ANTIMICROBIAL MIXTURE CONTAINING 4-(3-ETHOXY-4-HYDROXYPHENYL) BUTAN-2-ONE, AND COSMETIC COMPOSITION CONTAINING SAME

Abstract

The invention relates to an antimicrobial mixture containing 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and an additional compound chosen from a monovalent or divalent metal salt of pyrithione, piroctone olamine, diazolidinylurea, a hexamidine compound, and imidazolidinylurea,

and also to a cosmetic composition containing such a mixture.

Application to caring for, making up and cleansing keratin materials.

Claims

1. An antimicrobial mixture comprising 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and an additional compound chosen from: i) a monovalent or divalent metal salt of pyrithione; ii) piroctone olamine; iii) diazolidinylurea; iv) a hexamidine compound chosen from hexamidine diisethionate, hexamidine diparaben and hexamidine paraben; v) imidazolidinylurea.

2. The antimicrobial mixture as claimed in claim 1, wherein the additional compound is a monovalent or divalent metal salt of pyrithione.

3. The antimicrobial mixture as claimed in claim 2, wherein the monovalent or divalent metal salt of pyrithione is chosen from the sodium, calcium, magnesium, barium, strontium, zinc, cadmium, tin and zirconium salts.

4. The antimicrobial mixture as claimed in claim 2, wherein the monovalent or divalent metal salt of pyrithione is the zinc salt or the sodium salt.

5. The antimicrobial mixture as claimed in claim 2, wherein the monovalent or divalent metal salt of pyrithione is the zinc salt.

6. The antimicrobial mixture as claimed in claim 2, which comprises 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and the monovalent or divalent metal salt of pyrithione in amounts such that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/pyrithione salt weight ratio ranges from 400 to 4500.

7. The antimicrobial antimicrobial mixture as claimed in claim 2, which has a 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/pyrithione salt weight ratio ranging from 400 to 2500, preferably ranging from 500 to 2200.

8. The antimicrobial mixture as claimed in claim 2, which has a 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/pyrithione salt weight ratio ranging from 800 to 4500.

9. The antimicrobial mixture as claimed in claim 1, wherein the additional compound is piroctone olamine.

10. The antimicrobial mixture as claimed in claim 9, which comprises 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and piroctone olamine in amounts such that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/piroctone olamine weight ratio ranges from 10 to 60.

11. The antimicrobial mixture as claimed in claim 1, wherein the additional compound is diazolidinylurea.

12. The antimicrobial mixture as claimed in claim 11, which comprises 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and diazolidinylurea in amounts such that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/diazolidinylurea weight ratio ranges from 0.5 to 2.5.

13. The antimicrobial mixture as claimed in claim 1, wherein the additional compound is a hexamidine compound chosen from hexamidine diisethionate, hexamidine diparaben or hexamidine paraben.

14. The antimicrobial mixture as claimed in claim 13, wherein the hexamidine compound is hexamidine diisethionate.

15. The antimicrobial mixture as claimed in claim 13, which comprises 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and the hexamidine compound in amounts such that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/hexamidine compound weight ratio ranges from 5 to 85.

16. The antimicrobial mixture as claimed in claim 1, wherein the additional compound is imidiazolidinylurea.

17. The antimicrobial mixture as claimed in claim 16, which comprises 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and imidiazolidinylurea in amounts such that the 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/imidiazolidinylurea weight ratio ranges from 0.1 to 0.8.

18. The antimicrobial mixture as claimed in claim 16, which has a 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/imidiazolidinylurea weight ratio ranging from 0.2 to 0.8.

19. The antimicrobial mixture as claimed in claim 16, which has a 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one/imidiazolidinylurea weight ratio ranging from 0.1 to 0.6.

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

21. The composition as claimed in claim 20, which comprises at least one additional ingredient chosen from water, oils, polyols containing from 2 to 10 carbon atoms, gelling agents, surfactants, film-forming polymers, colorants, fragrances, fillers, UV-screening agents, plant extracts, cosmetic and dermatological active agents, and salts.

22. The composition as claimed in claim 20, 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.

23. 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 20.

24. A process for preserving a composition comprising a physiologically acceptable medium, a cosmetic or dermatological composition, which comprises incorporating into said composition an antimicrobial mixture as defined in claim 1.

25. A process for preserving a composition comprising a physiologically acceptable medium which comprises including an antimicrobial mixture as defined in claim 1 in said composition.

Description

EXAMPLE 1: DETERMINATION OF THE SYNERGISTIC ANTIMICROBIAL ACTIVITY AS MIC

[0064] 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 additional compound (referred to as substance B) is 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 of B with A/MIC of B)

with: [0065] MIC of A with B: minimum concentration of product A in the combination A+B which makes it possible to obtain an inhibitory effect; [0066] MIC of B with A: minimum concentration of product B in the combination A+B which makes it possible to obtain an inhibitory effect; [0067] MIC of A: minimum inhibitory concentration of product A alone; [0068] MIC of B: minimum inhibitory concentration of product B alone.

[0069] 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.

[0070] 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 20%, or even less than 25%.

[0071] 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 20%, or even less than 25%.

