Combination of cyclopiroxolamine and piroctone olamine for fighting dandruff

Abstract

The present invention relates to the use of a combination of ciclopirox olamine and piroctone olamine without zinc hydroxypyrithione or a dermatological or cosmetic composition comprising said combination for combating dandruff and / or preventing the formation of dandruff.

Description

Technical Field

[0001] The present invention relates to an association of Ciclopiroxolamine and Piroctone Olamine and a composition comprising the association, and use thereof in the fields of cosmetics and dermatology for combating dandruff. Background Art

[0002] Dandruff affects one in two people in France. Its presence is benign, but it brings an unsightly appearance.

[0003] Dandruff consists of flakes of skin, more precisely, of the surface cells of the scalp that have shed but are abnormally large in size, thicker or more numerous than normal. Like all skin, the scalp normally renews itself by shedding surface cells from the epidermis. Dandruff is described as either dry or oily.

[0004] Dry dandruff is visible to the naked eye as flakes of the scalp's stratum corneum. It is white, flat and detaches spontaneously. It is often accompanied by an unpleasant itching sensation. It often accompanies a dry scalp.

[0005] Oily dandruff is small, round, yellowish and oily. It adheres to the scalp or hair. There it forms a yellowish sticky layer. It is accompanied by itching. Generally, it is a result of seborrhea and is therefore often associated with oily scalp and hair.

[0006] Dandruff is a problem with the formation of the epidermis. A healthy scalp produces dead cells every day, but they go unnoticed. This cell renewal takes place according to a regular cycle of about 28 days. In this process, the cells of the epidermis have time to properly complete their maturation, gradually separate from each other, and as soon as they reach the surface, they break away invisibly one by one. In the case of dandruff, due to inflammation of the scalp, the cells of the basal layer of the epidermis divide too quickly. Then, the cell renewal takes place within 5 to 14 days. The cells that rise to the surface of the skin do not have time to lose their water and harden. They reach the surface without sufficient drying, forming cell clusters on the scalp that become visible: this is dandruff.

[0007] There are two states of dandruff, depending on severity:

[0008] - Mild and unnoticeable dandruff: these are small white flakes, which correspond to clusters of very unstable dead cells, which fall from the scalp and sprinkle on clothes;

[0009] -Seborrheic dermatitis: This involves dandruff accompanied by intense inflammation of the scalp, causing redness and itching.

[0010] Seborrheic dermatitis is actually a common inflammatory skin dermatitis (observed in about 3% of the population) that manifests itself in the form of red plaques covered with oily yellowish flakes with varying degrees of itching, mainly occurring in areas rich in sebaceous glands, sebaceous glands.

[0011] The epidermis of the scalp is covered by a lipid membrane called sebum, which acts, among other things, to prevent the epidermis from drying out. Malassezia, sometimes also called Pityrosporum ovale, is the name of a yeast belonging to the class Fungi imperfecti, which is part of the human commensal flora. The genus Malassezia (M.) has long been known in human pathologies. Several species involved in these pathologies are divided into: M. furfur, M. sympodialis, M. globosa, M. restricta, M. obtusa. Malassezia are lipophilic and keratinophilic yeasts, which are lipid-dependent. It has been established that this fungus is a mild pathogen for humans. Malassezia furfur is present in virtually 100% of the population. However, it has also been established that in approximately 3% of the population, M. furfur is the cause of skin diseases such as adult seborrheic dermatitis. In healthy subjects, the most common species were M. sympodial, M. globosa and M. restrictosa, regardless of the culture medium used, sample collection method or country of study. M. restrictosa seems to be predominant on the scalp, while M. sympodial is predominant on the trunk and M. globosa is widely dispersed and evenly distributed in the sebaceous glands area. Malassezia species tend to grow in oily environments such as the scalp, where sebum secretion is particularly high, creating a favorable environment for its growth. The fungus can "digest" the lipids in the sebum and produce fatty acids that are particularly irritating to the skin and scalp. In seborrheic dermatitis, the exact pathogenic mechanism remains unclear, but several factors suggest that Malassezia species play a major role. In fact, it has been shown that: a) individuals with seborrheic dermatitis and the affected skin have a greater proportion of Malassezia than the healthy skin of patients with seborrheic dermatitis (Tajima et al., J Invest Dermatol, 2008, 128, 345–351) and b) antifungal treatment is effective in alleviating symptoms (Piérard–Franchimont et al., Dermatology, 2001, 202, 171–176). The current hypothesis is that seborrheic dermatitis is not caused by an overgrowth of Malassezia, but by an abnormal host response to these fungi. One hypothesis is that these yeasts produce lipases, the action of which converts the triglycerides of sebum into free fatty acids, which themselves cause inflammation. In fact, a recent study showed that the species Malassezia spherica possesses a gene LP1, the expression of which is able to produce lipases (DeAngelis et al., J Invest Dermatol 2007, 127, 2138–2146).

