Antimycotic preparations in the form of elastic liquid plasters

Antimycotic preparations in the form of elastic liquid plasters

BAYER AKTZENGESELLSCHAFT

C. 58900

Type V (Pha)

The present invention relates to certain novel formulations of antimycotic active compounds which may in themselves be known, which have a depot action, in spite of film formation, and a relatively high bioavailability 5 of the active compounds and thereby make short-term therapy possible.

formulations □f antimycotic derivatives for the treatment of mycoses in humans, above all mycoses of the skin, have already been disclosed. Using these formulations, 10 a therapy period of >.21 days has been required for a complete cure.

In order to shorten the period of therapy, a certain depot action and a relatively high bioavailability of the active compounds are required, in particular to eliminate 15 the germs and in order to achieve a mycological cure. The known formulations are suitable for this only to a limited extent, because only a small proportion of the available active compound is released in. the liquid volume at the site of infection. If a shortening of the period of therapy, 20 for example to one day and a single application, is to be achieved without a further increase in the concentration of active compound, optimum bioavailability of the active compound must be ensured.

According to the present invention we provide a 25 formulation of an antimycotic active compound which comprises 2 to 10% of. a spreading agent, 1 to 8% of a solubilising agent and, as a film-forming'agent, a quickdrying polyvinylpyrrolidone, a terpolymer of 30% of vinylpyrrolidone, 40% of vinyl acetate .nd 30% □f vinyl 30 propionate, or a vinyIpyrrolidone/vinyl acetate copolymer, which is soluble botn in water and in organic solvents, and any desired further formulation auxiliary or auxiliaries.

Le A 20 574

64436/2 . ׳.

The formulations according to the present invention make possible optimum release of the active compound and hence a therapy period which is shortened to one day by high concentrations of the active compound being achieved. This effect is achieved by the presence of spreading-oils and solubilising agents and by the addition of adherent film-forming agents which allow the release of active compounds to be increased up to ten-fold and the action of the active compound thereby to be increased.

More specifically the invention consists in antimycotic agents in the form of elastic liquid plasters which have relatively good release of active compounds and contain an imidazole derivative or a triazole derivative, solvents and customary formulation auxiliaries, characterised in that they contain 2-10% by weight of a spreading agent from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl stearate, caprylates/caproates of saturated fatty alcohols having the chain length of C_1o to C.״, wax-like fatty acid esters, silicone oils, isopropyl myristate/isopropyl palmitate/isopropyl stearate mixture, coconut fatty acid isopropyl ester as solubilizers, 1-8% by weight of a benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol or waxes and as a film-forming agent, a quick-drying polyvinylpyrrolidone, a terpolymer of 30% by weight of vinylpyrrolidone, 40% of vinyl acetate and 30% by weight of vinyl propionate, or a vinylpyrrolidone/vinyl acetate copolymer which is soluble both in water and in organic solvent.

The formulations according to the invention, which are elastic liquid plaster formulations, represent a new application principle for dermal treatment of mycoses which, in addition to being very effective in applying the active compounds, provides, as a result of sealing the infection site, protection

2a against infection of the surrounding area. The formulations according to the invention are particularly suitable for the treatment of nail mycoses.

The formulations according to the invention can be either a solution or a spray.

Active compounds which can be formulated in this manner are imidazole derivatives and triazole derivatives having an antimycotic action. They are present in the agents according to the invention in amounts of 0.05 - 1%, preferably 0.1-1% by weight.

The compounds with the following formulae may be mentioned as preferred examples:

(I)

<img file="IL64436A_D0001.tif" />

clotrimazole, trifonazole and

<img file="IL64436A_D0002.tif" />

lombazole

Numerous ether azole derivatives having an antimycotic action are known from DE-OS (German Published

Specification) 2,430,039 and Israel Patent No. 47531 (see also Israel Patents 30562 and 48704). They can likewise be used as the active compound in the agents according to the invention.

By spreading agents there are understood oily liquids which are particularly readily distributed on the skin [R. keymer, Parm. Ind. 32 (1970) 577 - 581], The compounds which follow are particularly suitable as spreading agents for the agents according to the invention: Silicone oils of various viscosities;

Fatty acid esters, such as isopropyl myristate, isopropyl palmitate, caprylic, capric acid esters of saturated fatty alcohols of ^chai^{n 1}®¹¹9th isopropyl stearate, waxy fatty acid esters, such as synthesised duck uropygial gland fat.

