FR2835745A1 - Retinoid containing cosmetic or dermatological composition used e.g. for combating skin aging, contains heat shock protein inducer, preferably Artemisia salina extract - Google Patents

Abstract

Use of heat shock protein (HSP) inducing agent(s) (I) is claimed in: (1) reducing the secondary effects of retinoids (II); (2) maintaining a physiological HSP level in cells and/or skin during treatment with (II), (3) regulating the inflammatory cytokine level in cells and/or skin during treatment with (II) and/or (4) protecting cells and/or skin against external stress during treatment with (II). An Independent claim is included for cosmetic, pharmaceutical or dermatological compositions comprising (I) and (II) in a suitable medium.

Description

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The present invention relates to a cosmetic or pharmaceutical composition comprising at least one retinoid and one inducer of Heat Shock Proteins (HSP).

The invention also relates to methods of cosmetic or dermatological treatment of the skin, in particular to limit the side effects of retinoids.

The family of retinoids includes compounds with a biological activity profile similar to that of retinoic acid all-trans (also called vitamin A acid, tretinoin, retinoic acid) or 9-cis-retinoic acid: they modulate the expression of certain genes through RAR receptors: retinoic acid receptors.

The cosmetic and / or dermatological compositions based on retinoids have undergone significant development in recent years. Their activities are described, among others, at the level of differentiation and cell proliferation. Representative compounds of this group include retinol esters, retinoic acid and retinal, in the form of its different isomers.

Their pharmaceutical uses are very numerous as anti-cancer and in rheumatic, cardiovascular, respiratory and dermatological conditions.

For example, dermatologically and cosmetically, the use of retinoic acid for the treatment of acne is well known. In addition, it has been demonstrated that retinoids, and retinol in particular, have a favorable effect on improving the appearance and condition of the skin and help to combat the signs of aging. A method of treating aged skin using retinoids has been described in EP 0 379 367.

The treatment of the skin by retinoids is part of the preventive or curative care of skin manifestations of aging such as the appearance of wrinkles, fine lines, loss of elasticity, dryness and stains.

Retinoids are also used to fight against irregular hyperpigmentation, lentigines, roughness of the skin. Other patents, such as US Pat. Nos. 4,603,146, 4,887,805 and 4,888,342, describe the use of retinoids to diminish and prevent damage to the skin caused by light radiation.

Several patents describe improvements made to the treatment of certain skin conditions using retinoids, and this to reduce their irritancy, as the application FR9607110.

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 However, it has been established that the use of retinoids is extremely irritating to the skin during the first weeks of use. And although several methods and formulations have been proposed to reduce this strong retinoid-induced irritation, no solution is currently completely satisfactory.

So we see that there remains the need for a new product, exerting an action on treatments with retinoids, to offset the side effects of retinoids.

However, the Applicant has found, surprisingly and unexpectedly, that an effective amount of an inducer of Heat Shock Protems (HSP) has a beneficial effect on the skin treated with retinoids.

HSPs are among the oldest and most conserved proteins. There are homologues in all species and in all living kingdoms.

For example, dnaK, a single gene in the bacterium, has become the multigene complex of the HSP70 family in. Saccharomyces sp., In Drosophila and man.

If HSPs appeared early in the evolution, it was because of the extreme environmental conditions faced by organisms. During evolution, HSP proteins have maintained their vital role of protecting against stress, they have also taken on new functions, such as, for example, the transport of proteins inside the cell.

The essential defense mechanism of any organism is the conservation of its genetic, protein and membrane material. For this purpose, the HSP proteins, known as stress proteins or Heat hock Proteins (HSP), have the role of protecting or repairing the genetic material, the peptides and proteins deteriorated during a stress. The synthesis of HSPs is thus a generalized defense, developed by the cell to fight against the great diversity of possible aggressions.

In order to cope with stress, living organisms have developed several response mechanisms, depending on the type of sudden shock and the damage that may be caused.

In the absence of aggression, the cells contain a constitutive level of HSP induced by the cell cycle, development and differentiation, oncogenesis and proto-oncogenesis.

The constitutive expression of most HSPs indicates that they play a vital role in

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 the proper functioning of the cell by participating, among other things, in protein biosynthesis, signal transmission or cell proliferation.

