CA2705815A1 - Topical drugs for use in antifungal therapy - Google Patents

Abstract

The present invention relates to topical agents for antimycotic therapy, which contain at least one antimycotic active substance and at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives in a fixed combination.

Description

BHC 07 1 079-Foreign Countries 2007-11-08 Topical drugs for use in antifungal therapy The present invention relates to topical medicinal products with fixed combinations of active substances for antimycotic therapy of dermatologic diseases. The invention further relates to the use of the combinations of active substances according to the invention for the topical treatment of mycoses of the skin or mucosae.

Mycoses are infectious diseases caused by fungi, the pathogens being assignable to the group of the dermatophytes (e.g. Trichophyton spp., Microsporum spp., Epidermophyton spp.), the yeasts (e.g. Candida spp., Trichosporon spp., Cryptococcus neoformans) or the moulds (e.g. Aspergillus spp., Mucor spp., Penicillium spp.). The term dermatomycoses refers essentially to mycoses of the skin, its appendages (hair, nails) and mucosae. Frequently occurring symptoms are pruritus, burning pains, peeling of the skin, skin maceration, erythema, fissures, coatings on mucosae, nodules, papules, pustules, abscesses, hair loss and changes in pigmentation of the skin.

Numerous antimycotic active substances, in various dosage forms for topical application, are available for the topical treatment of dermatomycoses. The antimycotic active substances are essentially active substances from the substance classes of the azole derivatives (in particular triazoles and imidazoles), polyenes, thiocarbamates, allylamines, morpholine derivatives and hydroxypyridones.

The use of these known antimycotic agents is based on the fungistatic and/or fungicidal action of the antimycotic active substances that they contain, with which the aim is to remove the focus of infection.

It has, however, been found that the topical antimycotic products available in the prior art are often unsuitable for satisfactory attainment of the desired therapeutic outcome. The reasons for this are as follows:

In mycotic diseases of the skin or mucosae, inflammatory reactions often occur, leading to exacerbation of the symptoms. Moreover, as the disease progresses, cracks in the skin or even open wounds may develop, promoting secondary infections, e.g. bacterial infections.
However, the antimycotic products known in the prior art have inadequate anti-inflammatory (i.e. antiphlogistic) action, if any.

Some antimycotic active substances from the group of the azoles (e.g.
clotrimazole, bifonazole) are known to have a weak or even fairly strong antiphlogistic action in addition to their antimycotic action. As this "intrinsic" antiphlogistic action is, however, only present with certain antimycotic active substances from the azole group of active substances, and as the intrinsic antiphlogistic BHC 07 1 079-Foreign Countries action may be present to a varying extent, the therapeutic usability of this intrinsic action is only slight.

It must further be borne in mind that the areas of skin or mucosa affected by a mycosis as a rule already have tissue damage at the start of the antimycotic therapy. Therefore regeneration of the damaged tissue is of prime importance for successful healing. Generally, after the mycotic pathogens have been eradicated, it takes a period of some weeks for the skin structure damaged by the infection to be repaired by the process of natural regeneration. During this period the affected region of skin or mucosa is particularly vulnerable to other infectious agents (e.g. superinfections or secondary infections by fungi or bacteria).

The topical agents used in antimycotic therapy according to the prior art are not suitable for promoting skin regeneration and thus speeding up healing. Consequently, when using these known drugs there is a high risk of development of secondary infections.

Moreover, it is known that the topical use of antimycotic active substances may lead to undesirable side effects, e.g. pruritus, skin rash or erythema, having an unfavourable effect on healing and possibly necessitating changing the therapy to another active substance.

The problem to be solved by the present invention was therefore to provide medicinal products suitable for topical application for antimycotic therapy, which do not have the aforementioned disadvantages. In particular, the problem was to provide medicinal products of the aforesaid type, which are characterized by additional anti-inflammatory (antiphiogistic) action and/or by action that promotes regeneration of skin or mucosae.

Surprisingly, this problem could be solved according to the present invention by providing a topical agent, which contains at least one antimycotic active substance and additionally at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, in particular dexpanthenol, in a fixed combination. Topical application of the aforesaid fixed combination of active substances achieves not only an anti-infective action, but also antiphiogistic action and action that promotes skin regeneration. As a result, compared with known antimycotics, this provides more favourable and faster healing with reduced risk of development of secondary infection or superinfection.

Moreover, it was found, surprisingly, that by combining an active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, in particular dexpanthenol, with an antirnycotic active substance according to the present invention, the intrinsic antiphlogistic action of this antimycotic active substance can in consequence be intensified synergistically. As a BHC 07 1 079-Foreign Countries result - especially when using antimycotics that have an intrinsic anti-inflammatory action - there are exceptionally favourable effects on the inflammatory symptoms accompanying mycosis of the skin or mucosae, and ultimately faster and better healing. This applies in particular with reference to combinations of antimycotic active substances according to the invention, which contain one or more active substances from the group of azole derivatives.

