Combined treatment for skin diseases

 

The invention relates to the field of medicine and relates to a pharmaceutical for the treatment of skin diseases. The tool includes active principle is a combination of betamethasone dipropionate, clotrimazole and gentamicin sulfate, a basis consisting of a lipophilic component and hydrophilic component, emulsifier, Trilon B and, optionally, a buffering agent. New combined tool is characterized by multiple therapeutic effects: anti-inflammatory, antifungal and antibacterial, does not reduce the antibacterial effect with continued use and inhibits the development of microorganisms resistance to gentamicin sulfate. 6 C.p. f-crystals, 1 table.

The invention relates to the field of medicine and concerns of the combined drugs, which can be used to treat various forms of bacterial infected eczema and ringworm, candidiasis and multi-colored lichen, especially in the localization of lesions in the groin area and large skin folds.

Treatment of dermatoses of special importance in connection with the increase in their frequency, including among children, as well as due to increased heavy f which determines the relevance and socio-economic significance of the problem.

Significant place in the treatment of chronic dermatoses belongs rationally selected external therapy. Among the wide range used for this purpose medicines play a special role preparations containing corticosteroids. Glucocorticoids influence the organism's complex multilateral influence, possess strong anti-inflammatory activity, which can't compete with other drugs, as well as hiposensibilic and immunosuppressive properties.

Betamethasone (9-fluoro-11,17,21 trihydroxy-16-methylpregna-1,4-diene-3,20-dione) is a fluorinated synthetic glucocorticoid - is one of the most effective drugs in this group [Mashkovsky M. D. Drugs, so 2, ed. 13-E. Kharkov: Torsing, 1997, S. 38]. Betamethasone has a pronounced anti-inflammatory and anti-allergic effect and is used in various modifications (betamethasone dipropionate, valerate, disodium phosphate, acetate), preferably of betamethasone dipropionate. Compositions containing as active ingredient betamethasone, are in the form of various dosage forms: tablets, injections, suspensions, creams is rapie can cause severe complications (Cushing's syndrome, diabetes, problems with gastrointestinal tract and other), and local drug application allows you to avoid these side effects. As a result, we offer a wide range of compositions with betamethasone for external use.

For example, in U.S. patent 4489070, 1984, provides information about the pharmaceutical compositions on the basis of betamethasone dipropionate with the commercial name "Diprosone", which further comprises a base consisting of a lipophilic component (mineral oil, petrolatum) and the hydrophilic component (propylene glycol and water), emulsifier (monocationic ether of polyethylene glycol, cetosteatil alcohol), a pH regulator (phosphoric acid), preservative (4-chloro-m-cresol), and the buffer agent (monobasic nutrifaster).

However, this composition, as well as other known compounds with betamethasone (U.S. patent 4070462, 1978, 4370322, 1983, 4489070, 1984, 4489071, 1984), may not resolve the problem of activation of viral, bacterial and fungal infections, which is one of the most common side effects cutaneous use of glucocorticoids leads to the emergence and aggravation of complications during treatment. The development of these side effects is because glucocard the cells. It is the inhibition of proliferation of keratinocytes leads to thinning of the epidermis, delayed healing of wound surfaces, increases the susceptibility of the skin to infection.

One of the ways to reduce the likelihood of side effects, as well as complement and enhance the effects of betamethasone is the creation of medicines, which contain a combination of glucocorticoid other active ingredients.

In U.S. patent 5110809, 1992, reported a combined preparation "Lotrisone" containing betamethasone dipropionate to 0.05 wt.%, clotrimazole - 1 wt.%, auxiliary ingredients - the rest.

In U.S. patent 4298604, 1981, describes a pharmaceutical composition comprising about 0.001-of 0.33 wt.% betamethasone dipropionate, 0.01 to 10 wt.% clotrimazole and a pharmaceutically acceptable carrier. For example, the drug contains betamethasone dipropionate, clotrimazole, auxiliary ingredients and emulsifier (ether glycol, cetosteatil alcohol), a pH regulator (phosphoric acid), preservative (benzyl alcohol), a buffering agent (monohydrate nonoonono of nativespace) and base, which consists of a lipophilic component (mineral oil, petrolatum) and the hydrophilic component (propylene glycol and water).

Known cocney bacterial infection.

The latter can be solved by additional introduction of the antibiotic. Thus, the literature describes the use for the treatment and prevention of secondary bacterial or fungal infections accompanying dermatoses tool that contains a combination of betamethasone dipropionate, clotrimazole and antibiotic gentamicin sulfate cream "Triderm" firm Schering-plough (Register of medicines of Russia 97/98. M: Remake, 1997).

