The tool miconazole for the treatment of skin diseases

 

(57) Abstract:

The invention relates to medicine, in particular to pharmacology concerns the creation of tools for the treatment of skin diseases. The tool contains miconazole nitrate, proxanol is chosen-268, propylene glycol, polyethylene oxide-400, emulsifier 1-St kind and emulsifier of the 2nd kind on certain relationships. For the treatment of skin diseases expands the range and increases the levels of specific activity while reducing or eliminating side effects. 2 C.p. f-crystals.

The invention relates to chemical-pharmaceutical industry, in particular to the creation and production of tools for the treatment of skin diseases.

Known drug "Nizoral", containing the active ingredient ketoconazole (imidazoles) and excipients. The tool is used for treatment of fungal infections of the feet with minimal nail lesions. Efficacy of nizoral increased by combining it with a keratolytic agents (1).

Known drug "Nystatin" (an antibiotic) used in the surface forms of candidiasis, lesions of the mucous membranes and skin. The local application of ointment nystatin clinical symptoms is zabolevaniya (2).

Known drug "Clotrimazole", containing the active substance canesten and excipients. The tool is used externally in the form of creams, solutions, vaginal tablets with skin lesions and mucous membranes caused by yeast-like fungi of the genus Candida. However, dermatophytosis this drug is not effective (3).

Known drug "Daktarin" that contains the active ingredient miconazole nitrate and excipients. Means "Daktarin" in the form of a cream applied to fungal infections of the skin and nails, in the case of bacterial superinfection with mycosis (4).

Known drug "Decoder", containing as active ingredients miconazole nitrate and flupredniden-21-acetate as an auxiliary - triglycerides, Jean, propylene glycol, white petrolatum, purified water. The preparation is applied in the form of cream in the treatment of eczema, dermatitis, mycotic superinfection (5).

Known drug "Cnidocil", containing as active ingredients miconazole nitrate and benzoyl peroxide, as an auxiliary - cetyl alcohol, propylene glycol, stearyl alcohol, sodium dodecyl sulphate, grey wax, Estenne means "Monistat-derm", containing as the active ingredients miconazole nitrate, as an auxiliary - peroxy-7-stearate, pellicole-5-oleate, mineral mazlo, benzoic acid, bottled hydroxyanisol, purified water. The drug has a fungicidal activity and is used in the form of cream in the treatment of dermatomycoses (7).

Closest to the claimed is a composition of the medicinal product "Mikozolon" (Hungary Gedeon Richter), containing miconazole nitrate and ointment preconcentration based on the emulsion of the first kind (type of oil/water). The preparation is applied in the form of ointment in the treatment of fungal infections of the skin and nails, accompanied by severe inflammation and itching, as well as in the treatment of fungal infections, combined with superinfection caused by gram-positive bacteria (8).

The disadvantages of the prototype and analogues should be attributed;

- not wide enough range of actions, resulting in impact only on certain types of mushrooms;

- lack of activity or lack of it level against bacteria that when complicated by pyoderma mycotic process forces them to use an additional external application of antibacterial agents, including corticosteroids;
what about the action;

- the presence of negative side effects with prolonged use, and in the presence of corticosteroids increase in the number of contraindications.

The basis of the invention the goal is to create tools for the treatment of skin diseases by such qualitative and quantitative selection of components, which would provide a comprehensive exposure of the drug to the affected tissue, which results in a wide range and high level of specific activity with simultaneous reduction and avoidance of side effects.

The problem is solved in that the means for the treatment of diseases of the skin, containing miconazole nitrate, solvents and emulsifiers, in accordance with the invention further comprises proxanol is chosen-268 mol. m 9000-13000, as solvents used propylene glycol and polyethylene oxide-400, and as emulsifying agents - emulsifiers of the 1st and 2nd kind in the following ratio, wt.%:

Miconazole nitrate - 0,5-2,5

Proxanol is chosen-268 mol.m. 9000-13000 (hereinafter proxanol is chosen-268) - 10,0-20,0

Propylene glycol - 80,0-4,5

The polyethylene oxide-400 - 4,5-68,0

Emulsifier 1-St kind - 0,3-3,0

The emulsifier of the 2nd kind - 4,7-2,0

moreover, as the emulsion is sodium laurylsulfate, and as an emulsifier 2 kind of use alcohols of synthetic primary higher fatty fractions of C16-C20or alcohols of synthetic primary higher fatty fractions of C16-C21or cetosteatil alcohol.

