WO2008145854A1 - Pharmaceutical and/or cosmetic composition containing peptides - Google Patents

Pharmaceutical and/or cosmetic composition containing peptides Download PDF

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Publication number
WO2008145854A1
WO2008145854A1 PCT/FR2008/000577 FR2008000577W WO2008145854A1 WO 2008145854 A1 WO2008145854 A1 WO 2008145854A1 FR 2008000577 W FR2008000577 W FR 2008000577W WO 2008145854 A1 WO2008145854 A1 WO 2008145854A1
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WIPO (PCT)
Prior art keywords
composition
peptide
active agent
skin
group
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Application number
PCT/FR2008/000577
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French (fr)
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WO2008145854A8 (en
Inventor
Claude Dal Farra
Nouha Domloge
Jean-Marie Botto
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Societe D'extraction Des Principes Actifs S.A. (Isp Vincience)
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Publication of WO2008145854A1 publication Critical patent/WO2008145854A1/en
Publication of WO2008145854A8 publication Critical patent/WO2008145854A8/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/415—Cytochromes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/795—Porphyrin- or corrin-ring-containing peptides
    • C07K14/80—Cytochromes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention is in the cosmetic and pharmaceutical field, and more particularly in the field of dermatology.
  • the present invention relates to a cosmetic or pharmaceutical, and especially dermatological, composition comprising, in a physiologically suitable medium, peptides derived from cytochrome c, as active agent, alone or in combination with at least one other active agent.
  • the invention also relates to the cosmetic use of a composition stimulating the defenses and the protection of the skin, in particular vis-à-vis the oxidative damage.
  • the invention also relates to a cosmetic treatment method intended to protect the skin and the integuments from external aggressions and to fight against skin aging.
  • the active agent, derived from cytochrome c can also be used to prepare pharmaceutical compositions intended to prevent or combat pathologies related to oxidation processes or certain pathologies of aging.
  • “superficial body growths” encompasses all the keratinous appendages present on the surface of the body, in particular the hairs, the eyelashes, the eyebrows, the nails and the hair.
  • the skin is a vital organ that covers the entire surface of the body and provides protective, sensitive, immune, metabolic or thermoregulatory functions.
  • the skin like other organs, is subject to aging.
  • one of the major mechanisms involved in aging processes is the accumulation of oxidative damage in essential molecules such as membrane lipids, proteins, DNA and especially mitochondrial DNA (mtDNA).
  • Oxidative damage is caused by free radicals, chemically unstable and highly reactive species generated by intracellular metabolism or external aggression. These external aggressions include: UV radiation, toxins, air pollutants, food oxidants. In the skin, there is premature aging occurring in the areas exposed to radiation, characterized by phenomena of alterations of macromolecules (lipid peroxidation, carbonylation of proteins) affecting in particular elastin, collagen or fibronectin. It has also been possible to show a progressive decline in - -
  • the body has defense mechanisms capable of trapping or transforming free radicals (enzymes, glutathione, vitamins A and E, coenzyme Q10, etc.).
  • these antioxidant defense systems are often insufficient in the face of the many stresses and external aggressions to which the organisms and the skin in particular are subjected.
  • Cytochrome c is a small soluble protein of 15 kDa that plays an essential role in mitochondrial function and in cell survival. Cytochrome c is a highly conserved molecule in most eukaryotes; it is found in the mitochondria of plants, animals and many unicellular organisms. Cytochrome c has a protein structure organized around a porphyrin, consisting of four pyrrol nuclei, themselves linked to an iron atom.
  • Cytochrome c which is soluble, transports electrons from the El complex (coenzyme QH2-cytochrome c reductase) to complex IV (cytochrome oxidase). The electrons, which are the substrate for cytochrome oxidase, are then transferred by the enzyme to oxygen.
  • the main object of the present invention is to provide a new active agent capable of protecting the skin against external aggressions and of combating cutaneous aging.
  • the inventors have in fact demonstrated a cosmetic and therapeutic activity, especially dermatological, peptides derived from cytochrome c.
  • these peptides when applied to the skin, have a high protective activity with respect to the external aggressions suffered by the skin, demonstrated by a protection against damage. oxidation and a decrease in apoptosis.
  • These new active agents able to protect the skin from external aggressions thus open up new therapeutic and cosmetic perspectives.
  • active agent capable of protecting the skin from external aggressions means any substance capable of exhibiting protective properties or of reducing apoptosis in cells or tissues subjected to stress of physicochemical or environmental origin.
  • the subject of the invention is primarily a cosmetic or pharmaceutical composition, and especially a dermatological composition, comprising, in a physiologically adapted medium, peptides derived from cytochrome c, as active agent, alone or in combination with at least one other active agent.
  • said peptides derived from cytochrome c or their biologically active derivatives are peptides whose number of amino acids is between 3 and 13.
  • cytochrome c-derived peptides refers to any biologically active peptide fragment whose amino acid sequence is, wholly or partially, analogous or homologous to the peptide sequences of cytochrome c.
  • biologically active is meant “which has an activity in vivo or in vitro characteristic of the activity of the active agent according to the invention”.
  • the peptide has a sequence which corresponds to the general formula (I)
  • X 2 is leucine
  • X 3 is lysine
  • X 4 is threonine, serine, lysine, arginine or no amino acid
  • X 5 is valine, alanine, tyrosine, methionine or no amino acid
  • AA represents any amino acid, or a derivative thereof, absent from the cytochrome c sequence
  • n and p are integers inclusive between 0 and 4.
  • R 1 represents the primary amino function of the N-terminal amino acid, free or substituted with a protective group which may be chosen from an acetyl group, a benzoyl group, a tosyl group or a benzyloxycarbonyl group.
  • R 2 represents the hydroxyl function of the carboxylic acid of the C-terminal amino acid, free or substituted with a protective group that may be chosen from a C 1 to C 20 alkyl chain, or an NH 2 , NHY or NYY group with Y represents an alkyl chain of Ci to C 4 .
  • the biologically active peptide is of sequence:
  • the biologically active peptide corresponds to the sequence SEQ ID No. 1. According to another particularly interesting embodiment, the biologically active peptide corresponds to the sequence SEQ ID No. 2.
  • the invention also relates to homologous forms of these sequences.
  • the term "homologue” denotes, according to the invention, any peptide sequence identical to at least 50%, or preferably at least 80%, and even more preferably to at least 90% of said peptide sequence, chosen from SEQ ID sequences. No. 1 to SEQ ID No. 4.
  • "Peptide sequence identical to at least X%” is intended to designate a percentage identity between the amino acid residues of the two sequences to be compared, obtained after the optimal alignment of the two sequences. Optimal alignment is achieved by using local homology algorithms such as those used by BLAST P or T BLAST N computer software available on the NCBI site.
  • the term "homologue” may also denote a peptide which differs from the sequence of a peptide of sequence SEQ E) No. 1 to SEQ ID No. 4 by the substitution of chemically equivalent amino acids, that is to say by substituting one residue for another with the same characteristics.
  • the classical substitutions are between Ala, Val, Leu and De; 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.
  • amino acid refers herein to any natural or unnatural organic acid having the formula:
  • each -R is independently selected from hydrogen and an alkyl group having 1 to 12 carbon atoms.
  • at least one -R group of each amino acid is a hydrogen.
  • 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).
  • peptide refers to a sequence of two or more amino acids linked together by peptide bonds or modified peptide bonds.
  • 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 peptide or synthetic whose sequence is totally or partially constituted by the sequence of the previously described peptide.
  • 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 forms of biologically compatible protection can be envisaged.
  • the invention relates to a composition as defined above, characterized in that the peptide of general formula (I) has at least one functional group protected by a protective group, this protective group - -
  • the amino-terminus may be protected by an acetyl group, a benzoyl group, a tosyl group or a benzyloxycarbonyl group.
  • a protection based on the amidation of the hydroxyl function of the carboxy-terminal end is used by a NYY group with Y representing an alkyl chain of C 1 to C 4 , or esterification with an alkyl group. It is also possible to protect both ends of the peptide.
  • the peptide derivatives also relate to amino acids and peptides linked together by a pseudo-peptide bond.