[0012] Overproduction of fatty acids can cause inflammation at the origin of dandruff. Two species, Malassezia globosa and Malassezia restricta, currently seem to be more closely associated with the dandruff state. For about 50% of individuals, sebum and Malassezia coexist harmoniously. For the remaining 50%, an imbalance can occur, with several factors playing a role. People do not all secrete the same amount of sebum. Some secrete a large enough amount that favors an overgrowth of Malassezia, which leads to the formation of dandruff. In addition, the amount of sebum varies over time and depends in particular on hormone secretions. Finally, other factors can contribute to the appearance of dandruff, such as stress, fatigue, pollution, lack of sunlight, certain diseases such as Parkinson's disease, some medications such as antipsychotics, etc.

[0013] Dandruff usually appears during puberty in adolescents, when sebum secretion kicks in. Males seem to be more susceptible than females, no doubt due to the effects of androgens.

[0014] Antidandruff compositions, in particular in the form of shampoos, have been known for many years and are commercially available. They usually contain active chemicals such as ketoconazole, zinc pyrithione, octopirox, piroctone olamine, salicylic acid, selenium sulfide and azelaic acid. Certain compounds, in particular zinc pyrithione, are suspected of causing environmental problems, in particular ecotoxicity, which is toxic to fish. It is therefore important to find new active ingredients or new combinations of active ingredients which are environmentally friendly, in other words do not contain zinc pyrithione, and at the same time are highly effective and fast-acting.

[0015] Therefore, despite the many options currently available, consumers continue to need new products to combat dandruff and / or prevent dandruff from forming. Summary of the invention

[0016] Surprisingly, the inventors found that the combination of ciclopirox olamine and piroctone olamine exhibits synergistic activity against Malassezia furfur in the implemented model.

[0017] Therefore, the present invention aims to provide an effective treatment against dandruff and for the prevention and / or treatment of seborrheic dermatitis, which is free of zinc pyrithione. Such treatment is preferably carried out topically, which can improve the efficacy.

[0018] An important feature of the present invention is that the combination comprising ciclopirox olamine and piroctone olamine does not contain zinc pyrithione.

[0019] In fact, according to the present invention, it must be understood that each time a combination of ciclopirox olamine and piroctone olamine is mentioned, zinc pyrithione is absent.

[0020] The present invention therefore relates to a combination comprising ciclopirox olamine and piroctone olamine but without zinc pyrithione, its (preferably topical) use for the prevention and / or treatment of dandruff, in particular mild and unnoticeable dandruff, and / or its use for the prevention and / or treatment of seborrheic dermatitis.

[0021] Another object of the invention is the (preferably topical) use of a combination comprising ciclopirox olamine and piroctone olamine but without zinc pyrithione for the prevention and / or treatment of dandruff, in particular mild and unnoticeable dandruff, and / or for the prevention and / or treatment of seborrheic dermatitis.

[0022] Another object of the invention is the use of a combination comprising ciclopirox olamine and piroctone olamine, but without zinc pyrithione, for the preparation of a dermatological or cosmetic, preferably topical, composition intended for the prevention and / or treatment of dandruff, in particular mild and unnoticeable dandruff.

