COSMETIC PREPARATION WITH ANISIC ACID AND LEVULINIC ACID WITH SELECTIVE ANTIMICROBIAL ACTIVITY.

Abstract

The invention relates to cosmetic and dermatological preparations comprising a combination of levulinic acid and anisic acid. The preparations according to the invention are particularly suitable for application to the skin. These preparations exhibit selective antibacterial action on the skin, specifically targeting anaerobic bacteria of the skin flora, while having little or no bactericidal action against aerobic bacteria. The compositions according to the invention are therefore suitable for cosmetic skin care as well as for the dermatological treatment of certain skin conditions, such as acne.

Description

COSMETIC PREPARATION WITH ANISIC ACID AND LEVULINIC ACID WITH SELECTIVE ANTIMICROBIAL ACTIVITY The invention relates to cosmetic and dermatological preparations comprising a combination of levulinic acid and anisic acid. The preparations according to the invention are particularly suitable for application to the skin. These preparations exhibit selective antibacterial action on the skin, specifically targeting anaerobic bacteria of the skin flora, while having little or no bactericidal action against aerobic bacteria. The compositions according to the invention are therefore suitable for cosmetic skin care as well as for the dermatological treatment of certain skin conditions, such as acne. BACKGROUND OF THE INVENTION The human skin microbiome is a complex mixture of different groups of microorganisms: anaerobic bacteria, such as Cutibacterium acnes (C. acnes), colonize the skin in close proximity to aerobic bacteria, such as Staphylococcus epidermidis (S. epidermidis) and Staphylococcus hominis (S. hominis), as well as fungi. Interactions between *Saccharomyces epidermidis* and *Clapus acnes* are known to be particularly important for skin health. *Saccharomyces epidermidis* is a Gram-positive, aerobic, spherical bacterium that is catalase-positive and coagulase-negative. *Clapus acnes* is a Gram-positive, anaerobic bacterium. It is believed that these two microorganisms occur in healthy skin in a relatively stable balance, and an alteration of this balance, known as dysbiosis, can negatively impact skin condition, triggering skin blemishes or even skin diseases, or at least promoting their development.Therefore, it is especially important for the treatment or prevention of such skin impurities or diseases to provide products that can selectively modify the ratio of anaerobic to aerobic microorganisms in the skin flora, and in particular the ratio of S. epidermidis to C. acnes. Since the increased growth of anaerobic bacteria, such as P. acnes, can be associated with the development of skin diseases, preparations that are selectively effective against anaerobic bacteria are particularly necessary. Anisic acid is a methoxylated benzoic acid (4-methoxybenzoic acid) that is bacteriostatic and also has anti-inflammatory and fungicidal properties. Anisic acid is used, among other things, in cosmetic products as a preservative to prevent contamination by bacteria or fungi. For this purpose, anisic acid is added to these products at a concentration of 0.05–0.3%. Levulinic acid, also known as 4-oxopentanoic acid or 4-oxovaleric acid, is a chemical compound belonging to the γ-keto acids. Internationally recognized as levulinic acid, it and its salts are used in skincare products, primarily as a fragrance additive, given its characteristic scent, which is reminiscent of caramel or vanilla. Levulinic acid also possesses antibacterial and antifungal properties. This makes it a valuable ingredient for treating dirty skin. Since levulinic acid is not listed as a preservative, it can be used effectively for preserving natural cosmetic products. Its use as a preservative in cosmetics has been extensively documented, with the substance being added to products at a concentration of 0.3-1.0%. Preservatives are regularly used in cosmetic products to protect them from bacterial and fungal contamination. The microbiological stability of cosmetic products is a crucial factor for their durability and the health and well-being of users. European cosmetics regulations define preservatives as substances used exclusively or predominantly to inhibit the growth of microorganisms in cosmetic agents. The substances authorized for this purpose are listed in the corresponding positive list in Annex V of EU KVO. The use of anisic acid and levulinic acid as preservatives has been described in the prior art. EP 1 541 124 A2 describes a synergistic action