NO158922B - PROCEDURE FOR THE MANUFACTURE OF AZOLD DERIVATIVE ANTIMYCOTIC AGENT WITH HIGH RELEASE OF ACTIVE SUBSTANCES. - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, NL, SE Antimycotic agents in emulsion form which have a higher degree of release of the active compounds and contain azole derivatives and customary formulation auxiliaries, characterised in that they contain as solubiliser 3 to 5% by weight of benzyl alcohol and as spreading agents 2.5 to 20% by weight of 2-octyldodecanol, oleic acid decyl ester, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C12 -C18 chain length, waxy fatty acid esters, silicone oils, and isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture or coconut oil acid isopropyl ester. 1. Claims for the Contracting State : AT Process for the preparation of antimycotics based on azole derivative active compounds and customary formulation auxiliaries, characterised in that the active compounds and formulation auxiliaries are formulated as an emulsion together with 3 to 5% by weight of benzyl alcohol as the solubiliser and with 2.5 to 20% by weight of 2-octyldodecanol, oleic acid decyl ester, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C12 -C18 chain length, waxy fatty acid esters, silicone oils, an isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture or coconut oil acid isopropyl ester as spreading agents, based in each case on the total weight.

Description

The invention relates to a method for manufacturing

of an azole-derivative antifungal agent with a high release of active substances, containing common formulation excipients, whereby a short-term therapy is made possible.

Preparations of antifungal derivatives are already known for the treatment of mycoses in humans, above all the mycoses of the skin and the skin attachment structures. With these preparations, 14-21 days of therapy are required for complete remediation.

For e.g., in the case of vaginal or buccal mycosis or dermatomycosis, a reduction in the duration of therapy is required especially for the elimination of the germs or to achieve

a mycologically assured remediation a higher release of the active substance in the aqueous environment. For this, the known formulations are only limitedly suitable because of the active, substance supply present, only a small part dissolves in the liquid plume at the inspection site. When, with or without a further increase in active substance concentration, a reduction in the duration of therapy will be achieved, e.g. to a day with a single application, one must ensure optimal biodisposability of the active substance.

The invention relates to a method for production

of an azole-derivative antifungal agent with a high release of active substances containing common formulation substances, the method being characterized by adding a mixture heated to 70°C of formulation aids and dispersing agent to 75°C hot demineralized water, possibly with added formulation aids, while stirring,

whereby, after slow cooling to 40°C with stirring, the azole derivative dissolved in benzyl alcohol is added to this mixture, after which the crude emulsion is homogenized at 20-25°C

in a high-pressure homogenizer, the proportions being chosen so that the total antifungal agent has a content of 3-5% benzyl alcohol and 2.5-20% dispersants.

In a preferred embodiment according to the invention, chlortrimazole with formula is used as azole derivative

The further preferred embodiment of the method according to the invention uses trifonazole as an azole derivative with the formula In a further preferred embodiment of the method according to the invention, lombazole is used as an azole derivative with the formula

In the method according to the invention, the quantity ratios are preferably chosen so that the agent has a content of antifungal azole derivative of 0.05-1%, preferably 0.1-1%.

Numerous additional antifungally active azole derivatives

are known from DE-OS 24 30 039. They can also serve as active substances in the agents produced according to the invention.

Dispersants are understood as oily liquids that distribute

feels particularly good on the skin [R. Keymer, Pharm. Ind. 32

[197Q], 577-581]. For the agents according to the invention, the following compounds are particularly suitable as dispersants:

Silicone oil of different viscosity.

Fatty acid esters, such as ethyl stearate, di-n-butyl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, medium chain branched fatty acid esters of saturated fatty alcohols ci£_C^g, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of chain length Ci2 -C18' isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duck fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ede. es*terb.landinger etc.

5E.i2iZ£SEi4§E'as caprylic/capric acid triglyceride, triglyceride mixtures with plant fatty acids of chain length cq~ c^ 2 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids possibly also containing hydroxyl groups, monoglycerides of Cg/ <C->^<->fatty acids etc.

E§i$alkoholé£ i as isotridecyl alcohol, 2-octyldodecanol, cetyls-tearyl alcohol, oleyl alcohol.

E§£ts.y;£er, SOItl e.g. oleic acid.

Particularly well-suited spreading oils are the following: isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of chain length C±2~ C18' v°kactic fatty acid esters such as artificial duck goiter fat, silicone oil, isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture.

The following additional aids and/or formulation-based aids can be used in the preparation of the agents according to the invention:

Furthermore, the following formulation aids can also be used: Glycerol, viscous paraffin, thin paraffin, triethanolamine, collagen, allantoin, novantisolic acid, perfume oil.

Furthermore, it is suitable:

a. Substances such as can stabilize a suspension, e.g.

colloidal silicic acid, montmorillonite etc.

b. Surfactants (including emulsifiers and wetting agents), e.g.

1. anion-active, such as Na-lauryl sulfate, fatty alcohol-ether sulfates, mono/dialkyl polyglycol ether-orthophosphoric acid ester-monoethane1aminsa1t,

2. cation active, such as cetyltrimethylammonium chloride,

3. ampholytic, such as Di-Na-N-lauryl-£S.-ininodipropionate or lecithin, 4. non-ionic, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, cetyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether. c. Stabilizers to prevent the chemical breakdown that occurs with some active substances such as antioxidants, e.g. tocopherol, butylhydroxyanisole.

d. Softeners, e.g. propylene glycol, glycerol, D.i-

and tripropylene glycol, triethanolamine, wax;'.etc.