[0023] The invention further relates to the combination according to the invention in the preparation of a dermatological composition for the treatment and / or prevention of seborrheic dermatitis.

[0024] According to another aspect, the present invention relates to the use of a combination according to the invention for the preparation of a skin cosmetic composition for combating dandruff and / or preventing the formation of dandruff.

[0025] Advantageously, the present invention also relates to a combination comprising or consisting of ciclopirox olamine and piroctone olamine as anti-dandruff active ingredient in a dermatological or cosmetic, in particular topical, composition for the prevention or treatment of dandruff.

[0026] Likewise advantageously, the present invention also relates to a combination comprising or consisting of ciclopirox olamine and piroctone olamine as antidandruff active ingredient in a dermatological or cosmetic (especially topical) composition for the prevention or treatment of seborrheic dermatitis.

[0027] In particular, the combination of ciclopirox olamine and piroctone olamine does not contain zinc pyrithione and advantageously, the combination is the only anti-dandruff active ingredient in the composition.

[0028] Another object of the present invention is a method for preventing and / or treating dandruff, which comprises administering, in particular topically, to a person in need thereof an effective amount of a combination comprising ciclopirox olamine and piroctone olamine, but without zinc pyrithione.

[0029] This particularly concerns mild and unnoticeable dandruff.

[0030] In the method according to the invention, the method does not provide for the use of zinc pyrithione. According to the invention, the combination of ciclopirox olamine and piroctone olamine is advantageously the only antidandruff active ingredient used in the method.

[0031] The present invention also relates to a cosmetic method for treating and / or preventing dandruff, which comprises applying, in particular topically, a combination comprising ciclopirox olamine and piroctone olamine but without zinc pyrithione. This particularly relates to mild and unnoticeable dandruff. In particular, the method does not provide for the use of zinc pyrithione.

[0032] Advantageously, according to the invention, the combination of ciclopirox olamine and piroctone olamine is the only anti-dandruff active ingredient of the composition and method according to the invention.

[0033] According to another aspect, the invention relates to a method for treating and / or preventing seborrheic dermatitis comprising administering, in particular topically to the scalp, a combination according to the invention or a composition according to the invention. DETAILED DESCRIPTION

[0034] Ciclopirox olamine and piroctone olamine are antifungal substances of the hydroxypyridone family. These compounds are commonly used in cosmetics for human medicine, for example piroctone olamine is used at a maximum concentration of 1% (rinsable products) or 0.05% to 0.1% (sufficient concentration in leave-on products). These two substances are very effective and are even considered to be second-generation antidandruff agents. In addition, their toxicity is very low. In addition, due to their solubility in aqueous or mixed (water-alcohol) surfactants, they are particularly suitable for the production of antidandruff shampoos and hair care products. Hydroxypyridone has antifungal and antibacterial properties and exhibits excellent diffusion capacity in keratin.

[0035] Piroctone olamine is the common name for this compound. It appears in the literature under the term Octopirox. It appears in the form of a salt, combined with ethanolamine, which also gives it the name of piroctone olamine salt. Its CAS number is 68890-66-4.

[0036] Ciclopirox olamine is also known as ciclopirox olamine, and its CAS number is 29342-05-0.

[0037] The anti-dandruff action of these two substances is attributed to their antibacterial and antifungal effects. The antifungal action of the hydroxypyridone family has been studied based on the model of cyclopiloside ethanolamine. Given that its antifungal activity is attributed to the hydroxypyridone group, this mode of action can be extrapolated to the entire family. The mode of action is complex and only partially understood. The antifungal activity seems to be caused by multiple metabolic processes within the target cells. Hydroxypyridones have a high affinity for trivalent metal cations such as iron and aluminum. However, this enzymatic cofactor is essential for mitochondrial cytochromes involved in electron transport, especially for complex I (NADH-ubiquinone oxidoreductase). Neutralization of iron and aluminum inhibits this metabolic reaction and thus inhibits cellular energy production. In addition, cyclopiloside inhibits the activity of catalases and intracellular peroxidases, which are responsible for the decomposition of toxic peroxides for cells. Studies have also shown that cyclopiloside inhibits the transmembrane transport mechanism of yeast. As a result, the absorption of nutrients by microorganisms is affected. In growing cells, the depletion of essential amino acids and nucleotides leads to a reduction in the synthesis of proteins and nucleic acids. Piroctone olamine also has an inhibitory effect on ADN replication. This hydroxypyridone has no direct effect on the replicative enzyme, but the decrease in ATP levels makes this synthesis impossible. Ciclopirox olamine also has anti-inflammatory effects by inhibiting 5-lipoxygenase and cyclooxygenase. Given the complexity of the mode of action of hydroxypyridones, it is unlikely that resistance will occur.

