WO2020126570A1

WO2020126570A1 - Antimicrobial mixture containing 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and niacinamide, and cosmetic composition containing same

Info

Publication number: WO2020126570A1
Application number: PCT/EP2019/084074
Authority: WO
Inventors: Sylvie Cupferman; Florence MENARD-SZCZEBARA; Véronique Chevalier
Original assignee: L'oreal
Priority date: 2018-12-21
Filing date: 2019-12-06
Publication date: 2020-06-25
Also published as: FR3090273A1

Abstract

The invention relates to an antimicrobial mixture containing 4-(3-ethoxy-4- hydroxyphenyl)butan-2-one and a niacinamide compound, and also to a cosmetic, pharmaceutical or nutritional composition containing such a mixture. Application to caring for, making up and cleansing keratin materials.

Description

Antimicrobial mixture containing 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and niacinamide, and cosmetic composition containing same

[0001 ] The present invention relates to an antimicrobial mixture containing 4-(3- ethoxy-4-hydroxyphenyl)butan-2-one and a niacinamide compound, and also to a cosmetic, pharmaceutical or nutritional composition containing such a mixture.

Technical field

[0002] 4-(3-Ethoxy-4-hydroxyphenyl)butan-2-one (ketone compound) is a beneficial substance as a preserving agent for cosmetic compositions, for protecting the compositions against microbial contamination, as described in patent application WO 2011/039445.

[0003] However, it is desirable to be able to incorporate said ketone compound in reduced concentration in compositions, notably cosmetic or pharmaceutical, dermatological or nutritional compositions, while at the same time maintaining good antimicrobial conservation performance. Combinations of the ketone compound with other compounds that have good antimicrobial efficacy are thus sought for this purpose.

[0004] The invention may be better understood on reading the following description accompanied with nonlimiting implementation examples thereof with reference to the appended drawings, in which:

[0005] The inventors have discovered, unexpectedly, that the combination of 4- (3-ethoxy-4-hydroxyphenyl)butan-2-one and salts thereof with an organic or inorganic acid or base, and solvates thereof such as the hydrates with a niacinamide compound and salts thereof with an organic or mineral acid, and solvates thereof such as the hydrates as described below, in particular niacinamide, makes it possible to obtain an antimicrobial mixture which has synergistic antimicrobial activity, in particular on molds, notably on Aspergillus niger or on the Gram-positive bacterium Staphylococcus aureus. The results of the Example 1 described below show the synergistic antimicrobial activity obtained with the minimum inhibitory concentration (MIC) measurements taken with several mixtures. The antimicrobial activity is considered as being synergistic when the antimicrobial mixture makes it possible to obtain a percentage of strain growth of less than or equal to 25%, or even less than or equal to 20%.

[0006] Patent application WO-A- 2018/001898 describes a liquid mixture of 4-(3- ethoxy-4-hydroxyphenyl)butan-2-one and a niacinamide compound, the 4-(3- ethoxy-4-hydroxyphenyl)butan-2-one/niacinamide compound weight ratio ranging from 12 to 250.

[0007] More precisely, a subject of the invention is an antimicrobial mixture comprising, or constituted of (or consisting of), 4-(3-ethoxy-4-hydroxyphenyl)butan- 2-one and a niacinamide compound, the 4-(3-ethoxy-4-hydroxyphenyl)butan-2- one/niacinamide compound weight ratio ranging from 0.018 to 0.35.

[0008] For the purposes of the present invention, and unless otherwise indicated: an " organic or inorganic acid salt' is more particularly chosen from salts chosen from a salt derived from i) hydrochloric acid HCI, ii) hydrobromic acid HBr, iii) sulfuric acid H2SO4, iv) alkylsulfonic acids: Alk-S(0)₂0H such as methanesulfonic acid and ethanesulfonic acid; v) arylsulfonic acids: Ar-S(0)₂0H such as benzenesulfonic acid and toluenesulfonic acid; vi) citric acid; vii) succinic acid; viii) tartaric acid; ix) lactic acid; x) alkoxysulfinic acids: Alk-0-S(0)0H such as methoxysulfinic acid and ethoxysulfinic acid; xi) aryloxysulfinic acids such as tolueneoxysulfinic acid and phenoxysulfinic acid; xii) phosphoric acid H3PO4; xiii) acetic acid CH₃C(0)OH; xiv) triflic acid CF3SO3H; and xv) tetrafluoroboric acid FIBF4;

an“organic or inorganic base salts " means salts of bases or alkaline agents as defined below, such as alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, or alkaline earth metal calcium hydroxide, ammonia, amines or alkanolamines.

