A novel composition comprising spilanthol and preparation method thereof

Abstract

The present invention relates to a novel pharmaceutical composition comprising spilanthol for use in the treatment of dermatological diseases associated with Demodex folliculorum and / or Demodex brevis and a preparation method thereof.

Description

[0001] A NOVEL COMPOSITION COMPRISING SPILANTHOL AND PREPARATION METHOD THEREOF

[0002] Technical Field

[0003] The present invention relates to a pharmaceutical composition comprising spilanthol for use in the treatment of dermatological diseases associated with Demodex mites. The composition according to the invention comprises 0.1% to 5% spilanthol.

[0004] Background of the Invention

[0005] Demodex mites (Demodex folliculorum (DF) and Demodex brevis) are ectoparasites living in pilosebaceous follicles. They are commensals in the human skin microflora. Demodex mites found in significant numbers on the cheeks, nose, chin, forehead, temples, eyebrows, eyelashes, balding skin, neck, and ears. They are also found in the sebum-rich nasolabial fold, around the eyes, in the middle and upper chest, and on the back.

[0006] During their life cycle, male and female Demodex mites transform from egg to larva, protonymph, deuto nymph, and adult form. The life span of the mites is around 15 days, and they spend all their life stages in hair follicles and sebaceous glands. An adult DF has a long, thin, clear head-body, abdomen, and four pairs of legs on the trunk to provide movementto the mite (8-10 mm / hour). DF uses sebum, and follicular and glandular epithelial cells as food sources. Electron microscopic examinations have shown that the mite, thanks to its piercing mouth structure on the legs, destroys the subcutaneous fat tissue and carries various bacteria. This is why both antiparasitic and antibacterial agents are currently used in the treatment of the infestation by Demodex mites (human demodicosis).

[0007] Although Demodex mites are usually considered non-pathogenic, they play a vital role in the pathogenetic process of many skin diseases due to some possible genetic and environmental factors. Mite density per cm2is important in determining the pathogenicity of the mite and is considered the main issue for the emergence of clinical symptoms. The density of DF in infected but asymptomatic people is usually less than 5 / cm2. In the literature, Demodex species are associated with dermatological diseases such as rosacea, pityriasis folliculorum, perioral dermatitis, seborrheic dermatitis, pustular eruption, blepharitis, seborrheic alopecia, as well as the etiopathogenesis of blepharitis, keratoconjunctivitis, recurrent chalazion, and meibomian gland dysfunction (Litwin D, Chen W, Dzika E, Koryciriska J. Human Permanent Ectoparasites; Recent Advances on Biology and Clinical Significance of Demodex Mites: Narrative Review Article. Iran J Parasitol 2017;12:12-21; Elston CA, Elston DM. Demodex mites. Clin Dermatol 2014;32:739- 43). Therefore, an acaricidal agent that is effective against Demodex species which is also safe for skin applications may benefit many diseases.

[0008] There are chemical and herbal products effective against Demodex mites in clinical practice. Common interventions used for Demodex infestation include metronidazole-based therapies, permethrin, ivermectin, sodium sulfacetamide, benzoyl benzoate, crotamiton, lindane, and sulfur (Jacob, S., VanDaele, M. A., & Brown, J. N. (2019). Treatment of Demodex-Associated Inflammatory Skin Conditions: A Systematic Review. Dermatologic Therapy, Nov;32(6):el3103). However, these molecules have been shown to cause many toxic effects. For example, a study investigating the toxic effects of repeated daily dermal application of permethrin emphasized that significant deteriorations were observed in complete blood count and liver and kidney function tests, and that repeated dermal applications may produce toxic results (Patel, A. K., Dewangan, G., Rajput, N., & Koli, S. (2024). Assessment of Permethrin Toxicity Following Subacute Dermal Exposure in Rats. Journal of Scientific Research and Reports, 30(1 ), 25-32). It has also been reported that permethrin has higher toxic effects, especially on children (Cox, C. (1999). Permethrin. Global Pesticide Campaigner, 9(3), 20). Similarly, ivermectin applications are known to have toxic effects on liver function and blood lipid profiles in addition to their neurotoxic effects (Johnson-Arbor, K. (2022). Ivermectin: a mini-review. Clinical toxicology, 60(5), 571-575; Qureshi, S. (2013). Biochemical toxicity of ivermectin in Wistar albino rats. Am-Eur J Toxicol Sci, 5(1 ), 15-9).

