FR3070110A1 - ANTIMICROBIAL MIXTURE CONTAINING 4- (3-ETHOXY-4-HYDROXYPHENYL) BUTAN-2-ONE AND A CRESOL 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 cresol compound, such as 4-isopropyl-3-methylphenol, 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 antimicrobial mixture containing 4- (3-ethoxy-4hydroxyphenyl) butan-2-one and a cresol compound, as well as a cosmetic composition containing such a mixture.

4- (3-ethoxy-4-hydroxyphenyl) butan-2-one (ketone compound) is a substance of interest as a preservative for cosmetic compositions for protecting the compositions from microbial contamination, as described in application WO2011 / 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 unexpectedly discovered that the combination of 4- (3-ethoxy-4hydroxyphenyl) butan-2-one with a cresol compound, in particular 4-isopropyl-3methylphenol, makes it possible to obtain an antimicrobial mixture having a synergy of antimicrobial activity, in particular on Gram + bacteria, in particular on Enterococcus faecalis, and on yeasts, in particular on Candida albicans. The results of Example 1 described below show the synergistic antimicrobial activity obtained with the minimum inhibitory concentration measurements (MIC) made with several mixtures. Antimicrobial activity is considered to be synergistic when the antimicrobial mixture makes it possible to obtain a growth percentage of the strain less than or equal to 20%.

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 of a particular cresol compound such as defined below.

The invention also relates to a composition, in particular cosmetic or dermatological, 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.

The subject of the invention is also a method of preserving a composition comprising a physiologically acceptable medium, in particular a cosmetic or dermatological composition, characterized in that it consists in incorporating into said composition an antimicrobial mixture as described above.

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

The cresol compound used according to the invention is a compound of formula (I):

in which R1 denotes H or an isopropyl radical.

The compound of formula (I) can be chosen from 3-methylphenol (CAS number 108-39-4), 2-methylphenol (CAS number 95-48-7), 4-methylphenol (CAS number 106-44-5), 4isopropyl-3-methylphenol (CAS number 3228-02-2). Preferably the compound of formula (I) is 4-isopropyl-3-methylphenol.

Advantageously, 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one and the cresol compound of formula (I) are present in said mixture in a content such that the weight ratio 4- (3ethoxy-4-hydroxyphenyl) butan-2-one / compound (I) ranges from 0.5 to 15, preferably ranges from 1 to 15, and more preferably ranges from 1 to 12.

Preferably, the antimicrobial mixture according to the invention contains 4-isopropyl-3methylphenol.

The antimicrobial mixture can have a weight ratio of 4- (3-ethoxy-4-hydroxyphenyl) butan-2one / cresol compound (I) (in particular 4-isopropyl-3-methylphenol) ranging from 2 to 15, preferably ranging from 2.2 to 15, and more preferably ranging from 2.2 to 12. Such a mixture has good antimicrobial activity on the bacterium Gram + Enterococcus faecalis

The antimicrobial mixture can have a weight ratio of 4- (3-ethoxy-4-hydroxyphenyl) butan-2one / cresol compound (I) (in particular 4-isopropyl-3-methylphenol), ranging from 0.5 to 15, preferably ranging from 1 to 15, preferably ranging from 1 to 12, and more preferably ranging from 2 to 8. Such a mixture has good antimicrobial activity on yeasts, in particular on Candida Albicans.

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 the cresol compound of formula (I).

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 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, lepentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol, diglycerin. Advantageously, the composition according to the invention comprises 1,3-propanediol, in particular in a content ranging from 0.1 to 20% by weight, relative to the total weight of the composition, and preferably ranging from 0.1 to 10 % by weight, preferably ranging from 0.5 to 5% by weight.

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 the cresol compound (I), and 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

The demonstration of a synergistic effect of antimicrobial activity with a mixture of 4- (3ethoxy-4-hydroxyphenyl) butan-2-one (called substance A) and 4-isopropyl-3-methylphenol (called substance B) is performed by calculating the synergy index (or FIC index), according to the following formula:

FIC Index = (CMI of A with B / CMI of A) + (CMI of B with A / CMI of B) with:

- MIC of A with B: minimum concentration of product A in the combination A + B allowing an inhibitory effect to be obtained;

- MIC of B with A: minimum concentration of product B in the combination A + B to obtain the inhibitory effect;

- MIC of A: minimum inhibitory concentration of product A alone;

- MIC of B: 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 20% to be obtained.

Concerning the associations tested, CMI of A with B and CMI of B 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 20%.

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 has been tested on the following strains Enterococcus faecalis and Candida albicans.

The microbial strain Enteroccoccus faecalis ATCC 33186 and a double-strength BHI (Brain Heart Infusion) broth culture medium were used.

The Candida albicans ATCC 10231 microbial strain and a Sabouraud broth liquid culture medium were used at double concentration.

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

The incubation time of the microplate for the above-mentioned strains is 24 h aerobically for Candida albicans.

24 to 48 hours aerobically for Enteroccoccus faecalis.

testing

For each compound:

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

B = 4-isopropyl-3-methylphenol 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 and B only pL of each of the daughter solutions obtained containing compound A or B is added to the wells of the microplate. We also add 100 pL of liquid nutritive broth from Sabouraud seeded at double concentration with the Candida albicans strain and 50 pL of 1% o aqueous agar solution.