HSPs are also called chaperone molecules because they associate with other molecules, either denatured or during biosynthesis. These molecular interactions are intended to prevent the aggregation of altered proteins or during biosynthesis, to participate in the acquisition of their three-dimensional structure, to eliminate abnormal proteins, to participate in the transport of proteins from the cytoplasm to the membrane or to organelles such as mitochondria, endoplasmic reticulum, lysosomes or the nucleus.

By interacting with certain proteins, HSPs will minimize the likelihood for these proteins to interact with others inappropriately. HSPs recognize and bind to molecules that are not in a native conformation, either after a denaturing stress, or on proteins being synthesized, folding, assembly, or because they are not localized in the correct form. subcellular compartment.

To the knowledge of the Applicant, it has never been described in the prior art the use of HSP inducers to treat and protect skin treated with retinoids.

The subject of the invention is therefore a cosmetic or pharmaceutical composition comprising, in a cosmetically or pharmaceutically acceptable medium, at least one retinoid and one inducer of Heat Shock Proteins (HSP).

The retinoids according to the invention are chosen from the group of retinol, all-trans retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, retinaldehydes, their salts and their salts. esters.

The retinoid salts according to the invention are chosen from the group containing the sodium, potassium, ammonium and C2-C30 alkanolamine salts.

According to the invention, the retinoids are present in the composition at a content of 0.0001-5% by weight, preferably 0.001-1%, relative to the total weight of the composition.

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This invention also includes an inducer of Heat Shock Proteins.

Thereafter the inductive term of Heat Shock Proteins must be understood by a compound which, applied on the skin or cells, will induce the synthesis of Heat Shock Proteins (also called heat shock proteins, HSP, stress proteins).

In the compositions of the invention, the Heat Shock Proteins inducer induces HSPs that belong to one or more of the HSP families: small HSPs (10-30 kDa), HSP40, HSP60, HSP70, HSP90, HSP 100- 110.

In the compositions of the invention, the Heat Shock Proteins inducer will make it possible to increase the HSP content at the cellular level.

According to an advantageous embodiment of the invention, the inducer of Heat Shock Proteins is an extract of Artemia salina zooplankton dormant.

According to another advantageous embodiment of the invention, the inducer of Heat Shock Proteins is previously solubilized in one or more cosmetically or pharmaceutically acceptable solvents such as water, petroleum jelly, a vegetable oil, propylene glycol, butylene glycol , dipropylene glycol, ethoxylated or propoxylated diglycols, ethanol, propanol or isopropanol.

According to yet another advantageous embodiment of the invention, the Heat Shock Proteins inducer is previously 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.

To give an order of magnitude, in the cosmetic or dermatological compositions of the present invention, the inducer of Heat Shock Proteins is present in the composition at a content of 0.0001-10% by weight, preferably 0.001-5%, and still more preferably 0.05-3% by weight, based on the total weight of the composition.

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 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 and / or dermatologically acceptable medium, that is to say compatible with the skin, hair or hair. These compositions may especially be in the form of creams, oil-in-water emulsions, water-in-oil or multiple emulsions, solutions, suspensions, or powders, suitable for application to the skin, lips and / or hair .

This composition may be more or less fluid and have the appearance of a cream, lotion, milk, serum, ointment, gel, paste or paste. a foam. It can also be in solid form, as a stick, or be applied to the skin as an aerosol. It can be used as a care product and / or as a make-up product for the skin.

These compositions comprise, in known manner, the adjuvants necessary for their formulation, such as solvents, thickeners, diluents, antioxidants, dyes, filters, pigments, fillers, preservatives, perfumes, odor absorbers. In all cases, these adjuvants, as well as their proportions, will be chosen so as not to harm the properties sought in 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 coemulsifiers used in the composition will be chosen from those conventionally used in the field under consideration. For example, they may 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.

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The present invention also relates to a method of cosmetic or dermatological treatment of the skin, wherein is applied to the skin, the composition defined above to limit the side effects of retinoids.

The present invention also relates to a cosmetic or dermatological treatment method for restoring a physiological level of Heat Shock Pro in skin and cells, consisting in applying to the skin treated with retinoids, the composition as defined above.

Subsequently, the term physiological level of Heat Shock Proteins must be understood as an expression rate of Heat Shock Proteins (stress proteins) which is of a physiological order.

