Pelargonic acid derivatives having soothing activity

Abstract

The present invention relates to the use of pelargonic acid derivatives as soothing anti-inflammatory agents. The present invention also relates to a cosmetic or pharmaceutical composition comprising one or more of said pelargonic acid derivatives. It has been observed that this composition benefits from the soothing anti-inflammatory action of the pelargonic derivatives of the invention, while improving the skin's sensitivity and resistance to aging, as well as offering an inhibitory effect on inflammatory factors and therefore an overall soothing effect.

Description

[0001] “PELARGONIC ACID DERIVATIVES HAVING SOOTHING ACTIVITY”

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The invention pertains to the technical field of dermatological products and specifically concerns the use of pelargonic acid derivatives as soothing anti-inflammatory agents. The present invention also relates to a cosmetic or pharmaceutical composition comprising one or more of said pelargonic acid derivatives. It has been observed that this composition benefits from the soothing anti-inflammatory action of the pelargonic derivatives of the invention, while improving the skin’s sensitivity and resistance to aging, as well as offering an inhibitory effect on inflammatory factors and therefore an overall soothing effect.

[0005] BACKGROUND ART

[0006] The rise in skin sensitivity problems is well known, primarily due to reduced air quality, the ever-increasing use of makeup, improper skin care, poor dietary habits, and irregular work-life schedules.

[0007] In particular, with the exponential increase in cosmetic use, the number of people suffering from skin inflammation and allergies has risen in recent years. Consumers are therefore very attentive and engaged in the search for products that effectively relieve skin discomfort, opting for cosmetics that can effectively improve and enhance skin resistance after use.

[0008] In this regard, it is known that these problems are addressed primarily by reducing common allergens, simplifying the list of ingredients in formulas, choosing more delicate and natural raw materials, or selecting aseptic and disposable packaging. Alternatively, people choose not to add flavourings and fragrances, as well as minimizing preservatives, which consequently also reduces the average shelf life of products.

[0009] It is therefore an object of the present invention to provide a solution to be used in dermatological products that has a satisfactory soothing and anti-inflammatory efficacy, which at the same time is compatible with cosmetic and pharmaceutical ingredients, i.e. such as not to alter their action.

[0010] SUMMARY OF THE INVENTION

[0011] This object has been achieved by pelargonic acid derivatives as soothing anti- inflammatory agents for use in the treatment of inflammatory skin conditions.

[0012] For the purposes of the present invention, said skin conditions are preferably spots, papules, vesicles, bullae, pustules, cysts, erosions, abrasions, redness, ulcers, cracks, sores, bedsores, scaling, erythema, crusts, lichenifications, abrasions, indurations, cuts, lacerations, diabetic lesions and ulcers, burns, eczema, rosacea, ulcers, erythema multiforme, bullous pemphigoid, ichthyosis, microbial skin infections, dermatophytosis, acne, psoriasis, urticaria, lichen planus, pityriasis rosea, hidradenitis suppurativa, seborrheic dermatitis, allergic dermatitis, scleroderma, contact dermatitis, atopic dermatitis, chronic actinic dermatitis, photodermatosis, as well as skin irritations induced by chemical, physical, or mechanical agents. Such skin conditions are understood to be present not only externally on the skin, but also internally on the mucous membranes and gingival tissue.

[0013] In addition, the present invention relates to the cosmetic use of pelargonic acid esters (C13-C17) as soothing agents.

[0014] In another aspect, the present invention concerns a cosmetic or pharmaceutical composition comprising at least one pelargonic acid derivative as a soothing antiinflammatory agent, and suitable excipients.

[0015] Furthermore, the present invention relates to the use of said composition in the treatment of inflammatory skin conditions.

