KR20070031472A - Use of a Substance Binding with the Peripheral Benzodiazepin Receptor for Treating Skin Stress - Google Patents

Abstract

The present invention relates to the use of a substance binding to benzodiazepines peripheral receptor (PBR) in the preparation of a composition for preventing and treating skin stress. The invention also relates to a composition comprising said substance. The composition may be for cosmetic or pharmaceutical use, in particular topical use in dermatology.

Skin Stress, Benzodiazepines Peripheral Receptors, Ligands

Description

Use of a Substance Binding with the Peripheral Benzodiazepin Receptor for Treating Skin Stress}

1 is an analysis of mitochondrial localization of PBR receptors in keratinocytes A431.

2 shows increasing expression of PBR from the basal layer to the stratum corneum.

3 shows the expression of PBR in keratinocytes and normal human skin systems.

4 shows the Scatchard study in keratinocytes A431.

5 shows the pharmacological profile of ligands for PBR in keratinocytes A431.

6 shows the involvement of PBR in the protection of hematopoietic cells from damage caused by oxidized radicals.

Figure 7 shows the major ligands for the central and peripheral receptors of benzodiazepines.

The present invention relates to a composition for topical use containing a ligand for a benzodiazepine peripheral receptor.

The present invention relates to the use of a substance that specifically binds to a benzodiazepine peripheral receptor (PBR) in the manufacture of a composition for preventing or treating skin stress.

The present invention also relates to compositions containing such materials. Such compositions may be cosmetic or pharmaceutical, and in particular topical dermatological compositions.

The term "skin stress" refers to a variety of cases that can cause damage to the epidermis, especially regardless of the factor causing the damage. Such factors may be external factors such as chemical or free radicals, or alternatively ultraviolet radiation, inside and / or outside of the body.

Thus, the composition according to the invention is intended to prevent and eliminate skin irritation, dry patches, erythema, perceptual sensation, heat sensation, pruritus of the skin and / or mucous membranes, and aging, for example psoriasis To be used in dermatological conditions such as pruritus, other diseases such as fibrosis and collagen maturation, skin diseases such as pruritic disease, herpes, photodermatitis, atopic dermatitis, contact dermatitis, thyroid gland, positivity, pruritus, insect bites Can be.

PBR ligands, also referred to as “substances,” contained in the composition may be non-peptide compounds, peptides, cell or tissue extracts of animal or plant origin, or products obtained by fermentation of microorganisms, eg, by fermentation of bacteria or fungi. have.

Many PBR ligands are disclosed in the literature. Examples that may be mentioned include Ro 5-4864 or chlorodiazepam, Ro 5-2807 or diazepam and PK 11195, see Peripheral Benzodiazepine Receptors, Ch. III, J. J. Bourguignon, Ed. E. Giesen-Crouse, Academic Press.

PBR is an 18-kd protein located in the outer membrane of peripheral tissue mitochondria. It consists of five transmembrane domains and a carboxy-terminal portion towards the cytosol. Some actions such as regulation of steroidogenesis, biosynthesis of heme, cell differentiation and growth, and control of mitochondrial respiration are considered to be due to PBR depending on tissue characteristics (Krueger KE, Biochimica and Biophysica Acta 1995, 1241, 453-470]. Although its exact function is not fully understood, some recent experimental data suggest that PBR can play an important role in the regulation of cell death methods and protection from free radicals.

It has been shown that PBR is closely related to apoptosis regulatory proteins such as Bcl2, which prevents rupture of mitochondrial membrane potential at the mitochondrial level, thus preventing apoptosis induced by the generation of reactive oxidative radicals (Marchetti P et al., J. Exp. Med. 1996, 184, 1155-1160, Marchetti P. et al., J. Immunol. 1996, 157, 4830-4836].

In the context of the present invention, direct observation of the role of PBR in protection from free radicals in cells of hematopoietic origin demonstrated a close correlation between PBR density and protection from free radicals. The same study also demonstrated that transfection of PBR with cells lacking these receptors protects against damage caused by oxidized species (Carayon P. et al., Blood 1996, 87, 3170-3178). ].

Several literature data suggest that PBR can play an important role in regulating apoptosis methods and protecting cells from damage caused by free radicals.

