WO2006103356A2

WO2006103356A2 - Use of compounds inducing synthesis of sirt proteins in or for preparing a cosmetic or pharmaceutical composition

Info

Publication number: WO2006103356A2
Application number: PCT/FR2006/000699
Authority: WO
Inventors: Claude Dal Farra; Nouha Domloge; Jean-Marie Botto
Original assignee: Societe D'extraction Des Principes Actifs Sa (Vincience)
Priority date: 2005-04-01
Filing date: 2006-03-30
Publication date: 2006-10-05
Also published as: FR2883751A1; FR2883751B1; WO2006103356A3

Abstract

The invention concerns a cosmetic or dermopharmaceutical or dermatological composition comprising, as active principle, in a cosmetically or pharmaceutically acceptable medium, at least one compound capable of activating the synthesis of SIRT proteins in the skin cells. The invention also concerns the use of said compositions.

Description

USE OF INDUCING COMPOUNDS OF SYNTHESIS OF SIRT PROTEINS IN OR FOR THE PREPARATION OF A COSMETIC OR PHARMACEUTICAL COMPOSITION.

The invention relates to the field of cosmetics and pharmaceuticals, particularly the field of dermatology. The subject of the present invention is a cosmetic or dermopharmacological or dermatological composition comprising, as active agent, in a cosmetically or pharmaceutically acceptable medium, at least one compound capable of activating the synthesis of SIRT proteins in the cells of the skin. The present invention also relates to the use of said composition.

The skin is a covering organ covering the entire surface of the body. It is a vital organ providing multiple functions such as sensory functions, protective against multiple external attacks, immune, metabolic or thermoregulatory. These roles are made possible by a complex structure that combines various tissue structures. The skin, as well as the integuments, are subjected constantly to nuisances of external origin which appear in different aspects. These aggressions can be important and they can threaten the balance and appearance of the skin. By way of example, mention may be made of visible or ultraviolet radiation, atmospheric pollutants, chemical products, stresses of mechanical origin, viral or bacterial infections, etc.

The skin is our first barrier against the external environment, however this barrier is not always sufficient and these attacks can have many harmful consequences for the body, both at this level and at the cellular level. The cells of the skin, in direct contact with the external environment, experience a lot of damage, including an alteration of their macromolecules. For example, damage to DNA (such as double or single-strand breaks, mutations, etc.), proteins (carbonylation of proteins, etc.), fatty acid modifications (lipid peroxidation). ...) resulting in damage to the cell membranes and an alteration of the skin barrier.

These alterations take place on all cutaneous cell types, but there may be mentioned in particular: keratinocytes, fibroblasts and melanocytes. These external aggressions often result in premature aging at the level of skin, depigmentation, inflammation phenomena. They can even sometimes lead to cancer processes and tissue necrosis. It is therefore important to develop systems capable of actively combating these attacks and their consequences. The search for ways to preserve the skin and integuments, or even protect them against all manifestations that could affect their functioning or appearance, mobilizes a very large number of researchers, particularly in the field of cosmetics.

Health and cosmetic professionals are therefore constantly looking for active ingredients that are effective, truly effective and have a broad spectrum of action. In addition, these assets must have a high dermatological compatibility so that all users, even the most sensitive, there is no irritation reaction. There is therefore still a need to develop dermatological and / or cosmetic active agents that have a very good efficacy as well as a broad spectrum of action on the skin and integuments. Now, applicants have recently discovered the involvement of a new protein in the mechanisms of skin cells that has an important role in aging and cell protection.

They have indeed demonstrated that the SIRT protein, and more specifically the SIRT1 protein, was expressed in the cells of the skin and that its expression was related to the various stresses that cutaneous cells encounter. They have notably demonstrated that the induction of the expression of this protein, by different agents, made it possible to protect the cells and to better help them fight against the stress and the intrinsic aging thereof.

SIRT proteins are part of the Sirtuine family, they are nuclear proteins, NAD + dependent, playing an important role in the deacetylation of histones. SIR (Silent Information Regulators) genes, encoding SER proteins, were first described in S. cerevisiae in 1979 (Rine J and AL, Genetics

1979). Later, it was shown that overexpression of the protein SIR2P, in C. elegans, allowed to increase the life of this organism (Tissenbaum and AL, Nature 2001). This study thus emits the hypothesis that these proteins are linked to longevity.

