LU87312A1 - PHARMACEUTICAL PREPARATIONS FOR TOPICAL USE - Google Patents

Description

4 - 1 - 4-16635 / + /

Pharmaceutical preparations for topical use

The invention relates to new antimicrobial pharmaceutical preparations for topical use. More specifically, the invention relates to antimicrobial pharmaceutical preparations for topical use, based on the fact that a compound from the group of active substances, which contains an imidazole substituted by a lower alkyl group in its molecule, is used in combination with one or more optionally substituted benzoic acids as the antimicrobial active substance the combination resulting in a synergistic antimicrobial effect.

EP-A-0007595 describes pharmaceutical preparations containing the antifungal active ingredient clotrimazole (l - [(2-chlorophenyl) di-phenylmethyl] -lH-imidazole) for external use, in particular a new gel, cream or containing this active ingredient also liquid preparations containing crotamiton (N-crotonyl-N-ethyl-o-toluidine) as a solvent.

Furthermore, EPA-0070525 describes pharmaceutical preparations containing antifungal agents which have an imidazole ring in the molecule, such as e.g. Miconazole, econazole or isoconazole, which are dissolved in crotamiton, peppermint oil or methyl salicylate, the latter also having pharmaceutical effects as skin preparations, but none of them is antifungal.

As a result of further investigations, as also described in more detail later, it was found, surprisingly and unexpectedly, that the combination consisting of an antimicrobial active ingredient from the "- 2 -

Group of active substances which contain in their molecule an imidazole substituted by a lower alkyl group, corresponding to a compound of the formula I.

8-1!

V

CH a— (jJH — 0 — GH 2— * y — Rz (I) A / cl

I II

V

il

wherein at least one of the substituents R 1, R 2 and R 3 is a halogen atom and the other are hydrogen, both also their pharmaceutically acceptable acid addition salts or corresponding to a compound of the formula II

· () · —-J <CsH5> 2 <n> • ·

1'-I

wherein R 1 represents a halogen atom, with one or more optionally substituted benzoic acids and optionally conventional pharmaceutical carriers and / or auxiliaries in pharmaceutical preparations for topical use, has an extraordinary synergistic antimicrobial effect.

Optionally substituted benzoic acids are those which contain one or more halogen atoms, hydroxyl or also lower alkoxy groups as a substituent in different positions of the benzene ring. Optionally, preference is given to monosubstituted benzoic acids which carry the substituent ortho to the carboxy group in the benzene ring.

Of particular interest in the combinations mentioned above is the use of o-hydroxy-benzoic acid, salicylic acid and / or the unsubstituted benzoic acid.

Halogen is bromine, iodine or fluorine, but especially chlorine.

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Lower alkoxy is ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, especially methoxy.

The combination of the above-mentioned active ingredients has an unexpected synergistic antimicrobial effect of the individual components.

The invention relates in particular to antimicrobial pharmaceutical preparations for topical use, consisting of the combination of a compound of the formula I in which at least one of the substituents R 1, R 2 and R 3 is a chlorine atom and the other hydrogen, and also their pharmaceutically acceptable acid addition salts, such as e.g. Miconazole (Ri = R2 = Cl, R3 = H), econazole (R2 = Cl, Ri a R3 = H) and isoconazole (Ri = R3 = Cl, R2 = H) or a compound of formula II, wherein Ri, is a chlorine atom means, such as Clotrimazole and one or more optionally substituted benzoic acids and optionally conventional pharmaceutical carriers and / or auxiliaries.

The invention relates in particular to those topically applicable pharmaceutical preparations which, because of the synergistic effect, have particularly effective antimicrobial properties, consisting of the combination of miconazole as a compound of the formula I, in which R 1 and R 2 are a chlorine atom and R 3 is hydrogen or a pharmaceutically acceptable acid addition salt thereof or from a compound of the formula II in which Rij is a chlorine atom, clotrimazole and salicylic acid and / or benzoic acid and, if appropriate, customary pharmaceutical carriers and / or if appropriate auxiliaries.

The invention preferably relates to those particularly effective topically applicable pharmaceutical preparations which contain a combination of micon azole nitrate or clotrimazole and salicylic acid and / or benzoic acid and, if appropriate, customary pharmaceutical carriers and / or auxiliaries.

All physiologically acceptable acids are suitable for the preparation of pharmaceutically acceptable acid addition salts of the compounds of the formula I. The following acids should be mentioned as examples, t - 4 -: hydrohalic acids, e.g. Hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, also sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, such as e.g. Formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malonic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, also p-aminobenzoic acid, p-aminobenzoic acid, also p-aminobenzoic acid, also p-aminobenzoic acid, also Methane, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, 1,5-naphthalenedisulfonic acid or sulfanilic acid, methionine, trypthophane, lysine or also arginine.