[0038] The use of cyclopiroxolamine and piroctone olamine is quite common, and one or the other can be found in many products, sometimes in combination with other antimicrobial agents, particularly zinc pyrithione. Examples include dermatological antidandruff shampoos containing piroctone olamine and salicylic acid. Anti-dandruff shampoo with piroctone olamine and zinc pyrithione or shampoo with ciclopirox for seborrheic dermatitis of the scalp or again On the other hand, to date, there is no zinc-pyrithione-free product that combines ciclopirox olamine and piroctone olamine.

[0039] Dermatological or cosmetic compositions

[0040] The invention also relates to a composition, in particular a dermatological or cosmetic (e.g. skin cosmetic) composition, for use in preventing and / or treating seborrheic dermatitis or in combating dandruff and / or preventing the formation of dandruff, in particular mild and unnoticeable dandruff, comprising a combination of ciclopirox olamine and piroctone olamine as defined above and a dermatologically or cosmetically acceptable excipient, more particularly an excipient acceptable for topical application.

[0041] The composition is therefore free of zinc pyrithione. Advantageously, the composition consisting of ciclopirox olamine and piroctone olamine represents the only antidandruff active ingredient in the composition.

[0042] The present invention also relates to a composition for use in preventing and / or treating seborrheic dermatitis, comprising as active ingredients a combination of ciclopirox olamine and piroctone olamine but without zinc pyrithione and at least one dermatologically or cosmetically acceptable excipient.

[0043] The present invention therefore relates to a composition for use in combating dandruff and / or preventing the formation of dandruff, comprising as active ingredients a combination comprising ciclopirox olamine and piroctone olamine but without zinc pyrithione and at least one dermatologically or cosmetically acceptable excipient.

[0044] As demonstrated in the examples of the present application, the combination of these two active ingredients has a very interesting anti-dandruff activity, which is reflected by its level of efficacy and also by its rapid action. This rapid inhibitory action on strains of Malassezia furfur represents a decidedly advantageous and surprising effect, thus enabling reduced and reasonable exposure times in the case of topical anti-dandruff treatments.

[0045] The combination according to the invention also has a very favorable effect on seborrheic dermatitis, as demonstrated by its action on Malassezia globosa which is involved in seborrheic dermatitis.

[0046] Therefore, the present invention relates to a hair treatment agent or an agent consisting of a combination of cyclopirox olamine and piroctone olamine for use in treating or preventing dandruff conditions. The hair treatment agent according to the present invention does not contain zinc hydroxypyrithione. In this specification, the combination of cyclopirox olamine and piroctone olamine is compared to a hair treatment agent.

[0047] Therefore, the present invention relates to a hair treatment agent or an agent consisting of a combination of cyclopirox olamine and piroctone olamine, for use in treating or preventing seborrheic dermatitis. The hair treatment agent according to the present invention does not contain zinc hydroxypyrithione. In this specification, the combination of cyclopirox olamine and piroctone olamine is compared to a hair treatment agent.

[0048] The present invention also relates to a hair treatment agent for treating or preventing dandruff conditions or an agent consisting of a combination of ciclopirox olamine and piroctone olamine. The hair treatment agent according to the present invention does not contain zinc pyrithione.

