AU670966B2

AU670966B2 - Combination of germicidal agents

Info

Publication number: AU670966B2
Application number: AU49509/93A
Authority: AU
Inventors: Winfried Klein; Eva Matthies; Gerhard Sauermann; Hartmut Schmidt-Lewerkuhne; Robert Schmucker; Bernd Traupe
Original assignee: Beiersdorf AG
Current assignee: Beiersdorf AG
Priority date: 1992-09-05
Filing date: 1993-08-20
Publication date: 1996-08-08
Anticipated expiration: 2013-08-20
Also published as: JPH08501091A; KR950702796A; JP3529093B2; CA2140920A1; WO1994005156A1; DE59308619D1; ATE166534T1; AU4950993A; ES2118250T3; EP0658082B1; DE4229707A1; EP0658082A1

Abstract

Combinations of imidazol and/or one or more imidazol derivatives with general structural formula (I) in which the residues may be as follows: R1 = H, C(1 - 25) alkyl, R2 = H, C(1 - 25) alkyl, R3 = H, C(1 - 25) alkyl, R4 = H, C(1 - 25) alkyl, where R4 may also, and preferably when R1, R2 and R3 are a hydrogen atom, be the residues -CH2-CH2-NR5R6 and -CH2-CH(NR5R6)-COOR7, where R5 = H, C(1 - 25) alkyl, R6 = H, C(1 - 25) alkyl, R7 = H, C(1 - 25) alkyl, and of a substance active against micro-organisms or a mixture from the lantibiotics group.

Description

OPI DATE 29/03/94 APPLN. ID 49509/93 II1111 1111 il I AOJP DATE 23/06/94 PCT NUMBER PCT/EP93/022381111111111 I AU9349509 INTERNATIONALE ZUSAMMENARIEIT AUF DEM GEI3IET DES PATENTWESENS (PCT) (51) Internationaole Patentkliisslflkatlon 5 (11) Interniationale Ver~iffentilchungsnumrner: WO 94/05156 AOI1N 63/02, A61IK 7/32, 7/48 Al (43) Interiiatlonales (AIN 63/02, 43:50, 25:22) Ver~ffentlilchungsdatum: 17. Mlrz 1994 (17.03.94) (21) Internatlonales Aktenzelchen: PCT/EP93/02238 (74) Gemelnsanier Vertreter: BET ERSDORF AG; Unnastra~e (22) lntcrnationales Ariineldedzaturn: 20, August 1993 (20,08,93) 4,D205Habr(E) (81) Bestlrnunuiigsstaaten: AU, CA, JP, KR, US, europtlisches Prloritlitsdaten.: Patent (AT, 13E, ClH, DE, DK, ES, FR, GB, GR, 113, IT, P 42 29 707.9 5, Septcember 1992 (05.09,92) DE LU, MC, NL, PT, SE).

(71) Annieler (1ir alle Iiestiniungsslaten ausser US): 13ll. Ver~ffentlichit ERSDORF AG LI)E/DE]; Unnastrage 48, D-20245 Alit internationalem Recherchenberich, H-amnburg (DE), (72) Erflnder; und Erfinder/Aninelder (nurfitr US) :KLEIN, Winfried IDE! DE]; Drcistflckcn I5, D-22297 Hamburg MATT- HIES, Eva [DE/DE]; Gernroder Weg 13, D-22453 Hamburg SAUERMANN, Gerhard [DE/DE, Hambrook 14, D-24649 Wiemersdorf (DE)

SCHMIDT-LE-

WERKOHNE, Hurtmut JDE/DE]; Hilnenkamp 1b, D- 22869 Schenefeld SCHMUCKER, Robert [DE/7 06 DE]; Klaus-Nanne.Str. 103, D-22457 Hamburg (DE).

TRAUPE, ernd [DE/DE]; Klaus-Nannc-Str. 61, D- 22457 Hamburg (DE).

(54) Title: COMBINATION OF GERMICIDAL AGENTS (54) Bezelchnung: GERMICIDE WI RKSTOFFKOM INATION EN

R

1

R

2 _C C- N (57) Abstract Combinations of imidazol and/or one or more imidazol derivatives with general structural formula in which the residues may be as follows: RPI 1 H, C(j 25 alkyl, R.

2 C(l 25) alkyl, R.

3 H, alkyl, P.

4 C(I 25) alkyl, where

P

4 may also, and preferably when 1. R 2 and R.

3 are a hydrogen atom be te residues -CH 2

-CH

2

-N

5 n

-CH

2

.CHI(NR

5

R

6 )-C00R 7 where R 5

C(

1 25) alkyl, P.

6

C(

1 25) alkyl, R 7 C(l 25) alkyl, and of a substance active against micro-organisms or a mixture from the lantibiotics group.

(57) Zusammenfassung Kombinationen aus Imidazol und/oder einem oder mehreren Derivaten des Imidazols, welche die allgemeine Strukturformel aufweisen, wobei die Reste folgende Bedeutung haben k6nnen: R, H, C( 1 .25) Alkyl, R.

2 =HI C( 1 25)Ii Alkyl, R.

3 H4, C(l 25) Alkyl, R.

4 C(l 25) Alkyl bedeuten, wobei R.

4 auch, und zwar bevorzugt dann, wenn RI, R 2 und P.

3 emn Wasserstoffatom darstellen, die Reste -CH 2 -C11 2

-NR

5

R

6 und -CH 2

-CH(NRSR

6

)-COOR

7 reprilsentieren kann, wobei R.

HC(

1 25) Alkyl, P.

6

=H,

1 .25 Alkyl, R 7 H, C( 1 5- Alkyl bedeuten, und einem, gegen Mikroorganismen wirksamen Stoff' oder einemGemrusch aus der Gruppe der Lantibiotika.