The pharmaceutical preparations according to the present invention have antimicrobial, in particular antifungal and antibacterial properties. So they are e.g. effective against those microorganisms that occur with dermal injuries and damage, e.g. Tri-chophyton species, for example Trichophyton mentagrophytes, Epiderma-phyton, for example Epidermaphyton floccosum, Microsporon, for example Microsporon felineum, Aspergillus species, such as e.g. Aspergillus niger and Aspergillus funigatus, yeasts such as Pytyrosporum species, Candida species such as Candida albicans and gram positive bacteria such as e.g. Staphylococcus species, for example Staphylococcus aureus, Pseudo-monas aeruginosa, Propioni bacterium and Coryne bacterium acnes. The enumeration of these microorganisms does not in any way limit the number of germs which can be controlled, but is only of an explanatory nature.

The pharmaceutical preparations which can be prepared according to the invention can be used as antifungal agents for the treatment of skin infections caused by dermatophytes and sprout fungi, such as e.g. Dermatomycoses and system mycoses or as an antibacterial agent for the treatment of acne, dandruff and other skin conditions. Furthermore, the combinations that can be produced according to the invention also have anti-pruritic properties and can be used for the treatment of pruritus diseases.

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In addition to the combinations of a compound of the formula I or II and one or more optionally substituted benzoic acids, the pharmaceutical preparations according to the invention for topical use also contain pharmaceutically acceptable carriers or auxiliaries. The daily dose of active ingredients depends on the age or other individual conditions of the patient and also on the type of formulation.

As the preferred concentration of the combined active ingredients in the formu- gated preparations, the range of 0.01-10% (weight) applies to the lower alkyl-substituted imidazoles of the formula I or II, preferably 0.1-2% (weight) and 0.5-25% (weight) for one or for several optionally substituted benzoic acids, but preferably 1-15% (weight).

Suitable pharmaceutical preparations for topical use include creams, ointments and gels, as well as powders, pastes, lotions, tinctures, foams, sprays, aerosols, solutions and balms.

Creams or lotions are oil-in-water emulsions that contain more than 50% water. Fatty alcohols, e.g. Lauryl, cetyl or stearyl alcohol, fatty acids e.g. Palmitic or stearic acid, liquid to solid waxes, e.g. Isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, e.g. Fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), furthermore polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. Sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are commonly used in the presence of fatty alcohols, e.g. Cetyl alcohol or stearyl alcohol. Additions to the water phase include Agents which prevent the creams from drying out, e.g. Polyalcohols, such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.

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Ointments or lotions are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phase. The fatty phase is primarily hydrocarbons, e.g. Vaseline, paraffin oil and / or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, e.g. Cetyl alcohol or wool wax alcohols or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), e.g. Sorbitan oleate and / or sorbitan isostearate. Additions to the water phase include Humectants such as polyalcohols e.g. Glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.

Microemulsions are isotropic systems, the basis of which consists of the following four components: water, an emulsifier, such as a surfactant, e.g. Eumulgin, a lipid such as a non-polar oil, e.g. Paraffin oil, and an alcohol with a lipophilic group, e.g. 2-0ctyldodecanol. If desired, other additives can be added to the microemulsions.

Fatty ointments are anhydrous and contain hydrocarbons, e.g. Paraffin, petroleum jelly and / or liquid paraffins, also natural or partially synthetic fat, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerin, e.g. Glycerol mono- and distearate, as well as e.g. the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments, which increase the water absorption capacity.

A distinction is made between aqueous, water-free or low-water gels, which consist of swellable, gel-forming materials. Transparent hydrogels based on inorganic or organic macromolecules are primarily used. High-molecular inorganic components with gel-forming properties are predominantly water-containing silicates, such as aluminum silicates, e.g. Betonite, magnesium aluminum silicates, e.g. Veegum, or colloidal silica, e.g.

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Aerosil. Natural, semisynthetic or synthetic macromolecules, for example, are used as high-molecular organic substances. Natural and semi-synthetic polymers are derived, for example, from polysaccharides with a wide variety of carbohydrate components, such as celluloses, starches, tragacanth, arabic gum, agar-agar, gelatin, alginic acid and their salts, e.g. Sodium alginate, and their derivatives such as lower alkyl celluloses, e.g. Methyl or ethyl celluloses, carboxy or hydroxy lower alkyl cellulose, e.g. Carboxymethyl or hydroxyethyl celluloses. The building blocks of synthetic, gel-forming macromolecules are, for example, appropriately substituted unsaturated aliphatics, such as vinyl alcohol, vinyl pyrrolidine, acrylic or methacrylic acid. Examples of such polymers are polyvinyl alcohol derivatives, such as polyviol, polyvinylpyrrolidines, such as Kollidon, polyacrylates or polymethacrylates, such as Rohagit S or Eudispert. Common additives, such as preservatives or fragrances, can be added to the gels.

Pastes are creams and ointments with secretion-absorbing powder components such as metal oxides, e.g. Titanium oxide or zinc oxide, also talc and / or aluminum silicates, which have the task of binding moisture or secretions.

Foams are e.g. administered from pressure vessels and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons such as chlorofluoro lower alkanes e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane can be used as blowing agents. The oil phase used includes Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, and / or other waxes. The emulsifiers used include Mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, there are the usual additives such as preservatives, etc.