־

The compounds which follow are particularly suitable spreading-oils: isopropyl myristate, isopropyl palmitate, isopropyl stearate, caprylic/capric acid esters of saturated fatty alcohols of ^8ו־^|-2ן ^chain length, waxy fatty acid esters, such as synthesised duck uropygial gland fat, silicone oils, an isopropyl myristate/isopropyl palmitate/isopropyl stearate mixture and coconut oil acid isopropyl ester.

Preferred suitable solubilising agents for use in the formulations according to the present invention are benzyl alcohol, 2-octyl-dodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, dipr.opylene and tripropylene glycol and waxes and other additives used in cosmetics.

The gel-forming and film-forming agents are those macromolecular compounds, as defined previously, which can dissolve or start to swell both in water and in organic solvents and form a type of film after drying.

Suitable solvents are water and any of the watermiscible solvents. Possible solvents are, for example, alkanols (such as ethanol and isopropyl alcohol), propylene glycol, Methylcellosolve, Cellusolve, esters, morpholines, dioxane, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and cyclohexanone.

One or more solvents can be employed in the preparation of the formulations according to the invention.

The auxiliaries which follow can, inter alia, be used as appropriate in practice to establish an optimum formulation: glycerol, viscous paraffin, highly liquid paraffin, triethanolamine, collagen, allantoin, novantisolic acid and perfume oils.

Further auxiliaries which are suitable are:

(a) Substances which, for example, can stabilise a suspension, for example colloidal silicic acid or montmorillonites;

(b) Surface-active agents (including emulsifiers and wetting agents), for example

1. anionic surface-active agents, such as Na lauryl sulphate, fatty alcohol ether-sulphates and׳ the monoethanolamine salts of mono-/di-alkyl polyglycol etherorthophosphates;

2. cationic surface-active agents, such as cetyl trimethylammonium chloride;

3. ampholytic surface-active agents, such as di-Na-Nlauryl-^ -iminodipropionate or lecithin; and

4. non-ionic surface-active agents, for example polyoxyethylated castor oil, polyoxyethylated sorbitane monocleate, sorbitane monostearate, cetyl alcohol, glycerol monostearate, polyoxyethylene stearate and alkylphenol polyglycol ethers;

(c) Stabilisers for preventing the chemical degradation which occurs in the case of.some active compounds, such as antioxidants, for example tocopherols and butylhydroxyanisole; and (d) Agueous solutions which have been rendered acid can be stabilised by the addition of preservatives which are

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־ ⁶ ־ customary in cosmetics, for example p-hydroxy.benzoic acid esters.

The following Examples illustrate formulations according to the present invention (in these Examples M.W.

indicates the weight average molecular weight).

<td colspan="2"> Example 1</td>

<td> Tfifonazole Benzyl alcohol</td><td> 3.000 g 4.000 g</td>

<td> Isopropyl myristate׳</td><td> 6.000 g</td>

<td> Vinylpyrrolidone/vinyl</td><td> acetate copolymer 12.500 g</td>

<td> Isopropanol</td><td> to 100 ml</td>

<td colspan="2"> The individual components were mixed with one another</td>

<td> at room temperature anc</td><td> I thereby dissolved. The formulations</td>

<td colspan="2"> of Examples'2 to 14 were prepared in the same way.</td>

<td> Example 2</td><td></td>

<td> Trifonazole</td><td> 1.00 g</td>

<td> 2-0ctyIdodencanol</td><td> 2.00 g</td>

<td> Isopropyl myristate</td><td> 6.00 g</td>

<td> Vinylpyrrolidone/vinyl</td><td> acetate copolymer 10.00 g</td>

<td> Isopropanol</td><td> to 100 ml</td>

<td> Example 3</td><td></td>

<td> Lombazole</td><td> 1.00 g</td>

<td> Benzyl alcohol</td><td> 5.00 g</td>

<td> Isopropyl stearate</td><td> 6.00 g</td>

<td> Vinylpyrrolidone/vinyl</td><td> acetate copolymer 10.00 g</td>

<td> Isopropanol</td><td> to 100 ml</td>

<td> Example 4</td><td></td>

<td> Lombazole</td><td> 0.10 g</td>

<td> Benzyl alcohol</td><td> 6.00 g</td>

<td> Isopropyl myristate</td><td> 6.00 g</td>

<td> Vinylpyrrolidone/vinyl</td><td> acetate copolymer 10.00 g</td>

<td> Isopropanol</td><td> to 100 ml</td>

<td> Example 5</td><td></td>

<td> Clotrimazole</td><td> 1.00 g</td>

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<td colspan="2"> Benzyl alcohol Isopropyl myristate Vinylpyrrolidone/vinyl acetate copolymer</td><td rowspan="2"> 5.00 6.00 12.50 100</td><td rowspan="2"> g g g ml</td>