[0016] BRIEF DESCRIPTION OF THE FIGURES

[0017] The characteristics and advantages of the present invention will be evident from the following detailed description, the embodiments provided by way of illustrative and non-limiting examples, and the accompanying figures, wherein:

[0018] - Figure 1 shows the results of the test to measure the soothing effect of butyl pelargonate (A), hexyl pelargonate (B), and 2-ethylhexyl pelargonate (C) on keratinocytes treated with TNF-a (TNF -alpha); the results are shown as % IL-6 production compared to the untreated control (NT). One-way ANOVA, followed by Dunnet's test for multiple comparisons, compared to the positive control treated with TNF-a alone, *p<0.05; ** p<0.01

[0019] - Figure 2 shows the results of the test to measure the soothing action of butyl pelargonate, hexyl pelargonate, and 2-ethylhexyl pelargonate, individually or combined in pairs (mix) at the concentrations (A, B, C) shown in Table 1; (in A: Butyl pelargonate + Hexyl pelargonate, in B: Hexyl pelargonate + 2 -Ethylhexyl pelargonate, in C: Butyl pelargonate + 2-Ethylhexyl pelargonate); the results are shown as % IL-6 production compared to the untreated control (NT). Two-way ANOVA analysis, followed by Tukey's test for multiple comparisons, compared to the positive control treated with TNF-a alone.

[0020] - Figure 3 shows the results of the cell viability test using the MTT assay on keratinocytes treated for 24 hours with butyl pelargonate (A), hexyl pelargonate (B), and 2-ethylhexyl pelargonate (C); the results are expressed as % cell viability compared to the untreated control (nt); 1% SDS was used as a positive toxicity control (tox).

[0021] - Figure 4 shows the results of the cell viability test using the MTT assay on keratinocytes treated for 24 hours with butyl pelargonate, hexyl pelargonate, and 2- ethylhexyl pelargonate, combined in pairs: A) Butyl pelargonate + Hexyl pelargonate, B) Hexyl pelargonate + 2-Ethylhexyl pelargonate, C) Butyl pelargonate + 2-Ethylhexyl pelargonate; using the MTT assay; results are expressed as % cell viability compared to the untreated control (nt); 1% SDS was used as a positive toxicity control (tox).

[0022] DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention concerns pelargonic acid derivatives as soothing antiinflammatory agents for use in the treatment of inflammatory skin conditions.

[0024] Pelargonic acid is a saturated C9 fatty acid, of plant origin. It is found naturally in the Pelargonium plants, of the Geraniaceae family, from which it takes its common name, and in other plant extracts.

[0025] Preferably, said pelargonic acid derivatives are pelargonic acid esters (having an overall number of C13-C17 carbon atoms), more preferably selected from butyl pelargonate (Cl 3), hexyl pelargonate (Cl 5), 2-ethylhexyl pelargonate (Cl 7), and mixtures thereof.

[0026] Such esters are preferably obtained by reacting pelargonic acid with a straightchain or branched-chain C4-C8 alcohol, according to methods known in the art.

[0027] These esters have shown an anti-inflammatory activity that allows them to be effectively used as soothing anti-inflammatory agents for the treatment of inflammatory skin conditions.

[0028] The term "soothing agent" refers to an ingredient capable of alleviating or calming pain and / or irritation, acting as a "palliative" for a local irritant condition.

[0029] The term "anti-inflammatory agent" refers to an ingredient that acts by directly or indirectly reducing inflammation in a tissue, resulting in resolution or alleviation of the inflammatory condition.

[0030] The term "treatment" refers to the effects of the derivatives of the invention, which are capable of providing a benefit to patients suffering from a skin condition, for example by improving the patient’s condition or delaying the progression of the condition itself.

[0031] Pelargonic acid derivatives according to the present invention have indeed proven to be effective in reducing inflammation triggered by an inflammatory insult in keratinocytes, by reducing the inflammatory marker IL-6 following stimulation with TNF-a. During chronic inflammation, suppression of IL-6 can reduce tissue damage.

[0032] Preferably, the derivatives of the invention are to be administered via topical - more preferably external -, subcutaneous, mucosal, gingival, intravesical, vaginal, rectal, or ocular route, most preferably via external topical route.

[0033] Based on the above, the derivatives of the invention are also conveniently and effectively used as soothing agents in cosmetics.

[0034] Therefore, in another aspect, the present invention also relates to the cosmetic use of pelargonic acid esters (C13-C17) as soothing agents.

[0035] Preferably, said pelargonic acid esters (Cl 3 -Cl 7) are selected from butyl pelargonate (Cl 3), hexyl pelargonate (Cl 5), 2-ethylhexyl pelargonate (Cl 7), and mixtures thereof.

