FR3068214A1 - ANTIMICROBIAL MIXTURE CONTAINING 4- (3-ETHOXY-4-HYDROXYPHENYL) BUTAN-2-ONE AND A CHLORHEXIDINE COMPOUND, AND COSMETIC COMPOSITION CONTAINING THE SAME - Google Patents

Abstract

The invention relates to an antimicrobial mixture containing 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one and a chlorhexidine compound selected from chlorhexidine digluconate and chlorhexidine chlorhydate, and a cosmetic composition containing such a mixture. . Application to the care, makeup and cleansing of keratin materials.

Description

The present invention relates to an antibacterial mixture containing 4- (3-ethoxy-4hydroxyphenyl) butan-2-one and a particular chlorhexidine compound, as well as a cosmetic composition containing such a mixture.

4- (3-ethoxy-4-hydroxyphenyl) butan-2-one (ketone compound) is an interesting substance as a preservative for cosmetic compositions to protect the compositions from microbial contamination, as described in application WO 2011/039445 .

However, it is desirable to be able to incorporate said ketone compound in reduced concentration in compositions, in particular cosmetic or dermatological, while retaining a good antimicrobial preservation performance. It is therefore sought for this purpose associations of the ketone compound with other compounds with antimicrobial efficacy.

The inventors have discovered, unexpectedly, that the combination of 4- (3-ethoxy-4hydroxyphenyl) butan-2-one with a chlorhexidine compound chosen from chlorhexidine digluconate and chlorhexidine hydrochloride makes it possible to obtain an antimicrobial mixture having a synergy of antimicrobial activity, in particular on molds, in particular on Aspergillus niger, and on yeasts, in particular on Candida albicans. The results of Example 1 described below show the synergistic antimicrobial activity obtained with the measurements of minimum inhibitory concentrations (MIC) made with several mixtures. Antimicrobial activity is considered to be synergistic when the antimicrobial mixture makes it possible to obtain a percentage of growth of the strain less than or equal to 25%, or even less than or equal to 20%.

Application FR-A-2962328 and FR-A-2973229 describe a cosmetic composition for treating body odors linked to human perspiration comprising a 2-alkoxy-4-alkylketonephenol compound, and optionally an additional deodorant active ingredient such as chlorhexidine and its salts.

These documents do not specifically describe an antimicrobial mixture consisting of the association of 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one with a chlorhexidine compound chosen from chlorhexidine digluconate and chlorhexidine hydrochloride, and do not suggest neither does such a mixture exhibit synergistic antimicrobial activity on molds, in particular on Aspergillus niger, and on yeasts, in particular on Candida albicans.

More specifically, the subject of the invention is an antimicrobial mixture comprising, or consisting of (or consisting of), 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one and a chlorhexidine compound chosen from chlorhexidine digluconate and chlorhexidine hydrochloride.

The subject of the invention is also a composition, in particular a cosmetic composition, comprising, in a physiologically acceptable medium, the said mixture described above.

The subject of the invention is also a process for the non-therapeutic cosmetic treatment of keratin materials comprising the application to the keratin materials of a composition as described above. The process can be a cosmetic process for caring for or making up or cleaning keratin materials.

4- (3-ethoxy-4-hydroxyphenyl) butan-2-one is a compound of formula

The chlorhexidine compound is chosen from chlorhexidine digluconate and chlorhexidine hydrochloride.

Advantageously, 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one and dehydroacetic acid or one of its salts are present in said mixture in a content such as the weight ratio 4- (3-ethoxy -4-hydroxyphenyl) butan-2-one / chlorhexidine compound ranges from 2 to 3500, preferably ranges from 2 to 250, and preferably ranges from 2 to 220.

The antimicrobial mixture according to the invention has a synergy of antimicrobial activity, in particular on molds, in particular on Aspergillus niger, and on yeasts, in particular on Candida albicans.

According to a first embodiment of the invention, the chlorhexidine compound present in the antimicrobial mixture is chlorhexidine digluconate.

