WO1998036731A1

WO1998036731A1 - Use of azoles

Info

Publication number: WO1998036731A1
Application number: PCT/EP1998/000695
Authority: WO
Inventors: Marianne Petersen-Braun; Norbert-Heinz Becker; Burghardt Bruhn
Original assignee: Bayer Aktiengesellschaft
Priority date: 1997-02-19
Filing date: 1998-02-09
Publication date: 1998-08-27
Also published as: AR011152A1; AU6296098A; ZA981321B; DE19706463A1

Abstract

The invention relates to the use of azoles in topical preparations for combating body odour and the smell of sweat.

Description

Use of azoles

The invention relates to the use of azoles in topical preparations for combating body and sweat odors.

The antifungal effects of azoles such as clotrimazole or bifonazole are known and have been used medicinally for many years. These agents are used successfully in the treatment of skin and vaginal mycoses. They act preferentially against dermatophytes, yeasts, molds and some gram-positive bacteria that are known to cause super infections in mycoses.

A typical representative of these antifungal azoles is clotrimazole (1 - [(2-chlorophenyl) diphenylmethyl] imidazole).

The development of body and sweat odors are very complex processes that have not yet been fully clarified. It is known that freshly secreted sweat is sterile and odorless. It is assumed that only the breakdown of apocrine sweat by enzymes creates the body or sweat odor. The density of the apocrine sweat glands is in the moist and warm areas of the body, e.g. on the feet and in the armpits particularly high, so that bacteria, which produce the corresponding sweat-reducing enzymes, also find an increased food supply in these areas of the body.

Depending on the expression and development, the body or sweat smell can be differentiated into two basic types:

a) The generally weaker "acidic type" is primarily associated with the activity of micrococci and is particularly common in women. Isovaleric acid has been detected as a characteristic odor component.

b) The stronger "stabbing biting type" is primarily associated with Corynebacteria and is found more frequently in males This type of smell is particularly important for the steroids 5-α-androstenol and 5-α-androstenone, as breakdown products of male sex hormones. So far it has been assumed that the 5-α-androstenol is excreted in sweat as an odorless ester of sulfuric acid or gluconic acid. Special esterases of the corynebacteria cleave them

Ester and release the volatile and very odor-intensive 5-α-androstenol, which is then partially converted to 5-α-androstenone in a further step.

To combat or prevent sweat and body odor so far

Antiperspirants and deodorants used. Antiperspirants reduce the activity of the sweat glands and thus sweat formation. The resulting lower bacterial growth together with the lower amount of sweat results in a corresponding reduction in body odor. Such antiperspirants are preferred for those with excessive or pathological perspiration

(Hyperhidrosis). Active substances that belong to the group of so-called astringents are predominantly used for this. These substances cause the skin to contract by denaturing proteins and mucilages on the surface of the skin, and at the same time narrow the exit channels of the ecrine sweat glands. Salts of metals have proven to be particularly effective astringents

Proven aluminum and zirconium. The particularly high effectiveness of these metals is due to the fact that their solutions penetrate into the upper region of the excretion channels of the ecrine sweat glands and, together with the mucilages, form adhering precipitates which are difficult to dissolve, which, as plugs, clog the gland outlet and thus prevent or reduce sweat drainage . From a medical point of view, the use of such antiperspirants to reduce or suppress physiologically sensible perspiration can only be assessed critically. Their routine use in people with normal skin functions is not recommended. The category of deodorants can be divided into several groups with different principles of action. Deodorants contain active ingredients that are either odor-absorbing, odor-masking, germ-inhibiting, enzyme-inhibiting or antioxidative.

Odor absorbers do not develop any effectiveness against bacteria or the welding fluid, but absorb odor-forming compounds, lower their partial vapor pressure and thus reduce the rate of spread of disturbing odor-forming substances.

Odor maskers can be used as classic means e.g. can be used in the form of perfumes. They mask the unwanted body odor without influencing the development of the smell itself.

Germ-inhibiting agents are used to prevent or reduce the formation of odor-generating substances. Preservatives such as e.g. Irgasanchlorhexidin, as well as fragrances with antimicrobial properties, such as essential oils, methanol or mint oil. Through the combined use of different antimicrobial substances, superadditive synergistic effects can be achieved. These germ-inhibiting agents show their primary effectiveness against gram-positive bacteria, which are significantly involved in odor formation.

Enzyme inhibitors are also used in deodorants, e.g. Hydergen deodorant used. Their effect is aimed at the fact that they are responsible for the enzymes responsible for the decomposition of sweat, e.g. inactivate the ester-cleaving lipases.

Surprisingly, it was found that the antimycotically active azoles, in particular the clotrimazole which has been used for more than 20 years, prevent the formation of an unpleasant sweat odor. The effect is obviously based on preventing the enzymatic decomposition of sweat. Despite many years

Use as an antifungal and a known antibacterial effect on special human pathogens (such as Corynebacterium minutissimum) is an effect of the azoles on the micrococcaceae (genus: Staphylococcus) involved in the formation of perspiration odors and Corynebacteriaceae (genus: Corynebacterium) have so far not become known. The use of the well-tolerated azoles to prevent the formation of body and sweat odors is surprising. The underlying principle of action has not yet been finally clarified. The

Prevention of the enzymatic decomposition can be based directly on an enzyme inhibition or on an inhibition of the multiplication of the bacteria involved. However, the convincing effect of the absence of sweat and body odor is clear.