SIRT1 protein is the most well-characterized human sirtuin, interacting with many transcriptional regulators. The human protein SIRT1 has been described as being involved in the regulation of p53 (Cheng HL et al., Proc Natl Acad Sci US A 2003), and, more recently, as a modulator of cellular senescence (Langley E and Al, EMBO J. 2002). Other Sir human proteins have been discovered (SIRT2, SIRT3, SIRT4-7). The human protein SIRT2 has been little studied, but some studies have demonstrated its role in the control of mitotic activity (Dryden SC and Al, Mol CeIl Biol 2003) and its involvement in the regulation of the p53 protein (Vaziri H and Al, CeIl 2001). To date, sirtuin deacetylases are considered to be an enzyme family that plays an important role in the regulation of cell death and in its life cycle (M. and Chiarugi A., Tr ends Pharmacol ScL, 2005) . The present invention relates to a cosmetic or pharmaceutical composition containing, in a cosmetically or pharmaceutically acceptable medium, at least one compound capable of activating the synthesis of SIRT proteins in the cells of the skin. Preferably, according to the invention, the compounds will activate a particular class of SIRT proteins, SIRT1 proteins. To date, no use of synthetic inducing compounds of SIRT family proteins in skin cells has been described.

By compound capable of activating the synthesis of SIRT proteins in the cells of the skin is meant essentially all compounds capable of promoting the endogenous production of SIRT proteins; and most particularly the molecules involved in the positive control of precursors such as DNA or RNA.

Among these compounds capable of activating the synthesis of SIRT proteins in the skin, mention may be made of various molecules including, for example, polyphenols. More particularly, mention may be made of: trans-stilbene derivatives (resveratrol, piceatannol), chalcone derivatives (isoliquiritigenin, butene), flavone derivatives (fisteine, luteoline, quercetin).

Preferably, according to the invention, the compounds capable of promoting the synthesis of SIRT proteins in the cells of the skin will be compounds of a peptide nature.

Among the compounds of peptide nature, mention may be made of protein fragments, peptide or polypeptide fragments, peptides and any sequence of two or more amino acids linked together by peptide bonds. Preferably, according to the present invention, said peptide fragments are peptide fragments whose number of amino acids is between 3 and 50, more particularly between 3 and 10. All these peptide fragments have a biological activity.

According to a particularly advantageous method of carrying out the invention, the compound capable of activating the synthesis of the SIRT proteins of the skin is a peptide of formula (I):

(I) (AA) n - Thr - GIn - Asn - Ile - Asp - Thr - Leu - (AA) n wherein (AA) is any amino acid, or a derivative thereof, and n is an integer between 0 and 3.

Moreover, according to a very particularly preferred embodiment of the invention, the compound, a SIRT protein inducer of the skin, possesses the Thr-GIn-Asn-Ile-Asp-Thr-Leu sequence.

By the expression "SIRT proteins of the skin" is meant all the proteins of the SIRT family, but preferentially, the term SIRT1 proteins is meant.

The invention also relates to variant forms of these sequences and / or fragments. The term "variant" herein refers to a polypeptide or peptide that differs from, for example, the sequence of a reference peptide while retaining its essential properties. Generally, the differences are limited so that the sequences of the reference peptide and those of the variant are quite similar and, in some regions, identical. A variant peptide and a reference peptide may thus differ from the amino acid sequence by one or more substitutions, additions, deletions in all combinations. Preferentially, the variant forms are those which vary from the reference sequences, by the substitution of chemically equivalent amino acids

(or homologues), that is to say by the substitution of a residue by another having the same characteristics. Thus, the classical substitutions are between Ala, Val, Leu and Ile; between Ser and Thr; between Asp and Glu acid residues; between Asn and GIn; and between the basic residues Lys and Arg; or between the aromatic residues Phe and Tyr.

In the invention, the term "amino acid" refers herein to any natural or unnatural organic acid having the formula:

-NHR-CR-C (O) -O- where each -R is independently selected from hydrogen and an alkyl group having 1 to 12 carbon atoms. Preferably, at least one -R group of each amino acid is a hydrogen. By the term "alkyl" is meant herein a carbon chain which may be linear or branched, substituted (mono- or poly-) or unsubstituted ; saturated, mono-saturated (a double or triple bond in the chain) or polyunsaturated (two or more double bonds, two or more triple bonds, one or more double bonds and one or more triple bonds in the chain).

