GB2137090A

GB2137090A - Antimycotic Bifonazole Solutions and Sprays

Info

Publication number: GB2137090A
Application number: GB08408066A
Authority: GB
Inventors: Karlheinz Adams
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1983-03-30
Filing date: 1984-03-29
Publication date: 1984-10-03
Also published as: DE3311700A1; ES530845A0; ES8601691A1; FR2543436A1; CH660304A5; ES8601690A1; ES8503946A1; KR840008283A; FR2543436B1; ES539274A0; CA1212328A; BE899277A; GR81880B; GB8408066D0; IT1173762B; AU564979B2; SE8401747L; JPS59184125A; ES539275A0; LU85272A1

Abstract

Antimycotic solution or spray compositions containing bifonazole as an antimycotic compound and including 10-60% by weight of a spreading agent e.g. isopropyl myristate, and 20-80% by weight solvent e.g. ethanol for topical application. The preparation of bifonazole is also described.

Description

SPECIFICATION Antimycotic Agents with a High Release of Active Compounds in Form of a Solution and Spray The present invention relates to novel formulations of the known antimycotic compound bifonazole of the formula

which have a depot action and a relatively high bioavailability of the active compound and thereby permit short-term therapy.

Formulations of antimycotic derivatives have already been disclosed for the treatment of mycoses in humans, above all mycoses of the skin. A therapy time of > 21 days has been required for complete cure using these formulations.

In order to shorten the duration of therapy, a certain depot action and a higher bioavailability of the active compound are required, in particular to eliminate the germs and in order to achieve a mycological cure. The known formulations are of only limited suitability here, because only a small amount of the available active compound dissolves in the volume of liquid at the infection site. Thus, if a shortening in the duration of therapy, for example to a few days with a single daily administration, is to be achieved without further increase in the concentration of active compound, optimum bioavailability of the active compound must be ensured.

It has now been found that those formulations of bifonazole which contain 1 0-60% of a spreading agent and 2080% of a solvent as well as conventional formulation auxiliaries permit optimum release of the active compound and thus, by achieving high concentrations of the active compound, a duration of therapy which has been shortened to a few days. This effect is achieved by the fact that the action of the bifonazole contained in the formulations is increased by the spreading agent and solvent and the release of active compound can thereby be increased up to ten-fold. The formulations according to the invention thus represent a new administration principle for bifonazole for dermal treatment of mycoses.

The formulations according to the invention can be either solutions or sprays. They are prepared by a process in which, in a manner which is known per se, either (a) the carbinol of the formula

is reacted with thionyl-bis-imidazole, if appropriate in the presence of a diluent, or (b) the halogeno-methane of the formula

either 1) is reacted with imidazole, if appropriate in the presence of an acid-binding agent and if appropriate in the presence of a diluent, or 2) is reacted with a silver salt or alkali metal salt of imidazole, if appropriate in the presence of a diluent, or 3) is reacted with trimethylsilylimidazole of the formula

if appropriate in the presence of a diluent, and, if appropriate, the azol-i -yl-methane thereby obtained is reacted with physiologically acceptable acids, the product thereby obtained is mixed with 1060% of a spreading agent and 2080% of a solvent and, if appropriate, the solution thus obtained is mixed with a propellant.

The agents according to the invention contain bifonazole in amounts of 0.051.5%, preferably 1%.

Spreading agents are understood as meaning oily liquids which distribute themselves particulariy readily on the skin (R. Keymer, Pharm. Ind. 32 (1970), page 77-page 81). The foliowing compounds are particularly suitable spreading agents for the agents according to the invention.

Silicone oils of various viscosities.

Fatty acid esters, such as ethyl stearate, di-n-butyl adipate, hexyl iaurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C,6C18- fatty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C12-C18 chain length, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters, such as synthetic duck uropygial gland fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter and the like.

Triglycerides, such as caprylic/capric acid triglyceride, triglyceride mixtures with vegetable fatty acids of C8-C12 chain length or other specifically selected naturally occurring fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, optionally also containing hydroxyl groups, monoglycerides of the C.B /C10-fatty acids and the like.

Fatty alcohols, such as isotridecyl alcohol, cetyl-stearyl alcohol and oleyl alcohol.

Fatty acids, such as, for example oleic acid.

The foilowing spreading oils are particularly suitable: isopropyl myristate, isopropyl palmitate, isopropyl stearate, caprylic/capric acid esters of saturated fatty alcohols of C12C18 chain length, waxy fatty acid esters, such as synthetic duck uropygial gland fat, silicone oils, a mixture of isopropyl myristate/isopropyl palmitate/isopropyl stearate, and coconut oil acid isopropyl ester.

Possible solvents are alkanols, such as ethanol and isopropyl alcohol, Methyl-Cellosolve, Cellosolve, esters, morpholines, dioxane, dimethalsulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone and the like.

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

Possible formulation auxiliaries are: a) Surfactants (including emulsifiers and wetting agents), for example 1. anionic, such as Na lauryl-sulphate, fatty alcohol ether-sulphates and monoethanolamine salts of mono/dialkyl polyglycol ether orthophosphates; 2. cationic, such as cetyltrimethylammonium chloride; 3. ampholytic, such as di-Na-N-lauryl-p-ininodipropionate or lecithin; and 4. nonionic, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, cetyl alcohol, glycerol monostearate, polyoxyethylene stearate and alkylphenol polyglycol ethers.

b) Stabilisers for preventing the chemical degradation which may occur to some active compounds, such as antioxidants, for example tocopherols and butylhydroxyanisole.