[0049] The present invention also relates to a method for preparing an anti-dandruff composition for topical application on the scalp and / or hair, said composition comprising a combination of ciclopirox olamine and piroctone olamine as active anti-dandruff agents, said method comprising the steps of: a) mixing the combination of ciclopirox olamine and piroctone olamine with a dermatologically or cosmetically acceptable carrier; and b) packaging the mixture obtained from step (a) in a suitable packaging. Advantageously, said method for preparing the composition does not provide for any addition of zinc pyrithione.

[0050] Another object of the invention is the (preferably topical) use of a dermatological or cosmetic (e.g. dermocosmetic) composition for the prevention and / or treatment of dandruff, in particular mild and unnoticeable dandruff, comprising a combination of ciclopirox olamine and piroctone as defined above and a dermatologically or cosmetically acceptable excipient (more particularly an excipient acceptable for topical application).

[0051] Another object of the invention is the (preferably topical) use of a dermatological composition for the prevention and / or treatment of seborrheic dermatitis, said composition comprising the combination of ciclopirox olamine and piroctone as defined above and a dermatologically acceptable excipient, more particularly an excipient acceptable for topical application.

[0052] Another object of the present invention is a method for preventing and / or treating dandruff, which comprises administering (particularly topically) to a person in need thereof an effective amount of a dermatological or cosmetic (e.g. dermocosmetic) composition comprising a combination of ciclopirox olamine and piroctone as defined above and a dermatologically or cosmetically acceptable excipient (more particularly an excipient acceptable for topical application). As indicated, advantageously, the combination of ciclopirox olamine and piroctone olamine is the only anti-dandruff active ingredient used in the method according to the invention.

[0053] The present invention therefore relates to a cosmetic method for treating and / or preventing dandruff, in particular mild and unnoticeable dandruff, comprising applying, in particular topically applying to the hair or scalp, a combination according to the invention or a composition according to the invention.

[0054] The present invention also relates to a cosmetic method for treating and / or preventing dandruff, in particular mild and unnoticeable dandruff, comprising applying, in particular topically, a dermatological or cosmetic (e.g. dermocosmetic) composition comprising a combination of ciclopirox olamine and piroctone as defined above and a dermatologically or cosmetically acceptable excipient (more particularly an excipient acceptable for topical application). As indicated, advantageously, the combination of ciclopirox olamine and piroctone olamine is the only anti-dandruff active ingredient used in the method according to the invention.

[0055] In the present invention, "dermatologically or cosmetically acceptable" means that it can be used to prepare dermatological or cosmetic compositions, is generally safe, non-toxic and neither biologically nor otherwise undesirable, and is acceptable for therapeutic or cosmetic use, especially by topical application.

[0056] The present invention also relates to a method for obtaining an anti-dandruff effect on the hair or scalp, comprising the steps of: - (i) wetting the hair with water; - (ii) applying an effective amount of an anti-dandruff composition as described in any one of claims 3 to 7 to the hair; - (iii) rinsing the anti-dandruff composition from the hair with water; - (iv) optionally repeating steps (ii) and (iii).

[0057] The present invention also relates to a method for killing Malassezia spp. (especially Malassezia spp. and / or Malassezia restricta) or slowing down the growth of Malassezia spp. (especially Malassezia spp. and / or Malassezia restricta), the method comprising the step of contacting Malassezia spp. (especially Malassezia spp. and / or Malassezia restricta) with a composition according to the present invention, the composition being effective in killing Malassezia spp. (especially Malassezia spp. and / or Malassezia restricta) or slowing down the growth of Malassezia spp. (especially Malassezia spp. and / or Malassezia restricta).

[0058] According to one embodiment, the present invention also relates to a method for obtaining an anti-seborrheic effect on the skin, comprising the steps of: - (i) optionally wetting the skin with water; - (ii) applying an effective amount of an anti-seborrheic composition as described in any one of claims 3 to 7 to the skin; - (iii) rinsing the anti-seborrheic composition from the skin with water; - (iv) optionally repeating steps (ii) and (iii).