Tinctures and solutions usually have an ethanol base, to which water may be added and which, among other things. Polyalcohols, e.g. Glycerin, glycols, and / or polyethylene glycol, as humectants to reduce evaporation, and refatting substances, such as fatty acid - 8 - esters with low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol, and, if necessary, other auxiliaries and additives are added.

The topical pharmaceutical preparations are prepared in a manner known per se, e.g. by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. When the active ingredient is administered as a solution, it is usually dissolved in one of the two phases before emulsification; when processed as a suspension, it is mixed with part of the base after the emulsification and then added to the rest of the formulation.

The superiority of the pharmaceutical preparations which can be produced and formulated according to the invention from the combination of active substances mentioned is based on the synergistic antimicrobial action of the individual active substance components.

Synergism

In the event that different active ingredients are added in a formulation, their properties can have counteracting, additive or synergistic effects. The synergistic effect is apparently the most desirable effect, since on the one hand this allows low doses and on the other hand an improvement in activity over that of the individual components. With the antimicrobial, in particular the antimycotically active compounds or combinations thereof, the ability to inhibit the growth of germs is determined by measuring the MIC (minimum inhibitory concentration) and killing rate on the basis of the measurement of the inhibition zone.

If the expression "Fractional Inhibitory Concentration (FIC)" as a fraction - 9 -

Minimum inhibitory concentration (MIC) of the active components in the combination product (the test is carried out with 2 or 3 active components in solution at the same time) FIC = -

If the minimum inhibitory concentration (MIC) of the individual active component is defined (the test is only carried out with an active component in solution), then EFIC is to be equated to the sum of the FIC values determined if there is no interaction between the individual components. In other words, if there is synergism, the sum of the FIC values of the individual components is smaller than the EFIC size for the combination of the active substances. The determined size EFIC provides information about the strength of the interaction of individual components of a combination.

The minimum inhibitory concentration (MIC) The minimum inhibitory concentration (MIC) in pg / ml for miconazole (miconazole is used as nitrate), salicylic acid, benzoic acid alone or in combination is shown in Table 1 below, whereas the results leading methods are described below.

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Table 1

Germ MIC (pg / ml) Fractional SUM

Miconazole S. B. Inhibitory Conc FIC

nitrates (FIC) (partial inhibitory concentration) C. albicans 4-8 1365 680 0.25 200 - 0.0625 + 0.146 = 0.2 0.5 - 200 0.125 + 0.294 = 0.389 0.25 100 100. 0.063 + 0.07 + 0.15 = 0.28 1 2 3 4 5 mentagrophytes 1 - 670 310 2 0.5 200 - 0.5 + 0.3 = 0.8 3 0.06 - 200 0.06 + 0.65 = 0.71 4 0.06 25 200 0.06 + 0.04 + 0.65 = 0.75 0.25 200 50 0.25 + 0.3 + 0.16 = 0.71 5 aureus 4 - S «salicylic acid, B = benzoic acid

The MIC values meet expectations. The values for miconazole show a good effect, whereas for benzoic or salicylic acid high concentrations, up to the limit of solubility, are required in order to achieve an MIC value. Subcultures from wells, which show no (microber) growth, showed that a concentration of - 11 -

Benzoic acid at or near the MIC also had a microbicidal effect, while the action of miconazole was primarily static, with new growth of microbes on the subcultures.

The MIC values determined for combinations of miconazole with salicylic acid or benzoic acid or both show higher than merely additive values of antimicrobial activity. The effect on the Candida albicans germ was much better for the combination of the active substances than would have been expected by adding the fractional inhibitory concentrations (FIC).

It was observed that concentrations that are considerably below the MIC values have a significant effect on growth. The observations made here that the individual components all contribute to the antimicrobial effect is important for the formulated product, where the diffusion of the individual products is limited per se.

The method of determining the vitro activities for miconazole, salicylic acid and benzoic acid in the germs Candida albicans, Trichophyton mentagraphytes and Staphylococcus aureus is described as follows.

The minimum inhibitory concentration (MIC) 1. Inoculum C. albicans N.C.Y.C. 610, T. mentagrophytes N.C.P.F. 80 and S. aureus N.C.T.C. 8532 are used as germs. C. albicans germs are grown overnight in SLM (Sabouraud Liquid Medium) at a temperature of 32 ° and the inoculum obtained is diluted approximately to 2 × 105 germs based on a total count of the germs. T. mentagrophytes microconidia germs are removed from a 12 day old culture, which are grown on SDA (Sabouraud Dextrose Agar) at a temperature of 32 °, and a washed aqueous suspension is stored in the frozen state. The in-vitro test is carried out in an appropriate dilution in SLM (Sabouraud Liquid Medium), as a nutrient medium with a germoculum of 2 x 105 germs / ml of substrate, based on a total count of the germs. A S. aureus culture grown at a temperature of 37 ° -12- (overnight) in "Isotonic Sensittest-Broth" (ISB) as a nutrient medium is diluted 1: 500 with ISB. This is followed by counting the living germs.

