Novel inhibitors of thymic stromal lymphopoietin

Abstract

The present invention generally relates to novel thymic stromal lymphopoietin (TSLP) inhibitors and their uses in cosmetics and therapy.

Description

[0001] Novel inhibitors of thymic stromal lymphopoietin

[0002] The present invention mainly relates to novel thymic stromal lymphopoietin (TSLP) inhibitors and their uses in cosmetics and therapy.

[0003] TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses and bacteria. It has an initialing role of barrier alterations. The injury of the epidermal barrier or microbial infection leads to TSLP being released from challenged keratinocytes. TSLP contributes to itch symptoms and Th2 / Th 22-type skin inflammation. It induces Th2 / Th22 immune cells to produce the cytokines IL-4, IL-5, IL-13 and TNFa and sebaceous glands to produce sebum, which contains anti-microbial molecules. TSLP is involved in the initiation, development and progression of atopic dermatitis (AD). It is further involved in psoriasis. Besides, TSLP is involved in allergic asthma. Recently it was shown that TSLP promotes sebum production in sebaceous glands and may have implications in acne.

[0004] It is hypothesized that reduction of TSLP upon inflammatory triggers will alleviate atopic dermatitis, psoriasis and acne vulgaris. Furthermore, it is hypothesized that reduction of TSLP aids in reducing sebum, pore size, and itching of skin.

[0005] Thus, an object of the present invention is to provide a technology for managing atopic dermatitis, psoriasis and acne vulgaris, and for reducing sebum, pore size, and itching of skin. The technology should be safe, have no or low side-effects, be suited for daily application to a human or animal and ideally be fully integratable into daily hygiene.

[0006] The object is achieved by the present invention. The present invention is based on the inventors’ observation that jasmol, vanillin, bisabolol, chicoric acid, gingerols, aventhramides, dihydroaventhramides, menthol, apigenin, Tetraselmis suecica extract and Laminaria Saccharina Ferment, i.e. compounds mainly sharing a polyphenol structure, inhibit TSLP induced by inflammatory triggers, thereby reducing TSLP level. This observation was not expected because these compounds and compositions have thus far not been linked to TSLP inhibition. Advantageously, the compounds and compositions are able to reduce TSLP level in keratinocytes. On the basis of their mode of action the compounds and compositions are assumed to aid in treating or preventing atopic dermatitis, psoriasis and acne vulgaris, reducing sebum on human or animal skin, reducing pore size of human or animal skin, and reducing itching of human or animal skin.

[0007] The compounds and compositions used in the invention are also referred to herein as “compounds and compositions of the invention”. This expression shall be understood to mean that all have the stated functions, but of course not that all of them have to be used in combination. For the purposes of the present invention it is rather sufficient that at least one of the compounds and compositions of the invention is used, and this is how the expression “compounds and compositions of the invention” shall be construed.

[0008] Advantagesouly, the compounds and compositions of the invention are substances established on the cosmetic sector and generally considered safe and well tolerated for use in skin products. They are thus not only effective, but also proven to be well-tolerated and can be rapidly included in cosmetic and hygiene products. They are hence suited for daily use, and in particular fully integratable into daily personal hygiene.

[0009] Generally, the technology disclosed herein is applicable for non-therapeutic, e.g., cosmetic, purposes, or therapeutic purposes. For instance, the compounds and compositions of the invention are capable to reduce TSLP level. Reduction of the TSLP level is not a therapeutic act as such. It rather depends on the specific circumstances whether TSLP reduction provides a therapeutic effect or merely a cosmetic effect. For instance, TSLP reduction in areas of the skin that are free of skin diseases such as AD, psoriasis and acne may result in a healthier appearance including less sebum, smaller pore size and possibly less itching, but may not, at least not necessarily, cure or prevent a disease. On the other hand, applying the compounds and compositions of the invention to areas of skin that show signs of skin diseases such as AD, psoriasis or acne, may in fact result in a therapeutic effect. In the context of the present invention, both therapeutic and non-therapeutic aspects are covered, and the differentiation between therapeutic and non-therapeutic uses herein is mainly due to different patent law treatment. Having this said, features and embodiments described in conjunction with a specific aspect of the invention shall form corresponding features and embodiment of all other aspects, unless the context dictates otherwise.