[0036] The present invention also relates to a cosmetic or pharmaceutical composition comprising at least one pelargonic acid derivative as a soothing anti-inflammatory agent, and suitable excipients.

[0037] It has been observed that this composition benefits from the soothing antiinflammatory action of the pelargonic derivatives of the invention, while improving the skin’s sensitivity and resistance to aging, as well as offering an inhibitory effect on inflammatory factors and therefore an overall soothing effect.

[0038] Preferably, said composition comprises n-butyl pelargonate, n-hexyl pelargonate, 2-ethylhexylpelargonate, or a mixture thereof.

[0039] More preferably, the composition of the invention comprises at least one of n- butyl pelargonate and n-hexyl pelargonate.

[0040] According to preferred embodiments, the composition of the present invention comprises a single pelargonic acid ester selected from n-butyl pelargonate, n-hexyl pelargonate, and 2-ethylhexylpelargonate, more preferably n-hexyl pelargonate.

[0041] According to further preferred embodiments, the composition of the present invention comprises at least two pelargonic acid esters selected from n-butyl pelargonate, n-hexyl pelargonate, and 2-ethylhexylpelargonate, more preferably n-butyl pelargonate and 2-ethylhexylpelargonate.

[0042] In further preferred embodiments, the composition of the present invention comprises 0.1-10 v / v% of pelargonic acid derivative, more preferably 0.25-5 v / v%, and even more preferably 0.5-2 v / v%, of the total volume of the composition.

[0043] In some embodiments, said at least one pelargonic acid derivative is the only soothing anti-inflammatory agent present in the cosmetic or pharmaceutical composition of the invention.

[0044] Preferably, the composition of the invention comprising at least one pelargonic acid derivative is administered via topical -more preferably external -, subcutaneous, mucosal, gingival, intravesical, vaginal, rectal, or ocular route.

[0045] Preferably, said composition is administered in a dose of 0.1 to 1500 mg per day, the effective dosage depending on the use and severity of the condition being treated.

[0046] In preferred embodiments, this composition is administered via external topical route in a dose of 1-1000 mg per day.

[0047] The term "excipient" refers to any substance, other than an active agent itself, that can be used as a carrier or vehicle for the administration of an active agent to a subject, or combined with an active agent to improve its handling or storage properties, or to enable or facilitate the formation of a dosage unit of the formulation.

[0048] Said acceptable excipients may include rheological additives, buffering agents, antioxidant agents, anti-isothermal agents, antistatic agents, absorbent agents, UV absorbers, astringents, chelating agents, skin conditioning agents, preservatives, masking agents, denaturing agents, depigmenting agents, emulsifying agents, film-forming agents, gelling agents, moisturizing agents, hydrotropic agents, binders, soothing agents, smoothing agents, matting agents, plasticizing agents, propellant agents, skin-protective agents, reducing agents, refreshing agents, sebum-regulating agents, solvents, stabilizing agents, emulsifying-stabilizing agents, toning agents, humectants, bulking agents, or mixtures thereof.

[0049] Preferably, the cosmetic or pharmaceutical composition according to the invention comprises at least one of a surfactant, preferably 1-15% by weight of a surfactant, a thickening agent, preferably 0.01-10% by weight of a thickening agent, a gelling agent, preferably 0.1-5% by weight of a gelling agent, a preservative, preferably 0.1-3% by weight of a preservative, an emollient, preferably 1-3% by weight of an emollient, a penetration enhancer, preferably 1-5% by weight of a penetration enhancer, a pH-regulating agent, preferably in an amount sufficient to maintain a pH of 5-7, and water (to 100%), based on the weight of the composition.

[0050] This composition may be in the form of an ointment, lotion, cream, emulsion, paste, gel, aqueous solution, spray, plaster, serum, impregnated gauze, bandage, or a combination thereof.

[0051] In preferred aspects, the present invention is directed to dermatological use of the composition comprising at least one pelargonic acid ester as a soothing anti-inflammatory agent.

[0052] Preferably, the cosmetic or pharmaceutical composition according to the invention comprises 0.1-10% by weight of the at least one pelargonic acid ester, more preferably 0.25-5%, even more preferably 0.5-2%, based on the total weight of the composition.

