ANTIMICROBIAL MIXTURE CONTAINING 4-(3-ETHOXY-4-HYDROXYPHENYL)BUTAN-2-ONE AND AN ACID OR SILVER-BASED COMPOUND, AND COSMETIC COMPOSITION CONTAINING SAME

Abstract

The invention relates to an antimicrobial mixture containing 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and an acid and/or silver-based compound, and also to a cosmetic, pharmaceutical or nutritional composition containing such a mixture.

Application to caring for, making up and cleansing keratin materials; to preserving foods and to water treatment.

Claims

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; and at least one acid compound chosen from: i) ethylenediaminedisuccinic acid and salts thereof; ii) jasmonate compounds (I) and salts thereof; ##STR00005## in which formula (I) R denotes a saturated or unsaturated linear hydrocarbon-based radical containing from 2 to 7 carbon atoms; iii) glycinate compounds of formula (II) and the salts thereof:
R.sub.1R.sub.2NCH.sub.2COO.sup.−X.sup.+  (II) R.sub.1 and R.sub.2 denoting a hydrogen atom or a hydroxy(C.sub.1-C.sub.4)alkyl group; X.sup.+ denoting a cationic counterion preferably chosen from alkali metals and alkaline earth metals such as sodium, calcium and aluminum, and preferably an alkali metal such as sodium; or at least one silver-based compound chosen from: i) silver I and II oxides, ii) silver particles; iii) Ag I or Ag II salts chosen from the following formulae: a) AgHal with Hal representing a halogen atom; b) AgHal.sub.2, with Hal being identical or different; and c) Ag.sub.xR.sup.3.sub.z and also solvates thereof, with R.sup.3, which may be identical or different, representing a group chosen from: sulfate; nitrate; hydroxy; (C.sub.1-C.sub.6)alkylcarboxylate in which the (C.sub.1-C.sub.6)alkyl group is linear or branched and is optionally substituted with one or more hydroxyl, carboxyl or carboxylate groups; an aryl group substituted with at least one carboxylate group and optionally substituted with one or more hydroxyl groups; and x and z are integers such that 1≤z≤6, 1≤x≤4.

2. The mixture as claimed in claim 1, wherein the salts are chosen from the salts of alkali metals or alkaline-earth metals, aluminum or zinc, or ammonium salts of (C.sub.1-C.sub.4)alkanolamine.

3. The mixture as claimed in claim 1, wherein 4-(3 ethoxy-4-hydroxyphenyl)butan-2-one and ethylenediaminedisuccinic acid or salts thereof are present in said mixture in a weight ratio such that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/ethylenediaminedisuccinic acid or salts thereof weight ratio ranges from 1.5 to 15.

4. The mixture as claimed in claim 1, wherein the compound of formula (I) is chosen from 3-hydroxy-2-[2-pentenyl]cyclopentaneacetic acid or 3-hydroxy-2-pentylcyclopentaneacetic acid and/or salts thereof.

5. The mixture as claimed in claim 1, wherein the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and the jasmonate compounds (I) are present in said mixture in a content such that the weight ratio ranges from 0.3 to 1.20.

6. The mixture as claimed in claim 1, wherein the glycinate compound (II) and the salts thereof are chosen from hydroxymethylglycinate salts.

7. The mixture as claimed in claim 1, wherein the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and the glycinate compounds of formula (II) and the salts thereof are present in said mixture in a content such that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/glycinate compounds of formula (II) or salts thereof weight ratio ranges from 10 to 80.

8. The mixture as claimed in claim 1, wherein the silver-based (Ag) compounds are chosen from silver (C.sub.1-C.sub.6)alkylcarboxylates.

9. The mixture as claimed in claim 1, wherein the 4-(3 ethoxy-4-hydroxyphenyl)butan-2-one and the silver-based compounds are present in said mixture in a content such that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/silver-based compound weight ratio ranges from 0.4 to 4.

10. A composition comprising, in a physiologically acceptable medium, an antimicrobial mixture as claimed in claim 1.

11. The composition as claimed in claim 10, wherein 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.

12. The composition as claimed in claim 10, wherein 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.

13. 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 claim 10.

14. A process for conserving a composition, comprising a physiologically acceptable medium, which comprises incorporating into said composition an antimicrobial mixture as claimed in claim 1.

15. A process for preserving a cosmetic or pharmaceutical composition which comprises incorporating into said composition an antimicrobial mixture as defined in claim 1.

16. A nutritional composition comprising an antimicrobial mixture as claimed in claim 10.

17. A process for preserving a nutritional composition, which comprises incorporating into said composition an antimicrobial mixture as claimed in claim 1.

18. A process for treating water which comprises incorporating the antimicrobial mixture as claimed in claim 1, into water chosen from domestic or industrial waters, waters from aquatic media, swimming pool/spa waters, and waters from air-conditioning systems.