an "alkyl radical' is a linear or branched hydrocarbonyl chain saturated;

moreover, the addition salts that may be used in the context of the invention with 4- (3-ethoxy-4-hydroxyphenyl)butan-2-one are especially chosen from addition salts with a cosmetically acceptable base such as basifying agents as defined below, for instance alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, aqueous ammonia, amines or alkanolamines; preferably 4-(3-ethoxy-4- hydroxyphenyl)butan-2-one can be in a salt form such as formula (G):

Formula (G) in which M⁺ represents a cationic counter ion especially an alkali metal such as sodium or potassium, or alkaline earth metal such as calcium or ammonium the term "at least one" is equivalent to the term "one or more".

[0009] A subject of the invention is also a composition comprising said antimicrobial mixture.

[0010] The composition may comprise a physiologically acceptable medium. The composition is notably a cosmetic or pharmaceutical or dermatological composition.

[0011 ] The composition may optionally be a nutritional composition (food).

[0012] A subject of the invention is also a process for the nontherapeutic cosmetic treatment of keratin materials, comprising the application to the keratin materials of a composition as described previously. The process may be a cosmetic process for caring for or making up or cleansing keratin materials.

[0013] A subject of the invention is also a process for conserving a composition, notably comprising a physiologically acceptable medium, in particular a cosmetic or dermatological composition, or a nutritional composition, characterized in that it consists in incorporating into said composition an antimicrobial mixture as described previously.

[0014] 4-(3-Ethoxy-4-hydroxyphenyl)butan-2-one is a compound of formula:

[0015] [Chem. 1 ]

and salts thereof with an organic or inorganic acid or base, and solvates thereof such as the hydrates.

[0016] The niacinamide compound is chosen from niacinamide (also known as vitamin B3), N,N-diethylniacinamide, N-picolylniacinamide and N-allylniacinamide and salts thereof with an organic or mineral acid, and solvates thereof such as the hydrates. According to a preferred embodiment, the niacinamide compound is niacinamide.

[0017] The antimicrobial mixture may have a 4-(3-ethoxy-4-hydroxyphenyl)butan- 2-one/niacinamide compound weight ratio ranging from 0.018 to 0.25, preferably ranging from 0.018 to 0.15, preferentially ranging from 0.018 to 0.08, more preferentially ranging from 0.018 to 0.04 and even more preferentially ranging from 0.02 to 0.03. Such a mixture has good antimicrobial activity on molds, notably on Aspergillus niger. Preferably, the composition comprising the antimicrobial mixture may comprise 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one in a content ranging from 0.02% to 0.09% by weight, preferentially ranging from 0.03% to 0.75% by weight, and better still ranging from 0.04% to 0.06% by weight relative to the total weight of the composition.

[0018] The antimicrobial mixture may have a 4-(3-ethoxy-4-hydroxyphenyl)butan- 2-one/niacinamide compound weight ratio ranging from from 0.05 to 0.35, preferably ranging from 0.1 to 0.35, preferably ranging from 0.15 to 0.35 and more preferentially ranging from 0.2 to 0.3. Such a mixture has good antimicrobial activity on the Gram-positive bacterium Staphylococcus aureus. Preferably, the composition comprising the antimicrobial mixture may comprise 4-(3-ethoxy-4- hydroxyphenyl)butan-2-one in a content ranging from 0.05% to 0.4% by weight, preferably from 0.08% to 0.4% by weight, preferably from 0.1 % to 0.4% by weight, preferably from 0.15% to 0.4% by weight, preferably from 0.15% to 0.35% by weight, relative to the total weight of the composition.

[0019] Another object of the invention is a composition, preferably a cosmetic, pharmaceutical or nutritional composition comprising

- at least one 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and salts thereof with an organic or mineral acid, and solvates thereof such as the hydrates ; and

- at least a niacinamide compound chosen from niacinamide, N,N- diethylniacinamide, N-picolylniacinamide and N-allylniacinamide, the 4-(3-ethoxy-4- hydroxyphenyl)butan-2-one/niacinamide compound weight ratio ranging from 0.018 to 0.35.