[0009] Another herbal agent commonly used for treatment of Demodex infestation is tea tree oil (TTO). It is distilled from the leaves of the Australian native plant Melaleuca Alternifolia (Myrtaceae) and exhibits anti-microbial effects. Although a dose study showed that 25% TTO was effective against Demodex infestation, another study reported that even 2.5% TTO could cause skin irritations (C- J, Chen L-W, Chen L-G, etal. Correlations of the components of tea tree oil with its antibacterial effects and skin irritation. J Food Drug Anal. 2013;21(2):169-176; Gao YY, Di Pascuale MA, Li W, et al. In vitro and in vivo killing of ocular Demodex by tea tree oil. Brit J Ophthalmol. 20 05;89(ll):1468- 1473). Therefore, there is still a need in the relavant technical field for products which have toxic effects in lower doses and safe for use without causing adverse effects.

[0010] Spilanthol is the main active metabolite of Spilanthes acmella (also known as Acmella oleracea) plant. Spilanthol has the molecular formula of N-isobutyl-2E,6Z,8E-decatrienamide. The molecular structure of spilanthol is given below.

[0011]

[0012] Spilanthol

[0013] The extracts of Spilanthes acmella have long been traditionally used in eastern Africa to control the Anopheles mosquito. The ethanol extract of the flower heads of Spilanthes acmella showed strong ovicidal, insecticidal, pupacidal, and larvicidal activity on mosquitoes (SarafDK, Dixit VK. Spilanthes acmella Murr.: study on its extract spilanthol as larvicidal compound. Asian Journal Experimental Science. 2002;16(l-2):9-19). It has been reported that its larvacidal activity does not result from its interaction with the cholinergic system (Spinozzi, Eleonora, et al. "Spilanthol-rich essential oil obtained by microwave-assisted extraction from Acmella oleracea (L.) RK Jansen and its nanoemulsion: Insecticidal, cytotoxic and anti-inflammatory activities." Industrial Crops and Products 172 (2021):114027). Similarly Saraf et al. reported that they detected abnormal movements in the pupae, such as shaking, turning, and uncoordinated muscle activity, indicating that the extract affects the nervous system. The death of pupae shortly after drug exposure is associated with spilanthol's disruption of histolysis and histogenesis processes.

[0014] Spilanthol has various biological and pharmacological effects, including analgesic, antioxidant, immunostimulant, anti-inflammatory, antimalarial and antifungal activities (Prachayasittikul V, Prachayasittikul S, Ruchirawat S, Prachayasittikul V. High therapeutic potential of Spilanthes acmella: A review. EXCLI J. 2013 Apr 4;12:291-312). In another study where the potential insecticidal activity of Spilanthes acmella Murr (Compositae) extracts was evaluated, electrophysiological experiments were carried out following the topical application of spilanthol on adult male cockroaches. The molecule has been shown to induce enormous depolarizing terminal potentials along with repetitive spikes in the cockroach ventral nerve cord and act on sodium channels in nerve terminals. It is reported that spilanthol exerts its toxic effect through interference with the nervous system and that it overlaps with the behavioral symptoms of poisoning, which include uncoordinated movements observed immediately after application and, eventually, paralysis (Kadir, H. A., Zakaria, M. B., Kechil, A. A., & Azirun, M. D. (1989J. Toxicity and electrophysiological effects of Spilanthes amelia Murr. extracts on Periplaneta americana L. Pesticide Science, 25(4), 329-335). It has been reported that spilanthol penetrates the skin upon application, resulting in high skin and plasma concentrations (De Spiegeleer B, Boonen / , Malysheva SV, Mavungu ]D, De Saeger S, Roche N, Blondeel P, Taevernier L, Veryser L. Skin penetration enhancing properties of the plant N- alkylamide spilanthol. J Ethnopharmacol. 2013 Jun 21;148(l):117-25). This may increase the effectiveness of spilanthol in the treatment of Demodex infestation, especially for conditions that create a barrier on the skin, such as reactive follicular hyperplasia, hyperkeratosis due to demodicosis, and increased sebum.