The term "peptide" refers to a sequence of two or more amino acids linked together by peptide bonds or modified peptide bonds; a polypeptide designating a larger peptide. By peptide is meant the natural or synthetic peptide of the invention as described above or at least one of its fragments, whether obtained by proteolysis or synthetically or any natural or synthetic peptide which the sequence is totally or partially constituted by the sequence of the peptide previously described.

It may be that for resistance to degradation, it is necessary to use a protected form of the peptide according to the invention. The form of protection must obviously be a biologically compatible form and must be compatible with use in the field of cosmetics or pharmacy. Many biologically compatible forms of protection can be envisaged, they are well known to those skilled in the art such as, for example, the acylation or acetylation of the amino-terminal end, or the amidation or esterification of the carboxy-terminal end. Thus, the invention relates to a use as defined above characterized in that the peptide is in protected form or not. Preferably, protection based on either acylation or acetylation of the amino-terminus, or amidation or esterification of the carboxy terminus, or both is used. The amino acid derivatives and the peptide derivatives also relate to amino acids and peptides linked together by a pseudo-peptide bond. The term "pseudo-peptide bond" means all types of bonds likely to replace the "conventional" peptide bonds.

In the field of amino acids, the geometry of the molecules is such that they can theoretically be in the form of different optical isomers. There is, indeed, a molecular conformation of the amino acid (AA) as it deviates on the right the plane of polarization of the light (dextrorotatory conformation or D-aa), and a molecular conformation of the amino acid ( aa) as it deviates on the left the plane of polarization of the light (laevorotatory conformation or L-aa). Nature has retained for natural amino acids only the levorotatory conformation. Consequently, a peptide of natural origin will consist only of amino acids of the L-aa type. However, chemical synthesis laboratory makes it possible to prepare amino acids having both possible conformations. From this basic material, it is thus possible to incorporate during the synthesis of peptide both amino acids in the form of optical isomers dextrorotatory or levorotatory. Thus, the amino acids constituting the peptide according to the invention can be in L- and D- configuration; preferably, the amino acids are in L form. The peptide according to the invention can therefore be in L-, D- or DL- form.

The peptides according to the invention can be prepared by any appropriate method, thus the peptides can be peptides isolated from naturally occurring peptides and proteins, recombinant peptides, synthetic peptides, or peptides produced by a combination of these methods. Of course, the methods for preparing the peptides according to the invention are well known to those skilled in the art. Thus, the peptide according to the invention may be a peptide of natural or synthetic origin. Preferably according to the invention, the peptide is obtained by chemical synthesis.

It is of course obvious that compounds capable of activating the synthesis of SIRT proteins in skin cells may be used alone or in combination with at least one other active agent, in or for the preparation of a cosmetic composition and or dermatological and / or pharmaceutical.

According to an advantageous embodiment of the invention, the abovementioned compounds, according to the invention, are previously solubilized in one or more cosmetically or pharmaceutically acceptable solvents, conventionally used by those skilled in the art, such as water or ethanol. propylene glycol, butylene glycol, dipropylene glycol, ethoxylated or propoxylated diglycols, cyclic polyols, petroleum jelly, a vegetable oil or any mixture of these solvents.

According to yet another advantageous embodiment of the invention, the abovementioned compounds are first solubilized in a cosmetic or pharmaceutical vector such as liposomes or adsorbed on powdery organic polymers, mineral supports such as talcs and bentonites, and more generally solubilized in or attached to any cosmetically or pharmaceutically acceptable carrier.

The composition, containing compounds capable of activating the synthesis of SIRT proteins in skin cells, can be a dermatological or pharmaceutical or cosmetic composition.

The composition according to the invention is preferably a cosmetic and / or dermatological composition, the excipients of which are suitable for administration by the route external topical; this composition advantageously comprising a cosmetically or pharmaceutically acceptable medium. Preferably, according to the invention, the composition is a cosmetic composition, because it is intended to improve the appearance and general cutaneous performance of the individual who makes use of it.