The antimicrobial mixture may have a 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine digluconate weight ratio ranging from 25 to 150, preferably ranging from 30 to 130, and preferably ranging from 45 to 90. A such a mixture has a synergistic antimicrobial activity on yeasts, in particular on Candida Albican.

The antimicrobial mixture can have a 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine digluconate weight ratio ranging from 10 to 75, preferably ranging from 10 to 60, and preferably ranging from 10 to 40. A such a mixture has good synergistic antimicrobial activity on molds, in particular on Aspergillus niger.

According to a second embodiment of the invention, the chlorhexidine compound present in the antimicrobial mixture is chlorhexidine hydrochloride.

The antimicrobial mixture may have a weight ratio of 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine hydrochloride ranging from 60 to 350, preferably ranging from 80 to 250, preferably ranging from 90 to 220. Such a mixture has good synergistic antimicrobial activity on yeasts, especially on Candida Albican.

The antimicrobial mixture can have a weight ratio of 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine hydrochloride ranging from 2 to 120, preferably ranging from 2 to 100, preferably ranging from 2 to 85. Such a mixture has good synergistic antimicrobial activity on molds, especially on Aspergillus niger.

The compound 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one may be present in the composition according to the invention, in a content ranging from 0.01% to 5% by weight, relative to the total weight of the composition, preferably ranging from 0.01% to 3% by weight, preferably ranging from 0.01 to 2.5% by weight, and more preferably ranging from 0.01 to 2% by weight.

The subject of the invention is also a composition comprising, in a physiologically acceptable medium, the antimicrobial mixture described above.

The term “physiologically acceptable medium” is intended to mean a medium compatible with keratin materials of human beings such as the skin, the scalp, the hair, the nails. Said medium can comprise one or more additional ingredients, distinct from the ketone compound and from said chlorhexidine compound.

The composition may comprise at least one additional ingredient chosen from water, oils, polyols having from 2 to 10 carbon atoms, gelling agents, surfactants, film-forming polymers, coloring matters, perfumes, fillers, UV filters, plant extracts, cosmetic and dermatological active ingredients, and salts.

The composition according to the invention can comprise an aqueous phase.

The composition can comprise water which can be present in a content ranging from 5% to 90% by weight, relative to the total weight of the composition, and preferably ranging from 35% to 75% by weight.

The composition may also comprise a polyol miscible with water at room temperature (25 ° C), in particular chosen from polyols having in particular from 2 to 10 carbon atoms, preferably having from 2 to 6 carbon atoms, such as glycerin, propylene glycol, 1,3-propanediol, butylene glycol, pentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol, diglycerin.

The compositions according to the invention can be in the form of oil-in-water (O / W) or water-in-oil (W / O) or multiple (triple: W / O / W or O / W / O) emulsions , oily solutions, oily gels, aqueous solutions, aqueous gels, solid compositions. These compositions are prepared according to the usual methods.

The compositions according to the invention may be more or less fluid and have the appearance of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, of a foam. They can optionally be applied to the skin in the form of an aerosol. They can also be in solid form, and for example in the form of a stick or compact powder.

The composition according to the invention may in particular be in the form:

- a make-up product, in particular the skin of the face, the body or the lips or the eyelashes;

- an after-shave gel or lotion; shaving product;

- a deodorant (stick, roll-on, aerosol)

- a depilatory cream;

- in the form of a body hygiene composition such as a shower gel or a shampoo;

- a pharmaceutical composition;

- a solid composition such as a soap or a cleaning bar;

- an aerosol composition also comprising a propellant under pressure .;

- a styling lotion, a styling cream or gel, a dye composition, a perm composition, a fall prevention lotion or gel, an after shampoo;

- a skin care or cleansing composition.

The subject of the invention is also a process for preparing a composition, in particular a cosmetic or dermatological composition, comprising a step of mixing 4- (3-ethoxy-4hydroxyphenyl) butan-2-one, of said chlorhexidine compound, and of one or more additional ingredients, in particular cosmetic or dermatological, such as those described above.