between two active ingredients used for preservation, specifically anisic acid and C6-14 fatty acid monoglycerides. The mixture ncnann / zznz / e / YiAi is said to exhibit antimicrobial activity, which can be used for the preservation of cosmetic formulations. Consequently, a broad antimicrobial environment is created in the formulations while maintaining good skin compatibility. EP 2 735 301 A1 discloses the combination of levulinic acid, the sodium salt of levulinic acid (sodium levulinate), and anisic acid for the preservation of a cosmetic product. While anisic acid and levulinic acid have been extensively tested in the preservation of cosmetic products, their use for the targeted modification of the skin flora composition is not yet known. As explained previously, there is a need for cosmetic and dermatological formulations that contribute to improving the overall condition and health of the skin by directly influencing its composition. At the same time, these formulations must be well-compatible with the skin. DESCRIPTION OF THE INVENTION The present invention is based on the surprising knowledge that anisic acid, in combination with levulinic acid, can be used to selectively reduce the concentration of anaerobic bacteria in the skin flora, particularly C. acnes. Accordingly, the invention relates to the use of a combination of anisic acid and levulinic acid for the reduction of anaerobic bacteria and the simultaneous preservation of aerobic bacteria on the skin. The combination according to the invention thus allows, after application to the skin, the development of a selective antibacterial action. The invention relates in a first aspect to a composition for the targeted modification of the skin flora, wherein the composition comprises the following: (i) anisic acid or an antimicrobial salt thereof, and (ii) levulinic acid or an antimicrobial salt thereof. In terms of consumption, the compositions preferably contain anisic acid. However, salts of anisic acid may also be used, provided they exhibit sufficient antimicrobial activity. Salts of anisic acid suitable for use within the scope of the present invention preferably exhibit antimicrobial activity that corresponds to at least 50% of the activity of anisic acid in a corresponding in vitro assay. This means that when equal amounts of anisic acid and anisic acid salt are used to determine antimicrobial activity in an in vitro assay, the anisic acid salt must exhibit at least half the antimicrobial activity compared to anisic acid. Salts suitable for use within the scope of the present invention are sodium anisate and potassium anisate. Suitable levulinic acid salts for use within the scope of the present invention preferably exhibit antimicrobial activity that corresponds to at least 50% of the activity of levulinic acid in a corresponding in vitro assay. This means that when equal amounts of levulinic acid and the levulinic acid salt are used to determine antimicrobial activity in an in vitro assay, the levulinic acid salt must exhibit at least half the antimicrobial activity compared to levulinic acid. Suitable salts for use within the scope of the present invention are sodium and potassium levulinate. In particular, the present invention relates to a composition for the targeted modification of the skin flora, wherein the composition (i) contains more than 0.3% (w / w) of anisic acid or an antimicrobial salt thereof, and (ii) contains more than 1.0% (w / w) of levulinic acid or an antimicrobial salt thereof. In a particularly preferred embodiment, the composition comprises at least 0.5% (w / w) of anisic acid or an antimicrobial salt thereof, and at least 1.5% (w / w) of levulinic acid or an antimicrobial salt thereof. The amount of anisic acid or anisic acid salt in the composition is preferably at least 0.75%, at least 1.0%, at least 1.5%, at least 2.0%, at least 2.5%, at least 3.0%, at least 3.5%, at least 4.5%, or at least 5.0% (w / w). The amount of levulinic acid or levulinic acid salt in the composition preferably amounts to at least 2.0%, at least 2.5%, at least 3.0%, at least 3.5%, at least 4.5% or at least 5.0% (weight / weight). In other words, the composition of the present invention preferably comprises between 0.5 and 5.0% (w / w) of anisic acid or an antimicrobial salt thereof, and between 1.5 and 5.0% (w / w) of levulinic acid or an antimicrobial salt thereof. A composition comprising between 1.0 and 4.0% (w / w) of anisic acid or an anisic acid salt and between 2.0 and 4.0% (w / w) of levulinic acid or a levulinic acid salt is particularly preferred. A composition