However, information about specific excipients in the preparation are not available. It is also known that many organisms have developed resistance to antibiotics, which can significantly reduce therapeutic efficacy of the drug. Thus, it was determined that resistance to gentamicin sulfate Pseudomonas aeruginosa (Pseudomonas aeruginosa or Staphylococcus aureus (Staphylococcus aureus) doubles almost every 2-4 days, and on the 16th day is the reduction of the initial sensitivity to gentamicin sulfate in Pseudomonas aeruginosa almost 47 times, and the Staphylococcus aureus - 16 times.

The present invention is to create a medicinal product in the form of soft medicinal forms, which comprehensively affects the diseased tissue is real, and does not reduce the latter with continued use.

To solve this problem is proposed combination drug comprising as an active start to the combination of betamethasone dipropionate, clotrimazole and gentamicin sulfate, a basis consisting of a lipophilic component and hydrophilic component, the emulsifier and the target additive - Trilon B in the following ratio of ingredients, wt.%: Betamethasone dipropionate - 0,01-0,2 Clotrimazole - 0,2-5,0 Gentamicin sulfate 0,02-0,5 Trilon B - 0,05-2,0 Emulsifier - 3,0-15,0 Basis, consisting of a lipophilic component and hydrophilic component Up to 100 Technical result to be obtained by the implementation of the invention is expressed in a complex impact on the affected tissue of the claimed combined funds and received multiple therapeutic effect and simultaneously prevent the development of microorganisms resistance to gentamicin sulfate and, as a consequence, weakening antibacterial activity.

By the beginning of the proposed drug is a combination of betamethasone dipropionate drug substances antimicrobial activity of gentamicin sulfate and clotrim of the drug. Clotrimazole is active against yeasts and fungi and dermatophytes.

Studies of antimicrobial activity showed that the proposed drug has strong antibacterial and antifungal action.

Used in the famous soft medicinal forms with anti-inflammatory action (U.S. patent 4489070, 4298604) such additives target as surfactants, performs the function of the emulsifier, for example an ether glycol, or a hydrophilic component basis, for example propylene glycol, reduce the production of antibiotic resistance.

However, experimental verification showed that the inclusion of a new means of these auxiliary substances are not completely prevent the development of resistance to the antibiotic gentamicin sulfate. In addition, the increase in the concentration of these substances in order to reduce the resistance of microorganisms reduces the concentration of active ingredients.

Studies on cultures Rseudomcnas aeruginosa and Staphylococcus aureus, representing respectively the gram-negative and gram-positive bacteria, showed that the drug for the claimed composition completely prevents the production of Barata with long-term, the course of treatment.

Declare qualitative and quantitative ratio of the components found experimentally, is optimal and allows you to retrieve the specified technical result.

As the basis of the carrier of the pharmaceutical composition used lipophilic-hydrophilic base emulsion type. As the lipophilic component framework can be used hydrocarbons such as vaseline, paraffin, vaseline oil, derivatives of fatty acids, such as lanolin, beeswax, castor oil, also known as hydrophobic bases commonly used in pharmaceutical practice, such as silicones, or mixtures of the above ingredients, preferably petrolatum or liquid paraffin, or a mixture. It is preferable to use liquid paraffin and vaseline in a mass ratio of 1: (1.5 to 4), which allows to improve softening and moisturizing action of the drug in the local application.

Examples of the hydrophilic component bases include water, pharmaceutically acceptable mono-, Li - or polynuclear organic alcohols as ethanol, propylene glycol, dipropyleneglycol, butyleneglycol, glycerin, and macrogol, such as glycols with an average molecular metilsulfate or mixture of such compounds, preferably propylene glycol, and water. The optimal mass ratio of propylene glycol and water is 1:(3-8,5), respectively.

As the emulsifier can be used high molecular weight alcohols, their oxyalkylene derivatives, sodium salts of sulfonic ethers of these alcohols, the twins, spiny, zhirosahar or mixtures of these substances. Examples of emulsifiers are cetyl alcohol, stearic alcohol, or emulsifier 1 (mixture of primary higher fatty alcohols with a number of carbon atoms of 16 to 20 and sodium salts of sulfonic ethers of such alcohols) or emulsifier brand "Lanette" (a mixture of high molecular weight alcohols with the number of carbon atoms from 14 to 20, mainly cetyl and stearic, and, optionally, materialrelated, mainly nutriceuticals and netresearchserver), or emulsifying wax (corresponding to the requirements of the British Pharmacopoeia 1998).

