JPS59184125A - Antimycotic - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention utilizes known antimycotic formulas that have a depot effect and a relatively high bioavailability of the active compound, thereby allowing short-term treatment. The present invention relates to a novel formulation of the compound bifonazole.

Compositions of anti-mycotic derivatives have already been disclosed for the treatment of human mycoses, in particular cutaneous mycoses, in order to shorten the duration of treatment, in particular to eliminate bacteria and mycological ( my
Some degree of cumulative effect and high bioavailability of the active compound is required to achieve cologic al) healing. The known compositions are suitable here only to a limited extent, since only small amounts of the active compound are dissolved in the volume of fluid at the site of infection. Thus, an optimal bioavailability of the active compound should be confirmed if the treatment period is shortened, for example to a few days, with once-daily administration without further increasing the concentration of the active compound.

10-60'l of spreading agent
nt) and 20 to 80% solvent and the usual pharmaceutical auxiliaries, the composition of pifonazole is shortened to a few days by optimal release of the active compound and thus high active compound concentrations are achieved. It was found that a longer period of treatment could be obtained. This effect is achieved in that the action of the bifonazole contained in the composition is increased by the extender and the solvent, and thereby the release of the active compound can be increased by up to 10 times. The composition according to the invention therefore represents a new administration principle for bifonazole for the skin treatment of mycoses.

The composition according to the invention can be either a liquid or a spray. These can be prepared by reacting (α) a carbinol of the following formula with thionyl-bis-imidazole in the presence of an appropriate diluent by a method known per se, or (b) reacting a carbinol of the following formula with thionyl-bis-imidazole in the following formula, where Bαl is a halodane atom. A halogeno-methane representing 1) is reacted with imidazole in the presence of an appropriate acid binder and an appropriate diluent, and 2) is appropriately diluted with a silver salt or alkali metal salt of imidazole. or 3) react with trimethylsilylimidazole of the following formula in the presence of an appropriate diluent, and optionally odor the obtained azol-1-yl-methane to physiological and the product thus obtained is treated with 10 to 60 acids of extender and 20 to 8
It is prepared either by mixing with 0 ml of solvent and optionally mixing the solution thus obtained with a propellant.

The drug according to the invention (αgent) has a range of 0.05 to 1.
Bifuonazole is included in an amount of 5 parts, preferably 1 part.

By extension agent is to be understood an oily liquid which itself distributes easily, especially on the skin [RlKeymer,
pharm, Ind, 32 (19'70), 77
Pages ~ 81]. The following compounds are particularly suitable spreading agents for the agents according to the invention: Silicone oils of various viscosities.

Di-n-butyl adipate, hexyl laurate, sopropylene glycol pelargonate, saturated 016~1g of medium-chain branched fatty acids with fatty alcohols, isozorobyl myristate, isopropyl palmitate, C□ ~C1, chain length saturated fatty alcohols Cagrilic acid/Cagliic acid esters, Isopropyl stearate, Oleyl oleate, Decyl oleate, Ethyl oleate, Ethyl lactate, Waxy fatty acid esters such as synthetic ducktail fat, Duptyl phthalate , soisoprobil asopate, ester mixtures regarding the latter, etc.

Triglycerides, preferably caprylic/capric triglycerides, CII to C1, mixtures of triglycerides with chain length vegetable fatty acids or other particularly selected naturally occurring fatty acids, partially containing saturated or unsaturated fatty acids, optionally also containing hydroxyl groups. Glyceride mixture, Cs/C+
. - Monoglycerides of fatty acids, etc.

oleyl, cetyl-atearyl alcohol and oleyl alcohol.

Fatty acids, such as oleic acid.

The following diffusing oils are particularly suitable: isozolovir myristate, isoglobil noglumitate, isopropyl stearate, caprylic/capric esters of saturated fatty acids with chain lengths from 012 to CI8, waxy fatty acid esters such as synthetic ducktail glands. Fat, silicone oil, mixture of ingropil myristate/isoglobil palmitate/isopropyl stearate, and palm oil acid isopropyl ester.

Possible solvents are alkanols such as ethanol and inzolovyl alcohol, methyl-cellosolve, phoxite, trimethylformamide, tetrahydrofuran, cyclohexanone and the like.

One or more solvents can be used in preparing the compositions according to the invention.

Possible formulation auxiliaries are: α) Surfactants (emulsifiers and wetting agents), such as 1.7-ionic ones such as Nα sulfate-lauryl, fatty alcohol sulfate ethers and orthophosphoric acid. 3. Monoethanolamine salts of mono/dialkyl polydalicol ethers; dicationic ones such as cetyltrimethylammonium chloride; 3. amphoteric ones such as Nα-N-lauryl-β-iminoduprobionate or lecithin; and 4. Non-ionic ones such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, cetyl alcohol, dalicerol monostearate, polyoxyethylene stearate and hyalkylphenol polyglycol ethers.

b) Stabilizers to prevent possible chemical deterioration of certain active compounds, such as antioxidants such as tocopherol and butylhydroxyanisole.

Testing of the activity of the agent according to the invention on guinea pigs infected with Trichophyton.