The anti-inflammatory action and the aforementioned synergistic increase in anti-inflammatory action of the combinations of active substances and medicinal products according to the invention can be demonstrated in vitro and in vivo with known standard experimental models and methods (e.g. transendothelial leukocyte migration test or UV-erythema test). The aforementioned improvement in skin regeneration can also be demonstrated with known in-vivo test models.

Another advantage of the medicinal product according to the invention is that the development of side effects, which are caused by the topical use of antimycotic active substances, is suppressed or reduced. This is evidently attributable to the additional presence of the active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives.

As antimycotic active substances, for the purposes of the present invention, basically all pharmacological active substances that have fungistatic or fungicidal action against fungal diseases may be considered. In particular these are antimycotic active substances that are selected from the classes of active substances of the azole derivatives, in particular triazole and imidazole derivatives, and the allylamines, thiocarbamates, thiocarbanilates, substituted pyridones, polyene antibiotics, morpholines, hydroxypyridones and glucan synthesis inhibitors.

According to a preferred embodiment, a topical agent according to the invention contains at least one antimycotic active substance from the group of allylamines, preferably selected from the group comprising terbinafine and naftifine, in a fixed combination with at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, dexpanthenol being especially preferred. The aforementioned medicinal products may be considered in particular for the treatment of dermatophytoses of the skin and mucosae.

According to another preferred embodiment, a topical agent according to the invention contains at least one antimycotic active substance from the group of azole derivatives, in particular the imidazole derivatives and triazole derivatives, in a fixed combination with at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, dexpanthenol being especially preferred.

BHC 07 1 079-Foreign Countries The group of azole derivatives comprises in particular miconazole, miconazole nitrate, ketoconazole, fluconazole, itraconazole, bifonazole, clotrimazole, econazole, clomidazole, isoconazole, tiabendazole, tioconazole, ketoconazole, sulconazole, oxiconazole, fenticonazole, omoconazole, sertaconazole, flutrimazole, croconazole, voriconazole and posaconazole.

Azole derivatives are generally characterized by a wide spectrum of action and can be employed for skin or mucosal mycoses due to dermatophytes, yeasts and moulds.

According to another preferred embodiment, a topical agent according to the invention contains at least one antimycotic active substance from the group of thiocarbamates and thiocarbanilates, with tolnaftate and tolciclate being especially preferred.

According to another preferred embodiment, a topical agent according to the invention contains at least one antimycotic active substance from the group of morpholines, amorolfine being especially preferred.

According to another preferred embodiment, a topical agent according to the invention contains at least one antimycotic active substance from the group of glucan synthesis inhibitors (echinocandins), caspofungin being especially preferred.

According to another preferred embodiment, a topical agent according to the invention contains at least one antimycotic active substance from the group of polyene antibiotics, preferably from the group comprising nystatin, natamycin, amphotericin B, hachimycin and pecilocin. Others that are preferred are macrolide antibiotics with fungicidal or fungistatic action, e.g. mepartricin, and other antimycotic antibiotics of bacterial origin, e.g. pyrrolnitrin or griseofulvin; and inhibitors of DNA, RNA or protein synthesis, e.g. flucytosine.

According to another preferred embodiment, a topical agent according to the invention contains at least one antimycotic active substance from the group of hydroxypyridones, with ciclopirox and ciclopiroxolamine being especially preferred.

All other antimicrobial or antiseptic substances with fungistatic or fungicidal action, which may belong to various classes of substances, can also come into consideration as antimycotic active substances. These include in particular the following active substances:
quinoline derivatives, in particular diiodohydroxyquinoline, clioquinol, chlorquinaldol, broxyquinoline, oxyquinoline;
antiseptic active substances such as dequalinium, clodantoin, bromochlorosalicylanilide (multifungin), bromosalicylic acid isopropylamide, methylrosaniline, tribromometacresol, policresulen, benzalkonium chloride, povidone-iodine, hexetidine, octenidine, polynoxylin, 2-(4-ch lorophenoxy)-ethanol, chlorphenesin, ticlatone, sulbentine, fenticlor, bithionol, ethyl BHC 07 1 079-Foreign Countries hydroxybenzoate, haloprogin, salicylic acid, selenium sulphide, dimazole, butenafine, dichlorophen; fatty acids, in particular undecylenic acid and octanoic acid.

The antimycotic active substances described in the above sections can be used individually or in combination, for example to obtain a wider spectrum of action or to reduce the risk of development of resistance. A medicinal product according to the invention can therefore contain one, two or more antimycotic active substances in a fixed combination with an active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, preferably dexpanthenol.
The group of pantothenic acid derivatives comprises in particular dexpanthenol, DL-panthenol, salts of pantothenic acid (e.g. Na-pantothenate, Ca-pantothenate), esters of pantothenic acid (e.g.
ethyl ester, methyl ester), panthenol ethers (e.g. ethyl or methyl ether), panthenol thioethers and panthenyl triacetate. Dexpanthenol (= D-(+)-pantothenyl alcohol) is the most preferred.