Tests of compounds A and B in a pL mixture of each of the daughter solutions obtained containing compound A and 50 pL of each of the daughter solutions obtained containing compound B are added to the wells of the microplate. We also add 100 μL of liquid nutritive broth from Sabouraud seeded at double concentration with the Candida albicans strain.

Microbial growth control

A positive microbial growth control was also performed. The positive microbial growth control corresponds to the mixture of 100 μl of an aqueous 1% o agar solution with 100 μl of liquid nutritive broth from Sabouraud seeded at double concentration with the Candida albicans strain in the absence of compounds A and B .

Control of absorbance of compounds A and B alone

At the same time, an absorbance control of compounds A and B was produced alone. This control corresponds to 100 μL of nutritive broth of liquid Sabouraud sterile at double concentration + 100 μL of compound A or B 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 Candida albicans strain present in the final volume of the wells (200 pL) and is between 2 and 6.10 ⁵ CFU / mL in Candida albicans.

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

The test as described above (tests, absorbance controls and growth control) was again carried out to test the association A + B on the strain Enteroccoccus faecalis.

The following results were obtained:

Candida Albicans

Concentrations tested (in% by weight) 0 of A 0.025 A 0.05 A 0.1 A 0.2 A Ode B 69 63 38 4 0.0025 B 87 77 63 41 6 0.005 B 82 58 54 28 2 0.01 B 73 52 41 18 (FIC 0.75) 2 0.02 B 35 18 (FIC 0.63) 8 (FIC 0.75) 3 (FIC 1) 1 0.04 B 1 1 1 1 0

CMI of A alone in% CMI of B alone in% MIC of each compound in mixture FIC Index Ratio AT% B% 0.2 0.04 0,025 0.2 0.63 1.25

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

i) 0.025% of A and 0.02% of B or A / B ratio = 1.25 ii) 0.05% of A and 0.02% of B or A / B ratio = 2.5 iii) 0.1% of A and 0.02% of B or A / B ratio = 5 iv) 0.1% of A and 0.01% of B or A / B ratio = 10

Enterococcus Faecalis

Concentrations tested (in% by weight) Ode A 0.0625 A 0.125 A 0.25 A 0.5 A 1 A Ode B 42 42 33 34 24 0.0125 B 45 41 41 37 40 21 0.025 B 44 36 38 30 36 -19 0.05 B 27 39 12 11 11 (FIC 0.625) (FIC 0.75) (FIC 1) -27 0.1 B 23 -18 7 8 -4 -90

CMI of A alone in% CMI of B alone in% MIC of each compound in mixture FIC Index Ratio AT% B% 1 0.1 0,125 0.05 0.63 1.25

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

i) 0.125% of A and 0.05% of B or A / B ratio = 1.25 ii) 0.25% of A and 0.05% of B or A / B ratio = 2.5 iii) 0.5% of A and 0.05% of B or A / B ratio = 5

Claims (13)

1. Antimicrobial mixture comprising 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one and a cresol compound of formula (I): Me (I) in which R1 denotes H or an isopropyl radical. 2. Mixture according to the preceding claim, in which the cresol compound of formula (I) is chosen from 2-methylphenol, 3-methylphenol, 4-methylphenol, 4-isopropyl-3-methylphenol. 3. Mixture according to one of the preceding claims, in which the cresol compound of formula (I) is 4-isopropyl-3-methylphenol. 4. Mixture according to one of the preceding claims, characterized in that it comprises 4 (3-ethoxy-4-hydroxyphenyl) butan-2-one and the cresol compound (I) in amounts such that the weight ratio 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one / cresol compound (I) ranges from 0.5 to 15, preferably ranges from 1 to 15, and more preferably ranges from 1 to 12. 5. Antimicrobial mixture according to one of the preceding claims, characterized in that it has antimicrobial activity on yeasts, especially on Candida albicans, and on Gram + bacteria, especially on Enteroccoccus faecalis. 6. Antimicrobial mixture according to claims 1 to 4, characterized in that it has antimicrobial activity on the yeast Candida Albicans. 7. Antimicrobial mixture according to claims 1 to 3, characterized in that it has a weight ratio 4- (3-ethoxy-4-hydroxyphenyl) butan-2-one / cresol compound (I) ranging from 2 to 15, of preferably ranging from 2.2 to 15, and more preferably ranging from 2.2 to 12. 8. Antimicrobial mixture according to the preceding claim, characterized in that it has antimicrobial activity on the bacterium Gram + Enteroccoccus faecalis. 9. Composition comprising, in a physiologically acceptable medium, an antimicrobial mixture according to one of claims 1 to 8. 10. 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. 11. Composition according to one of claims 9 or 10, characterized in that 4- (3-ethoxy4-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, preferably ranging from 0.01 to 2.5% by weight, and more preferably ranging from 0.01 to 2% by weight. 12. A method of non-therapeutic cosmetic treatment for care and / or make-up and / or cleaning of keratin materials comprising the application to said keratin materials of a composition according to any one of claims 9 to 11. 13. Method for preserving a composition comprising a physiologically acceptable medium, in particular a cosmetic or dermatological composition, characterized in that it consists in incorporating into said composition an antimicrobial mixture as defined in one of claims 1 to 8 .