[0015] In light of the above, it can be seen that although chemical and herbal products exist in the relavant technical field for the treatment of Demodex infestation and the skin conditions caused partly or completely due to Demodex infestation, the problems with the current compositions in terms of adverse effects and efficiency are yet to be solved. Therefore, there is a need in the technical field for novel compositions which are effective against Demodex species in lower doses and which have minimum adverse effects when applied to skin. The present invention provides such a composition and a preparation method thereof.

[0016] Brief Description of the Invention

[0017] In an aspect of the present invention, composition comprising spilanthol for use in the treatment of infestation with Demodex folliculorum and / or Demodex brevis and / or in the treatment of dermatological diseases associated with Demodex folliculorum and / or Demodex brevis is provided. The composition comprises 0.1% to 5% (w / w) spilanthol. More preferably, composition comprises 1% to 3% (w / w) spilanthol. In a most preferred embodiment, the concentration of spilanthol is 3% (w / w).

[0018] The dermatological disease may be selected from the group comprising rosacea, pityriasis folliculorum, perioral dermatitis, seborrheic dermatitis, pustular eruption, blepharitis, seborrheic alopecia, the etiopathogenesis of blepharitis, keratoconjunctivitis, recurrent chalazion, and meibomian gland dysfunction.

[0019] The composition according to the invention may further comprise at least one excipient selected from the group comprising solvents, humectants, emulsifiers, preservatives, permeation enhancers, gelling agents, stabilizers, pH adjusters, viscosity modifiers, anti-oxidants, surfactants, and emollients.

[0020] In a preferred embodiment, the composition comprises, in addition to spilanthol, at least one excipient selected from the group comprising water, polysorbate 80, isopropyl myristate, liquid paraffin, ceteareth-20, carbomer 980, triethanolamine, phenoxyethanol / ethylhexylglycerin, butylated hydroxytoluene (BHT), oleyl alcohol and coco caprylate / caprate.

[0021] In another aspect, present invention presents a method for preparation of the composition according to the invention. The method comprises the steps of: extracting Spilanthes acmella flowers, purifying spilanthol from the plant extract, obtaining a composition comprising spilanthol in a concentration of 0.1% to 5% (w / w).

[0022] Brief Description of the Figures

[0023] Figure 1 shows the survival times of Demodex folliculorum for different treatment and control groups.

[0024] Detailed Description of the Invention

[0025] In this detailed description, aspects and embodiments of the present invention are further described for better understanding of the subject matter.

[0026] With the present invention, it is aimed to present an anti-demodex composition which is effective in low doses and which does not have the drawbacks of the known medications. In order to achieve this aim, present inventors investigated the anti-demodex potential of spilanthol, a natural metabolite purified from Spilanthes acmella extract. It is also aimed to determine the minimum therapeutically effective dose of spilanthol in order to present a composition which provides benefits without causing adverse effects.