Interpretation of the FIC Index:

[0072] 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.

[0073] The summary of the results obtained is presented in the following tables.

[0074] The combination of compounds A and B was tested on the following strains or a part of these strains: Candida albicans, Staphylococcus aureus, Aspergillus niger.

[0075] The microbial strain Staphylococcus aureus ATCC 6538 and a double-concentration nutrient broth liquid culture medium were used.

[0076] The microbial strain Candida albicans ATCC 10231 and a double-concentration Sabouraud broth liquid culture medium were used.

[0077] The microbial strain Aspergillus niger ATCC 6275, and a double-concentration Sabouraud broth liquid culture medium supplemented with polyoxyethylenated (20 EO) sorbitan monopalmitate (Tween 40 from Croda) and Phytagel BioReagent were used.

[0078] A 96-well microplate at an incubation temperature of 32.5 C. is used.

[0079] The incubation time of the microplate for the abovementioned two strains is: [0080] from 18 to 24 h aerobically for Candida albicans and Staphylococcus aureus. [0081] from 24 hours to 48 hours aerobically for Aspergillus niger

Tests

[0082] For each compound:

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

[0083] 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.

Tests of Compounds A and B Alone

[0084] 50 l of each of the daughter solutions obtained containing compound A or B are added to the microplate wells. 100 l of Sabouraud liquid nutrient broth inoculated at double concentration with the Candida albicans strain and 50 l of aqueous 1 agar solution are also added thereto.

Tests of Compounds A and B as a Mixture

[0085] 50 l of each of the daughter solutions obtained containing compound A and 50 l of each of the daughter solutions obtained containing compound B are added to the microplate wells. 100 l of Sabouraud liquid nutrient broth inoculated at double concentration with the Candida albicans strain are also added thereto.

Microbial Growth Control

[0086] A positive microbial growth control was also prepared. The positive microbial growth control corresponds to the mixture of 100 l of aqueous 1 agar solution with 100 l of Sabouraud liquid nutrient broth inoculated at double concentration with the Candida albicans strain in the absence of compounds A and B.

Absorbance Control for Compounds A and B Alone

[0087] An absorbance control was performed in parallel on compounds A and B alone. This control corresponds to 100 l of double concentration sterile Sabouraud liquid nutrient broth+100 l of double concentration compound A or B.

[0088] In the three cases (absorbance control, growth control and test), the final volume present in each of the microplate wells is 200 l.

[0089] In the two cases (test and control), the inoculum represents the concentration of the Candida albicans strain present in the final volume of the wells (200 l) and is between 2 and 610.sup.5 cfu/ml of Candida albicans.

[0090] 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.

[0091] The test as described above (tests, absorbance control and growth control) was performed again to test the combination A+B on the Staphylococcus aureus strain and on the Aspergillus niger strain as appropriate.

[0092] The followings results were obtained with B1=zinc pyrithione compound (solution at 48% of starting material in water as a mixture with 2% of sodium polynaphthalenesulfonate and 0.28% cellulose gum*). * It is considered that the additives present at such a low concentration have no influence on the MIC results obtained.

Staphylococcus aureus

TABLE-US-00001 Concentrations tested (in weight %) 0 A 0.0625 A 0.125 A 0.25 A 0.5 A 0 of B1 87 77 78 4 0.00006 B1 34 42 51 40 1 0.00012 B1 26 11 7 1 0 (FIC 0.625) (FIC 0.75) (FIC 1) 0.00024 B1 0 0 1 0 0

TABLE-US-00002 MIC of each compound % MIC of A % MIC of B1 as a mixture FIC Ratio alone alone A % B1 % Index A/B1 0.5 0.00024 0.0625 0.00012 0.625 520

[0093] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.0625% of A and 0.00012% of B1, i.e. A/B1 ratio=520
ii) 0.125% of A and 0.00012% of B1, i.e. A/B1 ratio=1041
iii) 0.25% of A and 0.00012% of B1, i.e. A/B1 ratio=2083
Candida albicans

TABLE-US-00003 Concentrations tested (in weight %) 0 A 0.025 A 0.05 A 0.1 A 0.2 A 0 B1 84 71 48 10 0.000006 B1 80 83 60 47 14 0.000012 B1 42 30 28 25 5 0.000024 B1 34 15 13 14 5 (FIC 0.625) (FIC 0.75) (FIC 1) 0.000048 B1 18 9 6 12 4

TABLE-US-00004 MIC of each compound % MIC of A % MIC of B1 as a mixture FIC Ratio alone alone A % B1 % Index A/B1 0.2 0.000048 0.025 0.000024 1 1041

[0094] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.025% of A and 0.000024% of B1, i.e. A/B1 ratio=1041
ii) 0.05% of A and 0.000024% of B1, i.e. A/B1 ratio=2083
iii) 0.1% of A and 0.000024% of B1, i.e. A/B1 ratio=4166

EXAMPLE 2: DETERMINATION OF THE SYNERGISTIC ANTIMICROBIAL ACTIVITY IN MIC ON THE MICROBIAL STRAIN CANDIDA ALBICANS

[0095] 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 piroctone olamine (referred to as substance B2) is performed according to the protocol described in example 1.