I i i-il-i- riar* Beiersdorf Aktiengesellschaft Description Germicidal active compound combinations The present invention relates to active compound combinations for protection against microorganisms. It i furthermore relates to formulations, preferably cosmetic j and dermatological formulations, in particular cosmetic deodorants, comprising such active compound combinations.

It also relates to processes for stabilizing formulations, in particular cosmetic and dermatological formulations, against attack by microorganisms.

Active compound combinations for protection i against microorganisms are used, for example, in formulations which are applied to the skin or mucous membrane of a person or an animal in order to reduce or eliminate microorganism attack on or in the skin or to prevent attack by microorganisms. Such compositions include the terms topical dermatic agents and cosmetics.

However, protection against microorganism attack on formulations themselves, in particular cosmetic and dermatological formulations, is also regarded as protection against microorganisms in the context of the present invention. In technical terms, this protection is called preservation. Preservation in itself is not limited to cosmetic or dermatological formulations. Rather, it relates to protection of all organic materials against j microbial degradation.

Cosmetic formulations for protection against microorganisms are primarily deodorants, that is to say formulations which are intended to eliminate body odour.

Body odour is formed when fresh perspiration, which is in itself odourless, is decomposed by microorganisms. During this operation, a large number of highly volatile substances are formed, malodorous isovaleric acid being i mentioned only as an example.

16 -2- Deodorants: Cosmetic deodorants of the prior art are based on various action principles.

The formation of perspiration can be suppressed by astringents aluminium salts, such as aluminium hydroxychloride, are chiefly used. Apart from the fact that the associated denaturing of skin proteins is an undesirable secondary reaction, the substances used for this purpose furthermore intervene in the heat balance of the skin and should at best be used in exceptional cases.

The bacterial flora on the skin may be reduced by antimicrobial substances. In the ideal case, only the microorganisms causing an odour should be destroyed here.

In practice, however, it has been found that the entire microflora of the skin is harmed to the same extent. The microorganisms which cause no odour are occasionally even harmed more severely.

Finally, body odour can also be masked by fragrances, the classical method which, however, meets the aesthetic requirements of the consumer the least, since the mixture of body odour and perfume fragrance smells rather unpleasant.

Deodorants should meet the following conditions: The biological processes of the skin should not be impaired.

The deodorants should not have a pronounced intrinsic smell. I They must be harmless in the event of an overdose or other use not as specified.

They should not become concentrated on the skin after repeated use.

They should be easy to incorporate into commercially available cosmetic formulations.

Both liquid deodorants, for example aerosol sprays, roll-ons and the like, and solid formulations, for example deo sticks, powders, powder sprays, intimate cleansing compositions and the like, are known and RA4 customary.

An object of the present invention was thus to -0 E T 0-ri-cstmry -3develop cosmetic deodorants which do not have the disadvantages of the prior art. In particular, the deodorants should largely preserve the microflora of the skin, but selectively reduce the microorganisms which are responsible for body odour.

Topical dermatic agients: Some of the unpleasant or pathogenic germs attack the various layers of the skin, including the acne pathogen Propionibacterium acnes. P. acnes preferentially populates the hair follicles and therefore usually breaks out during puberty of the persons affected. The often considerable skin lesions associated with it are at best unattractive, but may also considerably trouble the patient emotionally.

Lantibiotics have also already been proposed as therapeutics against skin complaints caused microbially, namely acne. A disadvantage is that these formulations are stable for only a short time.

Another object of the present invention was thus to provide formulations and processes which remedy this shortcoming.

Stabilization of perfumed cosmetic formulations: Cosmetic formulations, that is to say deodorants, having an active content of lantibiotics are known from DE-A 39 38 140. The compositions described therein are distinguished by an outstanding action and tolerability.

However, the cosmetic deodorants described therein have the disadvantage that an addition of perfume constituentcs ineanudesirae manerizin atwviy whic he contituents redanuesirthe eodorizin atwviy ofic hes not et eenclarified exhaustively. Since almost all cosetiswhether deodorizing or not, comprise perfume contiuensthis reduction in action represents a consderbleproblem.

Another object of the invention was thus to suppress the harmful action of perfume constituents on active compound components in cosmetic formulations.

RA~z Description-of the invention: It was astonishing and not f oreseeable to the

TO

4 expert, and herein lies the achievement of all these objects, that combinations of imidazole and/or one or more derivatives of imidazole which can have the following general structural formula

R

/N

R

2 -C C-R C- N

R

4 5 wherein the radicals have the following io R, H or C(_ 25 alkyl, 0 0

R

2 H or CI ,5 alkyl, o. R 3 H or C( 25) alkyl,

R

4 H or C 25 alkyl, or R4 is, and preferably if RI, R 2 and R 3 are a hydrogen atom, one of the radicals

-CH-CH

2 -NRsR 6 *0 and -CH 2

-CH(NR

5

R

6

-COOR

7 wherein

R

5 H or Ci 25 alkyl,

R

6 H or C( 25, alkyl,

R

7 H or 2s) alkyl, and a lantibiotic or a mixture of two or more lantibiotics, would be stable during storage, would have a sufficiently high half-life on the skin, would be suitable for use as a cosmetic, do not allow interactions between lantibiotics and perfume constituents, would have a suitable stability when used in cosmetics,

R

A

t would be active selectively against odour-gener- S7" ating microorganisms, J trw_~

*I

would preserve the symbiotic microflora of the skin, would also be fully active when perfume components are used, would achieve a significant improvement in the deodorizing action compared with imidazole-free compositions, would have a suitable stability when used as preservatives, would have a suitable stability when used in foodstuffs.

In particular, it was astonishing that the compositions according to the invention not only are suitable for cosmetic purposes but moreover are more effective and gentler than the compositions of the prior art.