Recent phylogenetic studies reinforce the new view that PBR acts as an apoptosis regulator involved in antioxidant activity. The reason is also the PBR and photosynthetic bacteria bakteo spheroid's (Rhodobacter This is because there is a significant similarity between the protein CrtK of sphaeroides ). These bacterial proteins, acting as photosensitive oxygen detectors, regulate the expression of genes involved in photosynthesis in response to environmental changes in oxygen pressure and light intensity. Comparing PBR and CrtK revealed that the sequence was preserved between these two proteins with 35% identity and phylogenetically divergent two billion years ago. This homology suggests a highly differentiated and conserved function of PBR, which appears to be similar to the highly differentiated and conserved function of CrtK in bacteria. Specifically, it has recently been demonstrated that mammalian PBR transfected with Rhodobacter CrtK mutants complements the oxygen-detecting action of CrtK. Thus, this study suggests a major role of PBR in the transmission of oxygen-dependent signals (Yeliseev AA., Et al., Proc. Natl. Acad. Sci. 1997, 94, 5101-5106).

However, to date there is no substance exactly labeled as a ligand specific for the dermal PBR receptor, which is also why the locally active substance that specifically binds to the PBR receptor is not disclosed in the literature.

In the context of the present invention, it is now shown that PBR is abundantly expressed in the skin in various cell fractions consisting of keratinocytes, Langerhans cells, hair follicles and endothelial cells of the cutaneous vascular system. In the skin, expression of PBR follows a gradient that increases from the basal layer to the stratum corneum. These remarkable organic tissues, which favor the differentiated cells of the epidermis that are most exposed to external stress, are undoubtedly fundamentally physiologically important to protect the most vulnerable areas of the epidermis. Subcellular studies conducted by confocal microscopy show colocalization of PBR with Bcl2 in mitochondria as expected. Histological studies on skin samples revealed a surprising distribution of PBR (FIGS. 1 and 2).

Specifically, the expression of such receptors in the epidermis follows an increasing density gradient from the basal layer to the most differentiated layer of keratinocytes. This highly organized spatial distribution, favoring the outermost in terms of density, the most exposed cells of the epidermis, suggests that PBR in the skin can represent a natural protection system for free radicals generated by exposure to ultraviolet radiation. Let them assume In addition, the observation that the distribution of anti-apoptotic protein Bcl2 follows a strict inverse gradient suggests a complementary role of PBR to protect the most differentiated cells.

More specifically, this set of data suggesting a protective role of PBR in the epidermis led to the discovery of natural or synthetic ligands, which indicated that their interaction with PBR could be influenced by chemical or layu-radicals, or otherwise by UV. It has been shown that it can be beneficial in various skin stress states induced by exposure.

Thus, according to one aspect of the invention, the invention relates to the use of ligands specific for PBR, Ro 5-4864 in skin stress. Such ligands are PBR agonists.

According to another aspect of the present invention, and based on this observation, one could perform screening to find native PBR ligands and isolate some fractions that could interact with the receptor. The potential protective effects of these natural ligands were then evaluated in various experiments inducing skin stress, particularly in the case of skin erythema induced by UV irradiation. Radical-removing properties and skin regeneration ability were also studied.

Biochemical and pharmacological experiments have been used to demonstrate the activity and benefits of the material under various skin stress conditions.

Tests performed using PBR were to show that PBR is potentially involved in regulating apoptosis processes and protecting skin cells from various toxic stress conditions.

<Example 1>

Immunohistologic Study of Skin Localization of PBR

Six different human keratin using specific anti-PBR antibody Ac 8D7 (anti-PBR mouse mAb, isotype IgG1, Dussossoy et al., Cytometry, 1996, 24: 39-48) by Western blot analysis. Abundance of PBR could be demonstrated in cell lines and normal human skin systems (FIG. 1). At the subcellular level, analysis was performed by confocal microscopy to confirm colocalization at the mitochondrial level of keratinocytes (FIG. 2).

Immunohistologic studies performed with the same antibody in normal human epidermal specimens revealed that PBR expression is a very specific organic tissue because the expression of PBR increases from the basal layer to the stratum corneum. Thus, these receptors were the most differentiated and abundantly present in keratinocytes located just below the stratum corneum (FIG. 3).