[0053] According to the present invention, compositions comprising two or more pelargonic acid esters comprise 0.1-10% by weight, more preferably 0.25-5% by weight, even more preferably 0.5-2% by weight, of each ester, based on the total weight of the composition.

[0054] It should be understood that all the possible combinations of the preferred aspects of the ingredients, compositions, and uses, as indicated above, are also described and therefore similarly preferred.

[0055] It should be also understood that all aspects identified as preferred and advantageous for the ingredients are also to be considered similarly preferred and advantageous for their composition, preparation, and uses.

[0056] Working examples of the present invention provided for illustrative and nonlimiting purposes are reported herein below.

[0057] EXAMPLES

[0058] Example 1

[0059] With the aim to test the soothing efficacy of pelargonic acid derivatives, an in vitro model of skin inflammation was generated. HaCaT cells (human keratinocytes) were plated in 48-well multiwell plates at a density of 3 x 104 cells / well, in medium with 10% FBS. After 24 hours, the medium was replaced with 500 LIL of complete medium without FBS, and an inflammatory process was simultaneously induced by treatment with the inflammation inducer TNF-a at 20 ng / ml, maintained overnight.

[0060] The following day, the cells were treated with butyl pelargonate, hexyl pelargonate, and 2-ethylhexyl pelargonate, each in three different concentrations, for an additional 24 hours. An experimental group of untreated cells was also included as a negative control for inflammation, and a group of cells treated with TNF-a alone.

[0061] Specifically, each compound was tested at the following concentrations (volume / volume).

[0062] - butyl pelargonate: 7.5 - 3.75 - 1.875%

[0063] - ethylhexyl pelargonate: 7.5 - 3.75 - 1.875%

[0064] - hexyl pelargonate: 3.75 - 1.875 - 0.9375 %

[0065] After 24 hours of treatment, the culture medium was removed from each well for subsequent quantification of interleukin 6 (IL-6) in 100 LIL of culture medium by using ELISA test.

[0066] The results are shown in Figure 1.

[0067] As expected, TNF-a significantly increased IL-6 production compared to the untreated control.

[0068] Surprisingly, all tested compounds exhibited a soothing effect, as demonstrated by the statistically significant reduction in IL-6 levels compared to samples treated with the inflammatory stimulus alone (TNF-a).

[0069] Specifically, a statistically significant reduction in IL-6 was observed in samples treated with hexyl pelargonate at all concentrations tested, butyl pelargonate at the lowest concentration tested, and 2-ethylhexyl pelargonate at the highest concentration tested.

[0070] Example 2

[0071] The test in Example 1 was repeated to test the soothing effect of compositions comprising combinations of two pelargonic acid esters. Cells were then treated with TNF- a alone or with TNF-a followed by treatment with the compounds in Example 1, either individually or in combination (see matrices 1, 2, and 3 in Table 1).

[0072] It should be noted that for each compound, the maximum concentration tested corresponds to the minimum effective concentration in the soothing action test in Example 1.

[0073] The pairs of ingredients were mixed at these concentrations (mix A), then serial dilutions of 1:2 were performed, resulting in three compositions for each matrix with different concentrations (A, B, C) of each ester, as reported in Table 1 below. Figures 2A-C and Tables 2A-C below show the results for the combinations of matrices 1, 2, and 3, respectively, as well as the mean IL-6 values in the untreated and TNF-a-treated samples.

[0074] A tendency toward greater soothing effect was observed for the combination of butyl pelargonate with 2-ethylhexyl pelargonate, compared to the corresponding concentrations of the individual compounds.

[0075] Table 2A. Table 2B.

[0076] Table 2C. Example 3

[0077] Human keratinocytes (HaCaT cells) were plated in 96-well multiwell plates at a density of 104cells / well and cultured for one day in DMEM medium supplemented with 10% FBS, in a humidified atmosphere at 37°C and 5% CO2.

[0078] The next day, the medium was removed and replaced with 100 LLL of complete medium supplemented with 1% FBS. A cell viability test was performed by incubating the cells for 24 hours with hexyl pelargonate, butyl pelargonate, or 2-ethylhexyl pelargonate, each at the following graduated concentrations: 15%, 7.5%, 3.75%, 1.875%, 0.9%, 0.45%, 0.22%, 0.11%, 0.05%, 0.025% (volume / volume).