The invention also relates to the use-of one or more derivatives of imidazole which have the following general structural formula I R

N

2 -C C-R 3

C-N

R4 wherein the radicals can have the following meaning: R, H or C(i. 2, alkyl,

R

2 H or 25) alkyl,

R

3 H or C( 1 2 5 alkyl,

R

4 H or C( 2 2) alkyl, wherein R, can also, and preferably if R 1 R, and

R

3 are a hydrogen atom, be the radicals

-CH

2

-CH,-NRR,

A and -CH 2 -CH(NRsR 6

)-COOR

7 wherein -6- Rs H or C( 1 2 5 alkyl,

R

6 H or C 25) alkyl,

R

7 H or C( 1 25 alkyl, as the active principle in cosmetic deodorants.

Lantibiotics per se have been known for many years. They are polypeptides which are synthesized by microorganisms and are distinguished by representatives of the amino acid group of lanthionines as a structural element in the peptide sequence.

The lanthionines have the following structures: HOOC-CH (NH 2

-CH

2

-S-CH

2 -CH (NH 2

-COOH

also written as:

H

2 N-ala-S-ala-COOH (meso-lanthionine) COOH

NH

2 and

HOOC-CH(NH

2

-CH,-S-CH(CH

3

-CH(NH

2

-COOH

also written as:

H

2 N-ala-S-aba-C0OH (threo-methyl-lanthionine) COOH NH 2 Ring structures are formed in the lantibiotics with these lanthionines.

Examples of lantibiotics are nisin, epidermin, subtilin, cinramycin, duramycin, ancovenin, gallidermin and Pep The abovementioned substances are known per se and can be found under the Chemical Abstracts registry numbers: Nisin 1414-45-5 Epidermin 99165-17-0 Subtilin 1393-38-0 Pep 5 110655-58-8 0 Duramycin 1391-36-2 Ancovenin 88201-41-6 UjI 7 Gallidermin 117978-77-5 Nisin, for example, is a peptide of 34 amino acids synthesized by Streptococcus lactis.

Nisin has the following amino acid sequence (primary structure): I I

H

2 N-ile-dhb-ala-ile-dha-leu-ala-aba-pro-gly-ala-lys- L S J -met-lys-aba-ala-aba-ala-his-ala- I I

J

-ser-ile-his-val-dha-lys-COOH wherein dhb dehydrobutyrine dha dehydroalanine aba aminobutyric acid E. Gross, J.L. Morell, "The Structure of Nisin", J. Amer.

Chem. Soc. 93, pages 4634-4637 (1971).

The action mechanism of nisin and the lantibiotics related to nisin which have essentially the same action can be explained as follows: cell walls are destroyed by release of autolysines. Since channels are also formed in the cytoplasm membrane, low molecular weight cell constituents can diffuse out, whereby the (prokaryotic) cell is destroyed.

The accuracy of this explanation, however, is of no relevance to the invention. An attempt is merely being RAmade to explain the microbiological processes.

Eukaryotic cells, that is to say skin cells, L. I- J I i -L~ i; te. r r l 8 fungi and the like, are resistant to nisin and other lantibiotics.

Lantibiotics are practically non-toxic to warm-blooded animals. The LD50 for nisin, for example, is greater than 7 g/kg (determined for rats and cats). It is known that nisin and the other lantibiotics chiefly act against micrococci and coryneform bacteria. In some countries, chiefly in Eastern Europe, it is a substance which is approved as a foodstuffs preservative (not in Germany).

For traditional reasons, lantibiotics are often counted among the so-called "peptide antibiotics".

However, for various reasons they are not to be interpreted as conventional antibiotics, at least not all their representatives, least of all nisin. Everything suggests, rather, that they should be given the designation "bacteriocins". Bacteriocins are proteins-which are produced by bacteria and kill or inhibit the growth of related bacteria species or strains. They are usually coded by plasmids, the so-called bacteriocin factors.

Epidermin is a lantibiotic which has been isolated from microorganisms occurring on the human skin.

The use of epidermin as an antibiotic/therapeutic having a topical action is described in EP-A-0 181 578. It is used for combating infectious diseases,, Gallidermin is a lantibiotic which differs from epidermin by only one amino acid. EP-A-0 342 486 cites a cosmetic agent comprising gallidermin, but without cosmetics being disclosed and without the advantageous combination of lantibiotics and imidazole or derivatives thereof being obvious.

International Patent Application WO 89/12399 furthermore discloses combinations of nisin and complexing agents and/or emulsifiers for use as preservatives.

Imidazole is characterized by the structural formula SRA4/ Nt O I-1 r -9 H-C N .H

C/

'C-

Imidazole is likewise practically non-toxic to warmblooded animals, but acts as an antimetabolite against histamine and nicotinic acid in lower animals. Certain derivatives of imidazole are used as antimycotics.

Derivatives of imidazole which can likewise be used according to the invention are those of the general structural formula

R

R2-C\ C-R3

C-N

R4 wherein the radicals can have the following meaning: RI H or C, 2as alkyl,

R

2 H or C(i 2 5 alkyl, R, H or C( 25 alkyl, R4 H or C( alkyl, wherein R 4 can also, and preferably if Ri, R 2 and R 3 are a hydrogen atom, be the radicals

-HCH-H

2

-NR

5

R

6 and -CH 2 -CH (NR 5 R) -COOR,, wherein Rs H or C( 25 alkyl, R6 H or C( 1 25 alkyl, R, H or C, .2s) alkyl.

Among these derivatives of imidazole, those which are water- and/or alcohol-soluble are preferred. Those derivatives in which R, H are particularly preferred.

I I L .p 10 It is particularly advantageous to use the nonderivatized parent substance R 4 H) of imidazole.

The derivatives histidine

H

/N'

H-C C-H

C-N

HOOC-CH-CH

2

NH

2 and histamine H-C C-H

C-N

H

2

N-CH

2

-CH

2 are also advantageous.