[0059] In a particular embodiment, the dermatological or cosmetic composition according to the invention comprises at least one other antidandruff active ingredient different from zinc pyrithione (in particular an antifungal agent other than zinc pyrithione). Advantageously, the at least one other antidandruff active ingredient different from zinc pyrithione is chosen from pseudotine A, ketoconazole, miconazole, salicylic acid, selenium sulfide, coal tar, azelaic acid, climbazole, undecylenic acid and mixtures thereof.

[0060] The present invention preferably relates to compositions, in particular dermatological or cosmetic compositions, which are in a clean form and suitable for topical application, in particular topical application to the hair and / or scalp.

[0061] The dermatological or cosmetic compositions according to the invention may be present in the forms generally known for topical application, that is to say in particular lotions, shampoos, dry shampoos, conditioners, balms, foams, gels, dispersions, emulsions, sprays, serums, masks, creams and patches.

[0062] Advantageously, the composition according to the invention may be in a form generally known for topical application to the hair and scalp, that is to say in particular a shampoo, dry shampoo, conditioner, cream, lotion, mask or spray, in particular a leave-in spray.

[0063] It is therefore distinguished from formulated products that can be rinsed off and formulated products that do not require rinsing.

[0064] These compositions also usually contain a combination of ciclopirox olamine and piroctone olamine according to the invention, a physiologically acceptable medium, usually based on water or a solvent, such as an alcohol, ether or glycol. They can also contain surfactants, complexing agents, preservatives, stabilizers, emulsifiers, thickeners, gelling agents, humectants, emollients, trace elements, essential oils, perfumes, dyes, wetting agents or thermal water, etc.

[0065] Advantageously, the composition according to the invention comprises from 0.01 to 2%, preferably from 0.1 to 2%, more preferably from 0.5 to 2% by weight of ciclopirox olamine relative to the total weight of the composition. The composition preferably comprises 1.5% by weight of ciclopirox olamine relative to the total weight of the composition.

[0066] Advantageously, the composition according to the invention comprises from 0.01 to 1% by weight, preferably from 0.05 to 1%, more preferably from 0.1 to 1% by weight of piroctone olamine relative to the total weight of the composition. The composition preferably comprises 0.3% by weight of piroctone olamine relative to the total weight of the composition.

[0067] Thus, the composition of the invention advantageously comprises, expressed in %, from 0.05 to 1% of piroctone olamine and from 0.1 to 2% of cyclopiroxolamine, expressed in %, by weight of the final composition. In particular, the composition according to the invention comprises, expressed in %, about 0.3% of piroctone olamine and about 1.5% of cyclopiroxolamine, expressed in %, by weight of the composition. More particularly, the composition according to the invention comprises, expressed in %, about 0.15% of piroctone olamine and about 0.75% of cyclopiroxolamine, expressed in %, by weight of the composition.

[0068] The composition according to the invention comprises ciclopirox olamine and piroctone olamine, wherein the mass ratio of ciclopirox olamine: piroctone olamine is from 1:10 to 10:1, more particularly from 1:5 to 5:1.

[0069] In particular, when the amounts of ciclopirox olamine and piroctone olamine in the combination according to the invention are expressed in parts by weight, the combination comprises 0.5 to 2 parts of piroctone olamine and advantageously 1 to 10 parts of ciclopirox olamine. The combination according to the invention preferably comprises 1 part of piroctone olamine and 5 parts of ciclopirox olamine in parts by weight.

[0070] These compositions can be produced according to methods well known to those skilled in the art.

[0071] The following examples illustrate the invention without limiting the scope.