[0010] Generally, the compounds and compositions of the invention may be applied to the human or animal skin, including the scalp. In some cases, they are applied in seborrheic areas of the skin. In other cases, they are applied in non-seborrheic areas of the skin. Moreover, the skin on which the compounds and compositions of the invention are applied may in some cases be defined by AD, psoriasis and / or acne. In other cases, the skin on which the compounds and compositions of the invention are applied is free of (signs of) AD, psoriasis and / or acne. In some cases, the compounds and compositions of the invention may be used for therapeutic purposes, e.g. for treating or preventing AD, psoriasis or acne. In these cases, the compounds and compositions may be applied in seborrheic or non-seborrheic, preferably seborrheic, areas of the skin characterized by AD, psoriasis and / or acne. In other cases, the compounds and compositions of the invention are used for non-therapeutic purposes, in particular for cosmetic purposes, e.g., for reducing sebum on human or animal skin, reducing pore size of human or animal skin, or reducing itching of human or animal skin. In these cases, the compounds and compositions may be applied in seborrheic or non-seborrheic, preferably seborrheic, areas of the skin free of AD, psoriasis and / or acne.

[0011] Having this said, a first aspect of the present invention is the use of a compound or composition for reducing in a human or animal one or more of thymic stromal lymphopoietin (TSLP) level, sebum of skin, pore size of skin, and itching of skin, wherein the compound is selected from the group consisting of jasmol, vanillin, bisabolol, chicoric acid, gingerols, aventhramides, dihydroaventhramides, menthol and apigenin, wherein the composition comprises one or more of the aforementioned compounds, Tetraselmis suecica extract or Laminaria Saccharina Ferment. The use is preferably a non-therapeutic use.

[0012] Preferably, the TSLP level is reduced in keratinocytes. The term “reducing TSLP level” denotes a reduction in the active TSLP cell concentration, in particular in keratinocytes.

[0013] The compound or composition is preferably applied topically and / or locally. Preferably the compound or composition is applied in seborrheic areas of the skin. Preferably, the compound or composition is applied in areas of the skin free of atopic dermatitis (AD), psoriasis and / or acne, in particular free of skin diseases involving increased TSLP level, or even free of skin diseases in general.

[0014] The phrase “increased TSLP (level)” refers to a state of cells, in particular keratinocytes, having a TSLP level that is higher than normal. The normal TSLP level may be determined in cells of other (undamaged) skin regions of the same human or animal, or one or more different humans or animals. Preferably, the increased TSLP level occurs in seborrheic areas of skin and / or lung.

[0015] In a preferred embodiment of the invention, the compound or composition is applied at least once a week, preferably at least twice a week, more preferably at least three times a week, yet more preferably at least five times a week, most preferably at least once a day.

[0016] In a further preferred embodiment of the invention, the compound or composition is applied over a period of at least two consecutive days, preferably at least three consecutive days, more preferably at least five consecutive days, most preferably at least seven consecutive days.

[0017] In a yet further preferred embodiment of the invention, the compound or composition is applied in the form of a natural extract or a cosmetic formulation, preferably a dermatological, skin care or hair care product, preferably, wherein the cosmetic formulation further comprises water and at least one selected from the group consisting of dermatologically, skin care or hair care acceptable carriers, adjuvants and auxiliary substances, including alcohols, polyhydric alcohols, such as glycerol, high-molecular weight compounds, mono-, di- or polysaccharides, fats, fatty acids, oils, waxes, surfactants, emulsifiers, micelle water, tonics, soaps, tenside formulations, gels, preservatives and perfumes.

[0018] In a second aspect, the invention further provides a compound or composition for use in method of managing a condition caused by, promoted by, and / or associated with sebum production or overproduction, and / or a condition characterized by increased TSLP level, wherein the compound is selected from the group consisting of jasmol, vanillin, bisabolol, chicoric acid, gingerols, aventhramides, dihydroaventhramides, menthol and apigenin, wherein the composition comprises one or more of the aforementioned compounds, Tetraselmis suecica extract or Laminaria Saccharina Ferment. The method is preferably a therapeutic method. In this case, the term “managing” has the meaning “preventing or treating”. According to a preferred embodiment, the increased TSLP level occurs in seborrheic areas of skin and / or lung.

[0019] According to a further preferred embodiment, the condition is selected from the group consisting of seborrheic dermatitis, acne vulgaris, wound healing, postinflammatory hyperpigmentation, inflammatory conditions, dandruff, and pityriasis versicolor. Preferably, the inflammatory condition is selected from the group consisting of AD and psoriasis.

[0020] According to yet a further preferred embodiment, the compound or composition is applied topically and / or locally. Preferably, the compound or composition is applied in seborrheic areas of the skin. Preferably, the compound or composition is applied in areas of the skin characterized by AD, psoriasis and / or acne.

[0021] As regards frequency of the administration, it is preferred that the compound or composition is administered at least once a week, preferably at least twice a week, more preferably at least three times a week, yet more preferably at least five times a week, most preferably at least once a day.