comprising between 1.5 and 3.0% (w / w) of anisic acid or an anisic acid salt and between 2.0 and 3.0% (w / w) of levulinic acid or a levulinic acid salt is even more preferred. Even more preferred is a composition comprising between 2.0 and 3.0% (weight / weight) of anisic acid or anisic acid salt and between 2.5 and 3.0% (weight / weight) of levulinic acid or levulinic acid salt. The compositions according to the invention can be found as a uniform formulation or as components that are combined directly before application to the skin. In the latter case, the above quantity guidelines apply to the composition resulting from the combination of the components directly before application. The present invention also includes compositions in which the two antimicrobial components, specifically anisic acid or its salt and levulinic acid or its salt, are provided as separate formulations that are applied successively to the skin. Thus, the two antimicrobial components can be applied to the skin at time intervals of approximately 5, 10, 15, 20, 24, or 30 minutes. The compositions of the present invention can be found in various forms. These include, for example, a solution, a suspension, a water-in-oil (W / O) or oil-in-water (O / W) emulsion, or a multiple emulsion, such as a water-in-oil-in-water (W / O / W) or oil-in-water-in-oil (O / W / O) emulsion, a hydrodispersion or lipodispersion, or an aerosol, which are preferred forms of preparation. Preferably, the composition according to the invention is found as emulsions, which, in addition to the antimicrobial active components, contain other substances, such as fats, oils, waxes, and / or other fatty substances, as well as water and one or more emulsifiers, as are commonly used for this type of formulation. Such emulsions can be advantageously formulated as a cream or lotion.It is also possible and advantageous to introduce the combinations according to the invention of anisic acid and levulinic acid in aqueous systems or surfactant preparations for skin and / or hair cleansing. Naturally, the expert knows that cosmetic and therapeutic compositions are inconceivable in most cases without the usual adjuvants and additives. These include, for example, consistency agents, fillers, aromatic substances, colorants, emulsifying agents, additional active ingredients such as vitamins or proteins, photostabilizers, stabilizers, insect repellents, alcohol, water, salts, as well as substances with antimicrobial, proteolytic, or keratolytic action, etc., provided that their use does not significantly inhibit the antimicrobial activity of the combination according to the invention or otherwise conflict with it. Combinations of anisic acid and levulinic acid according to the invention can be advantageously incorporated into common cosmetic and dermatological preparations, which in turn can be found in various forms. The compositions can be found, for example, as creams, lotions, gels, ointments, pastes, or solid sticks. The compositions described above are particularly suitable for non-therapeutic, cosmetic, and / or therapeutic treatment of the skin, especially the skin of the human face. In one particular embodiment, the invention relates to a previously described composition for use in a procedure for treating a skin disease. The skin disease in question is preferably dermatitis. The treatment of acne (acne vulgaris) with the compositions described above is especially preferred. The therapeutic action of the compositions according to the invention advantageously results from the targeted modification of the concentration of anaerobic bacteria on the skin. The concentration of these anaerobic bacteria is reduced, while the concentration of anaerobic bacteria in the same environment remains largely unchanged or is not significantly reduced.This results in a shift in the ratio of anaerobic to aerobic bacteria in the skin, and in particular a shift in the ratio of C. acnes to S. epidermidis. ncnann / zznz / e / γΐΛΐ The compositions according to the invention are also suitable for non-therapeutic cosmetic use. Such non-therapeutic cosmetic use can serve to selectively reduce the number of anaerobic bacteria on the skin, and in particular to selectively reduce the number of C. acnes. In this way, skin impurities can be eliminated or prevented. In particular, blockages of sebaceous glands, such as those that occur, for example, in the case of comedones, can be prevented. Non-therapeutic cosmetic use can thereby considerably improve the skin's appearance. In another embodiment, the invention also relates