[0072] Example

[0073] Example 1: The effect of the combination of cyclopiloside olamine and piroctone olamine on the inhibition of Malassezia sphaeroides and restriction The role of Malassezia colony growth

[0074] The strains were derived from the Malassezia globosa (IP2387.96) collection of the Pasteur Institute (Fungal Collection, Paris, France) and the Malassezia restricta (CBS7877) collection of CBS-KNAW. These strains represent and correspond to the majority of strains involved in dandruff. The strains were incubated aerobically on modified Dixon agar at 30°C for 5 days. The inoculum suspension was prepared in sterile distilled water and concentrated to 10 7UFC / ml. The minimum inhibitory concentration (CMI) was determined by microtiter method in liquid medium. 100 μl of liquid culture medium was added to each well of a sterile 96-well microplate. 100 μl of the solution to be tested was added to the first well of a row of the plate. Wells 1 to 10 were then diluted 2-fold. A test suspension of each microorganism was prepared in tryptone salts immediately before use. 100 μl was added to each well of the second microplate, except column 11. The entire first plate was inoculated into the second microplate using a Denley multipoint inoculator. After incubation, the CMI was defined as the maximum dilution with no visible growth. Columns 11 and 12 were used as negative and positive controls for growth, respectively.

[0075] The products tested are:

[0076] - Ciclopirox ethanolamine, 3% (P / P) in sterile distilled water,

[0077] -Piroctone olamine, 0.3% (P / P) in 10% ethanol,

[0078] - Ketoconazole (positive control), 1000 μg / ml (P / P) in 10% DMSO,

[0079] - Piroctone olamine / cyclopiroxolamine combinations, at concentrations of 0.15% and 0.75%, respectively.

[0080] Prepare solutions at the time of testing and use immediately. Prepare ethanol controls as 10% solutions.

[0081] Determination of the minimum fungicide concentration (CMF) was performed by subculturing CMI microplates on agar medium using a Denley multi-point inoculator. After incubation, the CMF was defined as the maximum dilution with no visible growth. All tests were performed in duplicate.

[0082] The synergistic effect of two products was determined by calculating the synergistic index (FIC, Fractional Inhibitory Concentration).

[0083] FIC index = (CMI of combined product A) / (CMI of individual product A)+(CMI of combined product B) / (CMI of individual product B).

[0084] When the value of the FIC index was < 0.5, a synergistic effect was shown.

[0085] result

[0086] The following Table 1 (Malassezia globosa) and Table 2 (Malassezia restricta) present the CMI and CMF values ​​of the individual products and combinations in percentage (P / P) and mg / L.

[0087] The maximum tested concentration corresponds to the stock solution concentration / 2.

[0088] Table 1

[0089] [Table 1]

[0090]

[0091] PO: piroctone olamine; CPO: cyclopiloside olamine; Kéto: ketoconazole

[0092] Table 2

[0093] [Table 2]

[0094]

[0095] PO: piroctone olamine; CPO: cyclopiloside olamine; Kéto: ketoconazole

[0096] No activity was noted with ethanol under the conditions tested.

[0097] Tables 1 and 2 show that piroctone olamine and cyclopiroxolamine alone have strong inhibitory activity, as does ketoconazole as a positive control. The most striking results come from the combination of the two products; in fact, the CMI is reduced 10 to 100 times compared to the CMI of the individual products, showing a synergistic inhibitory effect. The results for the two strains tested are completely comparable.

[0098] The synergy between piroctone olamine and cyclopiloside olamine was indeed very clearly demonstrated when the synergy index was calculated, which only reached 0.16 for M. globosa and 0.28 for M. restricta.

[0099] This synergistic effect between piroctone olamine and cyclopiroxolamine, especially against Malassezia globosa, could also demonstrate a beneficial effect against seborrheic dermatitis.

[0100] Example 2: Effect of the combination of cyclopiroxolamine and piroctone olamine on anti-Malassezia activity

[0101] The ability of piroctone olamine and cyclopiroxolamine to inhibit the growth of Malassezia colonies is significant, but not sufficient to predict lethal activity against Malassezia and thus optimal dandruff removal. In fact, if Malassezia is not completely or adequately removed, it can reproduce again. Therefore, the effectiveness of dandruff active ingredients must also be shown by demonstrating their effect on the lethality of Malassezia. This item is usually measured by estimating the reduction of microbial colonies over time.

[0102] In the case of this work, the model has been optimized in terms of sample preparation, contact time, and sample evaluation concentration.

[0103] The purpose of the test described below is to evaluate the anti-Malassezia (M. globosa and M. restricta) activity of piroctone olamine, cyclopiloside olamine and their combination in a relevant manner and to compare it with ketoconazole.