[0027] The present invention provides a composition comprising spilanthol for use in the treatment of infestation with Demodex folliculorum and / or Demodex brevis and / or in the treatment of dermatological diseases associated with Demodex folliculorum and / or Demodex brevis. Present inventors found out that the composition is mostly effective when the concentration of spilanthol is in the range of 0.1% to 5% (w / w) in the composition. More preferably, concentration range of 1% to 3% (w / w) provided similar results with known medications in the relavant field. Specially of interest is a composition comprising 1%, 2% or 3% (w / w) spilanthol, since it enables the desired therapeutical effect with a lower dose as proved by the studies carried out by the present inventors. Also, compositions comprising 2% or 4% (w / w) spilanthol is in the scope of the invention. Dermatological disease to be treated is selected from the group comprising, but not limited to, rosacea, pityriasis folliculorum, perioral dermatitis, seborrheic dermatitis, pustular eruption, blepharitis, seborrheic alopecia, the etiopathogenesis of blepharitis, keratoconjunctivitis, recurrent chalazion, and meibomian gland dysfunction. It is clear that skilled persons in the art would contemplate other condisitons and diseases of the skin that are associated with infestation by Demodex folliculorum and / or Demodex brevis.

[0028] The composition of the invention may be in any topical dosage form, for example cream, gel, lotion, ointment, liniment, solution, emulsion or suspansion.

[0029] In further embodiments, the composition according to the invention further comprises at least one excipient selected from the group comprising, but not limited to, solvents, humectants, emulsifiers, preservatives, permeation enhancers, gelling agents, stabilizers, pH adjusters, viscosity modifiers, anti-oxidants, surfactants, and emollients.

[0030] The solvent according to the invention is preferably aqua (water).

[0031] Non-limiting examples of suitable humectants include glycerin and sorbitol.

[0032] Non-limiting examples of suitable emulsifiers include polyethylene glycol (PEG), PEG stearates, ceteareth-20, carbomer, glyceryl monostearate, glyceryl monoleate, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether and polyethylene glycol stearate.

[0033] Non-limiting examples of suitable preservatives include phenoxyethanol / ethylhexylglycerin, benzalkonium chloride, purite, peroxides, perborates, thimerosal, chlorobutanol, formaldehyde, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium and sorbic acid.

[0034] Non-limiting examples of suitable permeation enhancers include isopropyl myristate, oleyl alcohol, propylene glycol, cyclodextrins, dimethyl sulfoxide, cationic and anionic surfactants, and terpenes.

[0035] Non-limiting examples of suitable gelling agents include carbomer, for example carbomer 980, tragacanth, pectin, starch, sodium alginate, gelatin and cellulose derivatives.

[0036] Non-limiting examples of suitable pH adjusters include triethanolamine, sodium hydroxide, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Non-limiting examples of suitable viscosity modifiers include polyethylene glycol, hypromellose and carbomer.

[0037] Non-limiting examples of suitable anti-oxidants include butylated hydroxytoluene (BHT), vitamin E and vitamin C.

[0038] Non-limiting examples of suitable surfactants include polyoxyethylene alkyl ethers, sodium lauryl sulfate, polysorbate 20, polysorbate 80 and lecithin.

[0039] Non-limiting examples of suitable emollients include isopropyl myristate, mineral oil, liquid paraffin, coco caprylate / caprate, castor oil, coconut oil and lanolin alcohols.

[0040] In a preferred embodiment, the composition according to the invention comprises 0.1% to 5% (for example, 0.5%, 1%, 2%, 3% or 4%) (w / w) spilanthol and at least one excipient selected from the group comprising water, polysorbate 80, isopropyl myristate, liquid paraffin, ceteareth-20, carbomer 980, triethanolamine, phenoxyethanol / ethylhexylglycerin, butylated hydroxytoluene (BHT), oleyl alcohol and coco caprylate / caprate. Present inventors observed that a topical composition comprising these ingredients provide for the desired effect on Demodex mites without a risk of causing irritation or unwanted reactions.

[0041] Herein, spilanthol is an active agent, aqua (water) acts as a solvent, polysorbate 80 acts as a surfactant, isopropyl myristate and oleyl alcohol act as permeation enhancers, liquid paraffin acts as a mineral oil, ceteareth-20 acts as an emulsifier, carbomer 980 acts as a gelling agent, triethanolamine acts as a pH adjuster, phenoxyethanol / ethylhexyl glycerin acts as a preservative, BHT acts as an anti-oxidant and coco caprylate / caprate acts as an emollient

[0042] More specifically, the composition according to the invention may comprise the ingredients as shown in Table 1 below.