  • pseudo-peptide bond means all types of bonds likely to replace the "classical” peptide bonds.
  • 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 peptide of general formula (I) according to the invention can be obtained either by conventional chemical synthesis (in solid phase or in homogeneous liquid phase) or by enzymatic synthesis (Kullman et al., J. Biol Chem 1980, 225 , 8234), from constituent amino acids or their derivatives.
  • the peptide according to the invention can also be obtained by fermentation of a strain of bacteria modified or not, by genetic engineering, or by extraction of proteins of animal or plant origin, preferably of plant origin, followed by controlled hydrolysis which releases peptide fragments corresponding totally or partially to the peptides of general formula (I).
  • the peptide according to the invention may be of natural or synthetic origin.
  • the peptide is obtained by chemical synthesis.
  • the active agent can be a mixture of peptide derivatives and / or constituted by amino acid derivatives.
  • the active agent according to the invention is first solubilized in one or more solvents conventionally used by those skilled in the art, such as water, glycerol, ethanol, propylene glycol, butylene glycol, dipropylene glycol, ethoxylated or propoxylated diglycols, cyclic polyols, petroleum jelly, a vegetable oil or any mixture of these solvents.
  • solvents conventionally used by those skilled in the art, such as water, glycerol, ethanol, propylene glycol, butylene glycol, dipropylene glycol, ethoxylated or propoxylated diglycols, cyclic polyols, petroleum jelly, a vegetable oil or any mixture of these solvents.
  • the active agent according to the invention is solubilized beforehand 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.
  • 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 that may be used according to the invention may in particular consist of a composition for hair care, and in particular a shampoo, a conditioner, a setting lotion, a treatment lotion, a cream or a styling gel, a restructuring lotion for hair, a mask, etc.
  • the invention can be used in particular in the treatments implementing an application that is followed or not followed by rinsing, or in the form of shampoo.
  • It can also be in the form of dye or mascara to be applied with a brush or a comb, in particular on eyelashes, eyebrows or hair.
  • compositions according to the invention may be applied by any appropriate route, in particular oral, parenteral or external topical, and their formulation will be adapted by those skilled in the art, in particular for cosmetic or dermatological compositions.
  • the compositions according to the invention are in a form suitable for topical application.
  • These compositions must therefore contain a cosmetically and / or dermatologically acceptable medium, that is to say compatible with the skin and superficial body growths, and cover all cosmetic or dermatological forms.
  • These compositions may especially be in the form of creams, oil-in-water or water-in-oil emulsions or multiple emulsions, solutions, suspensions, gels, milks, lotions, sticks or even powders, suitable for application on the skin. , lips and / or integuments.
  • compositions comprise the excipients necessary for their formulation, such as solvents, thickeners, diluents, surfactants, antioxidants, dyes, preservatives, perfumes.
  • the compositions that can be used also contain at least one other active ingredient promoting the action of the peptides according to the invention.
  • the composition according to the invention can associate, with the active agent according to the invention, active ingredients having an antioxidant action, or stimulating the synthesis of dermal macromolecules, or stimulating the energy metabolism.
  • active ingredients having an anti-radical or antioxidant action mention may be made of vitamin C, vitamin E, coenzyme Q10 and polyphenolic extracts of plants.
  • the composition according to the invention may be a solar composition, that is to say a composition helping to protect against solar radiation.
  • assets assisting the sun protection such as, for example, sunscreens. It is obvious that the invention is directed to mammals in general, and more particularly to humans.
  • the effective amount of active agent corresponds to the amount necessary to obtain the desired result, namely, to stimulate the defenses of the skin and protect the latter vis-à-vis external aggressions, particularly oxidative damage, and more Generally, protect the skin and skin appendages from external aggressions and fight against skin aging.
  • the active agent according to the invention is present in the compositions of the invention at a concentration of between about 0.0005 and 500 ppm (parts per million), and preferably at a concentration of concentration between about 0.01 and 5 ppm relative to the total weight of the final composition.
  • 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.
  • 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. .
  • additives 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.
  • these adjuvants and their proportions are chosen so as not to harm the advantageous properties sought from the composition according to the invention.
  • These adjuvants may, for example, correspond to 0.01 to 20% of the total weight of the composition.
  • 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.
  • the active agent according to the invention can be used advantageously in a cosmetic composition or for the preparation of a pharmaceutical composition.
  • the active agent according to the invention may advantageously be used in a cosmetic composition intended to preventatively and / or curatively fight against the manifestations of cutaneous aging and, more specifically, in order to fight against and / or prevent photo-induced aging (photo-aging).
  • Skin manifestations of aging means any changes in the external appearance of the skin and skin growth due to aging such as, for example, wrinkles and fine lines, wilted skin, soft skin, thinned skin, lack of elasticity and / or tone of the skin, dull and lackluster skin or skin pigmentation spots, discoloration of the hair or spots on the nails, but also any internal changes in the skin that does not systematically result by a modified external appearance such as, for example, any internal degradation of the skin resulting from exposure to ultraviolet (UV) radiation.
  • UV ultraviolet
  • the active agent according to the invention, or the composition containing it will make it possible, in particular, to combat the loss of elasticity and firmness of the skin.
  • a particular aspect of the invention is the use of the active agent according to the invention, in a cosmetic composition for protecting the skin and the integuments with respect to oxidative damage.
  • Said active agent being advantageously used as an antioxidant and / or as an anti-radical agent and / or as an anti-glycation agent.
  • anti-radical agent is meant any compound capable of scavenging free radicals before the ultimate stages of degradation of the biological constituents of the skin, so-called antioxidant compounds.
  • anti-glycation agent is meant any compound capable of to limit cell damage caused by glycation or glycoxidation reactions.
  • the active agent according to the invention will make it possible to combat the cosmetic damage caused to the skin and / or the hair by free radicals.
  • the active agent can be used advantageously in a cosmetic composition for the protection of the skin and integuments against all types of external aggression.
  • aggressions means the aggressions that the environment can produce. .
  • aggressions such as pollution, UV, or irritating products such as surfactants, preservatives or perfumes.
  • Pollution is understood to mean both “external” pollution due for example to diesel particles, ozone or heavy metals, and “internal” pollution, which may be due in particular to solvent emissions from paints, glues, or wallpaper (such as toluene, styrene, xylene or benzaldehyde), or even cigarette smoke.
  • the active agent according to the invention can be advantageously used in a cosmetic composition or for the preparation of a pharmaceutical composition, as a photo-protective agent and, more particularly, as a so-called "secondary" photo-protective agent. ".
  • the primary photoprotective agents are distinguished from the secondary photoprotective agents.
  • Primary photoprotective agents are substances that exert physical power: they are able to absorb UV radiation and release it as heat to protect the skin.
  • Secondary photoprotective agents are substances that usually have a biological effect; these are, for example, the agents capable of limiting damage to DNA and membranes by the penetration of UV radiation into the skin.
  • the invention also relates to the use in a cosmetic composition of an effective amount of active agent as described above, to prevent damage to the skin caused by exposure to the sun or exposure to ionizing radiation during radiotherapy.
  • the subject of the invention is also the use in a cosmetic composition of an effective amount of active agent as described above, for protecting mitochondria, in particular on the areas of the body exposed to UV radiation.
  • the invention also consists in a pharmaceutical composition characterized in that the active agent according to the invention is formulated to attenuate a pathology related to oxidation processes or certain pathologies of aging.
  • the invention finally consists of a cosmetic treatment method intended to stimulate the defenses and to protect the skin and the integuments from external aggressions and to fight against skin aging, characterized by the application, on the skin or integuments to be treated, a composition containing an effective amount of the active agent according to the invention.
  • the purpose of this study is to determine the protective effect of peptide SEQ ID No. 2 vis-à-vis dermal fibroblasts subjected to oxidative stress caused by UVB radiation.
  • protein carbonylation assays were performed. The carbonylation of proteins results from the oxidative cleavage of proteins or from the oxidation of arginine, lysine, proline or threonine residues. The determination of protein carbonylation is carried out by an EIA (Enzyme Immuno Assay) technique.
  • Fibroblasts in culture were brought into contact with the peptide SEQ ID No. 2 at 1%, from a stock solution at 50 ppm, 72 hours before, during, and another 24 hours after UVB irradiation at 100 mJ. / cm 2 . Untreated controls are performed.