The technical result achieved by carrying out the invention, is expressed in the improvement and expansion of the level of specific activity while reducing or eliminating side effects.

Cited specific examples of carrying out the invention.

Example 1. Powder miconazole nitrate crushed in propylene glycol to obtain a suspension. Then proxanol is chosen-268, polyethylene oxide-400, the preparation of OS-20 (which is ethoxylated primary fatty alcohol with the number of carbon atoms of 16 to 21), alcohols of synthetic primary higher fatty fractions of C16-C20mixed and heated to melt the components. The resulting mixture was cooled to 35-40oC, after which it enter suspension of miconazole nitrate with stirring until creamy, which is cooled to 25oC and packaged.

The inventive solution has the following ratio of components, wt.%:

Miconazole nitrate - 2,0

Proxanol is chosen-268 - 16,016-C20- 4,0

Example 2. Powder miconazole nitrate crushed in propylene glycol to obtain a suspension. Then proxanol is chosen-268, polyethylene oxide-400, tween-80 and cetosteatil alcohol are mixed and heated to melt the components. The resulting mixture was cooled to 35-40oC, after which it enter suspension of miconazole nitrate with stirring until creamy, which is cooled to 25oC and packaged.

The inventive solution has the following ratio of components, wt.%:

Miconazole nitrate - 0,5

Proxanol is chosen-268 - 10,0

Propylene glycol - 80,0

The polyethylene oxide-400 - 4,5

Tween-80 - 4,7

Cetostearyl alcohol - 0,3

Example 3. Powder miconazole nitrate crushed in propylene glycol to obtain a suspension. Then proxanol is chosen-268, polyethylene oxide-400, sodium laurylsulfate and the alcohols of synthetic primary higher fatty fractions of C16-C21mixed and heated to melt the components. The resulting mixture was cooled to 35-40oC, after which it enter suspension of miconazole nitrate with stirring until creamy, which is cooled to 25oC and packaged.

The inventive solution has the following ratio of the components is d-400 - 68,0

Sodium dodecyl sulfate - 3,0

Alcohols of synthetic primary higher fatty fractions of C12-C21- 2,0

Qualitative and quantitative composition the proposed drug is completely solves the invention the task of creating a highly effective means for treatment of skin diseases, including ringworm.

The main active ingredient miconazole nitrate is a derivative of imidazoles, which has received in recent years widespread as specific antimycotic funds, directly affecting fungal cell, its structure and metabolism. Miconazole nitrate has fungicidal activity against dermatophytes, yeasts and other pathogenic fungi, and also against some gram-positive microorganisms. Its mechanism of action is related to inhibition of ergosterol biosynthesis and modification of the lipid composition of membranes. Inherent miconazole property is poorly absorbed into the systemic circulation, or to not be absorbed making it one of the most promising drugs for the local treatment of fungal infection, because it virtually eliminates the side effects characteristic made arealnykh infections creates significant challenges for diagnosis and therapy, confronts the necessity of using additional antibacterial drugs, or create a combination medication that combines antifungal and antibacterial activity (for example, the combination of miconazole nitrate and musipedia-corticosteroid in the prototype - ointment "Mikozolon"). It should be noted that the combination of miconazole with corticosteroid with the aim of inflammation for ringworm is not the best solution to this issue because of the possibility of acute mycotic infections and the emergence corticosteroidsleukotriene adverse reactions in the skin (striae, atrophy, Acme). In addition, the presence of corticosteroids increases the number of contra-indications for use: tuberculosis of the skin, herpes, chickenpox, smallpox.

Therefore, the authors proposed drug went another way: the question of the effectiveness of the drug was chosen not only due to the choice of antifungal substance, but largely at the expense of rational choice ointment bases. Analysis of the range of foreign counterparts has led to the conclusion that they are mostly made on the emulsion basics type of oil/water: dispersion medium is predominant is gnome action of miconazole.

In the process of research and experimentation in the creation of the proposed drug, it was found that of miconazole nitrate is highly soluble in propylene glycol and polyethylene oxide-400. It is the declared value of the quantitative content of these components provide the necessary level of solubility of miconazole nitrate, and hence the level of its specific activity.

Included in the proposed drug oxides block copolymers of propylene and ethylene - proxanol is chosen-268 - ensures the formation of a stable structure of the proposed drug in the form of cream, and adjustable level hyperosmolar activity.

