of the conducted experiments are given below. In the future, the proposed complex co 50 composition will be indicated as "Composition", the comparison drug - Miconazole-Darnytsia (Darnytsia, Ukraine), will be indicated as "Miconazole".

Specific pharmacological activity of the composition in "ip migo" experiments - Fungstatic action against the causative agent of candidomycosis - Sapaida a!risapv.

Method. The first series of studies was carried out in relation to Sapaid aiYrisapz - the causative agent of superficial candidiasis. The material isolated from the patient was used as a fungus culture, which increases the value of research, since the culture used was to some extent under the influence of adverse factors of the external environment and the influence of already widespread antifungal agents. Identification of the causative agent was carried out by direct microscopy, by the nature of the growth of the causative agent on selective media, by the nature of carbohydrate fermentation, and serologically, by performing an immunoenzymatic analysis. bo The isolated pure culture of S. aiIrisapz was sown on Sabouraud's agar medium with the addition of levomycetin (1 µg/ml) and cycloheximide (O0.5 µg/ml) to prevent bacterial and mold contamination (8).

A solution of "Composition" at a concentration of 0.01 was applied to the surface of the seeded agar in the wells; 0.1; 1 and 10 mg/l, and then cultured at a temperature of 277C and 17C for 48 to 72 hours. The results were taken into account according to the indicator of the growth delay of microorganisms in the diffusion zone of the drug in agar. The diameter of the growth retardation zone was measured with an accuracy of 0.1 mm. The results of the study are presented in Table 1.

y 0 dmoo composition Mkonayol» nin ns NO o NO nn nn nn BUT o 117083 nn t nn NOT WITH ЕЯ вв 11713633 лю 01171113, 15 As can be seen from the presented data, the most pronounced fungistatic effect of the "Composition" was manifested at its concentration of 20 mg/l. A further increase in the concentration of the "Composition" slightly enhanced its antimycotic effect, which may be related to the limited diffusion of the drug into the agar.

Cultivation of S. aiYrisapz in Sabouro's liquid medium (about T00CUU/ml) with the addition of "Composition" in increasing concentrations showed (Table 2) that the fungicidal effect of the studied preparation when visually considering the results (turbidity of the culture medium) is observed when its concentration is increased to 2O0mg / l. At increasing concentrations of "Composition" of more than 20 mg/l, its fungicidal effect is beyond doubt. The results are shown in Table 2. : : : : : : « o » sch - - Fungstatic effect of "Composition" on pathogens of trichophytosis (Tgisporpuiyup tepiadhorpuyez). with

This series of experiments was conducted to study the effect of the means in relation to Ttgisporpuip and tepiadhorpuyez isolated from pustular rashes on the inner surface of the patient's thighs. The causative agent is identified microscopically and morphologically.

Cultivation of the fungus was carried out on Sabouraud's medium with the addition of antibiotics. The "composition" was applied in concentrations (in terms of miconazole) of 1; 2; 4; 8; 16; 2 mg/l. Cultivation was carried out in a thermostat at a temperature of 2570 °C for 7 to 10 days. The activity of the drug was concluded by delaying the growth of the mycelium in the diffusion zone of the drug (Table 3). with

Concentration of "Composition", mg/l (according to miconazole) sp? nn shi shi shi shi de) t - nn shshshshishshEy vv zo tu s nn tires ше в 1ю11ов

From the above results, it can be seen that the drugs "Composition" and "Miconazole" in concentrations from 2 to 59 4 mg/l showed a pronounced fungistatic effect in relation to T. mepiadhorpuyez. Further increase in concentrations did not significantly increase the zone of growth retardation under the influence of "Miconazole", which may also be related to the limitation of diffusion of the drug into agar and fungal cells. At the same time, under the influence of "Composition", the zone of growth inhibition continued to expand with increasing concentration, which indicates a better penetration of the "Composition" drug into agar and fungal cells compared to the "Miconazole" drug. because the results of the conducted experiments show that both investigated medicinal products - our proposed version of the new original composition "Composition" and the reference drug Miconazole-Darnytsia (Darnytsia,