The invention relates to a cosmetic or dermatological treatment method for regulating the level of inflammatory cytokines induced by retinoids in the skin and cells, comprising applying to the skin treated with retinoids, the composition as defined above.

The invention finally relates to a cosmetic or dermatological treatment method for protecting external stresses (heat, solar radiation, heavy metals, solvents) during retinoid therapies, which consists in applying to the skin treated with retinoids, the composition such as than previously defined.

The invention relates to a cosmetic process for the treatment of aged skin, consisting in applying, on aged skin treated with retinoids, the composition as defined above.

The subject of the invention is the use, in the compositions of the invention, of at least one retinoid and an inducer of Heat Shock Proteins, to limit the side effects of retinoids.

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 Another subject of the invention is the use in the compositions of the invention, of at least one retinoid and a heat shock protein inducer, for regulating the level of inflammatory cytokines, during treatment with retinoids in cells and skin.

The invention further relates to the use in the compositions of the invention, of at least one retinoid and a Heat Shock Proteins inducer, for maintaining a physiological level of Heat Shock Proteins in cells and skin.

The invention further relates to the use in the compositions of the invention of at least one retinoid and inducer of Heat Shock Proteins, for maintaining a physiological level of Heat Shock Proteins in aged cells and aged skin.

The invention also relates to the use in the compositions of the invention, of at least one retinoid and a heat shock protein shield inducer, for protecting the cells and the skin from external stresses (heat, solar radiation, heavy metals, solvents ) during therapies using retinoids.

The invention finally relates to the use in the compositions of the invention, of at least one retinoid and an inducer of Heat Shock Proteins, for the treatment or prevention of signs of skin aging.

Other advantages and characteristics of the invention will appear better on reading the examples given by way of illustration and without limitation. EXAMPLE 1 Preparation of a Heat Shock Protein Inducer 50 grams of Artemia salina eggs are rehydrated for 30 minutes at 6 hours, at a temperature of 30 C to 65 C, in 1 liter of a suitable medium, mainly consisting of water, and at a pH between 4 and 7. Then, these eggs are crushed. The intracytoplasmic content obtained is centrifuged and filtered. The extract is finally sterilized by sterilizing filtration and heating to 65OC.

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An HPLC assay is performed to confirm a diguanosine tetraphosphate content greater than 150 mg / liter.

Example 2-Effects of retinoids and the extract of Example 1 on inflammation The Artemia extract of Example 1 was used at 3% in in vitro tests in order to highlight the benefits of its association with retinoids to reduce inflammation.

- Acide tout-trans rétinoïque pendant 6 jours - Acide tout-trans rétinoïque pendant 6 jours dont 48 heures avec l'extrait de l'exemple 1 Après les 6 jours, le dosage de l'IL-l alpha total est réalisé par ELISA. HaCat human keratinocytes are cultured in culture dishes of 100 mm in diameter. When the cells are at 50% confluency, concentrations of 3% of the extract of Example 1 were or were not applied to the cells for 48 hours. In parallel, concentrations of 10-7 M of all-trans retinoic acid are or are not applied. According to the boxes, different conditions are used: - No treatment - Extract of Example 1 for 48 hours

- All-trans retinoic acid for 6 days - All-trans retinoic acid for 6 days including 48 hours with the extract of Example 1 After 6 days, the total IL-1 alpha assay is performed by ELISA.

While the extract of Example 1 does not alter the inflammatory response (represented by the level of IL-1 alpha), treatment with retinoic acid significantly increases the concentration of IL-1alpha. The association between the retinoic acid and the extract of Example 1 makes it possible to preserve, in the cells, a physiological level of IL-1 alpha.

Inflammatory cytokines markedly overexpressed in treatment with retinoic acid are modulated by association with Artemia extract.

Artemia extract therefore reduces inflammation induced by retinoids.

des Heat Shock Proteins Example 3-Effects of retinoids and the extract of Example 1 on in vitro expression

Heat Shock Proteins

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 Immunoblotting studies were conducted on human fibroblasts cultured for 7 weeks at 37 C and 5% CO2 in a humid incubator.