The effective amount of active ingredient is the amount needed to achieve the desired result. According to one embodiment of the invention, the abovementioned compounds are present in the compositions of the invention in an amount representing between 10 ^-6 and 20%, approximately, and preferentially in an amount representing between 10 -4 and 5 About one percent of the total weight of the final composition According to a presently preferred embodiment, when the above-mentioned compound is peptide in nature, the peptide will be present in the compositions of the invention at a concentration of between 0.005 and 500 ppm ( parts per million), and preferably at a concentration of between 0.1 and 50 ppm approximately relative to the total weight of the final composition, whatever the form of the invention, the composition according to the invention can be injected or applied to the skin (on any cutaneous zone of the body), the hair, the nails or the mucous membranes Depending on the method of administration, the composition according to the invention may be s all galenic forms normally used.

Preferably, the compositions according to the present invention will be in a dosage form suitable for topical administration to the skin, and cover all cosmetic or dermatological forms. These compositions must therefore contain a cosmetically acceptable medium, that is to say, compatible with the skin, mucous membranes and integuments.

These compositions may especially be in the form of an aqueous solution, hydroalcoholic or oily; an oil-in-water, water-in-oil emulsion or multiple emulsions; they may also be in the form of creams, suspensions or powders, suitable for application to the skin, mucous membranes, lips and / or integuments. These compositions may be more or less fluid and have the appearance of a cream, lotion, milk, serum, ointment, gel, paste or paste. a foam. They can also be in solid form, as a stick or be applied to the skin in aerosol form. They can be used as a care product and / or as a make-up product for the skin. These compositions additionally comprise any additive commonly used in the field of application envisaged as well as the adjuvants necessary for their formulation, such as solvents, thickeners, diluents, antioxidants, dyes, sunscreens, self-tanning agents, pigments, fillers, preservatives, perfumes, odor absorbers, cosmetic or pharmaceutical active ingredients, essential oils, vitamins, essential fatty acids, surfactants, film-forming polymers, etc. .

In all cases, those skilled in the art will ensure that these adjuvants and their proportions are chosen in such a way as not to harm the desirable advantageous properties of the composition according to the invention. These adjuvants may, for example, correspond to 0.01 to 20% of the total weight of the composition. When the composition of the invention is an emulsion, the fatty phase may represent from 5 to 80% by weight and preferably from 5 to 50% by weight relative to the total weight of the composition. The emulsifiers and co-emulsifiers used in the composition will be chosen from those conventionally used in the field under consideration. For example, they can be used in a proportion ranging from 0.3 to 30% by weight, relative to the total weight of the composition.

Of course, those skilled in the art will take care to choose any additional compounds, active or non-active, and / or their amounts, so that the advantageous properties of the mixture are not, or not substantially, altered by the addition considered.

The compositions according to the invention find an application in particular as cosmetic or pharmaceutical compositions for the skin, mucous membranes and / or semi-mucous membranes. They find application as a protection product and / or skincare, or as an anti-wrinkle and / or anti-aging composition. It is also possible to envisage other applications in the field of compositions in combination, for example with other active agents. The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.

The recent discovery of the presence of SIRT proteins in skin cells, and more specifically the presence of the SIRT1 protein, as well as their involvement in many fundamental cellular mechanisms and, in particular, those involved in cellular stress, have allowed to consider multiple uses for compounds according to the invention. SIRT1 protein has a very important function in aging and cellular protection. Indeed, it has been shown that an increase in its expression allows the skin to better withstand the stress that surrounds it, that is to say to better fight against the phenomena of oxidation and, more generally, of better fight against aging. More generally, the induction of the expression of this protein in skin cells provides a general improvement of cell protection mechanisms and would increase the cell life.

Several uses of the previously defined compounds intended to activate the endogenous synthesis of SIRT proteins, in particular SIRT1 proteins, or compositions containing them, have therefore been envisaged. Thus, an essential aspect of the invention is the use of at least one inducing compound for the endogenous synthesis of SIRT proteins in skin cells, in or for the preparation of a cosmetic and / or pharmaceutical composition, the compound or the composition containing it being intended to provide care to the skin and / or integuments. More precisely among the compounds inducing the endogenous synthesis of proteins

SIRT ₅ may be compounds of peptide nature. Preferentially, the compounds capable of promoting the synthesis of SIRT proteins, and more particularly of SIRT1 proteins, will be peptides corresponding to formula (I). According to a currently preferred embodiment, the SIRT protein inducing compound of the skin has the Thr - GIn - Asn - Ile - Asp - Thr - Leu sequence.