As gel formers, such macromolecular compounds that dissolve or swell in water also form a type of film in organic solvents and after drying.

If one follows a division of the macromolecular excipients [Keipert et al., Die Pharmazie 28, 145-183 (1973)], then above all ionic macromolecules are used in their salt form. These are i.a. sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid and propylene glycol alginate as sodium salt, gum arabic, xanthan gum, guar gum.

Amphoteric macromolecules such as protein derivatives, e.g. gelatins, are also suitable as non-ionic polymers, e.g. methyl cellulose, hydroxypropyl cellulose and soluble starches that meet the above requirements.

As a solvent, water is suitable and also all water-miscible solvents. Taking into account e.g. alkanols such as ethanol and isopropyl alcohol, propylene glycol, methylcello solvents, cellulose solvents, esters, morpholines, dioxane, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone.

In the preparation of the formulations according to the invention, one or more solvents may be used.

Ekaemge.1^1 Emulsion, O/W

Phase 1

The mixture is stirred and melted at 70°C.

Phase jr

Demineralized water 58.00 g Phase III

To phase II heated to 75°C, phase I heated to 70°C is added while stirring. One lets. it slowly cools to 40°C, adds phase III and allows it to cool with stirring to room temperature. The raw emulsion is homogenized at 20-25°C in a high-pressure homogenizer.

Examples 2 and 2 are processed in an analogous way.

Example_2 Emulsion, O/W

Eksemgel_3 Emulsion O/W

Trifonazole mlcron. Example_4_ Cream, soft consistency O/W

Eksemrj§l_5_ Cream, soft consistency O/W Eczema gel_6 Cream, soft consistency O/W

Eczema<pe>l_7 Emulsion, non-greasy O/W

Phase. IN

Phase II

Disperse with Turrax, let it swell for 2 hours and then neutralize with 0.155 g of 45% caustic soda.

To 75°C warm phase II, the 70°C warm phase I is placed under: stirring and cooled to 45°C. At 45°C, carbopol slime is stirred in and cooled to 40°C further. At 40°C, 1.00 ■ collagen is added and cooled to 25°C. 1.0 g of lombazole is dissolved in 3.0 g of henzyl alcohol and added to phases I and II'.

Then 0.600 g of perfume is added and the raw emulsion is homogenised while stirring at 20°C-25°C in a high-pressure homogeniser. Examples 8, 9, 10 and 11 are processed in an analogous way.

Ex.emp_e.l_8 Emulsion, non-greasy O/W

Ek§emj3el__ Emulsion, non-fatty O/W

Eksemgel_10 Emulsion, non-greasy O/W

Ek_'emgel_ll Emulsion, non-greasy O/W.

__<&emgel>_12 Cream, soft consistency O/W

Eczema_e___3 Cream, soft consistency O/W

E<_>s<_>mpel_l<_>(Cream, soft consistency O/W) EIS.§§S!E§i._iå (Cream, transparent in gel form)

Effect investigation of the agent according to the invention on trichophyton-infected guinea pigs.

Trichophyton-infected Pirbright white guinea pigs with an average weight of 600 g were used as a test model for comparative effectiveness research of the formulations produced according to the invention. The animals were shaved on their backs with an electric shaver, so that approx. 1/10 mm long hair stubs.

The infection with Trichophyton mentagrophytes took place by light expulsion of a 24-hour Sabouraud nutrient solution inoculated spore suspension of producers of approx. 2 x 2 c: large area of the shaved back of the animals. It was applied per animal 0.5 ml germ suspension containing 1-3 x 10 5 infectious fungal particles.

With this mode of infection, the first symptoms of dermatophytosis such as reddening and crusting of the skin appear 2-3 days post-infection. In untreated animals, approx. 14 days p.i. the dermatophytosis was maximally pronounced: flat hair loss and bloody integument defects within an inflamed altered crusted border zone.

The formulations to be examined were once on the second day post infectionem applied locally to the irritated infection sites of the animals and expelled lightly with a horn spatula. It was applied each time 0.5 ml of the formulation is equal. 5 mg of active substance (1% formulation). The assessment of the infection course took place daily until the 20th day p.i.

The test results appear in the table below.

If, instead of the formulations produced according to the invention, formulations which do not contain benzyl alcohol and no dispersant are used, then an effect corresponding to that with the formulations produced according to the invention is only achieved after three applications.

Claims (5)

1.Procedure for the production of azole-derivative antifungal agents with a high release of active substances containing common formulation aids, characterized in that a mixture of formulation aids and dispersant heated to 70°C is added to 75°C warm demineralized water, possibly with formulation aids, while stirring, to this mixture, after slow cooling to 40°C with stirring, the azole derivative dissolved in benzyl alcohol is added, after which the raw emulsion is homogenized at 20-25°C in a high-pressure homogenizer, the proportions being chosen so that the total antifungal agent has a content of 3-5 % benzyl alcohol and 2.5-20% dispersant, 2. Method according to claim 1, characterized in that chlortrimazole with formula is used as an azole derivative 3. Method according to claim 1, characterized in that trifonazole with formula is used as an azole derivative 4. Method according to claim 1, characterized in that lombazole with formula is used as an azole derivative 5. Method according to claim 1, characterized in that the quantity ratios are chosen so that the agent has a content of antifungal azole derivative of 0.05-1%, preferably 0.1-1%.