[0020] A subject of the invention is also a composition comprising, in a physiologically acceptable medium, the antimicrobial mixture described previously. [0021 ] The term "physiologically acceptable medium" means a medium that is compatible with human keratin materials such as the skin, the scalp, the hair and the nails. Said medium may comprise one or more additional ingredients other than the ketone compound and the niacinamide compound.

[0022] 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, preferentially ranging from 0.01 % to 2.5% by weight, more preferentially ranging from 0.01 % to 2% by weight and better still ranging from 0.02% to 0.35% by weight, or else in the contents described previously.

[0023] The composition may comprise at least one additional ingredient chosen from water, oils, polyols containing from 2 to 10 carbon atoms, gelling agents, surfactants, film-forming polymers, dyestuffs, fragrances, fillers, UV-screening agents, plant extracts, cosmetic and dermatological active agents, and salts.

[0024] The composition according to the invention may comprise an aqueous phase.

[0025] The composition may also comprise a polyol that is water-miscible at room temperature (25°C), notably chosen from polyols notably containing from 2 to 10 carbon atoms, preferably containing from 2 to 6 carbon atoms, such as glycerol, propylene glycol, 1 ,3-propanediol, butylene glycol, pentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol or diglycerol. Advantageously, the composition according to the invention comprises 1 ,3-propanediol, notably in a content ranging from 0.1 % to 20% by weight, preferably ranging from 0.1 % to 10% by weight and preferentially ranging from 0.5% to 5% by weight, relative to the total weight of the composition.

[0026] The compositions according to the invention may be in the form of oil-in- water (O/W) emulsions, water-in-oil (W/O) emulsions or multiple emulsions (triple: W/O/W or O/W/O), oily solutions, oily gels, aqueous solutions, aqueous gels, or solid compositions. These compositions are prepared according to the usual methods.

[0027] The compositions according to the invention may be more or less fluid and may have the appearance of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste or a foam. They may be optionally applied to the skin in aerosol form. They may also be in solid form, for example in the form of a stick or a compact powder.

[0028] The composition according to the invention may notably be in the form of:

[0029] - a makeup product, notably for making up the skin of the face, the body, or the lips or the eyelashes;

[0030] - an aftershave gel or lotion; a shaving product;

[0031 ] - a deodorant (stick, roll-on or aerosol);

[0032] - a hair-removing cream;

[0033] - a body hygiene composition such as a shower gel or a shampoo;

[0034] - a pharmaceutical composition;

[0035] - a solid composition such as a soap or a cleansing bar;

[0036] - an aerosol composition also comprising a pressurized propellant;

[0037] - a hair-setting lotion, a hair-styling cream or gel, a dyeing composition, a permanent-waving composition, a lotion or a gel for combating hair loss, or a hair conditioner;

[0038] - a composition for caring for or cleansing the skin.

[0039] The nutritional composition (food) may comprise at least one foodstuff chosen from meats, fish, crustaceans, vegetables, fruit, cereals, eggs, butter, milk, vinegar, water, vegetable oils, sugars, salt, spices, emulsifiers, alcohols, thickeners and honey.

[0040] Preferably the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one is predissolved in a food-grade solvent before being added to the food. Solvents that may be used include ethanol, propylene glycol, isopropyl alcohol and mixtures thereof, optionally combined with water.

[0041 ] The food according to the invention may be, for example, in the form of bread, cake, sauce, candy, a cooked dish, confectionery, jelly, dessert, nougat, drinks, juice, syrup, wine, beer, ravioli, mousse, compote, mayonnaise, mustard, vinaigrette, crisps, sausage, gnocchi, polenta, pancakes, pates, cheeses, flour, delicatessen meats or soup. [0042] A subject of the invention is also a process for preparing a composition, notably a cosmetic or pharmaceutical or nutritional composition, comprising a step of mixing 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one, the niacinamide compound and one or more additional ingredients, notably cosmetic or dermatological or nutritional ingredients, such as those described previously.

[0043] The invention is illustrated in greater detail in the example that follows. The amounts of the ingredients are expressed as weight percentages.

Examples

[0044] Example 1 : Determination of the synergistic antimicrobial activity as MIC

[0045] The demonstration of a synergistic antimicrobial activity effect with a mixture of 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one (referred to as substance A) and of a niacinamide (referred to as substance B) is performed by calculating the synergy index (or FIC index) according to the following formula:

[0046] [Math. 1 ]

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

- MIC of A with B: minimum concentration of product A in the combination A + B which makes it possible to obtain an inhibitory effect;

- MIC of B with A: minimum concentration of product B in the combination A + B which makes it possible to obtain an 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 described for the first time in the article by F.C. Kull, P.C. Eisman, H. D. Sylwestrowka, and R.L. Mayer, Applied Microbiology 9:538-541 , 1961.