Said compounds being also advantageously used in order to fight in a curative and / or preventive manner against the manifestations of skin aging, but also in order to improve the appearance of the skin and / or integuments.

By the care of the skin and / or integuments, we mean all the actions intended to maintain or restore a good functioning of the skin and / or superficial body growths or any means which serves to preserve or improve their appearance and / or their appearance. So the care includes hydration, soothing, protection against all types of aggression, including sun protection, the fight and the prevention of the manifestations of aging. By cutaneous manifestations of aging is meant any changes in the external appearance of the skin due to aging, such as, for example, wrinkles and fine lines, wilted skin, soft skin, thinned skin, lack of elasticity and / or skin tone, dull and lackluster skin but also any internal changes in the skin that do not always translate into an external appearance modified, for example, any internal skin damage resulting from exposure to ultraviolet radiation. The term "improve the appearance of the skin" means all phenomena that are likely to result in a visual improvement of the state of the skin. The skin will look better; it will be, for example, much more beautiful, firm and / or smooth. All small imperfections will be diminished or removed. The papery appearance of the skin will, for example, be attenuated.

In addition, the active ingredient according to the invention, or the composition containing it, may be intended to protect keratinous substrates, and more particularly to protect the skin and / or integuments against all types of external aggression. The use of these active agents, or a composition containing them, will allow the keratinous substrates to be protected and to better withstand the stress that the environment produces on them. The term "external aggression" is understood to mean the aggressions that the environment can produce. These attacks can be of chemical, physical, biological or thermal origin. In another aspect, the compounds will be advantageously used to reduce and / or prevent inflammatory and / or skin irritant reactions. Indeed, the compounds according to the invention, intended to activate the endogenous synthesis of SIRT1 proteins, have anti-inflammatory and anti-irritant effects. The use of the properties of these assets therefore makes it possible to have a skin that is more protected and much less sensitive to the various aggressions that it may encounter. The skin is soothed.

Moreover, the compounds according to the invention as defined above, stimulate the metabolic functioning of the cells of the skin. They thus make it possible to increase the synthesis of proteins essential to its functioning, in particular by increasing the synthesis of proteins constituting the extracellular matrix. The compounds according to the invention, or the composition containing them, thus have a positive action on tissue regeneration. The compounds according to the invention are particularly effective in treating cicatrization disorders.

These compounds, intended to activate the endogenous synthesis of SIRT proteins, previously defined, are thus used in or for the manufacture of a pharmaceutical and / or cosmetic composition, for topical use. They will be used, more generally, to treat dermatological conditions.

Dermatological conditions are all diseases affecting the skin and having or not visible consequences. As such, for example: disorders related to cell differentiation and proliferation problems, problems with keratinization, inflammatory or allergic disorders, disorders related to sebaceous functions, dermal or epidermal proliferations (benign or malignant); cutaneous disorders due to exposure to UV radiation, pathologies associated with chronological or actinic aging.

Furthermore, according to another aspect, the compounds according to the invention, as described above, intended to activate the endogenous synthesis of SIRT proteins in the cells of the skin, will be used for the manufacture of a medicament intended for the treatment of affections dermal. The present invention also relates to the use, as a medicament, of the compounds described above.

According to another aspect, the present invention relates to a cosmetic treatment method for care of the skin and / or superficial body growth consisting in applying to the surface of the skin an effective quantity of active agent, or of the cosmetic composition containing it, as defined above, in order to obtain the desired action. These methods may especially be used in order to preventatively and / or curatively treat the manifestations of cutaneous aging, but also in order to protect the skin and / or integuments against external aggressions such as the harmful effects of radiation, in particular UV radiation. or to fight against the manifestations of inflammation and skin irritation.

The cosmetic treatment method of the invention may be implemented in particular by applying the cosmetic compositions as defined above, according to the usual technique of use of these compositions, for example: application of creams, gels, serums , lotions, milks, shampoos or sunscreens, on the skin or on the hair, or application of toothpaste on the gums.

Particular embodiments of this cosmetic treatment method also result from the foregoing description. Other advantages and characteristics of the invention will appear better on reading the examples given by way of illustration and not limitation.