<Example 2>

Binding and specificity studies

Binding studies were performed in keratinocyte line A-431 (human dermal epidermal carcinoma (ATCC, CRL-1555)) by substitution of the reference ligand [ ³ H] -PK11195. Scatchard analysis showed a single binding site, a density of about 470000 receptors per cell and high affinity of ligand (KD = 1.5 nM) (FIG. 4). Pharmacological studies showing that the efficacy of the reference peripheral ligand (PK 11195) substitutions are reduced by the following ligands confirmed the specificity of binding to peripheral receptors produced by keratinocytes: Ro 5-4864 = (IC ₅₀ ≒ 25 nM)> diazepam (IC ₅₀ ≒ 100 nM) >>> clonazepam (inactive at 3200 nM). This reminded us that the last compound was the ligand of the central receptor for benzodiazepines, the diazepam was mixed and Ro 5-4864 was specific for PBR (FIG. 5).

<Example 3>

Relevance of PBR in Protection Against Oxidized Radicals

Two types of experiments are described in FIG. 6. The first was to compare different cell lines of lymphoid or myeloid origin regarding their ability to resist the toxicity of oxidized radicals related to PBR expression levels. This result showed a very strong correlation between the number of PBR sites per cell and resistance to toxicity induced by H ₂ O ₂ . In addition, this time there was a similar correlation when considering the expression level of Bcl2, a protein known to protect cells from oxidative damage. Combined with the fact that Bcl2 and PBR are proteins located on the outer membrane of the mitochondria, these data suggest that they may have a common function in cell protection. Interestingly, the expression of PBR follows an increasing density gradient from the basal layer to the tip of the stratum corneum, but the literature data suggests that Bcl2 expression is the opposite, which protects PBR from free radicals in place of Bcl2 during differentiation of keratinocytes. It is suggested that it can work.

In the second experiment, the possible role of PBR in the protection from free radical toxicity from the demonstration of better viability of PBR + transfected Jurkat cells compared to homologous PBR- cells in the presence of H ₂ O ₂ was enhanced.

<Example 4>

The anti-apoptotic activity of the active agent was inoculated in 35 mm Petri dishes (5 x 10 ⁵ cells / well) in DMEM (Dubelco's Mode Eagle Medium) supplemented with 10% fetal bovine serum until congenital growth. Measurements were made on proliferated human keratinocytes and fibroblasts (ATCC). This culture medium was then removed, cells were rinsed, and 0.1% fetal bovine serum was added in the presence of saline solution. The material to be studied was added at increasing concentrations. After 24 hours, apoptosis was measured with an ELISA (enzyme-linked immunosorbent assay) assay kit.

Keratinocytes were exposed to type B ultraviolet radiation (UVB) at a dose of 250 J / m ² for 16 hours (J. Invest. Dermatol. 1995., 104: 922-927). In the presence of PBR ligand Ro 5-4864, it was shown that the cell damage method induced by irradiation was prevented in the ligand concentration range of 10 nM to 10 μm.

<Example 5>

The photoprotective effect of the ligand was evaluated by application to the skin of white guinea pigs.

The skin topical route was used to reproduce conditions of use in humans.

France Harley Guinea Pig from Charles River France, 76410 Séle Saint Aubin-les-Elbo, was used.

Twenty four hours before the start of treatment, the animals were shaved and haired on the right and left posterior abdomen.

The animals were irradiated with radiation just before the first treatment. After checking the energy, each radiation irradiation was performed in the right and left flanks with a UVB spectrum of dose of 4000 mJ / cm ² .

Immediately after irradiation and 2 and 5 hours after irradiation, the right flank of the animal was treated with 0.2 ml of ligand solution.

Irradiated with xenon high pressure steam lamp (IDEM 300).

Local reactions were analyzed before treatment and after 5 and 24 hours of irradiation.

Erythema and edema were evaluated as follows:

Examples of natural ligands for PBR receptors produced by fermentation are described below along with their activity.

Screening was performed on microbial extracts carried out in solid or liquid medium to select three strains of microorganisms (microbial fungi and bacteria).