[0096] The following results were obtained:

Candida albicans

TABLE-US-00005 concentrations tested (in weight %) 0 A 0.025 A 0.05 A 0.1 A 0 B2 52 31 18 0.00125 B2 35 21 14 7 0.0025 B2 0 0 1 0

TABLE-US-00006 MIC of each compound as a mixture FIC Ratio % MIC A MIC B2 A % B2 % Index A/B2 0.1 0.005 0.025 0.00125 0.75 20

[0097] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.025% of A and 0.00125% of B2, i.e. A/B2 ratio=20
ii) 0.05% of A and 0.00125% of B2, i.e. A/B2 ratio=40

EXAMPLE 3: DETERMINATION OF THE SYNERGISTIC ANTIMICROBIAL ACTIVITY AS MIC

[0098] 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 diazolidinylurea (referred to as substance B3) is performed according to the protocol described in example 1.

[0099] The following results were obtained:

Candida albicans

TABLE-US-00007 Concentrations tested (in weight %) 0 A 0.025 A 0.05 A 0.1 A 0.2 A 0 B3 71 65 44 4 0.0625 B3 55 26 17 7 1 (FIC 0.75) (FIC 1) 0.125 B3 10 5 4 1 0

TABLE-US-00008 MIC of each compound % MIC of A % MIC of B3 as a mixture FIC Ratio alone alone A % B3 % Index A/B3 0.2 0.125 0.05 0.0625 0.75 0.8

[0100] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.05% of A and 0.0625% of B3, i.e. A/B3 ratio=0.8
ii) 0.1% of A and 0.0625% of B3, i.e. A/B3 ratio=1.6.

EXAMPLE 4: DETERMINATION OF THE SYNERGISTIC ANTIMICROBIAL ACTIVITY AS MIC

[0101] 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 hexamidine diisethionate (referred to as substance B4) is performed according to the protocol described in example 1.

[0102] The following results were obtained:

Candida albicans

TABLE-US-00009 Concentrations tested (in weight %) 0 A 0.025 A 0.05 A 0.1 A 0.2 A 0 B4 83 71 46 6 0.00125 B4 78 4 1 0 1 (FIC 0.375) (FIC 0.5) (FIC 0.75) 0.0025 B4 59 0 0 0 0 (FIC 0.675) (FIC 0.75) (FIC 1) 0.005 B4 3 0 0 0 0

TABLE-US-00010 MIC of each compound % MIC of A % MIC of as a mixture FIC Ratio alone B4 alone A % B4 % Index A/B4 0.2 0.005 0.025 0.00125 0.375 20

[0103] The results obtained show synergistic inhibitory activity for the mixtures: 71719399.1

i) 0.025% of A and 0.00125% of B4, i.e. A/B4 ratio=20
ii) 0.05% of A and 0.00125% of B4, i.e. A/B4 ratio=40
iii) 0.1% of A and 0.00125% of B4, i.e. A/B4 ratio=80
iv) 0.025% of A and 0.0025% of B4, i.e. A/B4 ratio=10
v) 0.05% of A and 0.0025% of B4, i.e. ratio A/B4=20
vi) 0.1% of A and 0.0025% of B4, i.e. ratio A/B4=40.

EXAMPLE 5: DETERMINATION OF THE SYNERGISTIC ANTIMICROBIAL ACTIVITY AS MIC

[0104] 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 imidiazolidinylurea (referred to as substance B5) is performed according to the protocol of example 1.

[0105] The following results were obtained:

Aspergillus niger

TABLE-US-00011 Concentrations tested (in weight %) 0 A 0.0625 A 0.125 A 0.25 A 0 B5 85 43 4 0.0625 B5 98 94 44 10 0.125 B5 97 92 40 5 0.25 B5 92 68 16 3 (FIC 0.75) 0.5 B5 38 24 5 1 (FIC 1) 1 B5 2 1 1 1

TABLE-US-00012 MIC of each compound % MIC of A % MIC of as a mixture FIC Ratio alone B5 alone A % B5 % Index A/B5 0.25 1 0.125 0.25 0.75 0.5

[0106] The results obtained show synergistic inhibitory activity for the mixture: [0107] i) 0.125% of A and 0.25% of B5, i.e. ratio A/B5=0.5 [0108] ii) 0.125% of A and 0.5% of B5, i.e. ratio A/B5=0.25
Candida albicans

TABLE-US-00013 Concentrations tested (in weight %) 0 A 0.025 A 0.05 A 0.1 A 0 B5 56 39 17 0.0625 B5 43 38 26 15 0.125 B5 23 20 16 9 (FIC 0.75) (FIC 1) 0.25 B5 17 14 12 6

TABLE-US-00014 MIC of each compound % MIC of % MIC of as a mixture FIC Ratio A alone B5 alone A % B5 % Index A/B5 0.1 0.25 0.025 0.125 0.75 0.2

[0109] The results obtained show synergistic inhibitory activity for the mixtures:

i) 0.025% of A and 0.125% of B5, i.e. A/B5 ratio=0.2
ii) 0.05% of A and 0.125% of B5, i.e. A/B5 ratio=0.4