The presence in the composition of complexing agents - trylon B (or disodium salt ethylenediaminetetraacetic acid) removes the necessity of introducing into the composition of the preservative, such as, for example, analogs (U.S. patent 4489070, 4298604), acting irritant to the skin and further enhances therapeutic (anti-inflammatory is predpochtitelnei number of trylon B is 0.1 to 1.0 wt.%.

Specific anti-inflammatory activity proposed composition was studied on a model of acute aseptic dextranomer inflammation of the foot rats, double skin applications (for 30 minutes and at the time of introduction phlogogenic agent) in sexually Mature rats male.

As evidenced by the experimental data, two-treatment-and-prophylactic skin application of study drug cause a marked statistically significant anti-inflammatory effect, which is manifested in the reduction of gain swelling of the foot compared to control untreated animals. The inhibiting effect of the new tools in the investigated dose after 1 h after injection phlogogenic agent is 32,0%, at the peak of the inflammatory response (after 3 h)-56,5%, increasing to 24 h to 89.3%. Anti-inflammatory effect of the cream "Triderm" respectively equal to 18.6%, 35,0% 63,3%. Thus, during the first three hours after induction of inflammation, the trend toward higher anti-inflammatory activity of the proposed drug, which for 24 h becomes statistically significant. The cumulative effect of the proposed drug, calculated as area under the curve "time-effect" is 149,1% compared with the data parasailing activity allow us to conclude that that developed the drug is the active anti-inflammatory agent.

The inventive tool may further include a buffering agent, preferably one-deputizing sodium phosphate (NaH2PO4), which together with Trilon B maintains optimal pH of the composition (in the range of 4.5-6.0). A suitable amount of the buffer agent is 0.01 to 1.0 wt.%.

The inventive tool can be obtained by the known methods used for the preparation of soft medicinal forms, such as the addition of a solution and/or suspension of the active ingredients in the hydrophilic component basis or part of it to the other ingredients and then mixing the final mixture until smooth.

Specific examples of carrying out the invention is presented below (see table).

Example 1. A mixture of 0.7 wt.% the trylon B, 0.3 wt.% sodium one-deputizing phosphate dihydrate, 10.0 wt.% vaseline oil, 15.0 wt.% vaseline medical and 10.0 wt.% emulsifier (cetosteatil alcohol and cetosteatil ether of polyethylene glycol in a weight ratio of 3:1) is heated to 65-75oC and mix until smooth, then alternately add pre preeaster rate 0.162 wt.% gentamicin sulfate with activity 590 IU/mg (0.1 wt.% in terms of waterless gentamicin base) and a suspension of 1.0 wt.% clotrimazole in the remainder of the propylene glycol, stirred at 50oWith until smooth, then cool. Get the cream is white, which meets the requirements of the pharmaceutical agent. pH of 5.0. The mass ratio of propylene glycol and water in the final composition of 1:3.

Examples 2, 3 perform similarly, with the difference that in example 2 as a lipophilic component, a mixture of paraffin oil and paraffin wax, an emulsifier is a mixture of primary higher fatty alcohols of fractions16-C21and sodium salts of sulfonic ethers of these acids and the ratio of propylene glycol and water is 1:8.5 and example 3 as a hydrophilic component using a mixture of glycerin, propylene glycol and water in a mass ratio of 1:5:23,7, as an emulsifier is a mixture of emulsifiers brands Lanette and OS-2, and the ratio of the component parts of the lipophilic component is a paraffin oil and vaseline is 1:4.

The obtained composition satisfy the requirements of the pharmaceutical agent. The results of the preparation of compounds presented in the table.

Claims

1. For the treatment of skin diseases, including active principle is a combination of betamethasone dipropionate, a clot is alligator and Trilon B in the following ratio of ingredients, wt.%:

Betamethasone dipropionate 0,01 - 0,2

Clotrimazole 0,2 - 5,0

Gentamicin sulfate 0,02 - 0,5

Trilon B 0,05 - 2,0

Emulsifier 3,0 - 15,0,

A basis consisting of lipophilic

component and a hydrophilic component To 100

2. Means under item 1, which comprises a lipophilic component, fundamentals of liquid paraffin and vaseline in a mass ratio of 1:(1.5 to 4), respectively.

3. Means under item 1, which contains as a hydrophilic component framework propylene glycol and water in a mass ratio of 1:(3-8,5), respectively.

4. A tool according to any one of paragraphs.1-3, which contains Trilon B in an amount of 0.1 to 1.0 wt.%.

5. A tool according to any one of paragraphs.1-4, which further comprises a buffering agent.

6. Means under item 5, which contains as a buffering agent sodium phosphoric acid one-deputizing.

7. A tool according to any one of paragraphs.1-6, which is made in the form of cream.

 

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