According to other preferred embodiments, it is envisaged that a topical agent according to the invention contains one of the combinations of active substances stated hereunder:

a) one or more antimycotic active substances from the group of azoles, preferably from the group comprising clotrimazole, bifonazole, fluconazole, miconazole, econazole, tioconazole, fenticonazole, oxiconazole and ketoconazole, in combination with dexpanthenol;

b) terbinafine and/or naftifine in combination with dexpanthenol;
c) tolciclate and/or tolnaftate in combination with dexpanthenol;
d) amorolfine in combination with dexpanthenol;

e) caspofungin in combination with dexpanthenol;

f) one or more antimycotic active substances from the group comprising nystatin, natamycin, amphotericin B, hachimycin and pecilocin in combination with dexpanthenol;

g) one or more antimycotic active substances from the group comprising mepartricin, pyrrolnitrin, griseofulvin and flucytosine in combination with dexpanthenol.

According to another preferred embodiment, the medicinal products according to the invention additionally contain at least one further active substance, which is preferably selected from the group comprising topical antihistamines, topical glucocorticoids, local anaesthetics and antipruritics.

BHC 07 1 079-Foreign Countries The active substance class of the topical antihistamines comprises in particular the following active substances: ketotifen, thonzylamine, mepyramine, thenalidine, tripelennamine, chloropyramine, promethazine, tolpropamine, dimetindene, clemastine, bamipine, loratadine, isothipendyl, diphenhydramine, diphenhydramine methyl bromide, chlorphenoxamine, pheniramine, diphenylpyraline, dioxopromethazine, dimenhydrinate, thiethylperazine and meclozine, azelastine, levocabastine, astemizole, mebhydrolin, terfenadine, mequitazine, cetirizine, emedastine, mizolastine, olopatadine, epinastine and antazoline. Especially preferred antihistamines are: bamipine, clemastine, chlorphenoxamine, azelastine, terfenadine, loratadine.
The active substance class of the topical glucocorticoids comprises in particular hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, methylprednisolone acetate, clobetasone butyrate, fluocinolone acetonide, fluocortolone, prednicarbate, beclomethasone dipropionate, betamethasone-l7-valerate, betamethasone- 17,2 1 -dipropionate, budesonide, desonide, diflucortolone valerate, fluclorolone acetonide, fluocinonide, flumethasone pivalate, fluprednylidine acetate, fluticasone, halcinonide, triamcinolone acetonide, clobetasol propionate.

The active substance class of the local anaesthetics comprises in particular lidocaine, tetracaine and benzocaine.

The active substance class of the antipruritics comprises in particular crotamiton, bufexamac, isoprenaline, camphor, tar preparations, topical antihistamines, avenathramide and synthetic or natural derivatives thereof, glycyrrhetinic acid, glycyrrhizinic acid or their potassium salts and tannins.

According to another preferred embodiment, the medicinal products according to the invention additionally contain at least one extract of the plant Centella asiatica, preferably a titrated extract of Centella asiatica. Extracts of Centella asiatica preferably contain active substances from the group comprising asiatic acid, asiaticoside, madecassic acid, madecassoside and terminoloside and can be obtained as described in W02004/062678.

The medicinal products according to the invention contain the extracts of the plant Centella asiatica, preferably a titrated extract of Centella asiatica, especially preferably the active substances from the group comprising asiatic acid, asiaticoside, madecassic acid, madecassoside and terminoloside at a content of 0.5 to 1.5 wt.% relative to the total weight of the medicinal product.

BHC 07 1 079-Foreign Countries Preferably the extract of Centella asiatica contains the active substances madecassoside and/or terminoloside and/or asiaticoside at a content of more than 75 wt.%, preferably more than 85 wt.%
relative to the total weight of the extract. Especially preferably the extract of Centella asiatica contains the active substances madecassoside and/or terminoloside at a content of more than 75 wt.%, preferably more than 85 wt.%, especially preferably more than 95 wt.%
relative to the total weight of the extract.