  • the measurement of carbonylation consists in using DNP (dinitrophenyl) which has the property of binding specifically on the carbonyl groups of the proteins.
  • DNP dinitrophenyl
  • the fixed DNP will then be assayed by an ELISA method, using a biotinylated anti-DNP antibody (DNP-KLH, Molecular Probes).
  • DNP-KLH biotinylated anti-DNP antibody
  • a range of oxidized BSA bovine serum albumin
  • results obtained show a 39% decrease in carbonylation of the proteins when the cells are treated with the peptide SEQ ID No. 2 according to the invention, compared with the untreated cells. More particularly, a 21% decrease in carbonylation is observed when the cells treated with the peptide SEQ ID No. 2 are subjected to irradiation with UVB, compared to cells irradiated but not treated with the active agent.
  • Peptide SEQ ID No. 2 limits the carbonylation of unstressed cells and effectively protects the skin cells against oxidative damage caused by UVB radiation.
  • Human skin biopsies are maintained in culture ex vivo, treated with a 1% solution, a stock solution at 50 ppm of peptide SEQ ID No. 2, 24 hours before, and another 24 hours after contacting with a glycating agent (methyl glyoxal 5 or
  • Hematoxylin-Eosin (H & E) histological sections and stainings are used to evaluate the quality of cutaneous structures.
  • Peptide SEQ ED No. 2 effectively protects the skin from the stress induced by glycation. - -
  • the aim of this study is to determine the protective effect of peptide SEQ ID No. 2 vis-à-vis dermal fibroblasts subjected to oxidative stress, caused by oxygenated water (H 2 O 2 ) or irradiation.
  • UVB oxygenated water
  • Annexin V a marker of changes in the cell membrane that occurs early in apoptosis, is used for this test: the asymmetry of membrane lipids is disturbed and the phosphatidyl serine is exposed on the surface of the cell. The fluorinated annexin V can then bind to the phosphatidyl serine and mark the apoptotic cells. Protocol:
  • the human dermal fibroblasts are treated with a 1% solution of a 50 ppm stock solution of peptide SEQ ID No. 2 for 72 hours and then subjected to oxidative stress caused by H 2 O 2 to 2 mM for 30 minutes or at UVB irradiation at 50 mJ / cm 2 .
  • Controls not treated with peptide or H 2 O 2 . or non-irradiated, as well as controls treated only by the peptide, are carried out under the same conditions.
  • the cells are washed, fixed and labeled with fluorinated annexin V to reveal membrane disruption, an early sign of apoptosis.
  • Peptide SEQ ID No. 2 protects cutaneous cells against oxidative stress and irradiation with UVB and appreciably decreases the number of apoptotic cells.
  • phase A and phase B are separately heated between 70 ° C. and 75 ° C.
  • Phase B is emulsified in phase 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.
  • phase A Prepares phase A with stirring. Incorporate the xanthan gum gradually, with deflocculating stirring. Phases C and D will be incorporated once the gel is complete.
  • phase E previously prepared until perfect dissolution of the DHA, will be added later. Adjust the pH if necessary to 4 - 4.5. Color and perfume.
  • phase A Prepare and melt phase A at 65-70 ° C. Heat phase C at 65-70 ° C. Phase B is added to phase A just before emulsifying A in B. At about 45 ° C, the carbomer is neutralized by addition of phase D. Phase E is then added with gentle stirring and cooling is continued to 25 ° C. Phase F is then added if desired.
  • phase A Prepare phase A and heat to 75 ° C with stirring.
  • Prepare phase B by dispersing the carbopol, then the xanthan gum with stirring. Let rest. Heat to 75 ° C. At temperature, emulsify A in B with rotor-stator stirring. Neutralize with phase C with rapid stirring. After cooling to 40 ° C., add phase D and then phase E. Cooling is continued with gentle stirring and phase F added.

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Abstract

The present invention relates to a cosmetic or pharmaceutical, and in particular dermatological, composition comprising, in a physiologically suitable medium, cytochrome c-derived peptides, as active agent, alone or in combination with at least one other active agent. The invention also relates to the use of cytochrome c-derived peptides, as active agent, in a cosmetic composition for stimulating the defences and protection of the skin, in particular against oxidative damage. The invention also relates to a cosmetic treatment process for protecting the skin and the appendages against external attacks and for combating skin ageing.

Description

COMPOSITION PHARMACEUTIQUE ET/OU COSMETIQUE CONTENANT PHARMACEUTICAL AND / OR COSMETIC COMPOSITION CONTAINING
DES PEPTIDESPEPTIDES
La présente invention se situe dans le domaine cosmétique et pharmaceutique, et plus particulièrement dans le domaine de la dermatologie. La présente invention concerne une composition cosmétique ou pharmaceutique, et notamment dermatologique, comprenant, dans un milieu physiologiquement adapté, des peptides dérivés du cytochrome c, en tant qu'agent actif, seul ou en association avec au moins un autre agent actif. L'invention est également relative à l'utilisation cosmétique d'une composition stimulant les défenses et la protection de la peau, en particulier vis-à-vis des dommages oxydatifs. L'invention porte encore sur un procédé de traitement cosmétique destiné à protéger la peau et les phanères des agressions extérieures et à lutter contre le vieillissement cutané. L'agent actif, dérivé du cytochrome c, peut également être utilisé pour préparer des compositions pharmaceutiques destinées à prévenir ou lutter contre les pathologies liées à des processus d'oxydation ou encore, certaines pathologies du vieillissement.The present invention is in the cosmetic and pharmaceutical field, and more particularly in the field of dermatology. The present invention relates to a cosmetic or pharmaceutical, and especially dermatological, composition comprising, in a physiologically suitable medium, peptides derived from cytochrome c, as active agent, alone or in combination with at least one other active agent. The invention also relates to the cosmetic use of a composition stimulating the defenses and the protection of the skin, in particular vis-à-vis the oxidative damage. The invention also relates to a cosmetic treatment method intended to protect the skin and the integuments from external aggressions and to fight against skin aging. The active agent, derived from cytochrome c, can also be used to prepare pharmaceutical compositions intended to prevent or combat pathologies related to oxidation processes or certain pathologies of aging.
Le terme « phanères » selon l'invention englobe l'ensemble des annexes kératiniques présentes à la surface du corps, en particulier les poils, les cils, les sourcils, les ongles et les cheveux.The term "superficial body growths" according to the invention encompasses all the keratinous appendages present on the surface of the body, in particular the hairs, the eyelashes, the eyebrows, the nails and the hair.
La peau est un organe vital qui recouvre toute la surface du corps et assure des fonctions protectrices, sensitives, immunitaires, métaboliques ou encore thermorégulatrices. La peau, comme les autres organes, est soumise au vieillissement. Or, un des mécanismes majeurs impliqués dans les processus du vieillissement est l'accumulation de dommages oxydatifs dans des molécules essentielles telles que les lipides membranaires, les protéines, l'ADN et tout particulièrement l'ADN mitochondrial (ADNmt).The skin is a vital organ that covers the entire surface of the body and provides protective, sensitive, immune, metabolic or thermoregulatory functions. The skin, like other organs, is subject to aging. However, one of the major mechanisms involved in aging processes is the accumulation of oxidative damage in essential molecules such as membrane lipids, proteins, DNA and especially mitochondrial DNA (mtDNA).
Les dommages oxydatifs sont provoqués par les radicaux libres, des espèces chimiquement instables et très réactionnelles générées par le métabolisme intracellulaire ou les agressions extérieures. Parmi ces agressions extérieures, on peut citer : les rayonnements UV, les toxines, les polluants atmosphériques, les oxydants alimentaires. Dans la peau, on observe un vieillissement prématuré survenant dans les zones exposées aux rayonnements, caractérisé par des phénomènes d'altérations des macromolécules (péroxydation lipidique, carbonylation des protéines) touchant en particulier l'élastine, le collagène ou la fibronectine. On a également pu montrer un déclin progressif des - -Oxidative damage is caused by free radicals, chemically unstable and highly reactive species generated by intracellular metabolism or external aggression. These external aggressions include: UV radiation, toxins, air pollutants, food oxidants. In the skin, there is premature aging occurring in the areas exposed to radiation, characterized by phenomena of alterations of macromolecules (lipid peroxidation, carbonylation of proteins) affecting in particular elastin, collagen or fibronectin. It has also been possible to show a progressive decline in - -
fonctions mitochondriales avec l'âge, probablement lié à l'accumulation de mutations sur l'ADNmt (K. Singh, Ann. N.Y. Acad. Sci. 1019, 2004).mitochondrial functions with age, probably related to the accumulation of mutations on mtDNA (K. Singh, Ann N.Y. Acad Sci 1019, 2004).