2. Solutions

Solutions of miconazole, salicylic acid and / or benzoic acid in meat broth are prepared by dilution to twice. At higher concentrations of salicylic acid and benzoic acid, the concentration of active ingredient in solution is checked by preparing a saturated solution, which is filtered through a 0.45 pm membrane filter. The resulting filtrate, which is used to achieve a double dilution for the MIC determination, is analyzed by HPLC (high pressure liquid chromatography), DMF (0.5%) is used as solvent for miconazole and was present in this concentration in all media.

3. In vitro test procedure

The MXC values of the individual active ingredients are determined by oculating 100 μΐ volume wells in a microtiter plate. An equal volume of inoculum is added and the plates are incubated at a temperature of 32 ° for both fungal germs and at a temperature of 37 ° for S. aureus. Combinations of 2 compounds each are prepared for the MIC values, and solutions are then made from them in 3 different required concentrations and then 75 μl of each compound and each inoculum are fed to the wells of the microtiter plate and incubated, as described. A three component system is also tested using 50 μ 50 volume to inoculate the plates.

Results

The results are read 24 hours after incubation for C. albicans and S. aureus and 6-7 days for T. mentagraphytes. The endpoints are determined visually and by measuring the "optical density" using a vertical scanning photometer at 450 nm. In particular, the reading of the optical density enables the effect of the concentrations below the MIC values on the growth to be investigated.

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The antimicrobial effects of various cream formulations are examined by estimating the zones of inhibition according to the following methods.

Measurement of inhibition zones (spread plate)

Inoculated approximately 1 x IO1 * germs / ml of each germ to be examined on the surface of an agar plate (SDA for yeast and fungal germs and TSA for bacteria) and dried for 30 minutes. Wells are made in the agar of the plate with a number 3 cork borer and these are filled with approx. 100 mg cream.

The plates are incubated overnight (longer in the case of fungal germs) at a temperature of 32 ° and the diameter of the zones of inhibition measured (see table).

Germs used; Candida albicans, Trichophyton mentagrophytes, Staphy-lococcus aureus, Pseudomonas aeruginosa.

A comparison of all agar diffusion tests shows that the combination MSB (miconazole + salicylic acid + benzoic acid) is significantly more effective than the others, namely miconazole alone or the combination SB (salicylic acid + benzoic acid).

Summarized results of the cream formulations MSB = cream contains miconazole, salicylic acid and benzoic acid, SB = cream contains salicylic acid and benzoic acid D = Daktarin® (2% miconazole) (cream manufactured by Janssen Pharmaceuticals, Belgium) M = miconazole 2%.

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Table 2

Organisms (germs) cream formulations

Inhibition zones (diameter, mm)

MSB SB M D

C.albicans (NCYC610) (1) 27 17.7 9.2 17.2 (2) 33.7 24.7 16.7 39.8 (3) 29.3 * 11.3 24.0 T. mentagrophytes 55 38 30.5 43 NC0F80, pregerminated T. mentagrophytes (1) 54.3 52.5 37.8 43 NCPF80, microconidia (2) 49.0 55.3 45.3 40.8 (3)> 80 * 43.5 54 T. mentagrophytes ATCC 18748 52.3 50.3 41.8 37 (Spread Plate results) T. mentagrophytes 56 54.6 28 * C. albicans 24 20 15.6 * T. mentagrophytes 44.6 34.9 * 30.9 MSB v D and M is significant at 0.05% (level) MSB v SB is significant at 2.5% (level) * = not measured - 15 -

Diffusion studies

Most pharmaceutical preparations consist of the active substance and the excipients and it is therefore extremely important to check the activity of the compound (active substance) in the chosen formulation. For topical usability, the diffusion of the active substance or substances from the formulation must be determined and for this purpose the plate diffusion test is used to check the usability of the product. The results are shown in Table 3. Formulations 1 to 7 all contain the same basic composition, but the active substances are different. The abbreviations used are self-evident, for example M2S3 stands for 2% miconazole and 3% salicylic acid. DJ stands for Daktarin® Janssen, AJ stands for Acnidazil® Janssen. When reviewing the data, it can be seen that the combination of miconazole, benzoic acid and salicylic acid is the most suitable for the microorganisms (germs) used. It should be noted that comparisons of all formulations were made at the same time because comparisons on different days do not give the same results. The relative ranking remains the same.

Determination of the antimicrobial activity of a cream formulation using a selection of germs

Table 3

Germ inhibition zones (diameter mm = the cream formulation 1. 2. 3. 4. 5. 6. 7. 8. 9.

M2S3 M2 S3B6 S3 B6 M2B6 M2S3B6 DJ AJ (C. albicans) 15.3 9.2 17.7 0 11.2 23 27 17.2 * (N.C.Y.C.610) T. mentagrophytes (N.C.P.F.80) 34 30.5 38 27.3 37.3 47.5 55 43 *

Pregerminated - 16 -

Germ inhibition zones (diameter mm = of the cream formulations 1. 2. 3. 4. 5. 6. 7. 8. 9.