19. A continuous or discontinuous water treatment process comprising at least one step of placing a water sample to be treated or a water stream to be treated, said water being chosen from domestic or industrial waters, waters from aquatic media, swimming pool/spa waters, and waters from air-conditioning systems, in contact with the antimicrobial mixture as claimed in claim 1.

20. The mixture as claimed in claim 2, wherein the salts are chosen from the salts of alkaline-earth metals.

Description

EXAMPLES

Example 1: Determination of the Synergistic Antimicrobial Activity as MIC

[0117] 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 an acid compound (referred to as substance B) was performed by calculating the synergy index (or FIC index) according to the following formula:

FIC Index=(MIC of A with B/MIC of A)+(MIC B with A/MIC of B)  [Math. 1]

with: [0118] MIC of A with B: minimum concentration of product A in the combination A+B which makes it possible to obtain an inhibitory effect; [0119] MIC of B with A: minimum concentration of product B in the combination A+B which makes it possible to obtain an inhibitory effect; [0120] MIC of A: minimum inhibitory concentration of product A alone; [0121] 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.

[0122] 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%.

[0123] 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%.

[0124] Interpretation of the FIC Index:

[0125] 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.

[0126] The summary of the results obtained is presented in the following tables.

[0127] The combination of compounds A and B was tested on the following strains or a part thereof: Aspergillus niger, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, Candida albicans.

[0128] The microbial strain Aspergillus niger ATCC 6275, and a double-concentration Sabouraud broth liquid culture medium supplemented with polyoxyethylenated (20 OE) sorbitan monopalmitate (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).

[0129] The microbial strain Staphylococcus aureus ATCC 6538 and a double-concentration nutrient broth liquid culture medium were used.

[0130] The microbial strain Pseudomonas aeruginosa ATCC 9027 and a double-concentration nutrient broth liquid culture medium were used.

[0131] The microbial strain Enterococcus faecalis ATCC 33186 and a double-concentration BHI (Brain Heart Infusion) broth liquid culture medium were used.

[0132] The microbial strain Candida albicans ATCC 10231, and a double-concentration Sabouraud broth liquid culture medium were used (i.e. a mixture of 5 g of Phytagel+0.6 g Tween 40+60 g of Sabouraud broth).

[0133] A 96-well microplate at an incubation temperature of 32.5° C. is used.

[0134] The incubation time of the microplate is: [0135] from 24 to 30 h under aerobic conditions for microbial Aspergillus niger ATCC 6275; [0136] from 18 to 24 h under aerobic conditions for Candida albicans ATCC 10231, Pseudomonas aeruginosa ATCC 9027 and Staphylococcus aureus ATCC 6538; [0137] from 24 to 48 h under aerobic conditions for Enterococcus faecalis ATCC 33186.

[0138] Tests

[0139] For each compound:

[0140] A=4-(3-ethoxy-4-hydroxyphenyl) butan-2-one compound

[0141] B=acid compound

[0142] A 10% (weight/volume) stock solution was prepared by mixing 1 g of compound in 9 ml of aqueous 1‰ agar solution. Successive dilutions were made with the 1‰ agar solution.

[0143] Tests of Compounds A and B Alone

[0144] 50 μl of each of the daughter solutions obtained containing compound A or B are added to the microplate wells. 100 μl of Sabouraud liquid nutrient broth inoculated at double concentration with the Aspergillus niger strain and 50 μl of aqueous 1‰ agar solution are also added thereto.

[0145] Tests of Compounds A and B as a Mixture

[0146] 50 μl of each of the daughter solutions obtained containing compound A and 50 μl of each of the daughter solutions obtained containing compound B are added to the microplate wells. 100 μl of Sabouraud liquid nutrient broth inoculated at double concentration with the strain Aspergillus niger are also added thereto.

[0147] Microbial Growth Control

[0148] A positive microbial growth control was also prepared. The positive microbial growth control corresponds to a mixture of 100 μl of aqueous 1‰ agar solution with 100 μl of Sabouraud liquid nutrient broth inoculated at double concentration with the strain Aspergillus niger in the absence of compounds A and B.

[0149] Absorbance Control for Compounds A and B Alone

[0150] An absorbance control was performed in parallel on compounds A and B alone. This control corresponds to 100 μl of double concentration sterile Sabouraud liquid nutrient broth+100 μl of double concentration compound A or B.

[0151] In the three cases (absorbance control, growth control and test), the final volume present in each of the microplate wells is 200 μl.

[0152] 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 μl) and is between 2 and 6×10.sup.5 cfu/ml of Aspergillus niger.

[0153] 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.