Ukraine) have pronounced antifungal properties. However, a comparative analysis of the results of experiments conducted to study specific antimycotic activity shows that the zones of inhibition of the growth of infectious agents are significantly larger for the drug with the proposed composition when using the "Composition" than the reference or comparison drug - Miconazole-Darnytsia (Darnytsia, Ukraine). The proposed drug "Composition" has the following differences: a) a higher degree of penetration of the "Composition" into the adjacent areas of agar and a wider diameter of the zone of influence of the "Composition" on the studied species of fungi; b) more active penetration of the drug "Composition" into the cells of fungi and its bactericidal effect than in the comparison drug "Miconazole".

The mechanism of these differences is determined and is the result of the inclusion in the "Composition" of dimethyl sulfoxide and ethyl alcohol, which by themselves penetrate well through biological membranes, and when used together, they can act as a kind of transport system or promoter for the 7/0 MAIN antifungal compound "Composition " - miconazole. Thus: - the proposed composition significantly exceeded the fungistatic properties of the comparison drug Miconazole-Darnytsia (Darnytsia, Ukraine); - The composition showed higher fungicidal activity compared to the prototype drug

Miconazole-Darnytsia (Darnytsia, Ukraine); - the zone of inhibition of growth in fungal cultures turned out to be significantly larger in area when using the proposed composition than with the comparison drug Miconazole-Darnytsia (Darnytsia, Ukraine); - the composition had a higher anti-inflammatory activity than that found in the comparison drug

Miconazole-Darnytsia (Darnytsia, Ukraine); - the composition had a higher antibacterial activity in relation to the most widespread and concomitant mycosis strains of coccal flora than the comparison drug Miconazole-Darnytsia (Darnytsia, Ukraine).

References: 1. Mycoses in Europe. Report on WHO meetings. -- Hamburg, 1993 2. Mamchur V.Y., Fedotov V.P., Mamchur L.A., Dudyun AD. Ztiotropic pharmacotherapy of mycoses (Antifungal agents). Dnipropetrovsk, 2000. -- 163 p. 3. Beloborodova N.V., Bohdanov M.B., Chernenkaya T.V. Algorithm! antibiotic therapy. -- M., 1999, -- 144 p. 4. Feyer Z., Olakh D., Satmary Sh. Medical mycology and fungal diseases. Publishing House of the Academy of Sciences of Hungary, " 1966. 5. Stepanova Zh.V. Fungal diseases. -- M.: KRON-PRESS, 1996. 176 p. 6. Smirnov V.V., Yarosh O.K. Clinical pharmacology of modern antifungal agents. J. Herald of pharmacology of health and pharmacy. 2001, Mo5 - 6, pp. 15 - 20. 7. Belousov Yu.B., Moiseev V.S., Lepakhin V.K. Clinical pharmacology and pharmacotherapy (Manual for doctors). M.: "Universum Publishing", 1997. -- 530 p. "- 8. Medical microbiology // Ed. YOU. Pokrovsky, O.K. Pozdeeva. -- ""ZOTAR" Medicine, M,., 1998. -- 1184 p. p. 9. Mashkovsky M.D. Medicines. -- M.: Medicine, 1997, Vol. 1 - 2. 10. Compendium 1999 /2000 -- medicinal products / Edited by V.N. Kovalenko, A.P. Viktorova -- K.:

MORION, 1999. -- 1200 p.

Claims (1)

The formula of the invention h - s Means for the prevention and treatment of fungal lesions contains the antimycotic substance miconazole, which differs in that it additionally contains dimethyl sulfoxide (dimexide) and ethyl alcohol as components with the following ratio of components: ml 35 Miconazole 0.5-10 g Dimethylsulfoxide (dimexide) 110-100 g of ethyl alcohol up to 100 ml. - ka 20 Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2002, M 12, 15.12.2002. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. R 60 b5