Example: Preparation of compositions.

The quantities indicated are given as a percentage of weight. 1 - Anti-wrinkle cream:

The constituents of phase A and phase B are heated separately at a temperature between 65 ° C and 70 ° C, phase C is incorporated, then phase A is emulsified in phase B. The carbomer is neutralized with the phase D at a temperature around 45 ° C. Phase E is then added with stirring and cooling is continued to 25 ° C.

2 - Anti-aging body milk:

The components of phase A and phase B are heated separately at a temperature between 70 ° C and 75 ° C. Phase B is emulsified in A with stirring "Staro". After cooling to 50 ° C, the mixture is neutralized with phase C. Phase D is then added when the temperature is below 40 ° C. Cooling is continued to 25 ⁰ C with slow stirring.

3 - Sun protection cream:

The components of phase A and phase B are heated separately at a temperature between 70 ° C and 75 ° C. Phase B is emulsified in A with stirring. Phase C is added at 45 ° C, increasing stirring. Phase D is then added when the temperature is below 40 ° C. Cooling is continued up to 25 ° C with vigorous stirring.

Claims

1. Cosmetic or pharmaceutical composition characterized in that it contains, in a cosmetically or pharmaceutically acceptable medium, at least one compound capable of activating the synthesis of SIRT proteins in skin cells.

2. Composition according to claim 1 characterized in that the excipients of this composition are suitable for external topical administration.

3. Composition according to claim 1 or 2 characterized in that the SIRT proteins are SIRTl proteins.

4. Composition according to any one of the preceding claims, characterized in that the compounds capable of activating the synthesis of SIRT proteins in skin cells are compounds of a peptide nature.

5. Composition according to claim 4, characterized in that the compound is a peptide of formula (I): (I) (AA) n-Thr-GIn-Asn-Ile-Asp-Thr-Leu-(AA) n in which (AA) is any amino acid, or a derivative thereof, and n is an integer of 0 to 3.

6. Composition according to claim 4 characterized in that the peptide has the sequence Thr - GIn - Asn - Ile - Asp - Thr - Leu.

7. Composition according to any one of claims 1 or 2 characterized in that said compound, capable of activating the synthesis of SIRT proteins, is present in an amount representing between 10 ^"6 and 20% approximately, and preferably in a quantity representing between 10 ^-4 and 5% relative to the total weight of the final composition.

8. Composition according to any one of claims 3 to 6 characterized in that the compound of peptide nature is present in the composition at a concentration between about 0.05 and 500 ppm, and preferably at a concentration between 0 , 1 and 50 ppm about the total weight of the final preparation.

9. Use of at least one compound capable of activating the endogenous synthesis of SERT proteins in skin cells, in or for the preparation of a composition, the compound or the composition being intended for skin care and / or or dander.

10. Use of at least one compound capable of activating the endogenous synthesis of SIRT proteins in skin cells, in or for the preparation of a composition, the compound or the composition being intended to protect the skin and / or dermers against all types of external aggression.

11. Use of at least one compound capable of activating the endogenous synthesis of SERT proteins in skin cells, in or for the preparation of a composition, the compound or the composition being intended for reducing and / or preventing inflammatory and / or irritating skin reactions

12. Use of at least one compound capable of activating the endogenous synthesis of SERT proteins in skin cells, for the manufacture of a medicament for the treatment of dermal conditions.

13. Use according to any one of claims 9 to 12, characterized in that the SERT proteins are SERTI proteins.

14. Use according to any one of claims 9 to 13 characterized in that the compound is a peptide of formula (I):

(I) (AA) n - Thr - Gm - Asn - Ile - Asp - Thr - Leu - (AA) n wherein (AA) is any amino acid, or a derivative thereof, and n is an integer between 0 and 3.

15. Use according to claim 14 characterized in that the peptide has the sequence Thr - GIn - Asn - Ile - Asp - Thr - Leu.

16. Use according to any one of claims 9 to 15 characterized in that the composition contains cosmetically or pharmaceutically acceptable excipients.

17. Use according to claim 16 characterized in that the excipients are suitable for external topical administration.

18. Process for the cosmetic treatment of the skin and / or superficial body growths, characterized in that a cosmetic composition as defined in any one of Claims 1 to 8 is applied to the skin and / or to the integuments.