L'organisme possède des mécanismes de défense capables de piéger ou de transformer les radicaux libres (enzymes, glutathion, vitamines A et E, coenzyme QlO, etc.). Cependant, ces systèmes de défense an ti oxydants s'avèrent souvent insuffisants devant les nombreux stress et agressions extérieures auxquels sont soumis les organismes et la peau en particulier.The body has defense mechanisms capable of trapping or transforming free radicals (enzymes, glutathione, vitamins A and E, coenzyme Q10, etc.). However, these antioxidant defense systems are often insufficient in the face of the many stresses and external aggressions to which the organisms and the skin in particular are subjected.
Dans ce contexte, les propriétés particulières du cytochrome c apparaissent comme particulièrement intéressantes : Le cytochrome c est une petite protéine soluble de 15 kDa qui joue un rôle essentiel dans la fonction mitochondriale et dans la survie cellulaire. Le cytochrome c est une molécule hautement conservée chez la plupart des eucaryotes ; on la trouve dans les mitochondries des plantes, des animaux et de nombreux organismes unicellulaires. Le cytochrome c présente une structure protéique organisée autour d'une porphyrine, constituée de quatre noyaux pyrrol, eux-mêmes liés à un atome de fer.In this context, the particular properties of cytochrome c appear to be particularly interesting: Cytochrome c is a small soluble protein of 15 kDa that plays an essential role in mitochondrial function and in cell survival. Cytochrome c is a highly conserved molecule in most eukaryotes; it is found in the mitochondria of plants, animals and many unicellular organisms. Cytochrome c has a protein structure organized around a porphyrin, consisting of four pyrrol nuclei, themselves linked to an iron atom.
Le rôle principal du cytochrome c est d'assurer le transfert d'électrons, grâce au changement de valence de l'atome de fer. Le cytochrome c, qui est soluble, transporte ainsi les électrons depuis le complexe El (coenzyme QH2-cytochrome c réductase) jusqu'au complexe IV (cytochrome oxydase). Les électrons, qui sont le substrat de la cytochrome oxydase, sont alors transférés par l'enzyme vers l'oxygène.The main role of cytochrome c is to ensure the transfer of electrons, thanks to the change of valence of the iron atom. Cytochrome c, which is soluble, transports electrons from the El complex (coenzyme QH2-cytochrome c reductase) to complex IV (cytochrome oxidase). The electrons, which are the substrate for cytochrome oxidase, are then transferred by the enzyme to oxygen.
La recherche de composés pouvant stimuler les défenses de la peau ou protéger cette dernière afin de prévenir ou de lutter contre les signes du vieillissement cutané, ou les dommages causés par les agressions extérieures, telles que les rayonnements UV, les radiations, ou les expositions à des toxines ou à des polluants, est une préoccupation importante de la recherche médicale et de la cosmétique. A cet égard, il a été proposé des compositions cosmétiques ou thérapeutiques contenant du cytochrome c modifié, rendu soluble ou stabilisé (GB990082, CA 1272958), ou encore des polypeptides de grande taille, dérivés de domaines structuraux du cytochrome c (WO0212320). Mais à la connaissance de la demanderesse, aucune composition cosmétique ou pharmaceutique comprenant des peptides dérivés du cytochrome c, tels que divulgués dans la présente invention, n'a encore été décrite. La présente invention a pour principal objectif de fournir un nouvel agent actif, capable de protéger la peau des agressions extérieures et de lutter contre le vieillissement cutané. Les inventeurs ont en effet mis en évidence une activité cosmétique et thérapeutique, notamment dermatologique, des peptides dérivés du cytochrome c. D a en particulier été mis en évidence que ces peptides, lorsqu'ils sont appliqués sur la peau, ont une forte activité protectrice vis-à-vis des agressions extérieures subies par la peau, démontrée par une protection vis-à-vis des dommages oxydatifs et une diminution de l'apoptose. Ces nouveaux agents actifs capables de protéger la peau des agressions extérieures permettent ainsi d'ouvrir de nouvelles perspectives thérapeutiques et cosmétiques.The search for compounds that can stimulate the skin's defenses or protect the skin in order to prevent or fight against the signs of skin aging, or the damage caused by external aggressions, such as UV radiation, radiation, or exposure to skin. toxins or pollutants, is a major concern of medical research and cosmetics. In this regard, it has been proposed cosmetic or therapeutic compositions containing modified cytochrome c, made soluble or stabilized (GB990082, CA 1272958), or large polypeptides derived from structural domains of cytochrome c (WO0212320). But to the knowledge of the applicant, no cosmetic or pharmaceutical composition comprising peptides derived from cytochrome c, as disclosed in the present invention, has yet been described. The main object of the present invention is to provide a new active agent capable of protecting the skin against external aggressions and of combating cutaneous aging. The inventors have in fact demonstrated a cosmetic and therapeutic activity, especially dermatological, peptides derived from cytochrome c. In particular, it has been demonstrated that these peptides, when applied to the skin, have a high protective activity with respect to the external aggressions suffered by the skin, demonstrated by a protection against damage. oxidation and a decrease in apoptosis. These new active agents able to protect the skin from external aggressions thus open up new therapeutic and cosmetic perspectives.
On entend par « agent actif capable de protéger la peau des agressions extérieures », toute substance capable de présenter des propriétés protectrices ou de diminuer l'apoptose dans des cellules ou des tissus soumis à un stress d'origine physico-chimique ou environnementale. Ainsi, l'invention a pour objet premier une composition cosmétique ou pharmaceutique, et notamment dermatologique, comprenant, dans un milieu physiologiquement adapté, des peptides dérivés du cytochrome c, en tant qu'agent actif, seul ou en association avec au moins un autre agent actif.The term "active agent capable of protecting the skin from external aggressions" means any substance capable of exhibiting protective properties or of reducing apoptosis in cells or tissues subjected to stress of physicochemical or environmental origin. Thus, the subject of the invention is primarily a cosmetic or pharmaceutical composition, and especially a dermatological composition, comprising, in a physiologically adapted medium, peptides derived from cytochrome c, as active agent, alone or in combination with at least one other active agent.
Préférentiellement, selon la présente invention, lesdits peptides dérivés du cytochrome c ou leurs dérivés biologiquement actifs sont des peptides dont le nombre d'acides aminés est compris entre 3 et 13.Preferentially, according to the present invention, said peptides derived from cytochrome c or their biologically active derivatives are peptides whose number of amino acids is between 3 and 13.
L'expression « peptides dérivés du cytochrome c » désigne tout fragment peptidique biologiquement actif dont la séquence en acides aminés est, entièrement ou partiellement, analogue ou homologue des séquences peptidiques du cytochrome c. Par l'expression « biologiquement actif », on entend « qui possède une activité in vivo ou in vitro caractéristique de l'activité de l'agent actif selon l'invention ».The term "cytochrome c-derived peptides" refers to any biologically active peptide fragment whose amino acid sequence is, wholly or partially, analogous or homologous to the peptide sequences of cytochrome c. By the term "biologically active" is meant "which has an activity in vivo or in vitro characteristic of the activity of the active agent according to the invention".