[0022] As regards duration of the administration, it is preferred that the compound or composition is administered over a period of at least two consecutive days, preferably at least three consecutive days, more preferably at least five consecutive days, most preferably at least seven consecutive days.

[0023] Moreover, the compound or composition is preferably administered in the form of a pharmaceutical formulation, preferably a dermatological formulation. Preferably, the pharmaceutical formulation further comprises water and at least one selected from the group consisting of dermatologically acceptable carriers, adjuvants and auxiliary substances, including alcohols, polyhydric alcohols, such as glycerol, high-molecular weight compounds, mono-, di- or polysaccharides, fats, fatty acids, oils, waxes, surfactants, emulsifiers, micelle water, tonics, soaps, tenside formulations, gels, preservatives and perfumes.

[0024] In a third aspect of the invention, a method of reducing in a human or animal one or more of TSLP level, sebum of skin, pore size of skin and itching of skin, comprises applying a compound selected from the group consisting of jasmol, vanillin, bisabolol, chicoric acid, gingerols, aventhramides, dihydroaventhramides, menthol and apigenin, or a composition comprising one or more of the aforementioned compounds, Tetraselmis suecica extract or Laminaria Saccharina Ferment, to a human or animal. The method is preferably a non- therapeutic method, in particular a cosmetic method.

[0025] Preferably, the compound or composition is administered topically and / or locally. Preferably, the compound or composition is administered in seborrheic areas of the skin. Preferably, the compound or composition is administered in areas of the skin free of AD, psoriasis and / or acne.

[0026] The compound or composition is preferably administered in the form of a cosmetic formulation, preferably a dermatological, skin care or hair care product, preferably, wherein the cosmetic formulation further comprises water and at least one selected from the group consisting of dermatologically, skin care or hair care acceptable carriers, adjuvants and auxiliary substances, including alcohols, polyhydric alcohols, such as glycerol, high- molecular weight compounds, mono-, di- or polysaccharides, fats, fatty acids, oils, waxes, surfactants, emulsifiers, micelle water, tonics, soaps, tenside formulations, gels, preservatives and perfumes.

[0027] Irrespective of whether a therapeutic or non-therapeutic purpose is envisaged, the compounds and compositions of the invention are preferably administered at least once a week, preferably at least twice a week, more preferably at least three times a week, yet more preferably at least five times a week, most preferably at least once a day. Moreover, the compound or composition may be administered over a period of at least two consecutive days, preferably at least three consecutive days, more preferably at least five consecutive days, most preferably at least seven consecutive days.

[0028] In the following, the invention is explained in more detail with reference to representative examples and with reference to the drawings which show:

[0029] Fig. 1 Approach for deteremining the inhibiting effect of test substances on TSLP gene expression in keratinocytes. Examples:

[0030] Following the approach schematically depicted in Fig. 1 , the influence of different tests substances on TSLP gene expression in keratinocytes was determined. To this end, keratinocytes were seeded in wells of a multititerplate and allowed to adhere to the surface at 37°C for 24 h under 5% CO2 atmosphere. Then, one test substances is given into each well and incubated for another 24 h. Atopic dermatitis was induced by adding a cytokine cocktail to each well (IL-4, IL-5, IL-13, TNFa) and incubating for 2 h. TSLP expression was measured by RT-PCR. Expression data were normalized to geometric mean of Housekeeping genes RSP 9, HRPT1 and GAPDH. The results are summarized in the following tables:

[0031]

[0032]

[0033] The data demonstrate that jasmol, vanillin, bisabolol, chicoric acid, gingerols, aventhramides, dihydroaventhramides, menthol, apigenin, Tetraselmis suecica extract and Laminaria Saccharina Ferment are capable to inhibit TSLP.

Claims

Claims:

1. Use, preferably non-therapeutic use, of a compound or composition for reducing in a human or animal one or more of: thymic stromal lymphopoietin (TSLP) level, sebum of skin, pore size of skin, and itching of skin, wherein the compound is selected from the group consisting of jasmol, vanillin, bisabolol, chicoric acid, gingerols, aventhramides, dihydroaventhramides, menthol and apigenin, wherein the composition comprises one or more of the aforementioned compounds, Tetraselmis suecica extract or Laminaria Saccharina Ferment.

2. Use of claim 1 , wherein the TSLP level is reduced in keratinocytes.

3. Use of any of the preceding claims, wherein the compound or composition is applied topically and / or locally; and / or in seborrheic areas of the skin; and / or in areas of the skin free of atopic dermatitis (AD), psoriasis and / or acne.