The applicability of the azoles according to the invention can be determined in various test methods. The microbiological method is used to determine the specific effectiveness on microorganisms, e.g. to determine the antibacterial effect on gram-positive bacteria. Here, both the potency and the potency spectrum of the azoles are measured using conventional methods, e.g. the inhibitor test, the

KWI test or the suspension test.

The Sniff test method uses the olfactory assessment of body odor under the conditions of test experiments.

The panel test can also be used. This broad application test, which can be carried out under open or controlled conditions, is used for the subjective overall assessment of deodorants. In addition to effectiveness, cosmetic aspects are also included.

The use according to the invention preferably relates to azoles of the general formula (I)

in which

A and B • are the same or different and each stand for = N- or = CH-,

R represents hydrogen or a radical from the group -SH, -SR ⁴ , -SO ₃ H or -S ₂ -R ⁴ , in which

R ^{4 represents} alkyl, alkenyl, optionally substituted aryl or aralkyl optionally substituted by halogen,

R ¹ , R ² and R ^{3 are the} same or different and each represents hydrogen or optionally substituted alkyl, alkenyl, cycloalkyl, aralkyl, aralkenyl, aroxyalkyl, aryl or heteroaryl,

as well as their salts.

Compounds of the general formula (I) in which

B stands for the group = CH-,

A stands for = N-,

R represents hydrogen, and

R ¹ , R ² and R ^{3 are} identical or different and each represents hydrogen or aryl having 6 to 10 carbon atoms, where each of these radicals can be substituted 1 to 3 times, identically or differently, by halogen, nitro, alkyl, Alkoxy, alkyl mercapto each having 1 to 4 carbon atoms, or by phenyl, the alkyl, phenyl and alkoxy radicals in turn being optionally substituted by fluorine or chlorine. Of particular interest is the use of compounds of the general formula (I) in which

B for. the group = CH- stands

A stands for = N-,

R represents hydrogen, and

R ¹ , R ² and R ³ each represent phenyl, at least one phenyl group being substituted by chlorine, phenyl, trifluoromethyl or methoxy.

Particular emphasis is given to all topically applicable azole derivatives which are active against gram-positive bacteria, in particular against Micrococcaceae (genus: Staphylococcus), and against Corynebacteriaceae (genus: Corynebacterium).

The following active ingredients are mentioned as examples: bifonazole.

Fenticonazole, miconazole, econazole, oxiconazole, ketoconazole, isoconazole, climbazole,

Lanoconazole, Butoconazole, Croconazole, Flutrinazole, Omoconazole, Terconazole.

Sertaconazole and sulconazole.

A sniff test (n = 4) shows after 12 even after physical exertion

Hours a significant odor inhibition.

The prior art contains no information about the corresponding effects of azoles. This may be due to the fact that none for the experts

There was reason to investigate the azole effect on non-pathogenic germs.

The invention also relates to all forms of preparation which are customary for topical use, such as Creams, ointments, solutions, sprays, pump sprays, aerosols, powder, shower gel, shampoo, soap, deodorant stick, deodorant roller and the like.

For this purpose, the azoles are mixed with customary auxiliaries and carriers and, if appropriate, in combination with other active ingredients in suitable topical preparation forms transferred. Here, the active principle of the azoles according to the invention can of course also be combined with the previously known active principles for deodorants such as, for example, odor masking by perfume or odor absorber.

The following exemplary embodiments illustrate possible application forms without restricting them.

example 1

Canesten cream

A clotrimazole cream according to the invention has the following composition:

Clotrimazole 1.00 g

S orbitan stearate 2.00 g

Polysorbate 60 1.50 g

Cetyl palmitate 3.00 g

Cetylstearyl alcohol 10.00 g

Octyldodecanol 13.50 g

Benzyl alcohol 1.00 g

Water 68.00 g

S orbitan mono stearate, polysorbate 60, cetyl palmitate, cetyl stearyl alcohol and octyldodecanol are introduced and melted at 70 ° C. Clotrimazole is dissolved in the melt (70 ° C).

Water is heated to 75 ° C in a separate batch tank with stirring.

Benzyl alcohol is added to the heated water phase and dissolved at 75 ° C.

The heated fat phase is incorporated into the hot water phase with stirring and homogenized under vacuum. Then, with homogenization, the mixture is first cooled to 45 ° C., then to 36 ° C., discharged and filled.

Example 2

Clotrimazole cream

A clotrimazole cream according to the invention with a higher active ingredient concentration has the following composition: Clotrimazole 5.00 g

S orbitan stearate 2.00 g

Polysorbate 60 1.50 g

Cetyl palmitate 3.00 g

Cetylstearyl alcohol 10.00 g

Octyldodecanol 13.50 g

Benzyl alcohol 1.00 g

Water 64.00 g

Sobitan monostearate, polysorbate 60, cetyl palmitate, cetylstearyl alcohol and octyldodecanol are initially introduced and melted at 70.degree. Clotrimazole is dissolved in the melt (70 ° C).