The activity of selected compositions [sic] according to the invention decreases in the following sequence: Imidazole (unsubstituted) histamine histidine It is of course clear to the expert that the use of histamine in products which [lacuna] into direct Scontact with the human or animal organism, that is to say, for example, cosmetics and foodstuffs, would not be acceptable, since histamine, as a tissue hormone, can bring about undesirable reactions: histamine occurs in an increased amount with allergies and anaphylaxes.

The use of the combination according to the invention of histamine and lantibiotics should therefore be subject to medical supervision.

The combination [sic] according to the invention are advantageously characterized by a content of L. I: L 4 -LL__ 11 0.01 99.99 by weight of an imidazole component and 99.99 0.01 by weight of an individual substance or a mixture from the group of lantibiotics, based on the total weight of the combination.

The combination [sic] according to the invention are particularly advantageously characterized by a content of 0.1 99.9 by weight of an imidazole component and 99.9 0.1 by weight of an individual substance or a mixture from the group of lantibiotics, based on the total weight of the combination.

The combination [sic] according to the invention are especially advantageously characterized by-a content of 99.0 by weight of an imidazole component and 99.0 1.0 by weight of an individual substance or a mixture from the group of lantibiotics, based on the total weight of the combination.

The lantibiotics are preferably present in the final formulations in concentrations of 0.1 10000 ppm.

The lantibiotics are particularly preferably present in the final formulations in concentrations of 0.1 750 ppm, especially preferably in concentrations of 0.5 400 ppm. The concentration data in each case relate to the content of pure active compound and to the total weight of the composition.

Formulations having an active content of nisin, epidermin and/or gallidermin have proved to be particularly advantageous. However, the other lantibiotics mentioned are also particularly suitable for the use according to the invention.

RAL/\ It is especially advantageous to use nisin.

It is possible and, where appropriate, 1, r IC2-CH2 -NR 5

R

12 advantageous to employ a mixture of lantibiotics as the active principle of the compositions according to the invention.

It is particularly advantageous to buffer the compositions according to the invention to a pH range of 6.5. It is particularly favourable to choose the pH in the range of 3.5 4.8.

The concentrations of imidazole are advantageously 0.01 5.00% by weight, based on the total weight of the composition, preferably 0.10 2.00% by weight, especially preferably 0.25 1.00% by weight.

Compositions which are particularly advantageous are those which comprise combinations having a content of 0.1 10000 ppm of lantibiotics, in particular nisin, and 0.01 5.00 by weight of imidazole, preferably 750 ppm of lantibiotics, in particular nisin, and 0.10 2.00 by weight of imidazole, particularly preferably 400 ppm of lantibiotics, in particular nisin, and 0.25 1.00 by weight of imidazole, in each case based on the total weight of the formulation.

Those formulations which comprise 0.4 0.6% by weight of imidazole or derivatives thereof are particularly preferred.

Perfume oils which cause lasting deactivation of lantibiotics in particular are listed in Table 1. However, if lantibiotics are present in combination with imidazole or derivatives thereof, the destabilization is compensated.

Table 1 Aldehyde C12 Hydroxycitronellol Allyl amyl glycolate Isoeugenol RA4N Ambrettolide Isoraldein SAmyl-cinnamaldehyde Jonol T. j 'w/v O

'I

13 Anisaldehyde Lilial (Firmenich) Aurantesin Lyral Benzyl acetate Methyl dihydrojasmonate Benzyl salicylate Musk ketone Castoreum p-Hydroxybenzylacetone Cedryl ketone Patchouli oil Eugenol Phenylethyl alcohol Florol (Firmenich) Phenylethyl phenylacetate Gamma decalactone Phenylethyl privalate [sic] Geraniol Tagetes oil Geranium oil Bourbon Terpentine oil Geranyl acetate Vertosine Helosine Ylang-ylang-oil Hexenyl salicylate Zibeth Hydrocarboresin Cinnamaldehyde Hydroxycitronellal (Firmenich) Cinnamyl alcohbl Apart from the perfume oil labelled otherwise, the perfume oils listed in Table 1 are marketed by the company Haarmann Reimer.

Stabilization with respect to the substances mentioned in Table 1 is claimed according to the invention, but is not to be limited thereto.

The invention thus also relates to the use of one or more derivatives of imidazole which have the following general structural formula

R

C- N R4 wherein the radicals can have the following meaning: Ri H or 1 2 5 alkyl, L H, C

O

2 5 Alkyl, R 6 H, Cn 25)" Alkyl, R 7 H, C( 25) Alkyl bedeuten, und einem gegen Mikroorganismcn wirksamen Stofodor einem Gemisch aus der Gruppe der Lantibiotika.

I

14 R, H or 25 alkyl,

R

3 H or 2 5 alkyl,

R

4 H or C( 5) alkyl, -wherein R 4 can also, and preferably if R 1

R

2 and

R

3 are a hydrogen atom, be the radicals

-CH

2

-CH

2 -NRsR 6 and -CH 2

-CH(NRR

6

-COOR,,

wherein

R

5 H or C 1 25 alkyl,

R

6 H or 25 alkyl,

R

7 H or 25 alkyl, for stabilizing lantibiotics.

The deodorizing cosmetic compositions according to the invention can be in the form of a preparation which can be sprayed from aerosol containers, squeeze bottles or by a pump device, or in the form of a liquid composition which can be applied by means of roll-on devices, but also in the form of a water-in-oil or oilin-water emulsion, for example a cream or lotion, which can be applied from normal bottles and containers. Other cosmetic deodorants can be in the form of deodorizing tinctures, deodorizing intimate cleansing compositions, deodorizing shampoos, deodorant soap, deodorizing shower or bath formulations, deodorizing powders or deodorizing powder sprays. However, customary deo stick bases can also serve as carriers for solid formulations and sticks.