In experiments to determine the interaction with PBR receptors, three strains selected after various studies conducted to optimize the conditions for producing significant amounts of culture extracts with good activity are identified by reference numbers SRL 4988, SRL 5168 and SRL 5189.

The three strains were deposited in the CNCM of the Pasteur Institute on August 27, 1999 under serial numbers I-2305, I-2306 and I-2307, respectively.

Strain SRL 4988, isolated from soil samples and classified as Nocardia species, was cultured in ISP2 medium at 28 ° C. for 2 weeks and then determined for ecology such as negative photodependent bacteria, organotrophs, thermophilic bacteria and negative basophils. Have physiological properties. It is a floating, open non-biotic mycelia.

Strain SRL 5186, isolated from soil samples and classified as Streptomyces spp., Was cultured in ISP2 medium at 28 ° C. for 2 weeks and then ecological-physiological such as negative photodependent bacteria, organotrophs, thermophilic bacteria and negative basophils were determined. Has a peculiar character. It is a floating, flexible dibiotic mycelium.

Strain SRL 5189, classified as an actinosinnema species, has ecological and physiological characteristics such as negative photo-dependent bacteria, organotrophs, thermophilic bacteria and negative basophils determined after incubation in ISP2 medium at 28 ° C. for 2 weeks. . It is a floating, adaptive monobial mycelium.

Thus, these strains and their proliferative mutants constitute another subject of the present invention.

After cultivation in nutrient agar medium and several subsequent passages to prepare a rich and pure culture, a stock batch 0 of the stock strain was followed by a first and second inoculation batch.

To accomplish this, spore suspensions were prepared from culture medium and absorption medium in nutrient agar medium in a Petri dish. Such medium contains an antifreeze to preserve good growth of the spores during freezing storage.

The resulting spore suspension was dispensed into cryotubes stored at -80 ° C, which constitute batch 0

A first inoculation batch was prepared according to the same protocol except that a tube from batch 0 was used. Next, according to the same protocol again, a second inoculation batch was prepared from the first inoculation cryotube. Preparation of inoculation batches 0, 1 and 2 maintains the long-lasting availability of the strains, thus maintaining the desired activity. Cultivating these three strains to obtain the natural ligands of the PBR receptor is a similar method using conventional aerobic culture methods, for example liquid in any volume of fermenter in-line of pH and aeration. Can be performed by monitoring.

<Example A SRL 4988>

As a culture example in an Erlenmeyer flask for strain SRL 4988, a second inoculation tube was used to inoculate a petri dish prepared with a medium that promotes actinomycetic sporulation according to the following composition.

Glucose 20 g Soyoptim (SIO) 10 g CaCO ₃ (OMYA) 3 g Agar Type E 20 g Distilled water qs 1 l

Cultures were incubated in dishes at 28 ° C. for 5 days. A spore suspension was then obtained by adding 10 ml of liquid medium of the composition described below to each Petri dish.

Glucose 30 g Job Team (SIO) 10 g Trypton U. S. P. (Biokar) 4 g Yeast Extract (Difco) 8 g NaCl 2.5 g CaCO ₃ 5 g Casein hydrolyzate 5 g Soy Papain Peptone 5 g

Their pH was adjusted to 7.0 and then sterilized.

5 ml of spore suspension was used to inoculate a sterile 250 ml flask containing 50 ml of the same medium to make up the preculture, and the speed of rotation of the system in a greenhouse or automatic incubator at 28 ° C. on a shelf shaker. Incubation was set at 210 rpm.

After shaking for 2 days, the preculture flask was used to inoculate the actual culture flask at a rate of 5 ml preculture medium per flask into a 500 ml Erlenmeyer flask containing the composition (100 ml) as follows.