<td> Isopropanol</td><td> to</td>

<td> 5 Example 6</td><td></td><td></td><td></td>

<td> Clotrimazole</td><td></td><td> 1 .00</td><td> g</td>

<td> Benzyl alcohol</td><td></td><td> 6.00</td><td> g</td>

<td> Isopropyl myristate</td><td></td><td> 6.00</td><td> g</td>

<td> VinyIpyrrolidone/vinyl acetate</td><td> copolymer</td><td> 10.00</td><td> g</td>

<td> 0ן Isopropanol</td><td> to</td><td> 100</td><td> ml</td>

<td> Example 7</td><td></td><td></td><td></td>

<td> Clotrimazole</td><td></td><td> 1.00</td><td> g</td>

<td> 2-0ctyldodecanol</td><td></td><td> 2.00</td><td> g</td>

<td> Isopropyl myristate</td><td></td><td> 6.00</td><td> g</td>

<td> 5ן VinyIpyrrolidone/vinyl acetate</td><td> copolymer</td><td> 10.00</td><td> g</td>

<td> Isopropanol</td><td> to</td><td> 100</td><td> ml</td>

<td> Example 8</td><td></td><td></td><td></td>

<td> Clotrimazole</td><td></td><td> 1.00</td><td> g</td>

<td> Benzylalcohol.</td><td></td><td> 4.00</td><td> g</td>

<td> 20 Isopropyl myristate</td><td> ״</td><td> 6.00</td><td> g</td>

<td> VinyIpyrrolidone/vinyl acetate</td><td> copolymer</td><td> 12.50</td><td> g</td>

<td> Isopropanol</td><td> to</td><td> 100</td><td> ml</td>

<td> Example 9</td><td></td><td></td><td></td>

<td> Lombazole</td><td></td><td> 1 .00</td><td> g</td>

<td> 25 2-0ctyldodecanol</td><td></td><td> 8.00</td><td> g</td>

<td> Isopropyl stearate/isopropyl nr</td><td> yristate/</td><td></td><td></td>

<td> isopropyl palmitate</td><td></td><td> 2.00</td><td> g</td>

<td> VinyIpyrrolidone/vinyl acetate</td><td> copolymer</td><td> 10.00</td><td> g</td>

<td> Isopropanol</td><td> to</td><td> 100</td><td> ml</td>

<td> 30 Example .10</td><td></td><td></td><td></td>

<td> Lombazole</td><td></td><td> 0.10</td><td> g</td>

<td> 2-0ctyIdodecanol</td><td></td><td> 1.00</td><td> g </td>

<td> Isopropyl myristate</td><td></td><td> 10.00</td><td> g</td>

<td> Vinylpyrrolidone/vinyl acetate</td><td> copolymer</td><td> 10.00</td><td> g</td>

<td> 35 Isopropanol</td><td> to</td><td> 100</td><td> ml</td>

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- .8 -

<td></td><td> Example 11 Clotrimazole</td><td></td><td> 1.0 .</td><td> g</td>

<td></td><td> Benzyl alcohol</td><td></td><td> 5.0</td><td> g</td>

<td></td><td> Isopropyl myristate</td><td></td><td> 6.0</td><td> g</td>

<td> 5</td><td> Polyvinylpyrrolidone</td><td></td><td> 12.5</td><td> g</td>

<td></td><td> Isopropanol Example 12</td><td> to</td><td> 100</td><td> ml</td>

<td></td><td> Lombazole</td><td></td><td> 1 .0</td><td> g</td>

<td></td><td> Benzyl alcohol</td><td></td><td> 5.,0</td><td> g</td>

<td> 10</td><td> Isopropyl myristate/isopropyl</td><td> palmitate/</td><td></td><td></td>