[0079] Sodium dodecyl sulfate (SDS) at a concentration of 1 mg / ml was used as a positive toxicity control.

[0080] At the end of each incubation, 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl- tetrazolium bromide (MTT) reagent was added to each well at a final concentration of 0.5 mg / mL, and the plates were incubated for an additional 2 hours at 37°C and 5% CO2. At the end of the incubation, the reduced MTT crystals were solubilized by removing the medium and adding 100 pL of dimethyl sulfoxide (DMSO) to each well. Finally, the absorbance of each sample at 595 nm was measured using an Infinite M NANO+plate reader (Tecan).

[0081] Cell viability after each treatment, expressed as a percentage of absorbance at 595 nm compared to untreated cells (NT), is shown in Figure 3.

[0082] The graph shows that, for all products, the only concentration at which significant in vitro toxicity was observed was the highest concentration tested (15%), where the level of cell viability was comparable to that of the positive toxicity control (SDS 1%, tox).

[0083] Regarding 2-ethylhexyl pelargonate, at a concentration of 7.5%, cell viability was observed at around 62%. For all other concentrations tested, cell viability was always above 70%.

[0084] Therefore, at concentrations lower than 7.5%, including those tested above for soothing efficacy, the pelargonic acid esters of the present invention showed no signs of toxicity in keratinocytes, thus confirming the high safety profile of these compounds.

[0085] Example 4

[0086] The test in Example 3 was repeated by incubating the cells with the same compounds, combined in pairs, at the concentrations shown in Table 1.

[0087] As can be clearly seen in Figure 4, none of the combinations resulted in cytotoxic effects, as cell viability remained consistently around 100% at all tested concentrations.

[0088] In conclusion, these examples confirm the soothing anti-inflammatory efficacy of hexyl pelargonate, butyl pelargonate, and 2-ethylhexyl pelargonate, at the tested concentrations, in the absence of cytotoxicity in vitro.

[0089] Furthermore, even when the molecules were combined together, no cytotoxicity was observed and an improvement in the soothing effect was observed.

Claims

CLAIMS1. An ester C13-C17 of pelargonic acid as an anti-inflammatory soothing agent for use in the treatment of inflammatory skin conditions.

2. The ester C13-C17 of pelargonic acid of claim 1, selected from butyl ester, hexyl ester, and ethylhexyl ester of pelargonic acid.

3. The ester C13-C17 of pelargonic acid of claim 2, said ester being n-butyl pelargonate.

4. The ester C13-C17 of pelargonic acid of claim 2, said ester being n-hexyl pelargonate.

5. The ester C13-C17 of pelargonic acid of claim 2, said ester being 2 -ethylhexyl pelargonate.

6. Cosmetic non-therapeutic use of an ester C13-C17 of pelargonic acid as a soothing agent.

7. Cosmetic or pharmaceutical composition comprising at least one ester C13-C17 of pelargonic acid as an anti-inflammatory soothing agent, and suitable excipients.

8. The composition of claim 7, comprising at least two different pelargonic acid esters.

9. The composition of claim 7 or 8, comprising n-butyl pelargonate.

10. The composition of claim 7 or 8, comprising n-hexyl pelargonate.

11. The composition of claim 7 or 8, comprising 2-ethylhexyl pelargonate.

12. Cosmetic non-therapeutic use of the composition of any of claims 7-11.

13. The composition of any one of claims 7-11 for use in the treatment of inflammatory skin conditions.

14. The composition for use of claim 13, wherein said inflammatory skin conditions are spots, papules, blisters, bullae, pustules, cysts, erosions, abrasions, redness, ulcers, cracks, sores, bedsores, scaling, erythema, crusts, lichenifications, abrasions, indurations, cuts, lacerations, diabetic lesions and ulcers, burns, eczema, rosacea, ulcers, erythema multiforme, bullous pemphigoid, ichthyosis, microbial skin infections, dermatophytosis,acne, psoriasis, urticaria, lichen planus, pityriasis rosea, hidradenitis suppurativa, seborrheic dermatitis, allergic dermatitis, scleroderma, contact dermatitis, atopic dermatitis, chronic actinic dermatitis, photodermatosis, as well as skin irritations induced by chemical, physical or mechanical agents.

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