Testing of the activity of the agents according to the invention on guinea pigs which have been infected with Trichophyton.

Trichophyton-infected Pirbright white guinea pigs weighing on average 600 g were used as the test model for comparative testing of the activity of the agents according to the invention. The backs of the animals were shaved with electric clippers so that stubble about 1/1 0 mm long remained.

The animals were infected with Trichophyton mentagrophytes by gently rubbing a spore suspension, which had been germinated in Sabouroud nutrient solution for 24 hours, of the pathogen over an approximately 2x2 cm area of their shaved backs. 0.5 ml of germ suspension containing 1-3 xl 05 infectious fungal particles was applied per animal.

With this mode of infection, the first symptoms of dermatophytosis manifest themselves as reddening and scaling of the skin 2-3 days after infection. In the case of untreated animals, the dermatophytosis is of maximum severity about 14 days after infection. Areas of hair loss and bloody integumentary defects within a scaly edge zone changed by inflammation.

The formulations to be tested were applied locally to the reddened infection site on the animals once, on the 2nd day after infection. In each case 0.5 ml of the formulations=5 mg of active compound ( 1% strength formulation) was applied. The progress of the infection was evaluated daily up to the 20th day after infection.

The formulations according to the invention exhibited a very good action in this test.

If formulations which, in addition to bifonazole, contain neither spreading agent nor solvent are used for comparison, only a weak action is achieved.

Recipes for agents according to the invention are given in the examples which follow. The individua-l components are mixed with one another at room temperature and thereby dissolve.

Preparation of the Active Compound Bifonazole

Process variant (a) 1 3.6 g (0.2 mol) of imidazole are dissolved in 1 50 ml of acetonitrile, and 3.5 ml of thionyl chloride are added at 1 0 C. 13 g (0.05 mol) of diphenyl-phenyl-carbinol are added to the solution of thionyl-bis-imidazole thus obtained. After the mixturntas been left to stand at room temperature for 1 5 hours, the solvent is removed by distillation in vacuo. The residue is taken up in chloroform and the mixture is washed with water. The organic phase is separated off, dried over sodium sulphate and filtered and the solvent is distilled off in vacuo. The oily residue is dissolved in ethyl acetate and the solution is freed from insoluble, resinous constituents by filtration.The solvent is distilled off again in vacuo and the residue is purified by recrystallisation from acetonitrile. 8.7 g (56% of theory) of diphenyl-imidazol- 1 -vI-phenyl-methane (bifonazole) of melting point 1 42 C are obtained.

Starting substance

38.8 g (0.15 mol) of 4-phenyl-benzophenone are dissolved-in 200 ml of methanol, and 3 g (0.075 mol) of sodium borohydride are added. After the mixture has been heated under reflux for 1 5 hours, the cooled reaction mixture is hydrolysed with water containing a small amount of hydrochloric acid. The solid thereby formed is purified by recrystallisation from ethanol. 36 g (89% of theory) of diphenylphenyl-carbinol of meiting point 72-730C are obtained.

Process variant (b/3.) 167 g (0.6 mol) of diphenyl-phenyl-chloro-methane and 92 g (0.66 moi) of trimethylsilylimidazole, dissolved in 500 ml of acetonitrile, are heated under reflux for 1 5 hours. After the solvent has been distilled off, the crystalline residue is purified by recrystallisation from ethyl acetate. 97 g (52% of theory) of diphenyl-imidazol-1-yl-phenyl-methane (bifonazole) of melting point 1 420C are obtained.

EXAMPLE 1 Bifonazole 1.0 g Isopropyl myristate 52.6 g -Ethanol 30.0 g 100 ml=83.6 g Action in the guinea pig test: very good action EXAMPLE 2 Bifonazole 0.5-1.5 g Isopropyl myristate 10-60 g Ethanol 20-80 g Action in the guinea pig test: very good action.

Sprays The bifonazole solutions prepared according to Example 1 and 2 can also be processed to sprays.

For this purpose, for example, 60-90% of solution are mixed with 2040% of customary propellants, for example N2, N20, CO2, propane, butane, a halogenohydrocarbon and the like.

Claims

1. Antimycotic agents having a relatively high release of the active compounds and containing bifonazole and conventional formulation auxiliaries, characterised in that they contain 1060% of a spreading agent and 2080% of a solvent.

2. Antimycotic agents according to claim 1, characterised in that they contain bifonazole in amounts of 0.051.5%, preferably 1%.

3. Antimycotic agent according to Claim 1, characterised in that it is a solution.

4. Antimycotic agent according to Claim 1, characterised in that it is a spray.

5. Process for the preparation of formulations of bifonazole, characterised in that, in a manner which is known per se, either (a) the carbinol of the formula

if appropriate in the presence of a diluent, and, if appropriate, the azol-1 -yl-methane thereby obtained is reacted with physiologically acceptable acids, the product thereby obtained is mixed with 1 0-60% of a spreading agent and 20-80% of a solvent and, if appropriate, the solution thus obtained is mixed with a propellant.

6. Antimycotic agent according to claim 1, substantially as described in Example 1 or 2.

7. Composition as defined in claim 1 for use in combating mycoses.