[0154] The test as described above (tests, absorbance control and growth control) was performed again to test the combination A+B on the following strains Enterococcus faecalis, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, where appropriate.

[0155] The following results were obtained with the compound B1=trisodium salt of ethylenediaminedisuccinic acid (as an aqueous solution at 30% by weight): sold under the name Natrlquest E30 by the company Innospec Active Chemicals.

[0156] Staphylococcus aureus

TABLE-US-00001 TABLES 1 Concentrations tested (in active material weight %) 0 A 0.0625 A 0.125 A 0.25 A 0.5 A 1 A 0 B1 76 72 71 40  −23 0.0375 B1 97 94 90 54 4 −13 (FIC 0.56) 0.075 B1 80 80 67 50 1 −13 (FIC 0.63) 0.15 B1 66 70 78 57 2 −1 (FIC 0.75) 0.3 B1 37 53 60 62 1 −2 (FIC 1) 0.6 B1 1 1 1 1 0 2

TABLE-US-00002 TABLES 2 MIC of each compound % MIC of % MIC of as a mixture FIC Ratio A alone B1 alone A % B1% Index A/B1 1 0.6 0.5 0.3 1 1.66

[0157] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.5% of A and 0.3% of B1, i.e. A/B1 ratio=1.66
ii) 0.5% of A and 0.15% of B1, i.e. A/B1 ratio=3.33
iii) 0.5% of A and 0.075% of B1, i.e. A/B1 ratio=6.66
iv) 0.5% of A and 0.0375% of B1, i.e. A/B1 ratio=13.33

Example 2: Determination of the Synergistic Antimicrobial Activity as MIC on Candida albicans

[0158] 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 the sodium salt of 3-hydroxy-2-pentylcyclopentaneacetic acid (referred to as substance B2) (as a solution at 34% by weight in a 45/21 w/w water/dipropylene glycol mixture; sold under the name Mexoryl SBO by the company Chimex) was performed according to the conditions described in Example 1.

[0159] The following results were obtained:

[0160] Candida albicans

TABLE-US-00003 TABLES 3 Concentrations tested (in active material weight %) 0 A 0.0625 A 0.125 A 0.25 A 0.5 A 0 B2 76 64 36  5 0.34 B2 43 34 23 9 1 (FIC 0.75) (FIC 1) 0.68 B2 6 3  1 1 0

TABLE-US-00004 TABLES 4 MIC of each compound % MIC of % MIC of as a mixture FIC Ratio A alone B2 alone A % B2% Index A/B2 0.5 0.68 0.25 0.34 1 0.73

[0161] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.25% of A and 0.34% of B2, i.e. A/B2 ratio=0.73
ii) 0.125% of A and 0.34% of B2, i.e. A/B2 ratio=0.37

Example 3

[0162] 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 silver citrate hydrate (referred to as substance B3) (reference 361259-10G from Sigma-Aldrich) was performed according to the conditions described in Example 1.

[0163] Aspergillus niger

TABLE-US-00005 TABLES 5 Concentrations tested (in weight %) 0 A 0.025 A 0.05 A 0.1 A 0 B3 44 32 13 0.025 B3 47 28 20 9 (FIC 0.75) 0.05 B3 40 20 20 7 (FIC 0.75) (FIC 1) 0.1 B3 9  4  6 2

TABLE-US-00006 TABLES 6 MIC of each compound % MIC of % MIC of as a mixture FIC Ratio A alone B3 alone A % B3% Index A/B3 0.1 0.1 0.05 0.05 1 1

[0164] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.05% of A and 0.05% of B3, i.e. A/B3 ratio=1
ii) 0.025% of A and 0.05% of B3, i.e. A/B3 ratio=0.5
iii) 0.05% of A and 0.025% of B3, i.e. A/B3 ratio=2

Example 4

[0165] 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 sodium hydroxymethylglycinate (in water at 50% by weight) (referred to as substance B4) was performed according to the conditions described in Example 1.

[0166] Enterococcus faecalis

TABLE-US-00007 TABLES 6 Concentrations tested (in active material weight %) 0 A 0.0625 A 0.125 A 0.25 A 0.5 A 0 B4 31 36 39 −9 0.005 B4 32 18 19 13 5 (FIC 0.63) (FIC 0.75) (FIC 1) 0.01 B4 11  6  7  3 2

TABLE-US-00008 TABLES 7 MIC of each compound % MIC of % MIC of as a mixture FIC Ratio A alone B4 alone A % B4% Index A/B4 0.5 0.1 0.25 0.005 1 50

[0167] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.25% of A and 0.005% of B3, i.e. A/B4 ratio=50
ii) 0.125% of A and 0.005% of B3, i.e. A/B4 ratio=25
iii) 0.0625% of A and 0.005% of B3, i.e. A/B4 ratio=12.5