Additionally the medicinal products according to the invention can contain vitamins and/or minerals. Vitamins comprise for example vitamin A, beta-carotene, vitamin C
(ascorbic acid), vitamin D3 (cholecalciferol), vitamin E (tocopherol acetate), vitamin B 1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinamide), vitamin B6 (pyridoxine), folic acid, vitamin B12 (cyanocobalamin), vitamin K1 and biotin. Minerals comprise for example iron salts, copper salts, calcium salts such as calcium carbonate, calcium phosphate, calcium glycerophosphate;
magnesium salts such as magnesium phosphates, magnesium sulphate (dihydrate) or magnesium oxide; zinc salts such as zinc citrate; strontium salts e.g. strontium ranelate, selenium or its salts for example sodium selenate; potassium iodide; manganese salts for example manganese sulphate;
molybdenum salts for example sodium molybdate; chromium salts for example chromium chloride; sodium chloride or potassium chloride. Salts of alkaline earth metals can be added against pruritus, for example barium, calcium, magnesium, strontium and/or beryllium salts. The salts can be for example carbonates, bicarbonates, sulphates, glycerophosphates, borates, chlorides, nitrates, acetates, hydroxides and persulphates and salts of a-hydroxy acids (citrates, tartrates, lactates, malates) or fruit acids, salts of amino acids (aspartate, arginate, glycocholate, fumarate) or salts of fatty acids (palmitate, oleate, caseinate, behenate).
The salt is selected for example from calcium nitrate, magnesium nitrate, calcium borate, magnesium borate, calcium chloride, magnesium chloride, calcium sulphate, magnesium sulphate, calcium acetate or magnesium acetate. The salt is preferably a magnesium salt or better still a strontium salt and in particular a chloride or nitrate.

The examples of substances given in the preceding paragraphs do not represent a complete and final list of active substances. Obviously, other active substances from the stated groups of active substances and from other groups of active substances not mentioned here can also be used in the sense of the invention. Furthermore, the stated active substances according to the present invention can also be used in the form of their pharmaceutically acceptable salts. For example, the following come into consideration as salts: hydrochloride, hydrobromide, sodium salts, phosphate, nitrate, sulphate, acetate, fumarate, citrate, propionate, oxalate, succinate, lactate, butyrate, methanesulphonate, aspartate, decanoate, maleate, tartrate, hydrogentartrate.

BHC 07 1 079-Foreign Countries When using the combination according to the invention, the action is observed to have an unexpected synergistic effect. Therefore the amounts of the active substances used in the combination can be reduced in comparison with monotherapy. Similarly, when using an equivalent amount of active substance in comparison with monotherapy, an unexpected better action can be observed.

The medicinal products according to the invention contain a combination of the stated active substances in the form of a "fixed combination"; this means that all active substances making up the particular combination of active substances are jointly present in a dosage form and are administered jointly.

In particular, the active substances can be present in the medicinal products in particulate, dispersed, dissolved, suspended or emulsified form.

The total content of active substance in the medicinal product according to the invention is preferably in the range from 0.05 to 90 wt.%, preferably in the range from 0.1 to 50 wt.%, especially preferably 0.5 to 20 wt.%, in each case relative to the total weight of the medicinal product. The proportion of active substance is established in a manner known by a person skilled in the art depending on the dosage form selected in each case, the active substance or substances selected in each case, and the dose that is suitable for the particular therapeutic purpose. The therapeutically appropriate dosages of the individual active substances are known by a person.
skilled in the art. For example, the daily dose in the case of the antimycotic azole derivatives is in the range from approx. 5 to 50 mg.

The proportion of the antimycotic active substance or substances is preferably 0.01 to 85 wt.%, preferably 0.05 to 45 wt.%, especially preferably 0.1 to 15 wt.%, in each case relative to the total medicinal product.

The relative proportion of the pantothenic acid derivative (preferably dexpanthenol) and/or of pantothenic acid can vary over a wide range. The proportion of dexpanthenol is preferably 0.01 to 85 wt.%, in particular 0.05 to 45 wt.%, especially preferably 0.1 to 15 wt.%, in each case relative to the total medicinal product.

The aforementioned advantageous effects are achieved in particular when the weight ratio of dexpanthenol (or of the pantothenic acid derivative or of pantothenic acid) to the stated at least one antimycotic active substance is in the range from 1:100 to 100:1, preferably in the range from 50:1 to 1:50, especially preferably in the range from 1:10 to 10:1.

BHC 07 1 079-Foreign Countries The proportion of the stated at least one additional active substance, which is preferably selected from the group comprising topical antihistamines, topical glucocorticoids, local anaesthetics and antipruritics, is preferably 0.05 to 50 wt.%, in particular 0.1 to 20 wt.%, in each case relative to the medicinal product.

Furthermore, it may be advantageous if the medicinal product according to the invention additionally contains one or more dermatologic and/or cosmetic ingredients.
These substances are preferably selected from the group comprising the zinc-containing agents (e.g.
zinc oxide, zinc sulphate), silicone-containing agents (e.g. dimethicone, phenylmethylpolysiloxane, polysiloxane), petroleum jelly, fat-containing agents (e.g. linoleic acid, ethyl linoleate, paraffin, petroleum jelly), urea-containing agents (e.g. urea, carbamide peroxide, allantoin), salicylic acid-containing preparations (e.g. acetylsalicylic acid, salicylic acid, bromosalicylic acid), skin-protection products (e.g. guaiazulene, sulphur-containing agents, glycerol, glucose, thymol), emollients (e.g. mineral oils or paraffin in the form of oil-in-water emulsions), moisturizers (e.g.
aloe vera, glycerol, 1,2-octanediol), UV-protectants (e.g. aminobenzoic acid, oxyl methoxycinnamate), surfactants (e.g.
dodecylbenzene sulphonic acid, dodecyltriphenylphosphonium bromide, sodium lauryl sulphate) and disinfectants (e.g. cetylpyridinium chloride, tributyltin(IV) benzoate, methenamine). The aforementioned dermatologic or cosmetic ingredients are known by a person skilled in the art.