T. mentagrophytes (N.C.P.F.80) 31.5 37.8 52.5 22.5 42 51.3 54.3 43 1

Microconidia S. aureus 49.3 24.5 42.8 43.2 34.2 35 48.9 30.2 20.3 (N.C.T.C.6749 S.D.A.plates)

Ps.aeruginosa 11.8 0 21.3 14.3 14.8 16.7 20.8 12.7 0 (NCTC10332 SDA plates) C. albicans 33.3 16.7 24.7 11.2 21.5 33.3 33.7 39.8 20.3 (NCYC610) T. mentagrophytes 50.5 41.8 50.3 28.3 47.8 54.2 52.3 37 32 (ATCC18748) T. mentagrophytes 61.8 45.3 55.3 36.8 45.8 60.3 49.0 40.8 33 (NCPF80) ~ not measured M = miconazole (%), B = benzoic acid (%) S = salicylic acid (%), DS = Daktarin® (Janssen), AJ = acnidazole ® (Janssen) - 17 -

Tested cream formulations (prepared and described in Examples 4-6)

Creme 1

Composition%

Soft paraffin (white) 23.75

Propylene glycol 11.40

Cetostearyl alcohol 23.75

Cetrimide 0.95

Methyl paraben 0.025

Propylparaben 0.015

Water 35.15

Miconazole nitrate 2.00

Salicylic acid 3.00

Benzoic acid 0.00

Cream 2

Composition%

Soft paraffin (white) 24.50

Propylene glycol 11.75

Cetostearyl alcohol 24.50

Cetrimide 0.98

Methyl paraben 0.025

Propylparaben 0.015

Water 36.25

Miconazole nitrate 2.00

Salicylic acid 0

Benzoic acid 0

Cream 3

Composition%

Soft paraffin (white) 22.75

Propylene glycol 10.92

Cetostearyl alcohol 22.75

Cetrimide 0.91

Methyl paraben 0.025

Propylparaben 0.015 - 18 -

Water 33.67

Miconazole nitrate 0.00

Salicylic acid 3.00

Benzoic acid 6.00

Cream 4

Composition%

Soft paraffin (white) 24.25

Propylene glycol 11.64

Cetostearyl alcohol 24.25

Cetrimide 0.97

Methyl paraben 0.025

Propylparaben 0.015

Water 35.89

Miconazole nitrate 0.00

Salicylic acid 3.00

Benzoic acid 0.00

Cream 5

Composition%

Soft paraffin (white) 23.50

Propylene glycol 11.28

Cetostearyl alcohol 23.50

Cetrimide 0.94

Methyl paraben 0.025

Propylparaben 0.015

Water 34.78

Miconazole nitrate 0.00

Salicylic acid 0.00

Benzoic acid 6.00

Cream 6

Composition%

Soft paraffin (white) 23.00

Propylene glycol 11.04

Cetostearyl alcohol 23.00

Cetrimide 0.92 - 19 -

Methyl paraben 0.025

Propylparaben 0.015

Water 34.04

Miconazole nitrate 2.00

Salicylic acid 0.00

Benzoic acid 6.00

Creme 7

Composition%

Soft paraffin (white) 22.25

Propylene glycol 10.68

Cetostearyl alcohol 22.25

Cetrimide 0.89

Methyl paraben 0.025

Propylparaben 0.015

Water 32.93

Miconazole nitrate 2.00 ^

Salicylic acid 3.00

Benzoic acid 6.00

Cream 8 Daktarin® (Janssen) 2% w / w miconazole nitrate

Cream 9 Acnidazil® (Janssen) 2% w / w miconazole nitrate and 5% w / w benzoyl peroxide

Fungicidal activity of miconazole with salicylic acid and / or benzoic acid

Subcultures of MIC tests carried out to determine the MBC (minimum bactericidal concentration = minimum bacteriocidal concentration) indicate that benzoic acid and salicylic acid had a fungicidal activity at concentrations which were only slightly higher than the concentrations of the MIC values determined. The micro-biocidal activity of active ingredients was tested using microconidia as germs, using the method to determine the kill rate.

* Concentration was reduced to 0.1% and no loss of activity was found.

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Concentrations of> 20 μ§ / τη1 of miconazole were fungicidal within 24 hours and benzoic acid and salicylic acid at concentrations of 400 - 600 μg / ml.

A combination of further low concentrations over a test period of 6 hours shows that salicylic acid increases the fungicidal rating of miconazole at a concentration of 20 or 10 μg / ml. The combination of benzoic acid and salicylic acid in turn results in an improved fungicidal activity.

Spore activity can be classified as both inhibitory and killing. Evidence is provided by measuring activity in the presence or after removal of active ingredients by measuring the ability to form colonies.

Miconazole (10 pg / ml) and salicylic acid (200 μg / ml) alone or combinations of both have an inhibitory effect, since germination is inhibited, but some germs survive.