<td></td><td> isopropyl stearate mixture</td><td></td><td> 6.0</td><td> g</td>

<td></td><td> Polyvinylpyrrolidone</td><td></td><td> 12.5</td><td> g</td>

<td></td><td> Isopropanol Example 13</td><td> to</td><td> 100</td><td> ml</td>

<td> 15</td><td> Clotrimazole</td><td></td><td> 1 .0</td><td> g</td>

<td></td><td> Benzyl alcohol</td><td></td><td> 2.0</td><td> g</td>

<td></td><td> Isopropyl myristate</td><td></td><td> 6.0</td><td> g</td>

Terpolymer of 30% of vinylpyrrolidone, 40% of vinyl acetate and 30% of vinyl

<td colspan="3"> propionate</td><td> 12.5</td><td> g</td>

<td> 20</td><td> Isopropanol Example 14</td><td> to</td><td> 100</td><td> ml</td>

<td></td><td> Lombazole</td><td></td><td> 1.0</td><td> g</td>

<td></td><td> Benzyl alcohol</td><td></td><td> 5.0</td><td> g</td>

<td> 25</td><td colspan="2"> Mixture of isopropyl myristate/isopropyl stearate and isopropyl palmitate</td><td> 6.0</td><td> g</td>

<td></td><td> Terpolymer of 40% of vinyl propionate</td><td> 30% of vinylpyrrolidone, acetate and 30% of vinyl</td><td> 12.5</td><td> g</td>

<td></td><td> Isopropanol</td><td> to</td><td> 100</td><td> ml</td>

Example 15

Sprays

The active compound solutions prepared according to Examples 1 to 14 could also be processed to sprays. For this purpose, for example, 60 to 90% of active compound 35 solution was mixed with 10 to 40% of a customary propellant, for example N^O, CC^, propane, butane or a halogenated hydrocarbon.

Le A 20 574 ־ 9 The following Example illustrates the activity of certain formulations according to the present invention.

Example A: . ^stin^.the_acti.voXy_of _the_agents.accpitijjig^tc^the^

......

Trichophyton-in fee ted Pirbright white guineapigs with an average weight of 600. g were used as a test model for a comparative examination of the activity of the agents according to the invention. The backs of the animals were shaved with electric hair-clippers such that hair stubble 10 about 1/10 mm long remained.

Infection with Trichophyton mentagrophytes was ’ effected by lightly 'rubbing in a spore suspension of the pathogen, which had been initially germinated for 24 hours in Sabouraud nutrient solution, over an approximately

2 x 2 cm area of the shaved back of the animals. 0.5 ml of germ suspension, whicn contained 1 - 3 x 10^ infectious fungus particles, were applied per animal.

In the case of this mode of infection, the first symptoms of dermatophytosis show as readdening and scaling 20 □f the skin 2-3 days after infection. In the case of untreated animals, the dermatophytosis is most pronounced about 14 days after infection: Loss of hair in patches and bloody integumentary defects within a phlogistically changed, scaly edge zone.

The formulations to be tested were applied locally once, on the 2nd day after infection, to the reddened infection sites on the animals. In each case 0.5 ml of the formulations (= 5 mg of active compound as 1 ?ס strength formulation) was applied. The course □f the infection was 10 evaluated daily up to the 20th day after infection.

The results are given in the following table (in which + = weak action, ++ = action, +++ = good action, ++++ = very good action).

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<td> Agent of Example</td><td> Action on Trichophytoninfected guineapigs</td>

<td> 1</td><td> +++</td>

<td> 2</td><td> ++++</td>

<td> 3</td><td> ++++</td>

<td> 4</td><td> ++++</td>

<td> 5</td><td> + +++</td>

<td> 6</td><td> ++++</td>

<td> 7</td><td> ++++</td>

<td> 8</td><td> ++++</td>

<td> 9</td><td> ++++</td>

<td> 10</td><td> +++</td>

<td> 11</td><td> ++++</td>

<td> T2</td><td> ' ++++</td>

<td> 13</td><td> ++++</td>

<td> 14</td><td> ++++</td>

If formulations which contained water-insoluble polymers, for example methacrylates, instead of the polymers mentioned were used instead of the formulations according to the invention, the mycosis is aggravated.

If formulations which, in addition to the active compound, contained only the polymers mentioned and neither spreading agents nor solubilising agents were used, only a weak action is achieved.