The medicinal products according to the invention are formulated as topical agents, which are suitable in particular for application on the skin, on hair-covered skin, on mucosae (for example of the oral, nasal or pharyngeal cavity or of the vagina) and on the appendages of the skin (e.g.
fingernails or toenails).

The medicinal products according to the invention can be formulated as solid, semi-solid or liquid dosage forms, preferably as powders, granules, tablet, lozenge, pastille, suppository, patch or plaster, solution, foam, gel, lotion, emulsion, cream, ointment, paste, oil, shampoo, nail varnish, film, aerosol, powder aerosol or spray.

The methods and the excipients suitable for the production of these dosage forms, and their relative proportions, are known by a person skilled in the art and are described in the technical literature.

For the therapeutic treatment of mycoses of the skin and its appendages, consideration is preferably given to the following dosage forms: powders, granules, patch or plaster, solution, foam, gel, lotion, emulsion, cream, ointment, paste, oil, shampoo, nail varnish, film, aerosol, powder aerosol or spray.

BHC 07 1 079-Foreign Countries For the therapeutic treatment of mycoses of the mucosae consideration is preferably given to the following dosage forms: powders, granules, tablet, lozenge, pastille, suppository, patch or plaster, solution, foam, gel, lotion, emulsion, suspension, cream, ointment, paste, oil, film, aerosol, powder aerosol or spray.

For the treatment of genital mycoses - for example vaginal mycoses -consideration is preferably given to the following dosage forms: powders, solution, foam, gel, lotion, emulsion, cream, ointment, paste, oil, aerosol, powder aerosol, spray, vaginal tablets, pessaries, vaginal capsules, vaginal gel, vaginal suppositories.

The following, for example, may be considered as excipients: particulate supports (e.g. talc, zinc oxide, starch, starch derivatives, kieselguhr); gel-forming substances (e.g.
gelatin, tragacanth, cellulose derivatives, alginates, polyacrylic acid); moistening agents (e.g.
urea, glycerol, propylene glycol), contact-adhesive polymers (e.g. polyacrylates, and adhesive resins);
ointment bases (e.g.
petroleum jelly, fats, cellulose derivatives, polyacrylic acid, polyethylene glycols); emulsifiers (e.g. wool wax, sorbitan esters, monoglycerides); preservatives (e.g.
benzalkonium chloride), antioxidants (e.g. butyl hydroxyanisole), thickeners (e.g.
hydroxypropylmethylcellulose), pH
correctants; binders (e.g. polyvinylpyrrolidone, starch, hydroxypropylmethylcellulose, polyethylene glycols), fillers (e.g. microcrystalline cellulose, sorbitol), dyes, aroma substances, sweeteners (e.g. sorbitol, aspartame); solvents (e.g. water, ethanol, ethanol-water mixtures);
solubilizers (e.g. glycerol, propylene glycol); skin-penetration improvers (e.g. propylene glycol);
plasticizers (e.g. sorbitol, glycerol, phthalates); wetting agents (e.g.
sodium lauryl sulphate, polysorbate); synthetic and natural oils (e.g. medium-chain triglycerides);
propellants for aerosol or foam sprays (e.g. norflurane, cryofluorane, dichlorofluoromethane, trichlorofluoromethane, propane, butane, isobutane, nitrogen).

The invention relates further to the use of a combination of active substances, which - as described in the preceding paragraphs - contains at least one antimycotic active substance and at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, in particular dexpanthenol, for the topical treatment of mycoses of the skin (including subcutaneous mycoses) and appendages of the skin or of mycoses of the mucosae.
The term "mycoses" essentially comprises dermatophytoses, mould mycoses and yeast mycoses.

The treatment generally involves local application of the antimycotic active substances contained in the combination of active substances, as a mixture of active substances, optionally together with one or more excipients, on the diseased areas of the body.

BHC 07 1 079-Foreign Countries Selection of a suitable antimycotic active substance or combination of antimycotic active substances is generally based on the type of mycosis to be treated, the type of pathogen involved and the spectrum of action of the active substance. The spectrum of action of the various antimycotic active substances is known by a person skilled in the art.
Generally the combinations of active substances according to the invention and medicinal products containing them can be used for the treatment of mycoses caused by dermatophytes, moulds or yeasts.