Selon une méthode particulièrement avantageuse de réalisation de l'invention, le peptide possède une séquence qui répond à la formule générale (I)According to a particularly advantageous method of carrying out the invention, the peptide has a sequence which corresponds to the general formula (I)
R1-(AA)n- X1-X2- X3- X4-X5- (AA)p-R2 Dans laquelle Xi est la tyrosine, - -R 1 - (AA) n - X 1 -X 2 -X 3 -X 4 -X 5 - (AA) p -R 2 In which Xi is tyrosine, - -
X2 est la leucine,X 2 is leucine,
X3 est la lysine,X 3 is lysine,
X4 est la thréonine, la serine, la lysine, l'arginine ou aucun acide aminé,X 4 is threonine, serine, lysine, arginine or no amino acid,
X5 est la valine, l'alanine, la tyrosine, la méthionine ou aucun acide aminé, AA représente un acide aminé quelconque, ou un de ses dérivés, absent de la séquence du cytochrome c, et n et p sont des nombres entiers compris entre 0 et 4.X 5 is valine, alanine, tyrosine, methionine or no amino acid, AA represents any amino acid, or a derivative thereof, absent from the cytochrome c sequence, and n and p are integers inclusive between 0 and 4.
R1 représente la fonction aminé primaire de l'acide aminé N-terminal, libre ou substituée par un groupement protecteur pouvant être choisi parmi un groupement acétyle, un groupement benzoyle, un groupement tosyle ou un groupement benzyloxycarbonyle.R 1 represents the primary amino function of the N-terminal amino acid, free or substituted with a protective group which may be chosen from an acetyl group, a benzoyl group, a tosyl group or a benzyloxycarbonyl group.
R2 représente la fonction hydroxyle de l'acide carboxyle de l'acide aminé C-terminal, libre ou substituée par un groupement protecteur pouvant être choisi parmi une chaîne alkyle de Ci à C20, ou un groupement NH2, NHY ou NYY avec Y représentant une chaîne alkyle de Ci à C4. Selon une méthode de réalisation de l'invention tout particulièrement préférée, le peptide biologiquement actif est de séquence :R 2 represents the hydroxyl function of the carboxylic acid of the C-terminal amino acid, free or substituted with a protective group that may be chosen from a C 1 to C 20 alkyl chain, or an NH 2 , NHY or NYY group with Y represents an alkyl chain of Ci to C 4 . According to a particularly preferred embodiment of the invention, the biologically active peptide is of sequence:
(SEQ ID n°l) Tyr-Leu-Lys-Lys-Ala (SEQ ID n°2) Tyr-Leu-Lys-Lys-Ala-NH2 (SEQ ID n°3) Tyr-Leu-Lys-Lys-NH2 (SEQ ID NO: 1) Tyr-Leu-Lys-Lys-Ala (SEQ ID NO: 2) Tyr-Leu-Lys-Lys-Ala-NH 2 (SEQ ID NO: 3) Tyr-Leu-Lys-Lys- NH 2
(SEQ ID n°4) Tyr-Leu-Lys(SEQ ID NO: 4) Tyr-Leu-Lys
Selon un mode de réalisation particulièrement intéressant, le peptide biologiquement actif correspond à la séquence SEQ ID n°l. Selon un autre mode de réalisation particulièrement intéressant, le peptide biologiquement actif correspond à la séquence SEQ ID n°2.According to a particularly interesting embodiment, the biologically active peptide corresponds to the sequence SEQ ID No. 1. According to another particularly interesting embodiment, the biologically active peptide corresponds to the sequence SEQ ID No. 2.
L'invention concerne aussi des formes homologues de ces séquences. Le terme « homologue » désigne, selon l'invention, toute séquence peptidique identique à au moins 50%, ou de préférence au moins 80%, et encore plus préférentiellement à au moins 90% de ladite séquence peptidique, choisie parmi les séquences SEQ ID n° 1 à SEQ ED n° 4. Par « séquence peptidique identique à au moins X% », on entend désigner un pourcentage d'identité entre les résidus d'acides aminés des deux séquences à comparer, obtenu après l'alignement optimal des deux séquences. L'alignement optimal est obtenu à l'aide d'algorithmes d'homologies locales tels que ceux utilisés par les logiciels informatiques BLAST P ou T BLAST N disponibles sur le site NCBI.The invention also relates to homologous forms of these sequences. The term "homologue" denotes, according to the invention, any peptide sequence identical to at least 50%, or preferably at least 80%, and even more preferably to at least 90% of said peptide sequence, chosen from SEQ ID sequences. No. 1 to SEQ ID No. 4. "Peptide sequence identical to at least X%" is intended to designate a percentage identity between the amino acid residues of the two sequences to be compared, obtained after the optimal alignment of the two sequences. Optimal alignment is achieved by using local homology algorithms such as those used by BLAST P or T BLAST N computer software available on the NCBI site.
Le terme « homologue » peut également désigner un peptide qui diffère de la séquence d'un peptide de séquence SEQ E) n° 1 à SEQ ID n° 4 par la substitution d'acides aminés chimiquement équivalents, c'est-à-dire par la substitution d'un résidu par un autre possédant les mêmes caractéristiques. Ainsi, les substitutions classiques se font entre AIa, Val, Leu et De ; entre Ser et Thr ; entre les résidus acides Asp et Glu ; entre Asn et GIn ; et entre les résidus basiques Lys et Arg ; ou entre les résidus aromatiques Phe et Tyr. Dans l'invention, le terme « acide aminé » se réfère ici à tout acide organique naturel ou non naturel ayant la formule :The term "homologue" may also denote a peptide which differs from the sequence of a peptide of sequence SEQ E) No. 1 to SEQ ID No. 4 by the substitution of chemically equivalent amino acids, that is to say by substituting one residue for another with the same characteristics. Thus, the classical substitutions are between Ala, Val, Leu and De; 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- où chaque -R est indépendamment sélectionné entre un hydrogène et un groupement alkyl ayant entre 1 et 12 atomes de carbone. Préférentiellement, au moins un groupement -R de chaque acide aminé est un hydrogène. Par le terme « alkyl », on entend ici une chaîne carbonée pouvant être linéaire ou ramifiée, substituée (mono- ou poly-) ou non- substituée ; saturée, mono-saturée (une double ou triple liaison dans la chaîne) ou poly- insaturée (deux ou plusieurs doubles liaisons, deux ou plusieurs triples liaisons, une ou plusieurs doubles liaisons et une ou plusieurs triples liaisons dans la chaîne). Le terme « peptide » désigne un enchaînement de deux ou plusieurs acides aminés liés entre eux par des liaisons peptidiques ou par des liaisons peptidiques modifiées.-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.
Par « peptide », il faut entendre le peptide naturel ou synthétique de l'invention tel que décrit ci-dessus ou au moins l'un de ses fragments, qu'il soit obtenu par protéolyse ou de manière synthétique, ou encore tout peptide naturel ou synthétique dont la séquence est totalement ou partiellement constituée par la séquence du peptide précédemment décrit. De façon à améliorer la résistance à la dégradation, il peut être nécessaire d'utiliser une forme protégée du peptide selon l'invention. La forme de protection doit évidemment être une forme biologiquement compatible et doit être compatible avec une utilisation dans le domaine des cosmétiques ou de la pharmacie. De nombreuses formes de protection biologiquement compatibles peuvent être envisagées. Ainsi, l'invention concerne une composition telle que définie précédemment, caractérisée par le fait que le peptide de formule générale (I) possède au moins un groupement fonctionnel protégé par un groupement protecteur, ce groupement protecteur - -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 peptide or synthetic whose sequence is totally or partially constituted by the sequence of the previously described peptide. In order to improve the resistance to degradation, it may be 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 forms of biologically compatible protection can be envisaged. Thus, the invention relates to a composition as defined above, characterized in that the peptide of general formula (I) has at least one functional group protected by a protective group, this protective group - -
étant soit une acylation ou une acétylation de l'extrémité amino-terminale, soit une amidation ou une estérifïcation de l'extrémité carboxy-terminale, soit les deux. L'extrémité amino-terminale peut être protégée par un groupement acétyle, un groupement benzoyle, un groupement tosyle ou un groupement benzyloxycarbonyle. De préférence, on utilise une protection basée sur l'amidation de la fonction hydroxyle de l'extrémité carboxy-terminale par un groupement NYY avec Y représentant une chaîne alkyle de C] à C4, ou l'estérification par un groupement alkyle. Il est également possible de protéger les deux extrémités du peptide.being either acylation or acetylation of the amino terminus, amidation or esterification of the carboxy terminus, or both. The amino-terminus may be protected by an acetyl group, a benzoyl group, a tosyl group or a benzyloxycarbonyl group. Preferably, a protection based on the amidation of the hydroxyl function of the carboxy-terminal end is used by a NYY group with Y representing an alkyl chain of C 1 to C 4 , or esterification with an alkyl group. It is also possible to protect both ends of the peptide.