Customary cosmetic carrier substances which can be employed for preparation of the deodorizing composi- !tions according to the invention are, in addition to water, ethanol, isopropanol, glycerol and propylene 2/ glycol, skincare fatty or fat-like substances, such as partial glycerides of fatty acid mixtures, oleic acid decyl ester, cetyl alcohol, cetyl stearyl alcohol and 2octyldodecanol, in the ratios of amounts customary for such preparations, as well as mucilaginous substances and thickeners, for example methylcellulose, polyacrylic acid and polyvinylpyrrolidone, and in addition also small

A

O amounts of cyclic silicone oils (polydimethylsiloxanes), Sas well as liquid polymethylphenylsiloxanes of low 15 viscosity.

Suitable propellants for deodorizing cosmetic compositions according to the invention which can be sprayed from aerosol containers in the form of a spray jet on actuation of the valve are the customary known highly volatile liquefied propellants, for example hydrocarbons (propane, butane and isobutane), which can be employed by themselves or as a mixture with one another. Compressed air can also advantageously be used, where appropriate.

Emulsifiers which have proved suitable for the preparation of the deodorizing cosmetic compositions according to the invention, which are preferably to be applied to the desired areas of skin as liquid formulations by means of a roll-on device, and can be used in the compositions in a small amount (for example) of 2 to by weight, based on the total composition, are nonionic types, such as polyoxyethylene fatty alcohol ethers, for example cetostearyl alcohol polyethylene glycol ether having 12 or 20 added-on ethylene oxide units per molecule of cetostearyl alcohol, and sorbitan esters and sorbitan ester-ethylene oxide compounds (for example sorbitan monostearate and polyoxyethylene sorbitan monostearate), as well as long-chain higher molecular weight waxy polyglycol ethers.

In addition to the constituents mentioned, it is possible to admix to the deodorizing cosmetic compositions according to the invention the pH of which is preferably brought to 2.5 to 6.5, in particular to 4.8, for example, by customary buffer mixtures 0 perfume, dyestuffs, antioxidants (for example alphatocopherol or butylated hadroxytoluene [sic] 2,6-ditert-butyl-4-methylphenol in amounts of 0.01 to 0.03%, based on the total composition), suspending agents, buffer mixtures or other customary cosmetic base substances, such as triethanolamine or urea.

Those substances and perfume oils which are AL4/ stable, do not irritate the skin and already have antibacterial (bacteriostatic) properties as such are No 1: I _I -16 also suitable, where appropriate, for perfuming.

In an individual case, however, it is to be weighed up whether the advantage which the highly selective antimicrobial action of the lantibiotics and, in particular, of the combinations according to the invention offers is to be reduced or not by other substances which, under certain circumstances, have a less selective action.

However, the invention is not limited to the formulations and compositions, auxiliaries and carrier substances mentioned.

The particular amounts of cosmetic carrier substances and perfume to be employed can easily be determined by the expert by simple trials, as a function of the nature of the particular product.

Apart from specific formulations which are noted in each case separately in the examples, the cosmetic compositions are prepared in the customary manner, usually by simple mixing while stirring, if appropriate with gentle heating. The preparation presents no difficulties. For emulsions, the fat, phase and the aqueous phase, for example, are prepared separately, if necessary with heating, and then emulsified.

Otherwise, the customary rules for composing cosmetic formulations, with which the expert is familiar, are to be observed.

The combinations according to the invention can be incorporated into the compositions according to the invention in a simple manner. They are preferably added in dissolved form (for example as an aqueous, alcoholic or alcoholic-aqueous solution) to the other consituents of the formulations. However, it is especially advantageous to incorporate lantibiotics into so-called powder sprays. It is also advantageous to avoid additives which can harm the natural microflora, since the combinations according to the invention in themselves selectively reduce the odour-generating microorganisms.

If the combinations according to the invention are to be incorporated into powder sprays, the suspension

F

INr T~ en"~i It was astonishing and not foreseeable to the

F

17 bases for this can advantageously be chosen from the group consisting of aerosil, kieselguhr, kaolin, talc, modified starch, titanium dioxide, zinc oxide, silk powder, nylon powder, polyethylene powder and related substances.

The following examples serve to describe the invention, without the intention being to limit the invention to these examples.

Perfume compositions: Perfume No. 1 Benzyl acetate 4.0% by weight Geraniol 5.0% by weight Phenylethyl alcohol 9.0% by weight Various other odoriferous substances to 100.0% by weight Perfume No. 2 Benzyl acetate 5.4% by weight Geraniol 8.0%-by weight Ylang-ylang oil 8.4% by weight Various other odoriferous substances to 100.0% by weight Perfume No. 1 [sicI Benzyl acetate 5.0% by weight Geraniol 12.0% by weight Hydroxycitronellal 7.0% by weight Various other odoriferous substances to 100.0% by weight Example 1 Pump spray Nisin (pure substance) Imidazole Ethanol phar,,. (96%) Perfume 1 Dyestuff Water Example 2 Pump spray Epidermin Imidazole Ethanol pharm. (96%) 0.025 g 5.000 g 354.875 g 10.000 g as desired to 1,000.000 g 0.010 g 3.500 g 354.875 g 18 Perfume 1 Dyestuff Water Example 3 Deodorant roller (roll-on) Nisin Imidazole Hydroxyethylcellulose Propylene glycol Ethanol pharm. (96%) Perfume 2 Dyestuff Water Example 4 Deodorant roller (roll-on) Epidermin Imidazole Hydroxyethylcellulose Propylene glycol Ethanol pharm. (96%) Perfume 2 Dyestuff Water Example Spray Nisin Imidazole Ethanol pharm. (96%) Propylene glycol Dimethyl ether Perfume 3 Water 10.000 g as desired to 1,000.000 g 0.150 g 8.000 g 5.000 g 5.000 g 355.850 g 10.000 g as desired to 1,000.000 g 0.120 g 6.500 g 5.000 g 5.000 g 355.850 g 10.000 g as desired to 1,000.000 g 0.200 1.500 150.000 50.000 300.000 10.000 to 1,000.000 Example 6 Spray Epidermin 0.150 g t JJj VV A& 'PA. W A. 41