The invention further relates to the use of a fixed combination of active substances, which - as described above - contains at least one antimycotic active substance and at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, in particular dexpanthenol, for the preventive topical treatment of mycoses of the skin and its appendages or mycoses of the mucosae. A preventive treatment may be considered in particular for patients at high risk for fungal infections, e.g. in patients with weakened immune systems or diabetics.

The invention further extends to the use of a combination of active substances according to the invention for reinfection prophylaxis against mycoses of the skin and its appendages or mycoses of the mucosae. Such a treatment may be considered in particular for persons who suffer frequently recurring fungal diseases such as athlete's foot, genital mycoses, in particular vaginal mycoses, or pityriasis versicolor.

Moreover, the combinations of active substances according to the invention can be used for the topical treatment of cutaneous or mucosal mycoses that develop during or after radiotherapy or chemotherapy, during or after immunosuppressive therapy, during or after systemic antibiotic therapy, or in the case of damage to the skin or mucosae caused by chemical or physical effects (e.g. injuries, burns).

Furthermore, the combinations of active substances and topical agents according to the invention can be used advantageously for (a) shortening the healing time in the topical treatment of mycoses, and/or (b) soothing pruritus occurring in fungal infections, and/or (c) reducing the intensity of the inflammatory reactions occurring in a fungal infection, and/or (d) during and/or after local antimycotic therapy, promoting the regeneration of the affected region of skin or rnucosa.

BHC 07 1 079-Foreign Countries The combinations of active substances and medicinal products according to the invention are suitable, owing to their anti-inflammatory properties, in particular for the topical treatment of inflammatory or eczematous dermatomycoses.

The combinations of active substances and medicinal products according to the invention can preferably be used for the topical treatment of the following mycotic diseases:

- tinea, in particular tinea pedis, tinea manuum, tinea capitis, tinea barbae, tinea favosa, tinea corporis, tinea faciei. Generally these are infections that are caused by Epidermophyton, Microsporum and Trichophyton species.

- pityriasis, in particular pityriasis versicolor;

- Candida mycoses of the skin or mucosae, in particular candidiasis of the oral mucosa (Candida stomatitis, thrush);

- onychomycosis, paronychia;
- interdigital mycoses;

- mycoses of the feet;

- perianal mycoses, genital mycoses, in particular vaginal mycoses, vulvitis, vulvovaginitis, balanitis;

- intertrigo, nappy rash, seborrhoeic eczema, drug-induced eczemas, mixed infections of the skin;
- mycoses of the eyelids or of the conjunctiva;

- mycoses of the outer ear or of the auditory canal;

- mycoses of the subcutaneous tissue (subcutaneous mycoses);

- opportunistic infections or mycotic superinfections, especially in the case of congenital or acquired lowered immunity, in eczemas, acne vulgaris, psoriasis, seborrhoeic dermatitis or neurodermatitis.

The combinations of active substances and topical agents according to the invention are therefore suitable for the treatment of cutaneous or mucosal mycoses of the most varied aetiology and localization.

BHC 07 1 079-Foreign Countries Preferably the combinations of active substances and medicinal products according to the invention are used in the area of human medicine, i.e. for the treatment of persons suffering from a dermatomycosis or mucosal mycosis. Furthermore, the invention also extends to the use of the combinations of active substances and medicinal products according to the invention in the area of veterinary medicine, i.e. for the treatment of animals, in particular domestic animals or pets that have a dermatomycosis or mucosal mycosis.

The invention further comprises a method of therapeutic treatment of a person suffering from a mycosis of the skin, its appendages or mucosa, and who requires a therapeutic treatment. Said therapeutic method has at least one treatment step, in which a combination of active substances according to the invention (or a medicinal product according to the invention that contains said combination of active substances) is administered topically at a therapeutically effective dose, i.e.
on the regions of the body affected by the mycosis. The following in particular may be considered as regions of the body to be treated: skin, scalp, hands, fingers, fingernails, feet, toes, toenails, mucosa, lips, oral cavity, tongue, gums, skin folds, body folds, inguinal region, genital region, anal region, eyelid, conjunctiva.

The invention further includes the use of a fixed combination of active substances, as described above, for the production of topical medicinal products for the therapeutic treatment of mycoses of the skin, mucosae or appendages of the skin in humans or animals.

Examples of application The invention is explained in more detail on the basis of the recipes given in the following examples:

Example 1:

Cream for the treatment of dermatomycoses 1 wt.% clotrimazole 5 wt.% dexpanthenol in a cream preparation of cetyl palmitate, cetyl stearyl alcohol, benzyl alcohol, 2-octyldodecanol, sorbitan stearate, polyoxyethylene (20)-sorbitan monostearate and purified water.