Les dérivés de peptides concernent aussi les acides aminés et les peptides reliés entre eux par une liaison pseudo-peptidique. On entend par « liaison pseudo-peptidique », tous les types de liaisons susceptibles de remplacer les liaisons peptidiques « classiques ».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 "classical" peptide bonds.
Dans le domaine des acides aminés, la géométrie des molécules est telle qu'elles peuvent théoriquement se présenter sous la forme d'isomères optiques différents. Il existe, en effet, une conformation moléculaire de l'acide aminé (AA) telle qu'elle dévie à droite le plan de polarisation de la lumière (conformation dextrogyre ou D-aa), et une conformation moléculaire de l'acide aminé (aa) telle qu'elle dévie à gauche le plan de polarisation de la lumière (conformation lévogyre ou L-aa). Les acides aminés naturels sont toujours de conformation lévogyre, en conséquence, un peptide d'origine naturelle ne sera constitué que d'acides aminés de type L-aa. Cependant, la synthèse chimique en laboratoire permet de préparer des acides aminés ayant les deux conformations possibles. A partir de ce matériel de base, il est ainsi possible d'incorporer lors de la synthèse de peptide aussi bien des acides aminés sous forme d'isomères optiques dextrogyre ou lévogyre. Ainsi, les acides aminés constituant le peptide selon l'invention peuvent être sous configuration L- et D- ; de manière préférentielle, les acides aminés sont sous forme L. Le peptide selon l'invention peut donc être sous forme L-, D- ou DL-.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). The natural amino acids are always levorotatory, therefore a naturally occurring peptide will consist only of L-aa amino acids. However, chemical synthesis in the 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.
Le peptide de formule générale (I) selon l'invention peut être obtenu soit par synthèse chimique classique (en phase solide ou en phase homogène liquide), soit par synthèse enzymatique (Kullman et al., J. Biol. Chem. 1980, 225, 8234), à partir d'acides aminés constitutifs ou de leurs dérivés. Le peptide selon l'invention peut également être obtenu par fermentation d'une souche de bactéries modifiées ou non, par génie génétique, ou encore par extraction de protéines d'origine animale ou végétale, préférentiellement d'origine végétale, suivie d'une hydrolyse contrôlée qui libère des fragments peptidiques correspondant totalement ou partiellement aux peptides de formule générale (I).The peptide of general formula (I) according to the invention can be obtained either by conventional chemical synthesis (in solid phase or in homogeneous liquid phase) or by enzymatic synthesis (Kullman et al., J. Biol Chem 1980, 225 , 8234), from constituent amino acids or their derivatives. The peptide according to the invention can also be obtained by fermentation of a strain of bacteria modified or not, by genetic engineering, or by extraction of proteins of animal or plant origin, preferably of plant origin, followed by controlled hydrolysis which releases peptide fragments corresponding totally or partially to the peptides of general formula (I).
De très nombreuses protéines trouvées dans les plantes sont susceptibles de contenir ces séquences au sein de leur structure. L'hydrolyse ménagée permet de dégager ces fragments peptidiques. Il est possible, mais non nécessaire pour réaliser l'invention, d'extraire soit les protéines concernées d'abord et de les hydrolyser ensuite, soit d'effectuer l'hydrolyse d'abord sur un extrait brut et de purifier les fragments peptidiques ensuite. D est également possible d'utiliser certains extraits hydrolyses sans en purifier les fragments peptidiques correspondant aux peptides de formule générale I selon l'invention, mais en s'assurant toutefois de la présence desdits fragments par des moyens analytiques appropriés.Many proteins found in plants are likely to contain these sequences within their structure. The controlled hydrolysis makes it possible to release these peptide fragments. It is possible, but not necessary to carry out the invention, to extract either the proteins concerned first and then hydrolyze them, or to carry out the hydrolysis first on a crude extract and then to purify the peptide fragments. . It is also possible to use certain hydrolysed extracts without purifying the peptide fragments corresponding to the peptides of general formula I according to the invention, but nevertheless ensuring the presence of said fragments by appropriate analytical means.
D'autres procédés plus simples ou plus complexes peuvent être envisagés par l'homme du métier connaissant le métier de synthèse, d'extraction et de purification des protéines et des peptides. Ainsi le peptide selon l'invention peut être d'origine naturelle ou synthétique. Préférentiellement selon l'invention, le peptide est obtenu par synthèse chimique.Other simpler or more complex processes can be envisaged by those skilled in the art of synthesis, extraction and purification of proteins and peptides. Thus the peptide according to the invention may be of natural or synthetic origin. Preferably according to the invention, the peptide is obtained by chemical synthesis.
Selon l'invention, l'agent actif peut être un mélange de dérivés peptidiques et/ou constitués de dérivés d'acides aminés.According to the invention, the active agent can be a mixture of peptide derivatives and / or constituted by amino acid derivatives.
Selon un mode de réalisation avantageux de l'invention, l'agent actif selon l'invention est préalablement solubilisé dans un ou plusieurs solvants classiquement utilisés par l'homme du métier, comme l'eau, le glycérol, l'éthanol, le propylène glycol, le butylène glycol, le dipropylène glycol, les diglycols éthoxylés ou propoxylés, les polyols cycliques, la vaseline, une huile végétale ou tout mélange de ces solvants.According to an advantageous embodiment of the invention, the active agent according to the invention is first solubilized in one or more solvents conventionally used by those skilled in the art, such as water, glycerol, ethanol, propylene glycol, butylene glycol, dipropylene glycol, ethoxylated or propoxylated diglycols, cyclic polyols, petroleum jelly, a vegetable oil or any mixture of these solvents.
Selon encore un autre mode de réalisation avantageux de l'invention, l'agent actif selon l'invention est préalablement solubilisé dans un vecteur cosmétique ou pharmaceutique comme les liposomes ou adsorbé sur des polymères organiques poudreux, des supports minéraux comme les talcs et bentonites, et plus généralement solubilisé dans, ou fixé sur, tout vecteur cosmétiquement ou pharmaceutiquement acceptable. La composition utilisable selon l'invention peut en particulier consister en une composition pour soins capillaires, et notamment un shampooing, un après-shampooing, une lotion de mise en plis, une lotion traitante, une crème ou un gel coiffant, une lotion restructurante pour les cheveux, un masque, etc. La composition cosmétique selon -o-According to yet another advantageous embodiment of the invention, the active agent according to the invention is solubilized beforehand 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 that may be used according to the invention may in particular consist of a composition for hair care, and in particular a shampoo, a conditioner, a setting lotion, a treatment lotion, a cream or a styling gel, a restructuring lotion for hair, a mask, etc. The cosmetic composition according to -o-
l'invention peut être utilisée notamment dans les traitements mettant en oeuvre une application qui est suivie ou non suivie d'un rinçage, ou encore sous forme de shampooing.the invention can be used in particular in the treatments implementing an application that is followed or not followed by rinsing, or in the form of shampoo.
Elle peut également se présenter sous forme de teinture ou de mascara à appliquer au pinceau ou au peigne, en particulier sur les cils, les sourcils ou les cheveux.It can also be in the form of dye or mascara to be applied with a brush or a comb, in particular on eyelashes, eyebrows or hair.
