RU2291692C2 - Anti-fungal preparation - Google Patents

Abstract

FIELD: medicine, dermatology, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an anti-fungal agent. Anti-fungal preparation comprises undecylenic acid and olive oil, clove carbon dioxide extract refined product prepared by distillation of clove carbon dioxide extract under vacuum under definite conditions wherein components are taken in the definite ratio. Proposed preparation promotes to effective treatment of cutaneous fungal diseases.

EFFECT: valuable medicinal properties of preparation.

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Description

The invention relates to the field of medicine and veterinary medicine, in particular to the field of chemotherapy of infectious diseases of humans and animals, and can be used for the preparation of highly active forms of antimicrobial preparations, in particular antifungal, intended for external use.

Currently, various antimycotic drugs are used in the treatment of fungal diseases for external use. For example, mycoseptin ointment is known (MD Mashkovsky. A manual for doctors. Medicines. M., part II, p. 434, 1993), containing 5 % undecylenic acid, 20% zinc salt of undecylenic acid and ointment base up to 100%. The ointment is rubbed into the skin or applied to a bandage and bandages are applied to the affected areas. The course of treatment of fungal skin diseases is 2-6 weeks.

The disadvantage of mycoseptin is that it has toxicity and requires long-term use (up to 6 weeks).

Closest to the claimed invention is an antifungal drug containing undecylenic acid and a fat base, while it additionally contains a solvent in the form of refined fennel oil, and olive oil as a fat base, in the following ratios of components, wt.%: Undecylenic acid - 2 -10, refined fennel oil -2-10, olive oil - the rest. The composition contains fennel oil, refined by vacuum distillation at 3-10 mm Hg. in the temperature range 135-145 ° C (patent RU No. 2214239, class A 61 K 31/16, 35/78, publ. 20.10.03, bull. No. 29).

A disadvantage of the known antifungal drug is that it does not have a wide enough spectrum of action, in particular with respect to concomitant microflora. This is expressed in the insufficient effectiveness of the treatment: the duration of the treatment and its results, as well as in the possibility of complications from concomitant microflora (for example, from Escherichia coli or Pseudomonas aeruginosa).

The objective of the invention is to remedy these disadvantages and increase efficiency, expand the spectrum of action and reduce the duration of treatment.

The problem is solved due to the fact that the antifungal drug containing undecylenic acid and olive oil additionally contains a refined clove carbon dioxide extract product obtained by vacuum distillation of clove carbon dioxide extract at a pressure of 3 to 10 mm Hg. in the temperature range from 80 to 130 ° C with the following ratio of components, wt.%: undecylenic acid - 5-10, the refined product of carbon dioxide extract of cloves - 5-10, olive oil - the rest.

The essence of the invention lies in the fact that the antimycotic effect of the basis of the drug, undecylenic acid, is supplemented by the antimicrobial effect of the solvent, the refined product of clove carbon dioxide extract (UEG). At the same time, the drug increases the antimycotic and antistaphylococcal effect, and drug treatment becomes more effective.

The process of extraction of clove buds is as follows. The crushed raw material is loaded into the extractor, hermetically closed the hatch, filled with solvent vapor to a pressure of 60-65 atmospheres, corresponding to the pressure of saturated vapors of carbon dioxide at 20-25 ° C. Then, for 45-50 minutes, liquefied carbon dioxide is pumped through the feed. The weight ratio of solvent to raw material is taken in the range from 1: 5 to 1: 8. The resulting extract is an anhydrous, oily, clear, reddish-brown liquid.

The refined product of vacuum distillation of clove carbon dioxide extract (UEG) was obtained as follows. Fractionated fractionation of clove carbon dioxide extract (obtained from spicy clove buds) was carried out at a pressure of about 5 mm Hg. in a stream of nitrogen with selection of fractions with a boiling point from a minimum (about 80 ° C) to 130 ° C. These fractions of clove carbon dioxide extract, as well as bottoms, were tested for antimycotic activity by the well method. A culture of mushrooms of the genus Trichophyton was seeded on Saburo's medium in Petri dishes, wells were made in the medium, 0.2 ml of each fraction of clove carbon dioxide extract was added to each of them, still bottoms and, as a control, the initial clove carbon dioxide extract. The experimental results are shown in table 1.

Table 1
Antimycotic activity of clove carbon dioxide extract fractions Fractions with t boiling, ° С 80-100 101-110 111-115 116-125 126-130 131-160 UEG, starting material (control) The diameter of the zone of growth inhibition, mm 80 70 75 80 70 thirty 35

Crops were incubated in an incubator at 29 ° C for 5 days, after which the diameter of the growth inhibition zone was measured. As can be seen from table 1, UEG fractions with a sublimation temperature of up to 100 ° C, 101-110 ° C, 111-115 ° C, 116-125 ° C, 126-130 ° C have a pronounced antimycotic activity. Their mixture (in order to increase the yield of the refined product) was selected as adjuvant of water-insoluble antimycotic drugs, in particular undecylenic acid. The oles of these fractions, tested by the same methods, gave a growth retardation diameter of 75 mm and will be further considered a refined product. Table 2 below gives a comparative assessment of the degree of antibacterial and antifungal activity of the UEG vacuum distillation product according to the results of titration of the minimum static doses in μg / ml on solid nutrient media (simple meat-peptone agar was used for titration of bacteriostatic doses, and Saburo agar was used for titration of fungistatic doses) Comparison with the refined product of clove carbon dioxide extract (UEG).