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Efficacy of salicylic acid and miconazole by demonstrating the viability and germination (%) of T. mentagrophytes microconidia

Table 4

Combination vitality (cfu / ml)% germinable pH

ability at time (h) at time (h) 6 24 6 24 control 3.5 x 105 2.4 x 105 12 65 MIO 5.9 x 105 7.0 x IO1 * 9 11 5.88 MIO / S 200 8.3 x 10 '2.3 x 10' 6 16 5.41 M10 / S 400 0 0 4 13 5.06 M20 3.3 x 105 4.6 x 105 7 5 5.84 M20 / S 200 2.2 x IO1 * 5.3 x 103 8 13 5.41 M20 / S 400 0 0 9 12 5.07 S 200 4.8 x 105 1.2 x 105 12 41 5.43 S 400 0 0 14 14 5.08 M »Miconazole, S = salicylic acid

Initial payment at Tq is 7.9 x 105 cfu / ml. Different concentrations of miconazole in the cream formulations are tested on T. mentagrophytes (Table 5). The formulations containing MSB are significantly better than those containing SB. The cream formulation containing 2% MSB was significantly better than the other tested, whereas those containing 0.1-1% miconazole are not significantly different, but above all significantly better than formulations containing SB or commercial products, which contain only 2% miconazole (Daktarin®).

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Effect of the concentration of miconazole in cream formulations containing salicylic acid (3%) and benzoic acid (6%) against T. mentagrophytes

Table 5

Crime inhibition zone diameter (mm) 12345 Mean S.D.

1st miconazole 2% 46 44 45.5 45 42.5 44.6 1.39 2nd miconazole 1% 40 40.5 43 44.5 43.44 42.2 1.89 3rd miconazole 0.5% 40.5 40.5 40.5 44 42 41.8 1.44 4th miconazole 0.25% 42.5 40.5 40 42 39 40.8 1.44 5. Miconazole 0.1% 42.5 40.5 40.5 40 42.5 41.2 1.20 6th Miconazole 0% 34 36 35.5 35 34 34.9 0.89 7th Miconazole 2% 33.5 30 31 29 NT 30.9 1.93 (Daktarin) T. mentagrophytes 7.5 x 101 *

Significance (0.05%)

Multiple-range test (Neuman Keuls) for significance (0.05%) 1 vs 2,3,4,5,6,7 significant differences 2 vs 3,4,5 no significant differences 2 vs 6,7 significant differences 3 vs 4.5 no significant differences 3 vs 6.7 significant differences 4 vs 5 no significant differences 4 vs 6.7 significant differences 5 vs 6.7 significant differences 6 vs 7 significant differences

Table 5 shows that the synergistic effect can be obtained over a wide range of different miconazole concentrations.

«- 23 - 2. A second proof of the synergism can be provided using the kinetic data in Table 6.

The mortality rate of T. mentagrophyte Microconidia is determined using miconazole (M) alone and in combination with benzoic acid (B) and salicylic acid (S).

Table 6

Time M20 M20 + S 200 M20 + B 200 MIO M10 + S 200 M10 + B 200 (hrs) 1 lxlO5 l.lxlO5 6.7x1ο1 * 2.0xl05 1.3xl05 1.2x1ο5 2 3.3x10 · * 1.2x10 '2.3x10 “9.2x10“ 5.8x10 "4.2x10" 4 2.2x10 "1.8xl03 1.9x10" 1.6xl05 1.5x10 "2.5x10" 6 1.4x10 "5.0xl02 1.2x10" 7.5x10 "8.3xl03 2.6x10" 24 8.3xl02 0 4.2xlOz 2.3x10 "3.3 xl02 1.7x10 “pH values before 5.98 5.57 5.50 5.94 5.54 5.49 after 5.95 5.54 5.50 5.93 5.53 5.48 S salicylic acid, B = benzoic acid Initial count at Tq gives 5.9 x 10® cfu / ml

All solutions are executed in SLM * (SLM + 0.5% DMF) the day before to guarantee a complete solution.

0.1 ml Trichophyton mentagrophytes microconidia are added to 9.9 ml of a sample (estimated T, ment, at 1 x 108 cEu / ml). The viable germs are counted from a germ solution. The removed 0.1 ml volume is carried out with a 100 μΐ pipette.

The samples are kept at a temperature of 32 ° C throughout.

- 24 - 1 ml is removed after 1, 2, 4, 6, 24 hours and the viable germs are counted.

The serial dilutions are made in 0.1% peptone water and are distributed on plates using the Miles and Migra method on SDA (Sabouraud Dextrose Agar). The plates are read after 6 and 14 days.

Sample concentration 1 M 20 pg / ml 2 M 20 + S 200 pg / ml 3 M 20 + B 200 pg / ml 4 M 10 pg / ml 5 M 10 + S 200 pg / ml 6 M 10 + B 200 pg / ml S * salicylic acid B e benzoic acid MIC values are carried out at the same in (SLM *) for miconazole.

The miconazole concentrations are: 4, 2, 1, 0.5, 0.25, 0.125 μg / ml (duplicates).

0.1 ml of T. microconidia is added to a final concentration of approximately 1 x 105 cfu / ml (the same seed lot as above).

The invention is illustrated, but not limited, by the following examples.