Glycerol 10 g Soluble Starch 30 g Job Team 15 g Trypton 2 g Yeast extract 5 g CaCO ₃ 5 g Trace element solution 10 ml Water qs 1 l pH 7

Composition of used trace element solution:

FeSO _{4 7} H ₂ O 1.0 g MnSO ₄ 4H ₂ O 1.0 g CaCl ₂ 2H ₂ O 0.025 g CaCl ₂ 2H ₂ O 0.10 g H ₃ BO ₃ 0.56 g (NH ₄ ) ₆ Mo ₇ O ₂₄ ㆍ 4H ₂ O 0.002 g ZnSO ₄ ㆍ 7H ₂ O 0.20 g Water qs 1 l

Thus, in this particular case, five preculture flasks were used to inoculate 40 culture flasks with 100 ml of culture medium per 500 ml Erlenmeyer flask and then shaken for 6 days in a greenhouse at 28 ° C. on a rotary shaker set at 210 rpm. Incubation gave 4 l of bacterial suspension.

Four liters of fermentation broth were centrifuged several times by means of a 13500 rpm method (ie 27500 xg with the rotor used) at a temperature of 4 ° C. to obtain biomass, ie pellets containing cells, with water from the nutrient medium. It was isolated from the culture supernatant, which consisted mainly and contained metabolites in solution and also metabolites produced and secreted by bacterial cells during various periods of bacterial growth.

The biomass and supernatant were then frozen at -20 ° C.

Extraction of Natural Ligands of the PBR Receptor

4 l of thawed supernatant was placed in a 10 l beaker. 400 g of Amberlite XAD 16 polystyrene-divinylbenzene resin (Rohm & Haas) was added to the solution. The supernatant was shaken using a motor equipped with a pedal axis and spun at 20 rpm for 15 hours. The solution was then filtered, the filtrate was removed and the drained resin was dissolved in 1 l of methanol. The mixture was stirred gently for 1 hour. The resin was filtered again and retreated with 1 l of methanol in the same manner. During the third run, the resin was retreated this time with 1 l of acetone. The drained resin was then removed and 3 l of the combined organic solvents were evaporated to dryness in a rotary evaporator under vacuum.

The evaporation residue (17.7 g) was slurried in 50 ml of methanol and the resulting suspension was centrifuged at 3000 rpm for 15 minutes, and the resulting stable supernatant constituted the culture supernatant extract.

These extracts were diluted to inhibit binding to the PBR receptor and tested to provide the activity evaluated at 1/200 dilution (50% inhibition).

2 l beaker polymerized biomass (199 g) was treated with a mixture of 750 ml of methylene chloride and 750 ml of methanol with stirring. Stirring was continued for 15 hours at room temperature. The suspension was then filtered and the resulting clear solution was concentrated in vacuo on a rotary evaporator. The evaporation residue (5.4 g) was then slurried in 50 ml of methanol, which constituted the biomass extract.

And the extract tested for inhibiting binding to the PBR receptor, yielding an activity measured in ^{_{1/2200 (ID 50 = 2200 -1)}} .

<Example B SRL 5168>

The same individual protocol and medium, i.e.

-Agar plate for subculture on Petri dish,

-Liquid preculture medium,

-Using liquid generation medium

A 14 x 500 ml Erlenmeyer flask containing 100 ml of 5% inoculated production medium was incubated for 6 days in a greenhouse at 28 ° C on a rotary shaker rotating at 210 rpm.

The resulting supernatant and biomass were centrifuged, stored for one or two days in a freezer at −20 ° C., and then thawed to extract this product.

Biomass (54.9 g) was treated with a mixture of 250 ml of dichloromethane and 250 ml of methanol for 10 hours with stirring in a beaker. The suspension was then filtered and the resulting clear solution was concentrated to dryness on a rotary evaporator.

The dry residue (1.4 g) was slurried in 17.5 ml of methanol and the resulting suspension was centrifuged at 3000 rpm for 15 minutes. The harvested centrifuge supernatant constituted the biomass extract.

These extracts were evaluated by dilution in binding inhibition experiment for the PBR receptor provides 50% inhibition at 1/3750 dilution (ID ₅₀ = 3750 ^-1).

160 g of XAD 16 polystyrene-divinylbenzene resin (Roam and Haas) was added to 1400 ml of thawed supernatant and the suspension was stirred for 15 hours. The resin was filtered off, the filtrate was removed and the resin was retreated with 200 ml of a 25% methanol containing solution in water for 3 hours.