[0043] Table 1. An Embodiment according to the Invention

[0044] A topical composition, for example a cream composition, comprising the ingredients in amounts as shown in Table 1 above, is shown to be effective against Demodex mites as explained in detail below in "Examples”. Therefore, it is put forward with the present invention for the first time that a topical composition comprising 0.1% - 5% spilanthol, and preferably above excipients, can effectively treat an infestation with Demodex folliculorum and / or Demodex brevis and / or the dermatological diseases associated with Demodex folliculorum and / or Demodex brevis.

[0045] Also of interest, spilanthol compositions comprising further anti-demodex agents, in addition to spilanthol. Spilanthol increases the permeability properties of the skin to other compounds. With this feature, it can also be used to increase the effectiveness of other topical drugs. Therefore, the compositions according to the invention may also comprise at least one further anti-Demodex agent, for example permethrin, ivermectin, sodium sulfacetamide, benzoyl benzoate, crotamiton, lindane, sulfur or tea tree oil. In embodiments of the present invention where the composition comprises another active agent, said active agent is present in the composition in the concentration of 0.05% to 2% (w / w), for example 1% (w / w). This way, the efficiency of the other agent is increased in lower doses by the virtue of permeability increasing property of spilanthol. Furthermore, a synergistic effect can be achieved by combining two active agents.

[0046] In a preferred embodiment, the composition comprises 0.05% to 2% (w / w) (for example 1% (w / w)J tea tree oil in addition to 1% to 3% (w / w) (for example 1% (w / w)) spilanthol. A synergistic effect of said combination of active ingredients provide for an efficient treatment.

[0047] In a further aspect, present invention presents a method for preparation of the composition according to the invention, comprising the steps of: extracting Spilcmthes acmella flowers, purifying spilanthol from the plant extract, obtaining a composition comprising spilanthol in a concentration of 0.1% to 5% (w / w).

[0048] The method according to the invention may comprise the further step of incorporating of at least one excipient to the composition. EXAMPLES

[0049] Extraction of Spilanthol from Spilanthes acmella Flowers

[0050] Spilanthol was extracted from Spilanthes acmella flowers by purifying it in column chromatography with hexane:acetone mobile phase using the supercritical carbon dioxide method. Supercritical CO2 with added ethanol and water was also used to extract spilanthol from dried and grinded Spilanthes acmella flowers. Spilanthol was purified from the ethanolic extract using column chromatography under a gradient elution hexane / ethyl acetate (5:1 to 2:1) using silica gel (70-230 mesh).

[0051] Compositions comprising spilanthol at the concentrations of 1%, 2%, 3%, 4%, and 5% were prepared (Doctor KLC Chemistry / Sakarya, Turkey) according to the above presented embodiment of the invention. These 5 compositions comprising spilanthol at the concentrations of 1%, 2%, 3%, 4%, and 5% constitute the treatment groups (Table 2). Standard immersion oil was used for the negative control group, and permethrin 5% (Jeomed Company, Turkey) was used for the positive control.

[0052] Table 2. Treatment Groups

[0053] In vitro Efficiency of Treatment and Control Groups against Demodex Mites

[0054] The study protocol was approved by the ethics committee of Sakarya University Faculty of Medicine, with the paper dated 11 / 06 / 2023 and numbered 1234567890. The study was carried out at the dermatology clinic of the Sakarya University Training and Research Hospital between May 2023 and December 2023, and the principles of the Declaration of Helsinki were used to conduct the study.

[0055] Seventy adult Demodex mites obtained from 70 different patients with the preliminary diagnosis of rosacea and perioral dermatitis, where DF is thought to be the causative agent. Patients using topical or systemic anti-inflammatory and antibacterial medications were excluded.