to the non-therapeutic use of a composition according to the invention defined above for the preparation for the care of acne-prone skin. The compositions can be applied to the skin, either as part of therapeutic or non-therapeutic cosmetic treatments, one or more times. In one embodiment, the compositions according to the invention are formulated for daily application to the skin. In an alternative embodiment, the compositions according to the invention are formulated for single application to the skin. Remarkably, the combination of anisic acid and levulinic acid in the compositions according to the invention acts selectively; that is, anaerobic bacteria such as C. acnes are reduced on the skin, while aerobic bacteria such as S. epidermidis are either unaffected or essentially unaffected. The advantage of the compositions according to the invention lies in their high antimicrobial selectivity. The compositions lead to a targeted and significant reduction in the number of anaerobic bacteria colonizing the skin, particularly C. acnes. At the same time, the compositions have no inhibitory effect, or only a negligible one, on aerobic bacteria, particularly S. epidermidis, whose numbers on the skin are not significantly reduced. As explained in the examples described below and shown in Figures 1-2, the use of the compositions according to the invention leads to a 90% reduction in anaerobic bacteria, while aerobic bacteria actually increase further during the study period. It is preferred that the number of anaerobic bacteria in a given area of ​​skin, after application of the composition according to the invention, decreases by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the number of cells in the respective area of ​​skin before application of the composition. Furthermore, it is preferred that the number of aerobic bacteria in this area of ​​skin simultaneously decreases by at most 25%, at most 20%, at most 15%, at most 10%, at most 5%, or less compared to the number of cells in the respective area of ​​skin before application of the composition. It is particularly preferred that the number of C. acnes cells in a given area of ​​skin, after application of the composition according to the invention, decreases by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the number of cells in the respective area of ​​skin before application of the composition. Furthermore, it is preferred that the number of S. epidermidis cells in this area of ​​skin simultaneously decreases by at most 25%, at most 20%, at most 15%, at most 10%, at most 5%, or less compared to the number of cells in the respective area of ​​skin before application of the composition. The activity of the compositions according to the invention was demonstrated in various studies, which are described in the following examples. In one trial, bacteria were obtained from the cheek using a swab scraping technique and incubated aerobically and anaerobically (i.e., with reduced oxygen content). After 14 days, bacteria were again extracted from the experimental subjects. Evaluation of all the data from the experimental subjects revealed a surprising picture. In the case of the aerobically cultured bacteria, no abnormalities were observed, while in the case of the anaerobically cultured bacteria, a significant reduction of more than 90% in the number of bacterial cells occurred after just one week. This selective behavior was confirmed in subsequent in vitro studies. EXAMPLES The following examples are intended to clarify, without limiting, the present invention. All indications of quantity, proportions, and percentages, unless otherwise indicated, refer to the total weight and quantity or the total weight of the respective preparations and compositions. Example 1: Preparation of bacterial suspensions and growth assays S. epidermidis (DSM 1798) was extracted from a cryotube (EN 12353), spread onto a CASO agar plate, and incubated at 37 °C for 24 h. A second passage was then applied. With the second passage, 10 ml of BHI medium and 5 g of glass beads (4 mm in diameter) were inoculated and shaken for 3 min. This reaction mixture was then adjusted to an OD600 of 0.1 and subsequently diluted 1:10 with diluent. This bacterial suspension was then used for the growth assay. Test – Growth assay with S. epidermidis In each well of a 24-well plate, 10 µL of bacterial suspension was added and allowed to dry completely (at least 45 min under a laminar flow hood). After drying, 10 mg of the formulation to be studied (see Table 1) was pipetted into the well using a T-shaped spatula. The control