The invention is illustrated in more detail in the following example. The contents of the ingredients are expressed as a percentage by weight.

Example 1: Determination of the synergy of antimicrobial activity in MIC

Demonstration of a synergistic effect of antimicrobial activity with a mixture of 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one (called substance A) and chlorhexidine digluconate (called substance B) and a mixture of 4- (3-ethoxy-4-hydroxyphenyl) butan-2one (called substance A) and chlorhexidine hydrochloride (called substance C) is carried out by calculating the synergy index (or FIC index) according to the following formula:

FIC Index = (CMIa with B / CMIa) + (CMIb with A / C MÏb) with:

CMIa with B: minimum concentration of product A in the combination A + B to obtain an inhibitory effect

CMIb with A: minimum concentration of product B in the combination A + B to obtain the inhibitory effect.

CMIa: minimum inhibitory concentration of product A alone.

CMIb: minimum inhibitory concentration of product B alone.

This formula was first described in the article by F.C. Kull, P.C. Eisman, H.D. Sylwestrowka, and R.L. Mayer, Applied Microbiology 9: 538-541, 1961.

For each compound tested alone, the MIC is considered to be the first concentration allowing a percentage of microbial growth less than or equal to 25% to be obtained.

Concerning the associations tested, CMIa with b and CMIb with a are the respective concentrations of A and B in the associations allowing the obtaining of a percentage of microbial growth less than or equal to 25%.

Interpretation of the FIC Index:

When the value of the FIC index is less than or equal to 1, it is considered that the combination of the tested compounds has a synergistic effect.

The synthesis of the results obtained is presented in the following tables.

The combination of compounds A and B and the combination of compounds A and C were tested on the following strains: Aspergillus niger and Candida albicans.

The microbial strain Aspergillus niger ATCC 6275 was used, and a Sabouraud broth liquid culture medium supplemented with polyoxyethylenated sorbitan monopalmitate (20 EO) (Tween 40 from Croda) and Phytagel © BioReagent, at double concentration.

The Candida albicans ATCC 10231 microbial strain and a double-concentration Sabouraud broth liquid culture medium were used (ie a mixture of 5 g of Phytagel + 0.6 g tween 40 + 60 g Sabouraud broth).

A 96-well microplate is used at an incubation temperature of 32.5 ° C.

The incubation time of the microplate is:

- 24 to 48 hours aerobically for Aspergillus niger;

- from 18 to 24 hours aerobically for Candida albicans.

testing

For each compound:

A = compound 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one

B = chlorhexidine digluconate compound (in aqueous solution at 20% active ingredient)

C = chlorhexidine hydrochloride compound

A 10% (weight / volume) stock solution was prepared by mixing 1 g of compound in 9 ml of 1% o aqueous agar solution. successive dilutions were made with the 1% o agar solution.

• Tests of compounds A, B and C alone

50 μL of each of the daughter solutions obtained containing compound A or B or C is added to the wells of the microplate. We also add 100μΙ of liquid nutritive broth from Sabouraud seeded with the Aspergillus niger strain and 50pL of 1% o agar aqueous solution.

• Tests of compounds A + B or A + C in mixture

50μΙ_ of each of the daughter solutions obtained containing compound A and 50μΙ_ of each of the daughter solutions obtained containing compound B or C are added to the wells of the microplate. We also add 10ΟμΙ of liquid nutritive broth from Sabouraud seeded at double concentration with the Aspergillus niger strain.

Microbial growth control

A positive microbial growth control was also performed. The positive microbial growth control corresponds to the mixture of 100 μΙ of an aqueous 1% o agar solution with 10Ο μΙ of liquid nutritive broth from Sabouraud seeded at double concentration with the Aspergillus niger strain in the absence of compounds A, B and C .

Control of absorbance of compounds A, B and C alone

At the same time, an absorbance control for compounds A, B and C was produced alone. This control corresponds to 10ΟμΙ of nutritive broth liquid from Sabouraud sterile at double concentration + 10ΟμΙ of compound A or B or C at double concentration.