Several conditions were tested: - Untreated cells - Cells treated with 10-7 M retinoic acid - Cells treated with 3% of the Artemia extract of Example 1 - Cells treated with 10-7 M of Retinoic acid and 3% of the Artemia extract of Example 1 The results showed that: On the young fibroblasts, the expression of the HSP 70 (Heat Shock Proteins 70) is decreased by the treatment with the retinoic acid. On the other hand, the combination with the Artemia extract of Example 1 makes it possible to restore a physiological level of HSP 70.

On the other hand, aging fibroblasts express much less HSP 70 than younger fibroblasts. In this case, treatment with retinoic acid slightly increases the expression of HSP 70, whereas treatment with Artemia extract in combination or not with retinoic acid restores a rate of Heat Shock Proteins close to that present in young fibroblasts.

These results show that the association between Artemia extract and retinoids helps maintain a physiological level of Heat Shock Proteins in young and old cells.

Since the involvement of Heat Shock Proteins in cell and skin protection has been extensively studied, these results prove that the association between retinoids and Artemia extract benefits from the benefits of retinoids without reducing the skin's defenses.

EXAMPLE 4 Effects of retinoids and the extract of Example 1 on cutaneous expression of Heat Shock Proteins Ex vivo studies have made it possible, by immuno-labeling, to highlight the expression of HSP 70 on samples of skins put in culture during 5 days. The samples

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 were treated or not with 10-7 M retinoic acid and the Artemia extract of Example 1 at 3%. The treatments were carried out twice a day during the 5 days of culture.

The skin samples were fixed with 9% saline formalin for 10 hours and then automatically included in the paraffin. Sections of 2 to 3 μm were then made to proceed to immuno-labeling.

Skins treated with retinoic acid express significantly less HSP 70 than untreated skins. On the other hand, skins treated with a combination of retinoic acid and Artemia extract express a level of HSP 70 comparable to that observed in untreated skins.

Thus, the extract of Artémia makes it possible, at the cutaneous level, to restore a physiological content in Heat Shock Proteins, and this, in spite of the reduction brought by the retinoids.

EXAMPLE 5 Effects of Retinoids and of the Extract of Example 1 on Cutaneous Expression of Heat Shock ProttM, Following UV Stress

The experiments carried out in Example 4 were repeated, but the skins were irradiated with UVB doses of 200 mJ / cm.

The expression of HSP 70 is amplified following UV stress. On the other hand, in the presence of retinoic acid, this expression is clearly diminished, and thus the defenses of the skin are reduced.

The combination with Artemia extract helps to restore the rate of Heat Shock Profeins, the skin can thus protect against UV stress.

While retinoids reduce the skin's defenses against external stress, the combination with Artemia extract helps to protect the skin treated with retinoids during stress.

 The advantages brought by this association make it possible to consider serenely the use of retinoids, knowing that the defenses of the skin will not be weakened but on the contrary reinforced.

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Example 6 Preparation of a Composition This composition is obtained by simple mixing of the various components. The quantities indicated are given as a percentage of weight.

1-Emulsion oil in water Oily phase:

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<tb> a <SEP> Montanov <SEP> 68 <SEP> (Ceteatyl <SEP> Alcohol <SEP> and <SEP> Cetearyl <SEP> Glucoside) <SEP> 5.00 <SEP>
<tb> a <SEP> Oil <SEP> of <SEP> Jojoba <SEP> 5.00 <SEP>%
<tb> a <SEP><SEP> Retinoic acid <SEP> 0.50 <SEP>%
<tb>"Oil<SEP> of <SEP> Vaseline <SEP> 5.00 <SEP>%
<tb>"Isopropyl<SEP> Palmitate <SEP> 7,00 <SEP>%
<Tb>
Aqueous phase :

<Tb>
<tb>#<SEP> glycerin <SEP> 5.00 <SEP>%
<tb>#<SEP> Allantoin <SEP> 0.10 <SEP>%
<tb>#<SEP> Extracted <SEP> from <SEP> Example <SEP> 1 <SEP> 3.00 <SEP>%
<tb>#SEP> Sepigel <SEP> 305 <SEP> (Polyacrylamide <SEP> and <SEP> C13-14 <SEP> Isoparaffin <SEP> and <SEP> laureth-7) <SEP> 0.30 <SEP >%
<tb>#<SEP> Conservative <SEP> 0.50 <SEP>%
<tb>#<SEP> Fragrance <SEP> 0.50 <SEP>%
<tb>#<SEP> Water <SEP> qsp <SEP> 100 <SEP>%
<Tb>