4. Use of any of the preceding claims, wherein the compound or composition is applied at least once a week, preferably at least twice a week, more preferably at least three times a week, yet more preferably at least five times a week, most preferably at least once a day; and / or over a period of at least two consecutive days, preferably at least three consecutive days, more preferably at least five consecutive days, most preferably at least seven consecutive days.

5. Use of any of the preceding claims, wherein the compound or composition is applied in the form of a natural extract or a cosmetic formulation, preferably a dermatological, skin care or hair care product, preferably, wherein the cosmetic formulation further comprises water and at least one selected from the group consisting ofdermatologically, skin care or hair care acceptable carriers, adjuvants and auxiliary substances, including alcohols, polyhydric alcohols, such as glycerol, high-molecular weight compounds, mono-, di- or polysaccharides, fats, fatty acids, oils, waxes, surfactants, emulsifiers, micelle water, tonics, soaps, tenside formulations, gels, preservatives and perfumes.

6. A compound or composition for use in a method, preferably therapeutic method, of managing a condition caused by, promoted by, and / or associated with sebum production or overproduction, and / or a condition characterized by increased TSLP level, wherein the compound is selected from the group consisting of jasmol, vanillin, bisabolol, chicoric acid, gingerols, aventhramides, dihydroaventhramides, menthol and apigenin, wherein the composition comprises one or more of the aforementioned compounds, Tetraselmis suecica extract or Laminaria Saccharina Ferment.

7. The compound or composition for use of claim 6, wherein the increased TSLP level occurs in seborrheic areas of skin and / or lung.

8. The compound or composition for use of claim 6 or 7, wherein the condition is selected from the group consisting of seborrheic dermatitis, acne vulgaris, wound healing, postinflammatory hyperpigmentation, inflammatory conditions, dandruff and pityriasis versicolor, wherein, preferably, the inflammatory condition is selected from the group consisting of AD and psoriasis.

9. The compound or composition for use of any of claims 6 to 8, wherein the compound or composition is applied topically and / or locally; and / or in seborrheic areas of the skin; and / or in areas of the skin characterized by AD, psoriasis and / or acne.

10. The compound or composition for use of any of claims 6 to 9, wherein the compound or composition is administeredat least once a week, preferably at least twice a week, more preferably at least three times a week, yet more preferably at least five times a week, most preferably at least once a day; and / or over a period of at least two consecutive days, preferably at least three consecutive days, more preferably at least five consecutive days, most preferably at least seven consecutive days; and / or in the form of a pharmaceutical formulation, preferably a dermatological formulation, preferably, wherein the pharmaceutical formulation further comprises water and at least one selected from the group consisting of dermatologically acceptable carriers, adjuvants and auxiliary substances, including alcohols, polyhydric alcohols, such as glycerol, high-molecular weight compounds, mono-, di- or polysaccharides, fats, fatty acids, oils, waxes, surfactants, emulsifiers, micelle water, tonics, soaps, tenside formulations, gels, preservatives and perfumes.1 1. Method, preferably non-therapeutic method, of reducing in a human or animal one or more of:TSLP level, sebum of skin, pore size of skin and itching of skin, wherein the method comprises: applying a compound selected from the group consisting of jasmol, vanillin, bisabolol, chicoric acid, gingerols, aventhramides, dihydroaventhramides, menthol and apigenin, or a composition comprising one or more of the aforementioned compounds, Tetraselmis suecica extract or Laminaria Saccharina Ferment, to a human or animal.

12. Method of claim 1 1 , wherein the method is a cosmetic method.

13. Method of claim 1 1 or 12, wherein the compound or composition is applied topically and / or locally; and / or in seborrheic areas of the skin; and / orin areas of the skin free of AD, psoriasis and / or acne.

14. Method of any of claims 1 1 to 13, wherein the compound or composition is administered at least once a week, preferably at least twice a week, more preferably at least three times a week, yet more preferably at least five times a week, most preferably at least once a day; and / or over a period of at least two consecutive days, preferably at least three consecutive days, more preferably at least five consecutive days, most preferably at least seven consecutive days.

15. Method of any of claims 1 1 to 14, wherein the compound or composition is administered in the form of a cosmetic formulation, preferably a dermatological, skin care or hair care product, preferably, wherein the cosmetic formulation further comprises water and at least one selected from the group consisting of dermatologically, skin care or hair care acceptable carriers, adjuvants and auxiliary substances, including alcohols, polyhydric alcohols, such as glycerol, high-molecular weight compounds, mono-, di- or polysaccharides, fats, fatty acids, oils, waxes, surfactants, emulsifiers, micelle water, tonics, soaps, tenside formulations, gels, preservatives and perfumes.

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