'-I

~.r 1 19 Imidazole Ethanol pharm. (96%) Propylene glycol Dimethyl ether Perfume 3 Water Example-7 Spray Nisin Imidazole Ethanol pharm. (96%) 2-Octyldodecanol Perfume 1 Dimethyl ether Example-8 Spray Epidermin Imidazole Ethanol pharm. (96%) 2 -Octyldodecanol Perfume 1 Dimethyl ether Example 9 Nisin :midazole Cetylsteary. alcohol 2 -Octyldodecanol Kaolin Talc Aerosil Perfume 3 Rice starch 2.000 150.000 50. 000 300. 000 10.000 to 1,000.000 0.180 17.000 497. 160 2.660 10. 000 to 1,000.000 0 .150 13.800 497.*160 2.660 10. 000 to 1,000.000 1.200 32.000 20. 000 20. 000 200.200 200.200 48. 200 10. 000 to 1,000.000 g g g i g g g g g g Example Epidermin Imidazole 1.000 27.000 Ancovenin 8214- 88201-41-6 1~ 20 Cetyistearyl alcohol 2 -Octyldodecanol Kaolin Talc Aerosil Perfume 3 Rice starch 20.000 20.000 200.200 200. 200 48.200 10.000 to 1,000.000 Examprle I11 Washing gel concentrate Nisin Imidazole Cocoamidopropylbetaine Tipa-lauryl ether sulphate Sodium chloride Perfume 2 Dyestuff citric acid Glycerol Water Example 12 Washing gel concentrate Epidermin Imidazole tCocoamidopropylbetaine Tripa-lauryl ether sulphate Sodium chloride Perfume 12 Dyestuff citric acid Glycerol Water 9.000 g 17.000 g 613.300 g 306.700 g as desired 40.000 g as desired 1.000 g 10.000 a, to 1,000.000 g 7.000 g 12.000 g 613.300 g 306.700 g as desired 40.000 g as desired 1.000 g 10.000 g to 1,000.000 g Example 13 Powder spray I a) Suspension base Polymethylsiloxane (Cyclomethicone) 72.000 g *11~* 21 Talc Bentonite gel IPM Nisin Imidazole Perfume 1 b) Finished spray Suspension base I Propane/butane Example 14 Powder spray II a) Suspension base Polymethylsiloxane (Cyclomethicone) Titanium dioxide Bentonite gel IPM Nisin Imidazole Perfume 3 b) Finished spray Suspension base I Propane/butane Example Powder spray III a) Suspension base Polymethylsiloxane (Cyclomethicone) Silk powder Bentonite gel IPM Nisin Imidazole Perfume 2 b) Finished spray Suspension base I Propane/butane 24.000 g 3.000 g 1.000 g 5.000 g 2.500 g 20.000 g 80.000 g 72.000 g 24.000 g -3.000 g 1.000 g 8.000 g 2.000 g 20.000 g 80.000 g

I

72.000 g 24.000 g 3.000 g 1.000 g 6.000 g 2.000 g 20.000 g 80.000 g i 22 The superiority of the present invention is demonstrated with the aid of the following experiments.

The compositions according to the examples were evaluated with the aid of the so-called "sniff test".

Experiment i: Compositions according to the invention from Example 1 were tested against a placebo, that is to say a composition which is identical apart from the content of active substance.

A group of 30 subjects were told to treat in each case one armpit with composition according to the invention and the other with placebo. The subjects then wore a shirt with slip inserts under the shoulders for three hours. After this period of time, the slip inserts were transferred to separate bottles. The smell of the inserts was evaluated by three test persons. The experiment was carried out as a double-blind experiment, so that neither the subjects nor the test persons knew which armpit had been treated with which composition.

It was found that the formulations containing active compound had a better action when evaluated sensorially than the corresponding placebos in each case in 29 out of 30 cases. In 1 out of 30 cases the test person stated that the treated and untreated samples did not differ from one another.

Experiment 2: Compositions from Example 4 (comprising imidazole, formulations C) according to the invention were tested against compositions identical to these without imidazole (formulations D).

A group of 30 subjects were told to treat in each case one arnmpit with formulation C and the other with formulation D. The subjects then wore a shirt with slip inserts under the shoulders for three hours. After this period of time, the slip inserts were transferred to separate bottles. The smell of the inserts was evaluated by five test persons. The experiment was carried out as Ra double-blind experiment, so that neither the subjects nor the test persons knew which armpit had been treated 9.J 0VT O 23 with which composition.

It was found that the formulations C had a better action when evaluated sensorially than formulations D in each case in 25 out of 30 cases.

In each case in 4 out of 30 cases, formulations D were evaluated as being better sensorially than formulations C.

In 1 out of 30 cases, the test person stated that the treated and untreated samples did not differ from one another.