[0056] Patients underwent standard superficial skin biopsy (SSSB) in order to obtain Demodex mites. SSSB was performed by pressing a glass slide containing a drop of cyanoacrylate glue onto the skin surface. After 60 seconds, the slide was gently removed. The most active Demodex mite in the sample was determined as the target (Yurekli, Aslan, and Ay^enur Botsali. "The comparative in vitro killing activity of tea tree oil versus permethrin on Demodex folliculorum of rosacea patients." Journal of cosmetic dermatology 21.5 (2022): 2268-2272). Different criteria can be used to determine the effectiveness of the drug / agent used in Demodex infestation, such as decrease in the number of mites and improvement or elimination of the symptoms. In the present invention, the time period to kill the parasite after drug treatment is calculated in order to evaluate the in vitro efficiency of spilanthol.

[0057] The studies in scope of the invention included seven groups: A, B, C, D, E, F, and G. Group A constituted the negative group and was treated with immersion oil only. Groups B, C, D, E, and F (treatment groups) were treated with spilanthol at the concentrations of 1%, 2%, 3%, 4%, and 5%, respectively. Group G was treated with permethrin 5% and was used as a positive control group. The study groups and the treatments administered to each group are given in the Table 3 below.

[0058] Table 3. Study Groups and Treatments

[0059] The most active adult Demodex mite in each sample was examined shortly (within the first hour) after being isolated from the patient skin. The study did not include small mites due to their increased sensitivity to treatment substances. The samples were also evaluated for the presence of live parasites at the zeroth minute before the drug was applied.

[0060] After these initial evaluations, 10 ml of the different concentrations of spilanthol as explained above, immersion oil, and 5% permethrin were added to the samples on the slide for each group. Monitoring was performed every 1-minute during the first hour, every 10-minutes during the second hour, and every 30-minutes during the third and fourth hours. Monitoring period ended at the end of 240 minutes, i.e. fourth hour. In order to measure the effectiveness of the drug during the evaluation, survival times were determined and recorded. For this, killing time was defined as the time between the addition of the test solution and the cessation of all movement of mite’s body, legs, mouth, and pedipalps for a minimum of 60 seconds.

[0061] All microscopic evaluations were performed under a light microscope (at magnifications ranging from 40-100X) and by two independent researchers. The entire study protocol was repeated ten times for each group with Demodex mites isolated from different patients.

[0062] Statistical analyses were performed using IBM SPSS (social science statistical package) for Windows, Version 20.0 package program. Numerical variables are shown as mean ± SD. Data between groups was evaluated with Kruskal Wallis and post hoc tests. In all comparisons, a p- value <0.05 was considered significant.

[0063] The treatment groups, which were treated with five different concentrations of spilanthol and the positive control group which was treated with 5% permethrin, all caused inhibition of Demodex movements in all ten repeats of the studies. However, movement inhibition occurred in only eight Demodex mites in the negative control groups after the 200th minute.

[0064] After the spilanthol application, it was observed that the Demodex mite performs contraction-like movements after the inversion movement Leg movements slowed down over time. Moreover, changes in their morphology, such as thinning and loss of volume between the head and body, were observed. Our experimental observations of the death processes of the mites in the groups for which spilanthol was applied also included contractions, suggestive of neurotoxicity.

[0065] The mean ST for group A was 227.5±12.52 minutes. In groups B, C, D, E, and F, survival times were determined as 27.5±5.48 minutes, 28.4±10.82 minutes, 13.1±1.85 minutes, 12.1±2.46 minutes, and 11.7±2.21 minutes, respectively. In the 5% permethrin group, survival time was 13.2±1.32 minutes (Figure 1). When the treatment groups and the positive control group were compared with the negative control group, an anti-demodex effect was demonstrated in all groups, creating a statistically significant difference (p<0.001) (Table 4). In comparison with the positive control group, statistically significantly longer STs were observed in the 1% and 2% spilanthol groups compared to the positive control, while the difference between 3%, 4% and 5% spilanthol groups and the positive control group did not reach statistical significance (Table 5). These results were interpreted as a similar potential effect When spilanthol concentrations were compared among groups B, C, D, E, and F, it was seen that 3% concentration was more effective than 1% and 2% concentrations at a statistically significant level, whereas higher concentrations (4% and 5%) did not make any additional contribution to survival time. Statistical results are summarized in Table 6. Table 4. Comparison of Survival Times of Groups B to G with Group A