The resin was filtered off and the second filtrate was removed. The resin was then treated similarly three times, twice with 200 ml of methanol and last with 200 ml of acetone. These last three filtrates were combined in a round bottom flask and then concentrated in a rotary evaporator under vacuum. The resulting dry residue (2.2 g) was then slurried in 17.5 ml of methanol and the resulting solution constituted the supernatant extract.

These extracts were evaluated by dilution in binding inhibition experiment for the PBR receptor provides 50% inhibition at 1/940 dilution (ID ₅₀ = 940 ^-1).

<Example C SRL 5189>

The same individual protocol and medium, i.e.

Agar medium for subculture on a petri dish,

-Liquid preculture medium,

-Using liquid generation medium

A 10 × 500 ml Erlenmeyer flask containing 100 ml of 5% inoculated production medium was incubated for 8 days in a greenhouse at 28 ° C. on a rotary shaker rotating at 210 rpm.

The resulting supernatant and biomass were centrifuged, stored for one or two days in a freezer at −20 ° C., and then thawed to extract this product.

Biomass (69.5 g) was treated with a mixture of 150 ml dichloromethane and 150 ml methanol for 10 hours with stirring in a beaker. The suspension was then filtered and the resulting clear solution was concentrated to dryness on a rotary evaporator. The dry residue (1.5 g) was slurried in 12.5 ml of methanol and the resulting solution was centrifuged at 3000 rpm for 15 minutes. The harvested centrifuge supernatant constituted the biomass extract. These extracts were evaluated by dilution in binding inhibition experiment for PBR receptors are provided the 50% inhibition at 1/2600 dilution (ID ₅₀ = 2600 ^-1).

100 g of XAD 16 polystyrene-divinylbenzene resin (Roam and Haas) was added to 1000 ml of thawed supernatant and the suspension was stirred for 15 hours. The resin was filtered off, the filtrate was removed and the resin was retreated with 150 ml of a 25% methanol containing solution in water for 3 hours. The resin was filtered off and the second filtrate was removed. The resin was then treated similarly three times, twice with 150 ml of methanol and last with 150 ml of acetone. These last three filtrates were combined in a round bottom flask and then concentrated in a rotary evaporator under vacuum. The resulting dry residue (1.7 g) was then slurried in 12.5 ml of methanol, and the resulting solution constituted the supernatant extract.

These extracts were diluted to inhibit binding to the PBR receptor and tested to provide 50% inhibition at 1/600 dilution (ID ₅₀ = ^500-1 ).

In the compositions according to the invention, the substances which bind to PBR are preferably used in amounts ranging from 0.00001% to 20% by weight of the total weight of the composition, and in particular in amounts ranging from 0.001% to 10% by weight of the total weight of the composition. .

The composition according to the invention may be in any provided form commonly used in topical application.

 The amounts of the various components in the compositions according to the present invention are those suitable for the amounts conventionally used in the art and their provided forms.

For topical application, the compositions of the present invention comprise a medium that is compatible with the skin. Such compositions are in particular in the form of creams or gels, micro-emulsions or aerosol-shaped aqueous, alcoholic or aqueous-alcoholic solutions, gels, water-in-oil or oil-in-water emulsions, or alternatively vesicular dispersions containing ionic and nonionic lipids. It may be in the form of. Such provided forms are prepared according to conventional methods in the art.

Compositions for such topical applications include, in particular, cosmetic or dermatological protective therapeutic or care compositions (such as day creams, night creams, sunscreen creams or oils or body milks) of face, neck, hands or body, makeup compositions (such as Foundation) or artificial tanning composition.

When the composition of the present invention is an emulsion, the aliphatic material is contained in a proportion in the range of 5% to 80% by weight, and preferably 5% to 50% by weight of the total weight of the composition. Aliphatic materials and emulsifiers used in the composition in emulsion form are typically selected from those used for cosmetic or dermatology.

As aliphatic materials which can be used in the present invention, mineral oil (petrolatum), vegetable oil (liquid fraction of karite butter) and hydrogenated derivatives thereof, animal oil, synthetic oil (perhydrosqualene), silicone oil (polydimethylsiloxane And fluoro oils. Other aliphatic materials that may also be mentioned include fatty alcohols (cetyl alcohol or stearyl alcohol), fatty acids (stearic acid) and waxes.