Water is heated to 75 ° C in a separate batch tank with stirring. Benzyl alcohol is added to the heated water phase and dissolved at 75 ° C.

Example 3

Clotrimazole solution

A solution according to the invention has the following composition:

Clotrimazole 1.00 g

Isopropyl alcohol 30.00 g

Macrogol 400 10.00 g

Isopropyl myristate 54.60 g Clotrimazole is dissolved in a template of isopropyl myristate and Macrogol 400. Isopropyl alcohol is then incorporated into this active ingredient solution.

Example 4

Clotrimazole solution

A solution according to the invention with a higher active ingredient concentration has the following composition:

Clotrimazole 5.00 g

Isopropyl alcohol 30.00 g

Macrogol 400 10.00 g

Isopropyl myristate 50.60 g

Clotrimazole is dissolved in a template of isopropyl myristate and Macrogol 400. Isopropyl alcohol is then incorporated into this active ingredient solution.

Example 5

Clotrimazole pump spray solution

A pump spray solution according to the invention has the following composition:

Clotrimazole 1.00 g

Isopropyl alcohol 72.10 g

Marcrogol 400 5.00 g

Isopropyl myristate 2.50 g

Clotrimazole is dissolved in a template of isopropyl myristate and Macrogol 400.

Isopropyl alcohol is then incorporated into this active ingredient solution and filled into suitable pump spray bottles. Example 6

Clotrimazole pump spray solution

A pump spray solution according to the invention with a higher concentration has the following

Composition:

Clotrimazole 10.00 g

Isopropyl alcohol 63.10 g

Marcrogol 400 5.00 g

Isopropyl myristate 2.50 g

Clotrimazole is dispersed in a template of isopropyl myristate and Macrogol 400. Isopropyl alcohol is incorporated into this active ingredient dispersion.

Example 7

Clotrimazole spray

The solution of Example 5 is filled together with a suitable propellant gas in suitable pressurized gas aerosol cans.

Example 8

Clotrimazole deodorant stick

Clotrimazole 1.00 g

Stearic acid 6.00 g

Sodium hydroxide 1.00 g

Propylene glycol 2.00 g

Perfume oil 3.00 g

Ethyl alcohol 96% ad 100.00 g Sodium hydroxide is dissolved in water. The alcohol is initially charged and heated to 70.degree. Clotrimazole and stearic acid are dissolved in the hot alcohol, then propylene glycol and perfume oil are added and the mass is poured into the intended molds.

Example 9

Clotrimazole syndet

Clotrimazole 5.00 g

Zetesap 5165 87.00 g

Disodium cocoamphodiacetate 6.00 g

Allantoin 1.00 g perfume oil 1.00 g

Zetesap is placed in a kneader and processed with the remaining ingredients to a homogeneous mass. The mass is further homogenized in a pilier mill, the homogenized chips are fed to an extrusion press and extruded. Immediately after the extrusion, the syndet pieces are pressed, cut and packaged.

Example 10

Clotrimazole powder

Clotrimazole 2.6 g

Starch 257.4 g

50% of the total amount of starch are placed in a mixer and with

Mixed clotrimazole. This premix is sieved and mixed with the remaining amount of starch.

Claims

claims

1. Use of Azoles of the General Formula (I)

in which

A and B are the same or different and each stand for -N- or = CH-,

R ¹ . R ² and R ^{3 are the} same or different and each represents hydrogen or optionally substituted alkyl, alkenyl, cycloalkyl, aralkyl, aralkenyl, aroxyalkyl, aryl or heteroaryl,

and their salts, in the manufacture of agents for combating and preventing sweat and body odor.

2. Use according to claim 1, characterized in that one uses azoles of the general formula (I) according to claim 1, in which

B stands for the group = CH-,

A stands for = N-, R represents hydrogen, and

R ¹ , R ² and R ^{3 are the} same or different and each represents hydrogen or aryl having 6 to 10 carbon atoms, each of these

Residues 1- to 3-fold, may be substituted identically or differently by halogen, nitro, alkyl, alkoxy, alkyl mercapto each having 1 to 4 carbon atoms, or by phenyl, the alkyl, phenyl and alkoxy radicals in turn optionally being substituted by fluorine or chlorine are substituted

as well as their salts.

3. Use according to claim 1, characterized in that azoles of the general formula (I) according to claim 1, in which

B stands for the group = CH-,

A stands for = N-,

R represents hydrogen, and

R ¹ , R ² and R ³ each represent phenyl, at least one phenyl group being substituted by chlorine, phenyl, trifluoromethyl or methoxy,

and their salts.

4. Use according to claim 1, characterized in that azoles are mixed with customary auxiliaries and carriers, if appropriate in combination with other active ingredients, and converted into topical preparations which are used as agents for

Combat and prevent sweat and body odor.