remained untreated. The plate was incubated for the duration of the incubation period (6 h / 24 h) in an incubator at 37 °C and 90% relative humidity without a lid. After the incubation period, 500 µL of wash buffer was added to each well, and the plates were washed for 1 min in an ultrasonic bath. 100 μL of the obtained supernatant was added to 900 μL of neutralizing agent and then plated on CASO agar using a spiral plating device.Agar plates were incubated at 37 °C for 24 h, and colonies were then counted using the l+L Countermat. C. acnes (DSM 1897) was spread from a cryotube (EN 12353) onto an agar plate (COST agar) and incubated at 37 °C for 5 days in an anaerobic dish. Using this culture, 10 ml of anaerobic medium was inoculated into a CELLSTAR CELLreactor tube and incubated for 18 h in the anaerobic dish. This reaction mixture was then adjusted to an OD600 of 0.5 and subsequently diluted 1:10 with anaerobic medium. This bacterial suspension was then used for the growth assay. Test - growth assay with C. acnes In each well of a 24-well plate, 10 µL of bacterial suspension was added and allowed to dry completely (at least 45 min under a laminar flow hood). After drying, 10 mg of the formulation to be studied (see Table 1) was pipetted into the well using a T-shaped spatula. The control remained untreated. The plate was kept uncovered in an anaerobic box (lined with cellulose and containing 50 mL of water) in an incubator at °C for the duration of the incubation (6 h / 24 h). After the incubation period, 500 µL of wash buffer was added to each well, and the plates were washed for 1 min in an ultrasonic bath. 100 μL of the obtained supernatant was added to 900 μL of neutralizing agent and then plated onto COST agar using a spiral plating device.Agar plates were incubated at 37 °C for 5 days, and colonies were then counted using the l+L Countermat. In the context of the evaluation, the reduction factor was determined. The reduction factor is the factor by which the number of cells (UFOs) is reduced at different time points compared to the control T0 or to each other. UFC (control) -----;-----------:---------r = reduction factor UFC (test substance) ncnann / zznz / e / γΐΛΐ The study design is designed so that antibacterial activity of the test formulations is detected by comparison with the untreated control. Formulation Number 1 2 3 4 5 6 INCI % % % % p-Anisic Acid 0.1 0.1 0.1 0.1 0.1 0.1 Levulinic Acid (Water / Glycerol / Sodium Levulinate) 0.5 0.5 0.5 0.5 0.5 0.5 Glycerol + Arctium Lappa Fruit Extract 1.2 1.2 1.2 0 0 0 Ethylhexylglycerol 0.1 0.1 0 0.1 0.2 0.1 Decylenoxyglycol 0 0.1 0.1 0.1 0 0 Sodium Hyaluronate + Water 0 0 0.1 0 0 0 Maltodextrin + Chamomilla Recutita Flower Extract 0 0 0 0.6 0 0 Dicaprylyl ether 2.8 3.5 0 3.5 2.8 2.8 Jojoba oil 3.5 3.5 0 3.5 3.5 3.5 Shea butter 2 2 0 2 3.5 2 Prunus Amygdalus Dulcis oil 3 3.5 0 3.5 5 3 Coco-caprylate / caprate 1.2 0 0 0 0 1.2 Formulation level 1 2 3 4 5 6 Argania Spinosa seed oil 0.1 o.1 0.1 0 0.1 0 Caprylic / capric triglycerides 0 1 0 1 0 0 Brassica Campestris seed oil 0 0 6 0 0 0 Glyceryl stearate 2 2 0 2 2 2 Glyceryl caprylate 0.3 0.3 0.3 0.3 0.3 0.3 Sodium stearoyl glutamate 0.3 0.3 0 0.3 0.3 0.3 Sodium cetearyl sulfate 0 0 0.2 0 0 0 Perfume 0.35 0.35 0.35 0 0.3 0.3 Glycerol 8.4 8.4 9 8.4 8.4 8.4 Cetearyl alcohol 5 5 0 5 5 5 Xanthan gum 0.3 0.3 0.2 0.3 0.3 0.3 Cetyl alcohol 0 0 3 0 0 0 Hydroxypropyl starch phosphate + water 0 0 3 0 0 0 Alcohol Denat. + water 4 4 4 4 4 4 Water add up to 100 add up to 100 add up to 100 add up to 100 add up to 100 add up to 100 Reduction factors 1 2 3 4 5 6 Staphylococcus epidermidis after 6 h 1 1 10 1 1 1 Cutibacterium acnes after 6 h 40 134 1651 214 813 71 ncnann / zznz / e / γΐΛΐ Table 1: Formulations subjected to testing and results of growth tests The count showed that the number of aerobic bacteria S. epidermidis 5 was either unchanged or essentially unaffected by the formulation containing anisic acid and levulinic acid. Only low reduction factors were measured in the S. epidermidis reaction mixtures. In contrast, the number of anaerobic bacteria C. acnes was significantly reduced by the formulations. Example 2: ATA Test The ATA test is used to determine the antibacterial activity of cosmetic formulations after twice-daily application. The test typically lasts for one week. The test formulation is applied and the activity is measured on the relevant area of ​​the user, the cheek. The target value is the number of aerobic and anaerobic bacteria. All experimental subjects underwent a 3-day preconditioning period using a predetermined