iA4/

II

NT o

Claims

24. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:- 1. A combination of imidazole and/or one or more derivatives of imidazole which have the following general structural formula R 1 N. C N R4 -wherein the radicals have the following meaning: *R H or C~l 25) alkyl, R2 =4 r -a k l *R3 H Or C~l 25) alkyl, R4 H or C( 1 25) alkyl, or R 4 is one of the radicals
4444- CH 2 -CH 2 -NRsR 6 to it or CH 2 CH (NRR) COOR 7 1 where in H Or C 25) alkyl, R6 H or C 1 alkyl, R 7 H Or C(I 25) alkyl, and a lantibiotic or a mixture of two or more lantibiotics, the imidazole and lantibiotic being present in an amount effective to protect against microorganisms. 2. A combination according to claim 1 wherein RI, R 2 and R 3 are hydrogen atoms and R 4 is -CH 2 -CH 2 -NRsRG or -CH 2 -CH (NRsR6) COOR 7 W'"4I 3. A combination according to claim 1 or 2 wherein the lantibiotics are chosen from the group consisting of nisin, epidermin, subtilin, cinramycin, duramycin, ancovenin, Pep and gallidermin. 4. A combination according to any one of claims 1 to 3, wherein the imidazole derivatives are chosen from the group consisting of unsubstituted imidazole, histidine and histamine. A combination according to any one of claims 1 to 4, 10 characterized by a content of 4 t 0.01 99.99 by weight of an imidazole component and S: 99.99 0.01 by weight of an individual substance or a mixture from the group of lantibiotics, based on the total weight of the combination. 15 6. A formulation comprising a combination according to any one of claims 1 to 5, wherein the lantibiotic(s) are #i present in a content of 0.1 10000 ppm, based on the total weight of the formulation. 1 7. A formulation comprising a combination according to any one of claims 1 to 5, wherein the lantibiotic(s) are present in a content of 0.1 750 ppm, based on the total weight of the formulation. 8. A formulation comprising a combination according to any one of claims 1 to 5, wherein the lantibiotic(s) are present in a content of 0.5 400 ppm, based on the total weight of the formulation. C -26- 9. A formulation comprising a combination according to any one of claims 1 to 5, wherein the imidazole derivative or derivatives are present in a concentration of 0.01 5.00% by weight, based on the total weight of the formulation. 10. A formulation comprising a combination according to any one of claims 1 to 5, wherein the imidazole derivative or derivatives are present in a concentration of 0,10 2.00% by weight, based on the total weight of the formulation. 11. A formulation comprising a combination according to any 10 one of claims 1 to 5, wherein the imidazole derivative or derivatives are present in a concentration of 0.4 0.6% by weight, based on the total weight of the formulation. 12. A formulation comprising a combination according to any one of claims 1 to 11, characterized in that they are in the form of deodorant sprays, roll-ons, pump sprays, S tinctures, intimate cleansing compositions, shampoos, ;shower or bath formulations, powders, powder sprays or deo sticks. 13. Use of one or more derivatives of imidazole which have the following general structural formula R R4 /N wherein the radicals have the following meaning: SRI H or C(i 25) alkyl, l.lt~.-i i lll il-~ I-I YiYli iil.ll__ ily-- -27- R, H or C( 1 25) alkyl, R 3 H or C( 25) alkyl, R4 H or C( 25) alkyl, or R 4 is one of the radicals -CH 2 -CH 2 -NRsR6 or -CH 2 -CH (NRsR 6 -COOR,, wherein R 5 H or C( 1 25) alkyl, R, H or C(i 25) alkyl, R7 H or C(1 25) alkyl, for stabilizing lantibiotics. 14. Use according to claim 13 wherein R,, hydrogen atoms and R 4 is -CH 2 -CH 2 -NR 5 R, or COOR 7 15. Use of combinations according to any 4 for combating Propionibacterium acnes. R 2 and R 3 are -CH 2 -CH (NRsR) one of claims 1 1 16. Use of combinations according to any one of claims 1 4 for the preparation of a dermatological formulation against acne. 20 17. A combination substantially as herein described with reference to any one of Examples 1 to DATED this 17th day of June, 1996 BBEIERSDORF AG Attorney: RUTH M. CLARKSON Fellow Institute of Patent Attorneys of Australia of SI-IELSTON WATERS R Abstract Combinations of imidazole and/or one or more derivatives of imidazole which have the following general structural formula N R 3 R 2 -C C-R 3 N wherein the radicals can have the following meaning: R, H or C( -25) alkyl, R, H or C( 25) alkyl, R3 H or C( 25 alkyl, R4 H or C(i 25) alkyl, wherein R 4 can also, and preferably if Ri, R 2 and R 3 are a hydrogen atom, be the radicals -CH 2 -CH 2 -NRsR 6 and -CH 2 -CH(NRsR 6 )-COOR,, wherein Rs H or C(i 25 alkyl, Rg H or C( 25) alkyl, R, H or C( 1 25 alkyl, and a substance which is active against microorganisms or a mixture from the group of lantibiotics. -L .1 %i II L~~CMYXIII~II. INTERNATIONAL SEARCH REPORT Inter nal Application No PCT/EP 93/02238 A. CLASSIFICATION OF SUBJECT MATTER IPC 5 A01N63/02 A61K7/32 A61K7/48 //(A01N63/02,43:50,25:22) According to Intemational Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC 5 A01N A61K Documentation searched other than miumum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropnate, of the relevant passages Relevant to claim No. X EP,A,0 451 002 (BRISTOL-MYERS) 9 October 13 1991 see claims 1,2 X EP,A,O 274 267 (UNILEVER) 13 July 1988 13 see page 5, line 15 line 28 A WO,A,91 07164 (BEIERSDORF) 30 May 1991 1-12 see claims DE,A,39 38 140 cited in the application SFurther documents are listed in the continuation of box C. Patent family members are listed in annex. Special categories of cited documents: T later document published alter the international filing date f t g s o t a w i n or priority date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international *X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventve step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 19 November 1993 0 3. 