Pirbright white guinea pigs infected with Oromycetes weighing an average of 6001 kg were used as a test model for comparative testing of the activity of the agents according to the invention. The animal's back was clipped with electric clippers to leave the hair at approximately the length of the animal.

Infect the animals with M. chinensis by gently placing a spore suspension of the pathogen developed in a 24-hour culture on the back along an approximately 2 × 20 area. I let it happen. 0.5 - of bacterial suspension containing 1-3 x 10 5 infectious mold particles per animal was applied.

With this mode of infection, the first signs of dermatophytosis become evident by themselves as redness and scaling of the skin 2-3 days after infection. In untreated animals, dermatophytosis reaches its peak approximately 14 days after infection. Hair loss and bleeding integuments are defective within the desquamated distal areas altered by inflammation.

The composition to be tested was applied once locally to the infected area of the animals, which developed redness on the second day after infection. In each case the composition 0.
5? m = 5 parts of active compound (1 part of the composition) applied.

Infection progress was assessed daily on day 20 post-infection.

In this test the composition according to the invention showed a very good effect.

If a composition containing neither extender nor solvent in addition to bifonazole is used for comparison, it works for only one week.

A prescription for a drug according to the invention is illustrated in the following example.

The individual components are mixed together at room temperature and are thereby dissolved.

Variant (α) Imidazole ia, 5f (Q, 2 mol) was dissolved in acetonitrile 150- and thionyl chloride 3.5- was added at 10°C. Duphenylphenyl-carbinol 13F (0.05 mol) was added to the solution of thionyl-bis-imidazole thus obtained. After the mixture was allowed to stand at room temperature for 15 hours, the solvent was removed by distillation in vacuo. The residue was taken up in chloroform and the mixture was washed with water. The organic phase was separated off, dried over sodium sulfate, filtered and the solvent was distilled off in vacuo.

The oily residue was dissolved in ethyl acetate and the solution was separated from insoluble resinous components by filtration. The solvent was distilled off again in vacuo and the residue was purified by recrystallization from acetonate. Diphenyl-imidazol-1-yl-phenyl-methane (bifunazole) with melting point 142°C 8.7? (coefficient of 56 of theoretical quantity) was obtained.

Starting material 4-phenyl-benzophenone 38.81F (0,15
mol) was dissolved in 200 tnl of ethanol and sodium borohydride CM (0,075 mol) was added. After heating the mixture under reflux for 15 hours, the cooled reaction mixture was hydrolyzed with water containing a small amount of hydrochloric acid. The resulting solid was purified by recrystallization from ethanol. There was obtained 362 (89 parts of theory) tunophenyl-phenyl-carbinol, melting point 72-73°C.

Sophenylphenylchloromethane 167f (0.6 mol) and trimethylsilylimidazole 92f (0.66 mol) dissolved in acetonitrile 500°C were heated under reflux for 15 hours. After evaporation of the solvent, the crystalline residue was purified by recrystallization from ethyl acetate. Melting point 142
Diphenyl-imidazol-1-yl-phenyl-methane (bifunazole) 91f (theoretical amount of 52 thi) was obtained at a temperature of <RTIgt;

Example 1 Bifuonazole 1.0f Isopropyl myristate 5262 Ethanol
30. Orl 00ml! =83
．． 6F Effect in guinea pig test: Very good effect Example 2 Bi7onazole 0.5-1.52 Isopropyl myristate 10-60 Taethanol
20-801 Effect in Guinea Pig Test: Very Good Effect Spray The bifonazole solutions prepared according to Examples 1 and 2 can also be processed into a propellant. For this purpose,
For example, 60-90% liquid agent and 20-40 inches of normal projectile agent, such as N, 1. Mixed with N, 0, CO2, prozene, butane, halogeno hydrocarbons, etc.

18

Claims (1)

Claims: 1. An antifungal agent having a relatively high release capacity of the active compound and containing bifonazole and the usual pharmaceutical auxiliaries, an extender of 10 to 60 and an extender of 20 to 80. An anti-fungal agent characterized by containing a solvent according to the invention. 2. The anti-fungal agent according to claim 1, characterized in that it contains bifuonazole in an amount of 0.05 to 1.5, preferably 1. 3. The anti-fungal agent according to claim 1, which is a liquid preparation. 4. Claim 1 characterized in that it is a spray agent.
Anti-fungal agent as described in section. 5(a) Carbinol of the following formula is converted into thionyl-
or (b) the Chiho formula, where Hαl represents a halogen atom, is reacted with halogeno-methane, 1) in the presence of imidazole and an appropriate acid binder, and optionally in the presence of a diluent. 2) React with a silver salt or alkali metal salt of imidazole in the presence of an appropriate diluent, or 3) React in the lower right of the following formula, and optionally smell. The resulting azol-1-yl-methane is reacted with a physiologically acceptable acid and the product thus obtained is treated with an extender of 10-60 and an extender of 20-8.
A process for producing a bifonazole preparation, characterized in that it is either mixed with a 0% solvent and, if appropriate, the solution thus obtained is mixed with a projectile agent.