table 2 Comparative antimicrobial activity of refined and initial UEG Nature of action Test microbe The minimum static dose, mcg / ml Refined UEG Original UEG Antibacterial activity Staphylococcus aureus 250 500 E. coli 500 1000 Pseudomonas aeruginosa 500 1000 Antifungal activity against dermatophytes Trichophyton red fifty one hundred Trichophyton interdigital fifty one hundred Trichophyton gypsum fifty one hundred Microspore fluffy fifty one hundred Antifungal candidiasis activity Candida Albicans 350 500

As can be seen from table 2, the refined product of vacuum distillation of UEG has twice as much antimicrobial activity, including against pyogenic bacteria, which often complicates fungal diseases than the original product.

When creating the finished dosage form, undecylenic acid was taken in a concentration of 5% - this is the minimum concentration used, for example, in such an official dosage form based on undecylenic acid, like mycoseptin (in zincundane - 10%, in undecine - 8%). To determine the optimal concentration of the refined UEG product, various amounts were added to 5% undecylenic acid and then olive oil was added to 100 ml so that dilutions were 1.25%, 2.5%, 5%, 7.5%, 10% , and as a control - a 5% solution of undecylenic acid in olive oil. The antifungal activity of these compositions was checked by the method of holes, as in the case of fungi of the genus Candida. The experimental results are shown in table 3.

Table 3 Anti-candida activity of refined UEG The concentration of the refined product of UEG in olive oil 0 1.25% 2.5% 5% 7.5% 10% The diameter of the zone of growth inhibition, mm thirty 40 fifty 70 75 80

As can be seen from table 3, the antifungal effect increased most strongly with increasing product concentration to 5%, after which the increase in antifungal activity slowed down. Therefore, the optimal amount of refined clove product in the proposed preparation is 5%. To identify the presence of synergism of undecylenic acid and refined clove product, the antimicrobial activity of the proposed preparation was compared with the prototype refined fennel product. The results of comparative tests are shown in table 4.

Table 4 Antimicrobial activity of refined products, μg / ml Test microbe Undecylenic Acid in Olive Oil Undecylenic acid in a 5% solution of refined fennel product in olive oil Undecylenic acid in a 5% solution of refined clove product in olive oil Staphylococcus aureus 500 one hundred fifty Trichophyton red fifty 10 5 Trichophyton interdigital fifty 10 5 Trichophyton gypsum fifty 10 5 Microspore fluffy twenty 10 5 Candida Albicans 500 200 one hundred E. coli more than 1000 1000 500 Pseudomonas aeruginosa more than 1000 1000 500 Note: the maximum tested concentration of 1000 μg / ml

As can be seen from table 4, the combination of undecylenic acid with a refined clove product has a pronounced synergism. It is important to note that the refined clove product not only increases the antifungal activity of undecylenic acid and its antistaphylococcal activity, but also expands the spectrum of action in relation to the concomitant microflora.

The final confirmation of the adjuvant properties of the refined clove product showed a comparative experimental chemotherapeutic test of dosage forms of undecylenic acid (a mixture of one part of a 50% solution of undecylenic acid in one case in a refined clove product, in another case with a refined fennel product, with nine parts of olive oil ) The test procedure was as follows: in three groups of guinea pigs, each animal was plucked out in the caudal region of the back in a 4 × 4 cm area, after which a dense standard suspension of a virulent laboratory strain of the fungus, gypsum trichophyton, was applied to the exposed area. One group of thus infected animals, which served as a control, was then left without any additional impact on the entire observation period (the final term for recording the results was 10 days from the moment of infection).

The test results were as follows. In the first control group (untreated), by the tenth day from the moment of infection, all signs of experimental mycosis (peeling, hyperemia, infiltration, crust formation) developed. In the second group of pigs treated with a preparation containing the refined product of fennel oil, by the tenth day, only five animals had peeling and three had peeling with mild hyperemia. In the third group of pigs treated with a preparation containing the refined product of clove carbon dioxide extract, three animals had smooth skin with no signs of mycosis by the 8th day. Two pigs have smooth skin without signs of mycosis - by the 10th day, three pigs - peeling, but without hyperemia by the tenth day. In no case of the use of both the claimed dosage form and the preparation containing fennel, were there any signs of skin-irritating effect.

Thus, an antimycotic drug containing a refined product of clove carbon dioxide extract allowed to reduce the treatment time for patients with fungal skin diseases. In addition, the proposed drug has a wider spectrum of action, in particular in relation to concomitant microflora and reduces the risk of complications.

Claims (1)

An antifungal preparation containing undecylenic acid and olive oil, characterized in that it further comprises a refined clove carbon dioxide extract product obtained by vacuum distillation of clove carbon dioxide extract at a pressure of from 3 to 10 mm Hg. in the temperature range from 80 to 130 ° C with the following ratios of components in the preparation, wt.%: Undecylenic acid 5-10 Refined product clove carbon dioxide extract 5-10 Olive oil Rest