washing gel. After cheek washing, the test formulation 5 described in Table 1 was applied according to the instructions. A Floq swab was then used to scrape the cheek. Three 10-stroke lines were scraped on a 5 cm x 5 cm area of ​​the cheek in a defined pattern. The swab scraping pattern is shown in Figure 3. During sampling cycles, the Floq swab was soaked in wash buffer, and after the third sampling, the swab remained in the wash buffer. The solution was then diluted directly, and each sample was plated using a spiral plating device onto two agar plates. Swabbing was then repeated at correspondingly determined intervals, in most cases after one week.Finally, half of the agar plates were incubated at 37 °C for 5 days in the absence of oxygen, and the other half of the agar plates were incubated at 37 °C for 24 h. The agar plates were then evaluated using the Countermat. The results of the ATA test are shown in Figures 1 and 2. Figure 1 shows the results of the anaerobic culture. It can be seen that the number of anaerobic bacterial cells clearly decreased after treatment with the test formulation, which contains a combination of anisic acid and levulinic acid. Such a reduction in cell count is not observed in Figure 2, which shows the results of the aerobic culture. In fact, an increase in cell count was even recorded in this case. Figures 1 and 2 therefore impressively demonstrate the selective activity of the combination of anisic acid and levulinic acid according to the invention. Example 3: Suspension tests The action of the formulations according to the invention was further studied in suspension tests with S. epidermidis and C. acnes. Glycerol stock cultures of S. epidermidis (DSM 1798) and C. acnes (DSM 1897), prepared according to European standard EN 12353, were stored in a refrigerator at 5 °C. A first passage was prepared from these liquid stock cultures. The corresponding culture was spread onto an agar plate (C. acnes: COST agar, S. epidermidis: COST agar) using a sterile disposable inoculating loop and then incubated. The C. acnes cultures were incubated for 5 days at 37 °C, while the S. epidermidis cultures were incubated for 24 hours at 37 °C. From this first pass, a second pass was then prepared, in which some colonies were taken with a sterile disposable inoculating loop and then spread onto a new agar plate.This second passage was then incubated for 5 days or 24 hours at the corresponding temperature. The resulting second passage was then used for the suspension assay. For the preparation of the suspensions, a few colonies were extracted from the second passage using a sterile inoculating loop and added to 10 ml of medium in an Erlenmeyer flask containing 5 g of glass beads (0.4 mm). The mixture was gently shaken for 3 min. The approximate number of cells per ml was then adjusted using optical density (OD). Optical density was determined with an Eppendorf photometer at 600 nm. The resulting OD was adjusted to approximately 0.8 (±0.01), and the suspension was then diluted again 1:50. This dilution strategy yielded a cell count of approximately 1 x 10⁶. In each case, 50 µL of the antimicrobial raw material solution and 450 µL of medium for the test formulations were placed in sterile Eppendorf reaction tubes (C. acnes: anaerobic medium, S. epidermidis: BHI medium). 500 µL of medium was used for the positive control. After the addition of 500 µL of the prepared culture suspension, 1:10 dilutions of all samples were prepared at different time points (after 1 h, 3 h, and 6 h). For the positive control, an additional dilution was prepared directly after the addition of the culture (0 min) and plated using a spiral plating device. Throughout the test, the samples were stored on an Eppendorf shaker at 1000 rpm and either 30 °C or 37 °C. For the 1:10 dilutions, 900 μI of neutralization medium were placed in Eppendorf reaction tubes and at the sampling times, 100 μI of the culture raw material suspension was added to this.After the test was completed, all agar plates were placed in the incubation oven for incubation and after incubation they were evaluated on the Countermat. The results are shown in Figures 4 and 5. It can be seen that the use of anisic acid, levulinic acid, or a combination of the two substances does not significantly alter the growth of the aerobic bacterium S. epidermidis. In contrast, in the case of the anaerobic bacterium C. acnes, while the use of anisic acid or levulinic acid alone does not lead to a reduction in the number of cells, the combined use leads to a significant selective antimicrobial action.