In the three cases (absorbance control, growth control and test) the final volume present in each of the wells of the microplate is 200 μL.

In both cases (test and control), the inoculum represents the concentration of the Aspergillus niger strain present in the final volume of the wells (200 μL) and is between 2 and 6.10 ⁵ cfu / ml in Aspergillus niger.

The minimum inhibitory concentration (MIC) of each compound A, B and C alone and in combination was determined in known manner using optical density measurements at the wavelength 620nm.

The test as described above (tests, absorbance controls and growth control) was again carried out to test the associations A + B and A + C on the Candida albicans strain.

The following results were obtained: (percentage by mass of active material)

A) Mixtures with compound B: chlorhexidine digluconate

Candida albicans

concentrations tested (in% by weight) 0A 0.025 A 0.05 A 0.1 A 0 B 63 47 22 0.00025 B 59 56 32 14 0.0005 B 32 16 (FIC 0.75) 6 (FIC 1) 1 0.001 B 3 0 0 1

CMI of A alone in% CMI of B alone in% Compound MIC AT % each mixed B% FIC Index 0.1 0,001 0,025 0.0005 0.75 A / B ratio = 50

The results obtained show a synergy of the inhibitory activity for the mixtures:

i) 0.025% of A and 0.0005% of B or A / B ratio = 50 ii) 0.05% of A and 0.0005% of B or A / B ratio = 100

Aspergillus niger

concentrations tested (in% by weight) 0A 0.0625 A 0.125 A 0.25 A 0 B 83 49 5 0.0025 B 98 1 1 (FIC 0.5 (FIC 0.75) (FIC 0.75) (FIC 1) 2 0.005 B 98 1 0.01 B 7 1 2 2

CMI of A alone in% CMI of B alone in% Compound MIC AT % each mixed B% FIC Index 0.25 0.01 0.0625 0.0025 0.50 A / B ratio = 25

The results obtained show a synergy of the inhibitory activity for the mixtures:

i) 0.0625% of A and 0.005% of B or A / B ratio = 12.5 ii) 0.125% of A and 0.005% of B or A / B ratio = 25 iii) 0.0625% of A and 0 0.0025% B or A / B ratio = 25 iv) 0.125% A and 0.0025% B or A / B ratio = 50

B) Mixtures with compound C: chlorhexidine hydrochloride

Candida albicans

concentrations tested (in% by weight) 0A 0.025 A 0.05 A 0.1 A 0.2 A OC 83 70 50 10 0.00025 C 82 67 62 32 1 0.0005 C 64 44 22 (FIC 0.75) 1 (FIC 1) 0 0.001 c 14 0 _ 0 _ 0 0

CMI of A alone in% CMI of C alone in% Compound MIC AT % each mixed VS % FIC Index 0.2 0,001 0.05 0.0005 0.75 A / C ratio = 100

The results obtained show a synergy of the inhibitory activity for the mixtures:

i) 0.05% of A and 0.0005% of C or A / C ratio = 100 ii) 0.1% of A and 0.0005% of C or A / C ratio = 200

Aspergillus niger

concentrations tested (in% by weight) 0A 0.025 A 0.05 A 0.1 A 0.2 A 0.4 A OC 228 109 73 72 6 0.025 C 194 3 (FIC 0.19) 3 (FIC 0.25) 2 (FIC 0.37) 2 (FIC 0.56) 8 0.05 C 121 3 (FIC 0.31) 3 (FIC 0.37) 3 (FIC 0.5) 2 (0.75) 1 0.1 C 137 2 (FIC 0.56) 3 (FIC 0.62) 2 (FIC 0.75) 2 (FIC 1) 2 0.2 C 2 2 2 4 4 8

CMI of A alone in% CMI of C alone in% Compound MIC AT % each mixed VS % FIC Index 0.4 0.02 0,025 0.0025 0.19 A / C ratio = 10