[0047] For each compound tested alone, the MIC is considered as the first concentration which makes it possible to obtain a microbial growth percentage of less than or equal to 25%. [0048] As regards the combinations tested, MIC of A with B and MIC of B with A are the respective concentrations of A and of B in the combinations which make it possible to obtain a microbial growth percentage of less than or equal to 25%.

[0049] Interpretation of the FIC Index:

[0050] When the FIC index value is less than or equal to 1 , it is considered that the combination of test compounds has a synergistic effect.

[0051 ] The summary of the results obtained is presented in the following tables.

[0052] The combination of compounds A and B was tested on the following strains: Aspergillus niger and Staphylococcus aureus.

[0053] The microbial strain Aspergillus niger ATCC 6275, and a double concentration Sabouraud broth liquid culture medium supplemented with polyoxyethylenated (20 OE) sorbitan monopalm itate (Tween 40 from Croda) and Phytagel© BioReagent were used (i.e. a mixture of 5 g of Phytagel + 0.6 g of Tween 40 + 60 g of Sabouraud broth).

[0054] The microbial strain Staphylococcus aureus ATCC 6538 and a double concentration nutrient broth liquid culture medium were used.

[0055] A 96-well microplate at an incubation temperature of 32.5°C is used.

[0056] The incubation time of the microplate is:

- from 18 to 24 h under aerobic conditions for Staphylococcus aureus ATCC 6538;

- from 24 to 30 h under aerobic conditions for microbial Aspergillus niger ATCC 6275.

[0057] Tests

[0058] For each compound:

[0059] A = 4-(3-ethoxy-4-hydroxyphenyl) butan-2-one compound

[0060] B = niacinamide compound

[0061 ] A 10% (weight/volume) stock solution was prepared by mixing 1 g of compound in 9 ml of aqueous 1 %o agar solution. Successive dilutions were made with the 1 %o agar solution.

[0062] [0063] Tests of compounds A and B alone

[0064] 50 mI of each of the daughter solutions obtained containing compound A or B are added to the microplate wells. 100 mI of Sabouraud liquid nutrient broth inoculated at double concentration with the Aspergillus niger strain and 50 mI of aqueous 1%o agar solution are also added thereto.

[0065] Tests of compounds A and B as a mixture

[0066] 50 mI of each of the daughter solutions obtained containing compound A and 50 mI of each of the daughter solutions obtained containing compound B are added to the microplate wells. 100 mI of Sabouraud liquid nutrient broth inoculated at double concentration with the strain Aspergillus niger are also added thereto.

[0067] Microbial growth control

[0068] A positive microbial growth control was also prepared. The positive microbial growth control corresponds to a mixture of 100 mI of aqueous 1%o agar solution with 100 mI of Sabouraud liquid nutrient broth inoculated at double concentration with the strain Aspergillus niger in the absence of compounds A and B.

[0069] Absorbance control for compounds A and B alone

[0070] An absorbance control was performed in parallel on compounds A and B alone. This control corresponds to 100 mI of double concentration sterile Sabouraud liquid nutrient broth + 100 mI of double concentration compound A or B.

[0071 ] In the three cases (absorbance control, growth control and test), the final volume present in each of the microplate wells is 200 mI.

[0072] In the two cases (test and control), the inoculum represents the concentration of the Aspergillus niger strain present in the final volume of the wells (200 mI) and is between 2 and 6x10⁵ cfu/ml of Aspergillus niger.

[0073] The minimum inhibitory concentration (MIC) of each compound A and B alone and in combination was determined in a known manner by means of optical density measurements at a wavelength of 620 nm. [0074] The test as described above (tests, absorbance control and growth control) was performed again to test the combination A + B on the following strains Staphylococcus aureus.