BHC 07 1 079-Foreign Countries The cream is used for the topical treatment of dermatomycoses that are caused by dermatophytes, yeasts, moulds or other fungi. It is suitable in particular for the treatment of tinea pedis, tinea manuum or pityriasis versicolor.

For use, the cream is applied once daily to the diseased areas of skin, and rubbed in.
Example 2:

Gel for the treatment of dermatomycoses 1 wt.% bifonazole 5 wt.% dexpanthenol in a gel preparation of isopropyl isostearate, benzyl alcohol, lactic acid, 96% ethanol (v/v), a-(hexadecyl, octadecyl)-w-hydroxypoly(oxyethylene)-x, PEG-glycerol-cocoate and purified water.
The gel is used for the topical treatment of dermatomycoses that are caused by dermatophytes, yeasts, moulds or other fungi. It is suitable in particular for the treatment of fungal diseases of the feet and hands (tinea pedis, tinea manuum), fungal diseases of the skin and skin folds (tinea corporis, tinea inguinalis), pityriasis versicolor, and for the treatment of superficial candidiasis.

For use, the gel is applied once daily to the diseased areas of skin, and rubbed in.
Example 3:

Spray for the treatment of dermatomycoses I wt.% bifonazole 5 wt.% dexpanthenol in a spray solution of ethanol and isopropyl myristate.
It is used as described under (2).

Example 4:
Vaginal tablets 0.2 g clotrimazole 0.1 g dexpanthenol BHC 07 1 079-Foreign Countries (the amounts stated are for 1 tablet) Excipients: finely-divided silicon dioxide, crospovidone, calcium lactate pentahydrate, lactose monohydrate, magnesium stearate, maize starch, hypromellose, microcrystalline cellulose and lactic acid.

The tablets are used for the treatment of vaginal fungal infections (dosage: 1 tablet daily).
Example 5:

Cream for the treatment of athlete's foot and pityriasis versicolor 1 wt.% terbinafine hydrochloride 2.5 wt.% dexpanthenol in a cream preparation of benzyl alcohol, polyoxyethylene (20)-sorbitan monostearate, stearyl alcohol, cetyl alcohol, cetyl palmitate, sorbitan stearate, isopropyl myristate, sodium hydroxide, ethanol and purified water.

For use, the cream is applied once daily on the diseased areas of skin and rubbed in gently.
Example 6:

Ointment for the treatment of Candida infections of the skin or mucosa nystatin 10 million IU/100 g ointment dexpanthenol 7.5 wt.%

in an ointment preparation of viscous paraffin, polyethylene, zinc oxide.

The ointment is used for the treatment of Candida infections of the skin, mucosa and the fingernails or toenails. For use, the ointment is applied on the affected regions of the body one or more times daily.

Example 7:

Cream for the treatment of inflammatory dermatomycoses I wt.% clotrimazole 1 wt.% hydrocortisone BHC 07 1 079-Foreign Countries wt.% dexpanthenol in a cream preparation of benzyl alcohol, cetostearyl alcohol, medium-chain triglycerides, triceteareth-4-phosphate, purified water.

The cream can be used for the treatment of inflammatory dermatomycoses that are caused by 5 dermatophytes, yeasts (especially Candida), moulds or other fungi. It is also suitable for the treatment of nappy rash, vulvitis, balanitis and intertrigo, if Candida yeasts are involved in these infections. For use, the ointment is applied on the affected regions of the body two or more times daily.

Example 8:

Solution for the treatment of inflammatory dermatomycoses I wt.% naftifine hydrochloride 2.5 wt.% dexpanthenol in a solvent mixture of propylene glycol, ethanol and purified water.

The solution can be used in particular for the treatment of dermatomycoses and onychomycoses that are caused by dermatophytes, yeasts or moulds.

Claims (16)