The claimed value of the combination of the emulsifiers of the 1st kind 2nd kind provide an effective and prolonged release of active ingredient is miconazole nitrate, and allow to absorb water more evenly over time, not overdrying healthy tissue. The ratio between the emulsifiers of the 1st kind 2nd kind, and their concentrations are selected in such a way that balanced high, but prolonged osmotic activity with the magnitude of the structural viscosity of the cream is needed for normal extrusion of tubes.

Violation of the qualities of the practical activity, and breach of the structural-mechanical and physico-chemical properties of the dosage form.

The proposed tool has been tested in laboratory and industrial conditions. The results are shown in the table.

As can be seen from the data presented in the table, the diameter of the zones of growth inhibition of microorganisms depends on the concentration of miconazole nitrate until its content of 0.5 to 2.5%. A further increase in its concentration is impractical because does not increase zones delays the growth of microbes (fungi and bacteria). On the contrary, in some cases there is a tendency to reduce them, which is probably due to the crystallization of miconazole, and thus reducing its concentration in a cream base.

Hydrophilic basis of the proposed drug enhances the antifungal and antibacterial effect miconazole nitrate in comparison with hydrophobic paraffin based emulsion and the basis of the first kind, which prepared the prototype - ointment "Mikozolon". In addition, the Foundation provides hyperosmolar activity, which is largely anti-inammatory and antiexudative action. This allows you to use the drug in the acute stage vospominanii skin - cream miconazole - by choosing the type and composition of the base has a wide range of highly effective antifungal action, antibacterial and antiexudative activity, if it is applied there are no side effects in the form of irritant and allergic effects on the skin, and absorption into the systemic circulation.

Literature

1. Potekaev N. C. , Sosnina E. A. Nizoral. Prospects of application and side effects, " Vestn. dermatology and venereology. - 1987, N 8, 20 C.-25.

2. Candidiasis of skin and mucous membranes/A. A. Antoniew, P. A. Vulvar, L. K. Glazkova and others - M.: Medicine, 1985, 156 S.

3. Silin C. A., Leshchenko C. M., Cheglakov N. D. Synthetic antifungal agents, " Vestn. dermatology and venereology. - 1988, N 10, S. 26-32.

4. Drugs: Book 2/Ed. by C. N. Kovalenko. - K.: "Morion Ltd., 1996, 512 S.

5. Rote Liste. Verzeichis pharmazeutisgher Speziapraparate. Ed. Cantor, 1994, N 31143.

6. Rote Liste. Verzeichis pharmazeutisgher Speziapraparate. Ed. Cantor, 1994, No. 31243.

7. Physicians Desk Reference. N. V., 1994, S. 1658.

8. Mikozolon - Hungarian antifungal agent for external use/N. D. Cheglakov, C. M. Rukavishnikov, V. M. Leshchenko, etc. In collection: Hungarian drugs used in dermatology. ): The and and emulsifiers, characterized in that it further comprises proxanol is chosen-268 mol. m 9000 - 13000, as solvents used propylene glycol and polyethylene oxide-400, and as emulsifying agents - emulsifiers of the 1st and 2nd kind in the following ratio, wt.%:

Miconazole nitrate - 0,5 - 2,5

Proxanol is chosen-268 mol.m. 9000 - 13000 - 10,0 - 20,0

Propylene glycol - 4,5 - 80,0

The polyethylene oxide-400 - 4,5 - 68,0

Emulsifier 1-St kind - 0,3 - 3,0

The emulsifier of the 2nd kind - 2,0 - 4,7

2. Means under item 1, characterized in that as an emulsifier 1-St kind used ethoxylated primary fatty alcohols with carbon atoms of 16 to 21, or tween-80, or sodium laurylsulfate.

3. Means under item 1, characterized in that the emulsifier of the 2nd kind use alcohols of synthetic primary higher fatty fractions of C16- C20or alcohols of synthetic primary higher fatty fractions of C16- C21or cetosteatil alcohol.

 

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SUBSTANCE: invention proposes the composition comprising xenon as NMDA-antagonist and alpha-2-adrenergic agonist used for treatment of tetanus or narcotics (alcohol) withdrawal syndrome, states with chronic pain syndrome. Also, invention relates to the anesthetic composition comprising xenon and alpha-2-adrenergic agonist and to a method for anesthesia. The synergistic interaction of xenon as NMDA-antagonist and alpha-2-adrenergic agonist provides reducing the dose and to maintain the prolonged effectiveness by prevention for arising the drug habitation to the claimed preparation.

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9 cl, 6 dwg, 6 ex

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