The results obtained show a synergy of the inhibitory activity for the mixtures:

i) 0.025% of A and 0.01% of C or A / C ratio = 2.5 ii) 0.05% of A and 0.01% of C or A / C ratio = 5 iii) 0.1% of A and 0.01% of C or ratio A / C = 10 iv) 0.2% of A and 0.01% of C or ratio A / C = 20

v) 0.025% of A and 0.05% of C or A / C ratio = 5 vi) 0.05% of A and 0.05% of C or A / C ratio = 10 vii) 0.1% of A and 0.05% C or A / C ratio = 20 viii) 0.2% A and 0.05% C or A / C ratio = 40 ix) 0.025% A and 0.0025% C or A / C ratio = 10

x) 0.05% of A and 0.0025% of C or A / C ratio = 20 xi) 0.1% of A and 0.0025% of C or A / C ratio = 40 xii) 0.2% of A and 0.0025% of C i.e. ratio A / C = 80

Claims (17)

1. Antimicrobial mixture comprising 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one and a chlorhexidine compound chosen from chlorhexidine digluconate and chlorhexidine hydrochloride. 2. Mixture according to the preceding claim, characterized in that it comprises 4- (3ethoxy-4-hydroxyphenyl) butan-2-one and a chlorhexidine compound chosen from chlorhexidine digluconate and chlorhexidine hydrochloride in amounts such as the ratio by weight 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine compound ranges from 2 to 3500, preferably ranges from 2 to 250, and preferably ranges from 2 to 220. 3. Antimicrobial mixture according to one of the preceding claims, characterized in that it has antimicrobial activity on molds, in particular on Aspergillus niger, and on yeasts, in particular on Candida albicans. 4. Antimicrobial mixture according to one of the preceding claims, characterized in that the chlorhexidin compound is chlorhexidine digluconate. 5. Mixture according to claim 4, characterized in that it has a weight ratio of 4- (3ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine digluconate ranging from 25 to 150, preferably ranging from 30 to 130, and preferably ranging from 45 to 90. 6. Mixture according to the preceding claim, characterized in that it has antimicrobial activity on yeasts, in particular on Candida Albican. 7. Mixture according to claim 4, characterized in that it has a weight ratio 4- (3ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine digluconate ranging from 10 to 75, preferably ranging from 10 to 60, and preferably ranging from 10 to 40. 8. Mixture according to the preceding claim, characterized in that it has antimicrobial activity on molds, in particular on Aspergillus niger. 9. Antimicrobial mixture according to one of claims 1 to 3, characterized in that the chlorhexidin compound is chlorhexidine hydrochloride. 10. Mixture according to claim 4, characterized in that it has a weight ratio 4- (3ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine hydrochloride ranging from 60 to 350, preferably ranging from 80 to 250, preferably ranging from 90 to 220. 11. Mixture according to the preceding claim, characterized in that it has antimicrobial activity on yeasts, in particular on Candida Albican. 12. Mixture according to claim 4, characterized in that it has a weight ratio 4- (3ethoxy-4-hydroxyphenyl) butan-2-one / chlorhexidine hydrochloride ranging from 2 to 120, preferably ranging from 2 to 100, preferably ranging from 2 to 85. 13. Mixture according to the preceding claim, characterized in that it exhibits antimicrobial activity on molds, in particular on Aspergillus niger. 14. Composition comprising, in a physiologically acceptable medium, an antimicrobial mixture according to one of claims 1 to 13. 15. Composition according to the preceding claim, characterized in that it comprises at least one additional ingredient chosen from water, oils, polyols having from 2 to 10 carbon atoms, gelling agents, surfactants, film-forming polymers, coloring matters, perfumes, fillers, UV filters, plant extracts, cosmetic and dermatological active ingredients, and salts. 16. Composition according to one of claims 14 or 15, characterized in that 4- (3ethoxy-4-hydroxyphenyl) butan-2-one is present in a content ranging from 0.01% to 5% by weight, relative to the total weight of the composition, preferably ranging from 0.01% to 3% by weight, and preferably ranging from 0.01 to 2.5% by weight. 17. Use of an antimicrobial mixture according to any one of claims 1 to 13 for the preservation of a composition comprising a physiologically acceptable medium.