Emulsifiers may be present in the composition in the range of 0.3% to 30% by weight, preferably 0.5% to 30% by weight of the total weight of the composition.

In known methods, the cosmetic or dermatological compositions of the invention are also conventional excipients in the corresponding art, for example hydrophilic or lipophilic gelling agents, preservatives, antioxidants, solvents, fragrances, fillers, screening agents and dyes. It may contain. Such compositions may also contain hydrophilic or lipophilic active agents. The amount of these various excipients or actives is used in amounts conventionally used in cosmetics or dermatology, for example 0.01% to 20% by weight of the total weight of the composition. Depending on their properties, such excipients or such active agents may be incorporated into the aliphatic, aqueous phase and / or lipid vesicles.

Among these active agents which the compositions of the present invention may contain, mention may be made of those which are particularly effective in the treatment of wrinkles and fine lines, in particular keratinizing actives. The term "keratolytic" refers to an active agent that has a dropping, peeling or scrubbing property, or an active agent capable of softening the stratum corneum.

Mention may be made of these active agents, in particular hydroxy acids and retinoids, which may be contained in the compositions of the invention which are effective in the treatment of wrinkles and fine lines.

The hydroxy acid can be, for example, α-hydroxy acid or β-hydroxy acid, which can be linear, branched or cyclic, and saturated or unsaturated. Hydrogen atoms of the carbon chain may also be substituted with halogen, halogenated, alkyl, acyl, acyloxy, alkoxycarbonyl or alkoxy radicals having 2 to 18 carbon atoms.

Hydroxy acids that can be used are, in particular, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, 2-hydroxyalkanoic acid, mandelic acid, salicylic acid and alkyl derivatives thereof, for example 5-n-octanoylsalicylic acid, 5-n- Dodecanoylsalicylic acid, 5-n-decanoylsalicylic acid, 5-n-octylsalicylic acid, 5-n-heptyloxysalicylic acid, or 4-n-heptyloxysalicylic acid and 2-hydroxy-3-methylbenzoic acid or alkoxylation thereof Derivatives such as 2-hydroxy-3-methoxybenzoic acid.

Retinoids can in particular be retinoic acid and derivatives thereof, retinol (vitamin A) and esters thereof such as retinyl palmitate, retinyl acetate or retinyl propionate and salts thereof.

Such active agents can be used in particular in concentrations ranging from 0.0001% to 5% by weight of the total weight of the composition.

Substances that specifically bind to the benzodiazepine peripheral receptor (PBR) according to the invention are useful for the preparation of compositions for preventing or treating skin stress.

Claims (10)

Ro 5-4864, or no Arcadia species (Norcadia) SRL 4988, Streptomyces species MRS (Streptomyces) SRL 5186 and evil Martino cinema species (Actinosinnema) SRL 5189 selected from the fermentation extract obtained from the culture, PBR (peripheral benzodiazepine receptor; peripheral benzodiazepine A topical composition for the treatment of skin stress, comprising one or more substances that bind to a receptor). Ro 5-4864, or furnace coupled to Arcadia species (Norcadia) SRL 4988, Streptomyces species MRS (Streptomyces), SRL 5186 and evil Martino cinema species (Actinosinnema) SRL 5189 selected from the fermentation culture extract obtained from water, PBR (peripheral benzodiazepine receptor) A topical composition for reducing wrinkles, reducing sun erythema, or protecting from free radicals, comprising one or more substances. The composition of claim 1 or 2, wherein the one or more materials are present in an amount ranging from 0.00001% to 20% by weight of the total weight of the composition. The composition of claim 1 or 2, wherein the at least one substance is present in an amount ranging from 0.001% to 10% by weight of the total weight of the composition. The composition of claim 1 or 2, further comprising a hydroxy acid, a retinoid, or a combination thereof. 6. A composition according to claim 5, wherein the hydroxy acid is selected from α-hydroxy acids and β-hydroxy acids which may be linear, branched or cyclic, and saturated or unsaturated. The composition of claim 6 wherein the retinoid is selected from the group comprising retinoic acid and derivatives thereof, and retinol and esters thereof. The cosmetic composition according to claim 1 or 2. The composition for dermatology according to claim 1 or 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition.

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