1. Claims `1. Topical agent for antimycotic therapy, which contains at least one antimycotic active substance and at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives in a fixed combination.
2. 2. Topical agent according to Claim 1, characterized in that the antimycotic active substance or substances are selected from the group comprising azole derivatives, in particular triazole and imidazole derivatives, and allylamines, thiocarbamates, thiocarbanilates, substituted pyridones, polyene antibiotics, morpholines, hydroxypyridones and glucan synthesis inhibitors.
3. 3. Topical agent according to Claim 1 or 2, characterized in that it contains at least one antimycotic active substance selected from the group of active substances comprising miconazole, miconazole nitrate, ketoconazole, fluconazole, itraconazole, clotrimazole, econazole, clomidazole, isoconazole, tiabendazole, tioconazole, ketoconazole, sulconazole, bifonazole, oxiconazole, fenticonazole, omoconazole, sertaconazole, flutrimazole, croconazole, voriconazole and posaconazole or in that it contains at least one antimycotic active substance from the group comprising terbinafine and naftifine or in that it contains at least one antimycotic active substance selected from the group comprising tolnaftate, tolciclate, amorolfine, caspofungin, nystatin, natamycin, amphotericin B, hachimycin, candicidin, pecilocin, mepartricin, pyrrolnitrin, griseofulvin and flucytosine or in that it contains at least one antimycotic active substance selected from the group of hydroxypyridones, with ciclopirox and ciclopiroxolamine being especially preferred.
4. 4. Topical agent according to one of the preceding claims, characterized in that it contains at least one antimicrobial active substance with fungistatic or fungicidal action, selected from the group comprising diiodohydroxyquinoline, clioquinol, chlorquinaldol, dequalinium, broxyquinoline, oxyquinoline, clodantoin, broinochlorosalicylic anilide, bromosalicylic isopropylamide, methylrosaniline, tribromometacresol, policresulen, benzalkonium chloride, povidone iodine, hexetidine, octenidine, polynoxylin, 2-(4-chlorophenoxy)-ethanol, chlorphenesin, ticlatone, sulbentine, fenticlor, bithionol, ethyl hydroxybenzoate, haloprogin, salicylic acid, selenium sulphide, dimazole, butenafine, dichlorophen, undecylenic acid and octanoic acid.
5. 5. Topical agent according to one of the preceding claims, characterized in that the group of pantothenic acid derivatives comprises dexpanthenol, DL-panthenol, salts of pantothenic acid, esters of pantothenic acid, panthenol ethers, panthenol thioethers and panthenyl triacetate.
6. 6. Topical agent according to one of the preceding claims, characterized in that it a) contains one or more antimycotic active substances from the group of azoles, preferably from the group comprising clotrimazole, bifonazole, miconazole, econazole, tioconazole, fenticonazole, oxiconazole and ketoconazole, in combination with dexpanthenol;
   or b) contains terbinafine and/or naftifine in combination with dexpanthenol; or c) contains tolciclate and/or tolnaftate in combination with dexpanthenol; or d) contains amorolfine in combination with dexpanthenol; or e) contains caspofungin in combination with dexpanthenol; or f) contains one or more antimycotic active substances from the group comprising nystatin, natamycin, amphotericin B, hachimycin and pecilocin in combination with dexpanthenol;
   or g) contains one or more antimycotic active substances from the group comprising mepartricin, pyrrolnitrin, griseofulvin and flucytosine in combination with dexpanthenol.
7. 7. Topical agent according to one of the preceding claims, characterized in that it additionally contains one or more active substances selected from the group comprising topical antihistamines, topical glucocorticoids, local anaesthetics and antipruritics.
8. 8. Topical agent according to one of the preceding claims, characterized in that it additionally contains at least one extract of the plant Centella asiatica.
9. 9. Topical agent according to one of the preceding claims, characterized in that it additionally contains at least one active substance from the group comprising asiatic acid, asiaticoside, madecassic acid, madecassoside and terminoloside.
10. 10. Topical agent according to one of the preceding claims, characterized in that it is in the form of a solid, semi-solid or liquid dosage form, preferably as powders, granules, tablet, lozenge, pastille, suppository, patch or plaster, solution, foam, gel, lotion, emulsion, cream, ointment, paste, oil, shampoo, nail varnish, film, aerosol, powder aerosol or spray.
11. 11. Topical agent according to one of the preceding claims, characterized in that the proportion of the antimycotic active substance(s) is 0.01 to 85 wt.%, preferably 0.05 to 45 wt.%, especially preferably 0.1 to 15 wt.%, in each case relative to the total medicinal product.
12. 12. Topical agent according to one of the preceding claims, characterized in that the proportion of dexpanthenol is 0.01 to 85 wt.%, in particular 0.05 to 45 wt.%, especially preferably 0.1 to 15 wt.%, in each case relative to the total medicinal product.
13. 13. Topical agent according to one of Claims 8 or 9, characterized in that the extract of the plant Centella asiatica, preferably a titrated extract of Centella asiatica, especially preferably the active substances from the group comprising asiatic acid, asiaticoside, madecassic acid, madecassoside and terminoloside, are present at a content from 0.5 to 1.5 wt.% relative to the total weight of the medicinal product.
14. 14. Use of a combination of active substances, which contains at least one antimycotic active substance and at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, for the production of a medicinal product for the topical treatment or preventive treatment of mycoses of the skin and its appendages or of mycoses of the mucosae or for reinfection prophylaxis against mycoses of the skin and its appendages or mycoses of the mucosae.
15. 15. Use of a combination of active substances, which contains at least one antimycotic active substance and at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, for the production of a medicinal product a) for shortening the healing time in the topical treatment of mycoses; or b) for alleviating pruritus occurring in fungal infections of the skin; or c) for reducing the intensity of inflammatory reactions in fungal infections;
    or d) for promoting regeneration of the skin or mucosae during or after local antimycotic therapy.
16. 16 Use according to one of Claims 14 to 15, characterized in that said combination of active substances is a combination according to one of Claims 1 to 13.