Claims (21)

 1. Cosmetic or pharmaceutical composition comprising, in a cosmetically or pharmaceutically acceptable medium, at least one retinoid and one inducer of Heat Shock Prenms (HSP). 2. Composition according to the preceding claim, wherein the retinoids are selected from the group of retinol, all-trans retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, retinaldehydes, their salts and their esters. The composition of claim 2, wherein the retinoid salts are selected from the group consisting of sodium, potassium, ammonium and alkanolamine salts. C2-C30. 4. Composition according to one of the preceding claims, wherein the retinoid (s) are present in the composition at a content of 0.0001-5% by weight, preferably 0.001-1%, relative to the total weight of the composition. . 5. Composition according to one of the preceding claims, wherein the inductor of Heat Shock Proteins induces HSPs that belong to one or more of the HSP families: small HSPs (10-30 kDa), HSP40, HSP60, HSP70, HSP90, HSP100-110. 6. Composition according to one of the preceding claims, wherein the inductor of Heat Shock Proteins will increase the level of HSP at the cellular level. 7. Composition according to one of the preceding claims, wherein the inductor of Heat Shock Proteins is a dormant arma salina extract. 8. Composition according to one of the preceding claims, wherein the inductor of Heat Shock Proteins is previously solubilized in one or more cosmetically or pharmaceutically acceptable solvents such as water, petroleum jelly, a vegetable oil, propylene glycol, butylene glycol, dipropylene glycol, ethoxylated or propoxylated diglycols, ethanol, propanol or isopropanol. <Desc / Clms Page number 13> 9. Composition according to one of the preceding claims, wherein the inductor of Heat Shock Proteins is previously 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 vector. 10. Composition according to one of the preceding claims, wherein the inductor of Heat Shock Protems is present in the composition at a content of 0.0001-10% by weight, preferably 0.001-5%, and more preferably 0.05-3% by weight, relative to the total weight of the composition. 11. Use of the cosmetic or dermatological composition according to one of claims 1 to 10, for the preparation of a medicament intended to be applied to the skin, in order to limit the side effects of retinoids. 12. Use of the cosmetic or dermatological composition according to one of claims 1 to 10 for the preparation of a medicament intended to be applied to the skin, to restore a physiological level of Heat Shock Protems in the skin and cells. .  13. Use of the cosmetic or dermatological composition according to one of claims 1 to 10 for the preparation of a medicament for application to the skin, for regulating the level of inflammatory cytokines induced by retinoids in the skin and cells.  14. Use of the cosmetic or dermatological composition according to one of claims 1 to 10, for the preparation of a medicament intended to be applied to the skin, to protect against external stresses (heat, solar radiation, heavy metals, solvents). ) during retinoid therapies. <Desc / Clms Page number 14> 15. Use of the cosmetic or dermatological composition according to one of claims 1 to 10 for the preparation of a medicament for application to the skin, for treating aged skin. 16. Use of at least one retinoid and a Heat Shock Proteins inducer, as defined in claims 1 to 10, for preparing a medicament for limiting the side effects of retinoids. 17. Use of at least one retinoid and inducer of Heat Shock Proteins, as defined in claims 1 to 10, for preparing a medicament for regulating the level of inflammatory cytokines, during treatment with retinoids in cells and skin. 18. Use of at least one retinoid and a Heat Shock Proteins inducer, as defined in claims 1 to 10, for preparing a medicament for maintaining a physiological level of Heat Shock Proteins in cells and skin. 19. Use of at least one retinoid and a Heat Shock Proteins inducer, as defined in claims 1 to 10, for preparing a medicament for maintaining a physiological level of Heat Shock Proteins in aged cells and aged skin. 20. Use of at least one retinoid and an inducer of Heat Shock Proteins, as defined in claims 1 to 10, for preparing a medicament for protecting cells and skin from external stresses (heat, solar radiation, heavy metals , solvents) during retinoid therapies.  21. Use of at least one retinoid and an inducer of Heat Shock Protems, as defined in claims 1 to 10, for preparing a medicament for treating or preventing signs of skin aging.