[0104] The test products, alone and in combination, at the specified concentrations were mixed with 7 UFC / ml of Malassezia suspension, the contact time is 5 minutes, 15 minutes and 30 minutes. After each contact time, a sample is taken, then diluted and filtered on a cellulose membrane. Then, each membrane is added to an agar medium (Dixon) and incubated at 30 ° C. After incubation, the colonies are counted.

[0105] The products tested are:

[0106] - Ciclopirox ethanolamine, 1.5% (P / P), diluted with sterile distilled water,

[0107] - Piroctone olamine, 0.3% (P / P), dissolved in ethanol and then added to water for injection (final ethanol concentration 9%),

[0108] - Ketoconazole (positive control), 2% (P / P), dissolved in DMSO and then added to water for injection (final DMSO concentration 9%),

[0109] - Piroctone olamine / cyclopiroxolamine combinations, at concentrations of 0.3% and 1.5%, respectively.

[0110] Prepare solutions at the time of testing and use immediately.

[0111] result

[0112] The results obtained using these different products are shown below in Table 3 (Malassezia globosa) and Table 4 (Malassezia restricta).

[0113] Table 3: Fungicidal activity of active ingredients against Malassezia globosa

[0114] [Table 3]

[0115]

[0116] Table 4: Fungicidal activity of active ingredients against Malassezia restricta

[0117] [Table 4]

[0118]

[0119] Ketoconazole was active against M. globosa and M. restricta at the three contact times studied, and this activity, although modest, enabled the experiment to be confirmed.

[0120] Piroctone olamine and cyclopiroxolamine show stronger anti-Malassezia activity than ketoconazole. Surprisingly, the combination of piroctone olamine and cyclopiroxolamine proved to be even more effective, particularly at a contact time of 5 minutes. In fact, this combination can reduce the viable cell count percentage of Malassezia globosa or Malassezia restricta by more than 99.99% after 5 minutes of contact. Therefore, the inventors have demonstrated the synergistic effect between piroctone olamine and cyclopiroxolamine on the two strains tested. Therefore, the combination of these two active ingredients shows a very interesting anti-dandruff activity, which, through its effectiveness level and also through its rapid action, shows a net beneficial effect, and can obtain a reduced and reasonable exposure time in the case of anti-dandruff treatment.

Claims

1. Use of a combination of ciclopirox olamine and piroctone olamine in the preparation of a dermatological composition for preventing and / or treating seborrheic dermatitis, wherein the ratio of ciclopirox olamine / piroctone olamine in the combination is 5:

1.

2. Use of a combination of ciclopirox olamine and piroctone olamine in the preparation of a skin cosmetic composition for combating dandruff and / or preventing dandruff formation, wherein the ratio of ciclopirox olamine / piroctone olamine in the combination is 5:

1.

3. The use according to claim 1 or 2, characterized in that The combination is in a form suitable for administration via the topical route.

4. Use of a composition for the preparation of a medicament for preventing and / or treating seborrheic dermatitis, wherein the composition comprises a combination of ciclopirox olamine and piroctone olamine as the sole active ingredient and at least one dermatologically acceptable excipient, wherein the ratio of ciclopirox olamine / piroctone olamine in the combination is 5:

1.

5. Use of a composition for the preparation of a cosmetic for combating dandruff and / or preventing the formation of dandruff, wherein the composition comprises a combination of ciclopirox olamine and piroctone olamine as the only active ingredients and at least one cosmetically acceptable excipient, wherein the ratio of ciclopirox olamine / piroctone olamine in the combination is 5:

1.

6. The use according to claim 4 or 5, characterized in that The composition comprises 0.01 to 2% by weight of ciclopirox ethanolamine relative to the total weight of the composition.

7. The use according to claim 4 or 5, characterized in that The composition comprises 0.01 to 1% by weight of piroctone olamine relative to the total weight of the composition.

8. The use according to claim 4 or 5, characterized in that The composition is in a form suitable for administration via the topical route.

Images