[0066] Table 5. Comparison of Survival Times of Groups A to F with Group G

[0067] Table 6. Comparison of Survival Times of Groups B to F The results as presented on Figure 1 and Tables 4 to 6 show that different concentrations of spilanthol might be effective on Demodex mites. It was observed that the effect of spilanthol on the killing time of Demodex mites depends on the concentration used. As the concentration increases up to 3%, mites are killed in a shorter time. However, it was observed that the 3%, 4% and 5% concentrations of spilanthol had a similar duration of action as the 5% concentration of permethrin, which is frequently used currently in the treatment of Demodex infestation and which was used as a positive control in the present invention.

[0068] Spilanthol, whose highly effective results against Demodex mites were proven with the studies conducted in scope of the present invention, has no restrictions on its use in cosmetic products according to the EU Cosmetics Regulation in terms of safety, and there is no data in the literature indicating that it is carcinogenic (Spinozzi, Eleonora, et al. "Spilanthol-rich essential oil obtained by microwave-assisted extraction from Acmella oleracea (L.) RK Jansen and its nanoemulsion: Insecticidal, cytotoxic and anti-inflammatory activities." Industrial Crops and Products 172 (2021):114027).

[0069] With the present invention, the dose-dependent anti-acaricidal effect of spilanthol on Demodex mites is shown for the first time. Even the 3% dose of spilanthol shows similar results to 5% permethrin, which makes the composition of the invention advantageous and preferable. Furthermore, it is an alternative to vegan products because it originates from a plant that can be produced worldwide and does not contain animal products, which is another important advantage of the composition of the invention.

Claims

CLAIMS1. A composition comprising spilanthol for use in the treatment of infestation with Demodex folliculorum and / or Demodex brevis and / or in the treatment of dermatological diseases associated with Demodex folliculorum and / or Demodex brevis, wherein the concentration of spilanthol is in the range of 0.1% to 5% (w / w).

2. The composition for use according to claim 1, wherein the concentration of spilanthol is in the range of 1% to 3% (w / w).

3. The composition for use according to claim 2, wherein the concentration of spilanthol is 3% (w / w).

4. The composition for use according to claim 1, wherein said dermatological disease is selected from the group comprising rosacea, pityriasis folliculorum, perioral dermatitis, seborrheic dermatitis, pustular eruption, blepharitis, seborrheic alopecia, the etiopathogenesis of blepharitis, keratoconjunctivitis, recurrent chalazion, and meibomian gland dysfunction.

5. The composition for use according to claim 1, wherein the composition further comprises at least one excipient selected from the group comprising solvents, humectants, emulsifiers, preservatives, permeation enhancers, gelling agents, stabilizers, pH adjusters, viscosity modifiers, anti-oxidants, surfactants, and emollients.

6. The composition for use according to claim 5, wherein the composition comprises at least one excipient selected from the group comprising water, polysorbate 80, isopropyl myristate, liquid paraffin, ceteareth-20, carbomer 980, triethanolamine, phenoxyethanol / ethylhexylglycerin, butylated hydroxytoluene, oleyl alcohol and coco caprylate / caprate.

7. A method for preparation of the composition for use according to any one of the preceding claims, wherein the method comprises the steps of: extracting Spilcmthes acmella flowers, purifying spilanthol from the plant extract, obtaining a composition comprising spilanthol in a concentration of 0.1% to 5% (w / w).

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