Example 1: A powder containing 2% miconazole nitrate, 2% salicylic acid and 3% benzoic acid is produced as follows:

composition

Miconazole nitrate 2%

Salicylic acid 2%

Benzoic acid 3%

Amorphous silica (silica) 0.1%

Talcum, cleaned and micronized ad 100% - 25 -

Miconazole nitrate, salicylic acid and benzoic acid are micronized in the presence of amorphous silica. The microfine mixture is then added in small amounts to the sterile micronized and cleaned talc.

Mixing continues until a homogeneous product is obtained.

Example 2 An aerosol formulation containing 3% miconazole nitrate, 3% salicylic acid and 6% benzoic acid is prepared as follows:

composition

Miconazole nitrates 3%

Salicylic acid 5%

Benzoic acid 6%

Tween 80 0.1%

Silica (silicon dioxide) amorphous 0.1% deodorized hydrocarbon gs.

A micronized mixture of miconazole nitrate, salicylic acid, benzoic acid and amorphous silicon dioxide is prepared (as described above in the powder production). Tween 80 is then sprayed on as an alcoholic solution at intervals to allow evaporation of the carrier material and an even distribution. The powder coated with Tween 80 is then suspended in deodorized hydrocarbon and then packaged using normal standard techniques. A non-flammable with suitable properties is selected as the hydrocarbon.

Example 3: A lotion formulation containing 1% miconazole nitrate, 3% salicylic acid and 6% benzoic acid is made as follows:

composition

Miconazole nitrate 1%

Salicylic acid 3%

Benzoic acid 6%

Butylated hydroxytoluene 2% - 26 -

Diethyltoluamide 2%

Polyethylene glycol 400 ad 100%

Miconazole nitrate, salicylic acid and benzoic acid are added in half of the total amount of polyethylene glycol 400 and butylated hydroxytoluene and diethyltoluene amide used until a clear solution is obtained. The remaining polyethylene 400 is then added for filling.

Example 4: A cream containing 2% miconazole nitrate, 3% salicylic acid and 6% benzoic acid is prepared as follows:

composition

Soft paraffin (white) 22.25%

Propylene glycol 10.68%

Cetostearyl alcohol 22.25%

Cetrimide 0.89%

Methyl paraben 0.025%

Propylparaben 0.015%

Water 32.93%

Miconazole nitrate 2.00%

Salicylic acid 3.00%

Benzoic acid 6.00%

A melting or dispersion technique can be used for the production. The white soft paraffin, propylene glycol and the cetostearyl alcohol are mixed and heated until a uniform viscous liquid is obtained. Miconazole nitrate, salicylic acid and benzoic acid are dissolved in this liquid with parabens. The cetrimide is dissolved in water at 60 ° and added to the oil phase with constant stirring. A homogeneous cream is obtained. The remaining water is added and the mixture is further homogenized.

- 27 -

Example 5: A crime formulation containing 2% miconazole nitrate and 3% salicylic acid is prepared as described in Example 4.

composition

Soft paraffin (white) 23.75%

Propylene glycol 11.40%

Cetostearyl alcohol 23.75% * cetrimide 0.95%

Methyl paraben 0.025%

Propylparaben 0.015%

Water 35.15%

Miconazole nitrate 2.00%

Salicylic acid 3.00%

Example 6: A Cream Formulation Containing 2% Miconazole Nitrate and 6%

Containing benzoic acid is prepared as described in Example 4:

composition

Soft paraffin (white) 23.00%

Propylene glycol 11.04%

Cetostearyl alcohol 23.00%

Cetrimide 0.92%

Methyl paraben 0.025%

Propylparaben 0.015%

Water 34.04%

Miconazole nitrate 2.00%

Salicylic acid 0.00%

Benzoic acid 6.00%

Example 7: A cream containing 2% clotrimazole, 3% salicylic acid and 6% benzoic acid is prepared as follows:

Compilation:

Soft paraffin (white) 22.25%

Propylene glycol 10.68%

Cetostearyl alcohol 22.25%

Cetrimide 0.89% * - 28 -

Methyl paraben 0.025%

Propylparaben 0.015%

Water 32.93%

Clotrimazole 2.00%

Salicylic acid 3.00%

Benzoic acid 6.00%, analogous to Example 4, one can produce a melt or a

Use dispersion technology. The white soft paraffin, propylene glycol and the cetostearyl alcohol are mixed and heated until a uniform, viscous liquid is obtained. Clotrimazole, salicylic acid and benzoic acid are dissolved in this liquid with paraben and added to the oil phase with constant stirring. A homogeneous crime is obtained. The remaining water is added and the mixture is further homogenized.