Claims

1. Composition for the targeted modification of the skin flora, wherein the composition comprises the following: (i) more than 0.3% (w / w) of anisic acid or an antimicrobial salt thereof, and (ii) more than 1.0% (w / w) of levulinic acid or an antimicrobial salt thereof.

2. Composition according to claim 1, comprising the following: (i) at least 0.75% (w / w) of anisic acid or an antimicrobial salt thereof, and (ii) at least 1.5% (w / w) of levulinic acid or an antimicrobial salt thereof.

3. Composition according to claim 2, comprising the following: (i) from 0.75 to 5.0% (w / w) of anisic acid or an antimicrobial salt thereof, and (ii) from 1.5 to 5.0% (w / w) of levulinic acid or an antimicrobial salt thereof.

4. Composition according to any one of claims 1-3, wherein the composition is in the form of a cream, lotion, gel, ointment, paste or solid bar.

5. Composition according to any one of claims 1-4 for use in a procedure for the treatment of a skin disease, in particular acne.

6. Non-therapeutic use of a combination of (i) anisic acid or an antimicrobial salt thereof and (ii) levulinic acid or an antimicrobial salt thereof for the selective reduction of the number of anaerobic bacteria on the skin. ncnann / zznz / e / γΐΛΐ 7. Non-therapeutic use according to claim 6, wherein the anaerobic bacteria are of the genus Cutibacterium, and in particular bacteria of the species Cutibacterium acnes.

8. Non-therapeutic use according to any one of claims 6-7, wherein the number of aerobic bacteria on the skin is not reduced significantly.

9. Non-therapeutic use according to claim 8, wherein the aerobic bacteria are bacteria of the genus Staphylococcus, and in particular bacteria of the species S. epidermidis.

10. Non-therapeutic use according to any one of claims 6-9, wherein it refers to the skin of the face.

11. Non-therapeutic use according to any one of claims 6-10, wherein the two components of the combination are applied simultaneously or successively to the skin.

12. Non-therapeutic use according to any one of claims 6-11, wherein the combination is administered in the form of a uniform composition, comprising from 0.01 to 5.0% (w / w), and preferably from 0.1 to 1.0% (w / w), of anisic acid or an antimicrobial salt thereof.

13. Non-therapeutic use according to any one of claims 6-12, wherein the combination is administered in the form of a uniform composition, comprising from 0.01 to 5.0% (w / w), and preferably from 0.1 to 1.0% (w / w), of levulinic acid or an antimicrobial salt thereof.

14. Non-therapeutic use of a combination of (i) anisic acid or an antimicrobial salt thereof and (ii) levulinic acid or an antimicrobial salt thereof for the care of acne-prone skin.