Les compositions selon l'invention pourront être appliquées par toute voie appropriée, notamment orale, parentérale ou topique externe, et leur formulation sera adaptée par l'homme du métier, en particulier pour des compositions cosmétiques ou dermatologiques. Avantageusement, les compositions selon l'invention se présentent sous une forme adaptée à l'application par voie topique. Ces compositions doivent donc contenir un milieu cosmétiquement et/ou dermatologiquement acceptable, c'est-à-dire compatible avec la peau et les phanères, et couvrent toutes les formes cosmétiques ou dermatologiques. Ces compositions pourront notamment être sous forme de crèmes, émulsions huile-dans-eau, ou eau-dans-huile ou émulsions multiples, solutions, suspensions, gels, laits, lotions, sticks ou encore de poudres, adaptés à une application sur la peau, les lèvres et/ou les phanères.The compositions according to the invention may be applied by any appropriate route, in particular oral, parenteral or external topical, and their formulation will be adapted by those skilled in the art, in particular for cosmetic or dermatological compositions. Advantageously, the compositions according to the invention are in a form suitable for topical application. These compositions must therefore contain a cosmetically and / or dermatologically acceptable medium, that is to say compatible with the skin and superficial body growths, and cover all cosmetic or dermatological forms. These compositions may especially be in the form of creams, oil-in-water or water-in-oil emulsions or multiple emulsions, solutions, suspensions, gels, milks, lotions, sticks or even powders, suitable for application on the skin. , lips and / or integuments.
Ces compositions comprennent les excipients nécessaires à leur formulation, tels que solvants, épaississants, diluants, tensioactifs, anti-oxydants, colorants, conservateurs, parfums. Avantageusement, les compositions utilisables contiennent en outre au moins un autre principe actif favorisant l'action des peptides selon l'invention. Ainsi, la composition selon l'invention peut associer, à l'agent actif selon l'invention, des principes actifs ayant une action antioxydante, ou encore stimulant la synthèse des macromolécules dermiques, ou encore stimulant le métabolisme énergétique. Par exemple, tant que principes actifs ayant une action anti-radicalaire ou antioxydante, on peut citer la vitamine C, la vitamine E, le coenzyme QlO et les extraits polyphénoliques de plantes.These compositions comprise the excipients necessary for their formulation, such as solvents, thickeners, diluents, surfactants, antioxidants, dyes, preservatives, perfumes. Advantageously, the compositions that can be used also contain at least one other active ingredient promoting the action of the peptides according to the invention. Thus, the composition according to the invention can associate, with the active agent according to the invention, active ingredients having an antioxidant action, or stimulating the synthesis of dermal macromolecules, or stimulating the energy metabolism. For example, as active ingredients having an anti-radical or antioxidant action, mention may be made of vitamin C, vitamin E, coenzyme Q10 and polyphenolic extracts of plants.
On peut également citer en tant que principes actifs stimulant les synthèses des macromolécules dermiques (laminine, fibronectine, collagène), par exemple le peptide de collagène commercialisé sous le nom « Collaxyl® » par la société Vincience. Enfin, en tant que principes actifs stimulant le métabolisme énergétique, on peut citer le principe actif commercialisé sous la dénomination « GP4G® » par la société Vincience. Selon un autre aspect, la composition selon l'invention peut être une composition solaire, c'est-à-dire une composition aidant à la protection contre le rayonnement solaire. Ainsi, il peut être avantageusement ajouté, à la composition selon l'invention, des actifs aidant à la protection solaire tels que, par exemple, des filtres solaires. II est bien évident que l'invention s'adresse aux mammifères en général, et plus particulièrement aux êtres humains.It may also be mentioned as active ingredients stimulating the synthesis of dermal macromolecules (laminin, fibronectin, collagen), for example the collagen peptide sold under the name "Collaxyl®" by Vincience. Finally, as active ingredients stimulating energy metabolism, mention may be made of the active ingredient sold under the name "GP4G®" by the company Vincience. According to another aspect, the composition according to the invention may be a solar composition, that is to say a composition helping to protect against solar radiation. Thus, it can be advantageously added to the composition according to the invention, assets assisting the sun protection such as, for example, sunscreens. It is obvious that the invention is directed to mammals in general, and more particularly to humans.
La quantité efficace d'agent actif correspond à la quantité nécessaire afin d'obtenir le résultat recherché, à savoir, stimuler les défenses de la peau et protéger cette dernière vis- à-vis des agressions extérieures, en particulier les dommages oxydatifs, et plus généralement, protéger la peau et les phanères des agressions extérieures et lutter contre le vieillissement cutané.The effective amount of active agent corresponds to the amount necessary to obtain the desired result, namely, to stimulate the defenses of the skin and protect the latter vis-à-vis external aggressions, particularly oxidative damage, and more Generally, protect the skin and skin appendages from external aggressions and fight against skin aging.
Selon un mode de réalisation avantageux de l'invention, l'agent actif selon l'invention est présent dans les compositions de l'invention à une concentration comprise entre 0,0005 et 500 ppm (parties par million) environ, et préférentiellement à une concentration comprise entre 0,01 et 5 ppm environ par rapport au poids total de la composition finale.According to an advantageous embodiment of the invention, the active agent according to the invention is present in the compositions of the invention at a concentration of between about 0.0005 and 500 ppm (parts per million), and preferably at a concentration of concentration between about 0.01 and 5 ppm relative to the total weight of the final composition.
Ces compositions pourront notamment se présenter sous forme d'une solution aqueuse, hydroalcoolique ou huileuse ; d'une émulsion huile-dans-eau, eau-dans-huile ou émulsions multiples ; elles peuvent aussi se présenter sous forme de crèmes, de suspensions, ou encore de poudres, adaptées à une application sur la peau, les muqueuses, les lèvres et/ou les phanères. Ces compositions peuvent être plus ou moins fluides et avoir l'aspect d'une crème, d'une lotion, d'un lait, d'un sérum, d'une pommade, d'un gel, d'une pâte ou d'une mousse. Elles peuvent aussi se présenter sous forme solide, comme un stick ou être appliquées sur la peau sous forme d'aérosol. Elles peuvent être utilisées comme produit de soin et/ou comme produit de maquillage de la peau. Ces compositions comprennent, en outre, tout additif communément utilisé dans le domaine d'application envisagé ainsi que les adjuvants nécessaires à leur formulation, tels que des solvants, des épaississants, des diluants, des anti-oxydants, des colorants, des filtres solaires, des agents auto-bronzants, des pigments, des charges, des conservateurs, des parfums, des absorbeurs d'odeur, des actifs cosmétiques ou pharmaceutiques, des huiles essentielles, des vitamines, des acides gras essentiels, des tensioactifs, des polymères fïlmogènes, etc.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. .
Dans tous les cas, l'homme de métier veillera à ce que ces adjuvants ainsi que leurs proportions soient choisis de telle manière à ne pas nuire aux propriétés avantageuses recherchées de la composition selon l'invention. Ces adjuvants peuvent, par exemple, correspondre à 0,01 à 20 % du poids total de la composition. Lorsque la composition de l'invention est une émulsion, la phase grasse peut représenter de 5 à 80 % en poids et de préférence de 5 à 50 % en poids par rapport au poids total de la composition. Les émulsionnants et co-émulsionnants utilisés dans la composition seront choisis parmi ceux classiquement utilisés dans le domaine considéré. Par exemple, ils peuvent être utilisés en une proportion allant de 0,3 à 30 % en poids, par rapport au poids total de la composition.In all cases, the skilled person will ensure that these adjuvants and their proportions are chosen so as not to harm the advantageous properties sought from 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.
Par ses activités particulières, l'agent actif selon l'invention pourra être utilisé avantageusement dans une composition cosmétique ou pour la préparation d'une composition pharmaceutique.By its particular activities, the active agent according to the invention can be used advantageously in a cosmetic composition or for the preparation of a pharmaceutical composition.