Example 8: A cream formulation containing 2% clotrimazole and 3% salicylic acid is prepared as described in Example 7.

composition

Soft paraffin (white) 23.75%

Propylene glycol 11.40%

Cetostearyl alcohol 23.75%

Cetrimide 0.95%

Methyl paraben 0.025%

Propylparaben 0.015%

Water 35.15%

Clotrimazole 2.00%

Salicylic acid 3.00%

Example 9: A cream formulation containing 2% clotrimazole and 6% benzoic acid is prepared as described in Example 7.

composition

Soft paraffin (white) 23.00%

Propylene glycol 11.04%

Cetostearyl alcohol 23.00% - 29 -

Cetrimide 0.92%

Methyl paraben 0.025%

Propylparaben 0.015%

Water 34.04%

Clotrimazole 2.00%

Salicylic acid 0.00%

Benzoic acid 6.00%

Claims (11)

1. New antimicrobial pharmaceutical preparations for topical use, characterized by the combination consisting of an antimicrobial active ingredient from the group of active ingredients which contain an imidazole substituted by a lower alkyl in their molecule, corresponding to a compound of the formula I II ÎÎ V * R \ _. CH2-ÇH-O-CH2- · (R2 (I) · / vcl R3 /, = * I II 3 V * ii wherein at least one of the substituents Ri, R2 and R3 represent a halogen atom and the other hydrogen, both also pharmaceutically acceptable acid addition salts or corresponding to a compound of formula II · () - (C6H5) 2 (II) • · 8-1 where R ^ is a halogen atom, with one or more optionally substituted benzoic acids and optionally conventional pharmaceutical carriers and / or auxiliaries. 2. New antimicrobial pharmaceutical preparations for topical use according to claim 1, characterized by the combination consisting of a compound of formula I, wherein at least one of the substituents R 1, R 2 and R 3 represents a chlorine atom and the other hydrogen, and also their pharmaceutically acceptable acid addition salts , such as Miconazole (Ri = R2 = Cl, R3 = H), econazole (R3 = CI, Ri = R3 = H) and isoconazole (Ri * R3 = Cl, R2 - H) or from a compound of formula II, wherein R ^ a Chlorine atom means, such as »* - 31 - * Clotrimazole and one or more optionally substituted benzoic acids and optionally conventional pharmaceutical carriers and / or excipients. 3. New antimicrobial pharmaceutical preparations for topical use according to claim 1, characterized by the combination consisting of miconazole as a compound of formula I, wherein R 1 and R 2. Chlorine atom and R3 are hydrogen or a pharmaceutically acceptable acid addition salt thereof or from a compound of the formula II in which R 1 is a chlorine atom, clotrimazole and salicylic acid and / or benzoic acid and optionally conventional pharmaceutical carriers and / or auxiliaries. 4. New antimicrobial pharmaceutical preparations for topical use according to claim 1, characterized by the combination consisting of miconazole nitrate and salicylic acid and / or benzoic acid and optionally conventional pharmaceutical carriers and / or auxiliaries. 5. New antimicrobial pharmaceutical preparations for topical use according to claim 1, characterized by the combination consisting of clotrimazole and salicylic acid and / or benzoic acid and optionally conventional pharmaceutical carriers and / or auxiliaries. 6. New antimicrobial pharmaceutical preparations for topical use, characterized in that they have 0.01-10% by weight of an imidazole of the formula I or II substituted by a lower alkyl group and 0.5-25% by weight of one or more optionally substituted benzoic acids contain together with usual carriers and / or excipients for topical application. 7. New antimicrobial pharmaceutical preparations for topical use, characterized in that these 0.1 - 2.0% in weight of an imidazole of formula I or II substituted by a lower alkyl group and 1.0 - 15.0% in weight of one or contain several optionally substituted benzoic acids together with conventional carriers and / or auxiliaries for topical use. ν ι · - 32 - 8. New antimicrobial pharmaceutical preparations for topical use, characterized in that they contain a synergistically effective amount of an imidazole of the formula I or II substituted by a lower alkyl group and one or more optionally substituted benzoic acids together with customary carriers and / or auxiliaries for topical application contain. 9. New antimicrobial pharmaceutical preparations for topical use according to claims 1 to 8, which in the form of a gel, cream, ointment, paste, powder, solution, tincture, foam, spray, aerosol, collodion or lotion are available. 10. A process for the preparation of an antimicrobial pharmaceutical preparation for topical use, characterized in that an antimicrobial active ingredient from the group of active ingredients which contains an imidazole substituted by a lower alkyl in its molecule, either a compound of the formula I Rl \ _. Ïh2-ch-o-ch8- ^ r2 (I) A / cl p / = 'î II Ra' ν 'ii wherein at least one of the substituents Ri, R2 and R3 represent a halogen atom and the other hydrogen, both also their pharmaceutically acceptable Acid addition salts or corresponding to a compound of the formula II · (_) —- J (C6Hb) 2 (II) • ·! —I in which Ri * denotes a halogen atom, with one or more optionally substituted benzoic acids and, if appropriate, customary pharmaceutical carriers and / or auxiliaries mixed. > * ♦ Λ - 33 - 11. Use of an antimicrobial pharmaceutical preparation according to one of claims 1-9, as an antifungal agent for the treatment of dermatophytes and fungus-related infections of the skin, as an antibacterial agent for the treatment of acne, dandruff and other skin disorders and as an anti-pruritically effective Agents for the treatment of pruritus diseases. FO 7.4 HFO / bg * / cs * V