[0075] The following results were obtained:

[0076] Staphylococcus aureus EZ content

[0077] [Tables 1]

[0078] [Tables 2]

[0079] The results obtained show synergistic inhibitory activity for the mixtures:

[0080] i) 0.0625% of A and 1 % of B, i.e. ratio A/B = 0.0625

[0081 ] ii) 0.125% of A and 1 % of B, i.e. ratio A/B = 0.125

[0082] iii) 0.25% of A and 1 % of B, i.e. ratio A/B = 0.25

[0083] Aspergillus niger

[0084] [Tables 3]

[0085] [Tables 4]

[0086] The results obtained show synergistic inhibitory activity for the mixtures:

[0087] i) 0.05% of A and 1 % of B, i.e. ratio A/B = 0.05

[0088] ii) 0.05% of A and 0.5% of B, i.e. ratio A/B = 0.1

[0089] iii) 0.05% of A and 0.25% of B, i.e. ratio A/B = 0.2

[0090] iv) 0.025% of A and 1 % of B, i.e. ratio A/B = 0.025

[0091 ] v) 0.025% of A and 0.5% of B, i.e. ratio A/B = 0.05.

Claims

[Claim 1 ] An antimicrobial mixture comprising 4-(3-ethoxy-4-hydroxyphenyl)butan- 2-one and salts thereof with an organic or inorganic acid or base, and solvates thereof such as the hydrates and a niacinamide compound chosen from niacinamide, N,N- diethylniacinamide, N-picolylniacinamide and N-allylniacinamide, the 4-(3-ethoxy-4- hydroxyphenyl)butan-2-one/niacinamide compound weight ratio ranging from 0.018 to 0.35.

[Claim 2] The mixture as claimed in the preceding claim, characterized in that the niacinamide compound is niacinamide.

[Claim 3] The mixture as claimed in either of the preceding claims, characterized in that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/niacinamide compound weight ratio ranges from 0.018 to 0.25, preferably from 0.018 to 0.15, preferentially from 0.018 to 0.08, more preferentially from 0.018 to 0.04 and even more preferentially from 0.02 to 0.03.

[Claim 4] The mixture as claimed in either of claims 1 and 2, characterized in that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/niacinamide compound weight ratio ranges from 0.05 to 0.35, preferably from 0.1 to 0.35, preferably from 0.15 to 0.35 and more preferentially from 0.2 to 0.3.

[Claim 5] A composition, preferably a cosmetic, pharmaceutical or nutritional composition comprising

- at least one 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and salts thereof with an organic or mineral acid, and solvates thereof such as the hydrates as claimed in anyone of claims 1 , 3 or 4 ; and

- at least a niacinamide compound chosen from niacinamide, N,N- diethylniacinamide, N-picolylniacinamide and N-allylniacinamide, the 4-(3-ethoxy-4- hydroxyphenyl)butan-2-one/niacinamide compound weight ratio ranging from 0.018 to 0.35 as claimed in any one of the claims 1 to 4.

[Claim 6] A composition comprising an antimicrobial mixture as claimed in one of claims 1 to 4.

[Claim 7] The composition as claimed in one of the preceding claims 5 or 6, characterized in that it is a cosmetic or pharmaceutical composition.

[Claim 8] The composition as claimed in any one of the preceding claim 5 to 7, characterized in that it comprises at least one additional ingredient chosen from water, oils, polyols containing from 2 to 10 carbon atoms, gelling agents, surfactants, film forming polymers, dyestuffs, fragrances, fillers, UV-screening agents, plant extracts, cosmetic and dermatological active agents, and salts.

[Claim 9] The composition as claimed in any one of claims 5 or 6, characterized in that it is a nutritional composition.

[Claim 10] The composition as claimed in the preceding claim, characterized in that it comprises a food chosen from meats, fish, crustaceans, vegetables, fruit, cereals, eggs, butter, milk, vinegar, water, vegetable oils, sugars, salt, spices, emulsifiers, alcohols, thickeners and honey.

[Claim 1 1 ] The composition as claimed in either of claims 5 and 6, characterized in that the 4-(3-ethoxy-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, preferentially ranging from 0.01 % to 2.5% by weight, more preferentially ranging from 0.01 % to 2% by weight and better still ranging from 0.02% to 0.35% by weight.

[Claim 12] A nontherapeutic cosmetic treatment process for caring for and/or making up and/or cleansing keratin materials, comprising the application to said keratin materials of a composition as claimed in any one of claims 5 to 8.

[Claim 13] A process for conserving a composition, comprising a physiologically acceptable medium, in particular a cosmetic or pharmaceutical or nutritional composition, characterized in that it consists in incorporating into said composition an antimicrobial mixture as defined in one of claims 1 to 4.