12. 93 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. (+31-70) 3402040, Tx. 31 651 cpo nl, DC T, D Fax 31.70) 340-3016 DECOR D Form PCT/ISA/210 (acond shet) (July 1992) i DNTRNATIONAL SEARCH REPORT -afrauionon atet fn-Ay mrnbrsI ntci nal Application No .nfrmaionn ~t~fl amly embrsPCT/EP 93/02238 Patent document Publication daetfmiyPbiatio cited in searchreport date member(s) a EP-A-045 1002 09-10-91 AU-B- 634643 25-02-93 AU-A- 7403591 10-10-91 t JP-A- 5097641 20-04-93 EP-A-0274267 13-07-88 AU-B- 602039 27-09-90 AU-A- 8281187 23-06-88 CA-A- 1306198 11-08-92 DE-A- 3780607 27-08-92 WO-A-9107164 30-05-91 DE-A- 3938140 08-08-91 AU-A- 6617290 13-06-91 EP-A- 0500605 02-09-92 JP-T- 5501875 08-04-93 DE-A-3938140 08-08-91 AU-A- 6617290 13-06-91 WO-A- 9107164 30-05-91 EP-A- 0500605 02-09-92 JP-T- 5501875 08-04-93 Form PCT/ISA/211 (patant family annax) (July 1993) L INTERNATIONALER RECHERCHENBERICHT Intel Weis Aktenzeiehen IPCT/EP 93/02238 A. KLASSIFIZIERUNG DES ANM ELDUNGSGEGENSTANDES IPK 5 A01N63/02 A61K7/32 A61K7/48 //(A01N63/02,43:50,25:22) Nach der Internationalen Patentklnasirikaton (IPK) oder nach der nationalen Klassifikation und der IPK B. RECHERCHIERTE GEI3IETE Recherchierter Mindestprilfstoff (Klassifikationssystem und Klassifikatiosymbole) I PK 5 A01N A61K Rccerchiertc aber nicht zum Miridcstpirilfstoff gehdrende Vcroffentlichungen, soweit chese unter die recherchxcrten Gcbiete fallen W&=red der internationalen Recherche konsultierte elektronische Datenbank (Name der Datenbank und evtl. verwendece Subegriffe) C. ALS WESENTLICH ANGESEHENE UNTERLAGEN Kategoric' &3zeichriung der Vcr~fecntlichung, soweit erforderlich uniter Angabe der in Betracht kommenden Tailc Belt. Aflspruch Nr. X EP,A,0 451 002 (BRISTOL-MYERS) 9. Oktober 13 1991 siehe AnsprUche 1,2 X EP,A,O 274 267 (UNILEVER) 13. Juli 1988 13 siehe Seite 5, Zeile 15 Zeile 28 A WO,A,91 07164 (BEIERSDORF) 30. Mai 1991 1-12 siehe AnsprUche DE,A,39 38 140 in der Anmeldung erwahnt SWctere Veroftentlichungen sind der Fortsetzung van Feld C zu MV1 Siehc Anhang aetmic *Besondere Kategonen von angegebenen Verdffentiehungen T' Spatere Veroffentlichuxig, die nach dem internationalen Anmeldedatum Verdfentlichung, die den allgemeincn Stand der Technik deaimrt, oe e roiisars eofnletwre a n i e aber nicht als besonders bedeutsam anzusehen is Anmeldung nicht kollidiert, sondern nur zumVerstAndnis des der E 6leresDokment da jedch rst m oer nch em itemtionien Erfindung zugrudeliegenden Prinzips oder der lihr zugrundeliegenden ters Doumct, as jdoc ert amodc nac dc inernaionlen Theonec angegeben ist Arneldedatum veroffentlicht warden ist WC Vcr&fcentlichung von besonderer Bedeutung; die beanspruchte Erfindu L' Verdffentlichung, die geeignet tst, einen PrioritAtsanspruch zweifielhaft er. kann allein aufgrund Wieser Verdifentlichung nicht als neu oder auf sdaeinen zu lassen, odcr durch die das Verbffentiiehungsdatum esner erfindenischer Tatsgkeit beruhend beltachtet werden anderen im Recherchenbericht genannten Ver~fecntlichung belegt werden 'Y Verolfentlichung von besonderer Bedeutung; die beanspnrzchtetErfindun soil odcr die aus cinem anderen besonderen Grund angegeben ist (wie kaxin nicht als auf erfinderischer Titigkeit beruhend betrachtet agefthrt) werden, wena die Verdifentiehung mit ciner oder mehreren anderen Veroffentlichung, die sich auf aine milndliche Offenbaning, Veroffenulichungen diescr Kategone in Verbindun gebraeht wird und cine Benulzung, eine Ausstellung oder andere Malinakimen bezieht diese Verbindung Mri einen Fachmann naheliegcnd sat Veroffentlichung, die vor dem intemationalen Anmcldedatuxn, aber nach dem becanspnsichten Priorititsdatum verclffentlicht warden is V& Verdifentliehung, die Mitglied derslben Patentfamilie ist Datum des Abschlusses der intemationalen Recherche Abscndedatum des intemationalen Recherchenbenchts 19. November 1993 0 3. 12. 93 Name und Postanschrift der Internationale Recherchenbehorde Bevollmicbtigter Bediensteter Europaisehes Patentaxnt, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. 31.70) 340-204, Tx. 31 651 epo WEORE Fax (1-31.70) SAN3016 DCRE lsrrnbiatt PCT/ISA/210 (Blatt 2) (Jull 1992) I tw It INTERNATIONALER RECHERCHENBERICHT Angaben zu Vcrdffcntiichui, 1 en, die zur seiben Patentfamlzc gehllren rIntet nales Aktenzcchcn l PCT/EP 93/02238 Im Recherchenbericht I Datum der j Mitglld(er) der Datum der aLngcfilhrtes Patentdokument Vcriiffentlichung Patentfanmilie Verdffentlichung EP-A-0451002 09-10-91 AU-B- 634643 25-02-93 AU-A- 7403591 10-10-91 JP-A- 5097641 20-04-93 EP-A-0274267 13-07-88 AU-B- 602039 27-09-90 AU-A- 8281187 23-06-88 CA-A- 1306198 11-08-92 DE-A- 3780607 27-08-92 WO-A-9107164 30-05-91 OE-A- 3938140 08-08-91 AU-A- 6617290 13-06-91 EP-A- 0500605 02-09-92 JP-T- 5501875 08-04-93 DE-A-3938140 08-08-91 AU-A- 6617290 13-06-91 WO-A- 9107164 30-05-91 EP-A- 0500605 02-09-92 JP-T- 5501875 08-04-93 Formblatt PCTIISA/210 (Anhang PstentaiffUo)(Jull 1992)