En particulier, l'agent actif selon l'invention pourra être utilisé avantageusement dans une composition cosmétique destinée à lutter de manière préventive et/ou curative contre les manifestations du vieillissement cutané et, plus spécifiquement, afin de lutter contre et/ou de prévenir le vieillissement photo-induit (photo-vieillissement). Par manifestations cutanées du vieillissement, on entend toutes modifications de l'aspect extérieur de la peau et des phanères dues au vieillissement comme, par exemple, les rides et ridules, la peau flétrie, la peau molle, la peau amincie, le manque d'élasticité et/ou de tonus de la peau, la peau terne et sans éclat ou les taches de pigmentation de la peau, la décoloration des cheveux ou les taches sur les ongles, mais également toute modification interne de la peau qui ne se traduit pas systématiquement par un aspect extérieur modifié comme, par exemple, toute dégradation interne de la peau consécutive à une exposition aux rayonnements ultraviolets (UV). L'agent actif selon l'invention, ou la composition le contenant, permettra de lutter, en particulier, contre la perte d'élasticité et de fermeté de la peau. L'utilisation de l'agent actif, ou d'une composition le contenant, va permettre à la peau et aux phanères d'être protégés et de mieux résister aux stress environnementaux. Ainsi, un aspect particulier de l'invention est l'utilisation de l'agent actif selon l'invention, dans une composition cosmétique pour protéger la peau et les phanères vis-à-vis des dommages oxydatifs. Ledit agent actif étant avantageusement utilisé en tant qu'agent antioxydant et/ou en tant qu'agent anti-radicalaire et/ou en tant qu'agent anti-glycation. Par agent anti-radicalaire, on entend tout composé capable de piéger les radicaux libres avant les étapes ultimes de dégradation des constituants biologiques de la peau, on parle alors de composés antioxydants. Par agent anti-glycation, on entend tout composé capable de limiter les dommages cellulaires causés par les réactions de glycation ou de glycoxydation. Ainsi, l'agent actif selon l'invention permettra de lutter contre les dommages esthétiques provoqués sur la peau et/ou les cheveux par les radicaux libres.In particular, the active agent according to the invention may advantageously be used in a cosmetic composition intended to preventatively and / or curatively fight against the manifestations of cutaneous aging and, more specifically, in order to fight against and / or prevent photo-induced aging (photo-aging). Skin manifestations of aging means any changes in the external appearance of the skin and skin growth due to aging such as, for example, wrinkles and fine lines, wilted skin, soft skin, thinned skin, lack of elasticity and / or tone of the skin, dull and lackluster skin or skin pigmentation spots, discoloration of the hair or spots on the nails, but also any internal changes in the skin that does not systematically result by a modified external appearance such as, for example, any internal degradation of the skin resulting from exposure to ultraviolet (UV) radiation. The active agent according to the invention, or the composition containing it, will make it possible, in particular, to combat the loss of elasticity and firmness of the skin. The use of the active agent, or a composition containing it, will allow the skin and integuments to be protected and to better withstand environmental stresses. Thus, a particular aspect of the invention is the use of the active agent according to the invention, in a cosmetic composition for protecting the skin and the integuments with respect to oxidative damage. Said active agent being advantageously used as an antioxidant and / or as an anti-radical agent and / or as an anti-glycation agent. By anti-radical agent is meant any compound capable of scavenging free radicals before the ultimate stages of degradation of the biological constituents of the skin, so-called antioxidant compounds. By anti-glycation agent is meant any compound capable of to limit cell damage caused by glycation or glycoxidation reactions. Thus, the active agent according to the invention will make it possible to combat the cosmetic damage caused to the skin and / or the hair by free radicals.
Aussi, l'agent actif peut être utilisé avantageusement dans une composition cosmétique pour la protection de la peau et des phanères contre tous les types d'agressions extérieures On entend par l'expression « agressions extérieures », les agressions que peuvent produire l'environnement. A titre d'exemple, on peut citer des agressions telles que la pollution, les UV, ou encore les produits à caractère irritant tels que les tensioactifs, les conservateurs ou les parfums. Par pollution, on entend aussi bien la pollution « extérieure » due par exemple aux particules de diesel, à l'ozone ou aux métaux lourds, que la pollution « intérieure » qui peut être due notamment aux émissions de solvants de peintures, de colles, ou de papier-peints (tels que toluène, styrène, xylène ou benzaldehyde), ou bien encore la fumée de cigarette.Also, the active agent can be used advantageously in a cosmetic composition for the protection of the skin and integuments against all types of external aggression. The expression "external aggressions" means the aggressions that the environment can produce. . By way of example, mention may be made of aggressions such as pollution, UV, or irritating products such as surfactants, preservatives or perfumes. Pollution is understood to mean both "external" pollution due for example to diesel particles, ozone or heavy metals, and "internal" pollution, which may be due in particular to solvent emissions from paints, glues, or wallpaper (such as toluene, styrene, xylene or benzaldehyde), or even cigarette smoke.
L'agent actif selon l'invention peut être avantageusement utilisé dans une composition cosmétique ou pour la préparation d'une composition pharmaceutique, en tant qu'agent photo-protecteur et, plus particulièrement, en tant qu'agent photo-protecteur dit « secondaire ». On distingue, en effet, les agents photo-protecteurs primaires des agents photo-protecteurs secondaires. Les agents photo-protecteurs primaires sont des substances qui exercent un pouvoir physique : ils sont en mesure d'absorber les rayonnements UV et de les restituer sous forme de chaleur afin de protéger la peau. Les agents photo-protecteurs secondaires sont des substances qui ont généralement un effet biologique ; ce sont, par exemple, les agents capables de limiter les dommages causés à l' ADN et aux membranes par la pénétration des rayonnements UV dans la peau.The active agent according to the invention can be advantageously used in a cosmetic composition or for the preparation of a pharmaceutical composition, as a photo-protective agent and, more particularly, as a so-called "secondary" photo-protective agent. ". In fact, the primary photoprotective agents are distinguished from the secondary photoprotective agents. Primary photoprotective agents are substances that exert physical power: they are able to absorb UV radiation and release it as heat to protect the skin. Secondary photoprotective agents are substances that usually have a biological effect; these are, for example, the agents capable of limiting damage to DNA and membranes by the penetration of UV radiation into the skin.
L'invention a également pour objet l'utilisation dans une composition cosmétique d'une quantité efficace d'agent actif tel que décrit précédemment, pour prévenir les dommages causés à la peau par une exposition au soleil ou une exposition à des rayonnements ionisants lors de radiothérapies.The invention also relates to the use in a cosmetic composition of an effective amount of active agent as described above, to prevent damage to the skin caused by exposure to the sun or exposure to ionizing radiation during radiotherapy.
L'invention a également pour objet l'utilisation dans une composition cosmétique, d'une quantité efficace d'agent actif tel que décrit précédemment, pour protéger les mitochondries, en particulier sur les zones du corps exposées aux rayonnements UV. L'invention consiste encore en une composition pharmaceutique caractérisée en ce que l'agent actif selon l'invention est formulé pour atténuer une pathologie liée à des processus d'oxydation ou encore, certaines pathologies du vieillissement.The subject of the invention is also the use in a cosmetic composition of an effective amount of active agent as described above, for protecting mitochondria, in particular on the areas of the body exposed to UV radiation. The invention also consists in a pharmaceutical composition characterized in that the active agent according to the invention is formulated to attenuate a pathology related to oxidation processes or certain pathologies of aging.
L'invention consiste enfin en un procédé de traitement cosmétique destiné à stimuler les défenses et à protéger la peau et les phanères des agressions extérieures et à lutter contre le vieillissement cutané, caractérisé par l'application, sur la peau ou les phanères à traiter, d'une composition contenant une quantité efficace de l'agent actif selon l'invention.The invention finally consists of a cosmetic treatment method intended to stimulate the defenses and to protect the skin and the integuments from external aggressions and to fight against skin aging, characterized by the application, on the skin or integuments to be treated, a composition containing an effective amount of the active agent according to the invention.
Des modes de réalisation particuliers de ce procédé de traitement cosmétique résultent également de la description précédente. D'autres avantages et caractéristiques de l'invention apparaîtront mieux à la lecture des exemples donnés à titre illustratif et non limitatif.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.
Exemple 1 : Evaluation de l'effet protecteur du peptide SEQ ID n°2 vis-à-vis des dommages oxydatifsEXAMPLE 1 Evaluation of the Protective Effect of Peptide SEQ ID No. 2 with Respect to Oxidative Damage
Le but de cette étude est de déterminer l'effet protecteur du peptide SEQ ID n°2 vis-à- vis de fibroblastes dermiques soumis à un stress oxydatif provoqué par des rayonnements UVB. Pour évaluer les dommages oxydatifs subis par les cellules, des dosages de la carbonylation des protéines ont été réalisés. La carbonylation des protéines résulte du clivage oxydatif des protéines ou d'une oxydation des résidus arginine, lysine, proline ou thréonine. Le dosage de la carbonylation des protéines s'effectue par une technique EIA (Enzyme Immuno Assay).The purpose of this study is to determine the protective effect of peptide SEQ ID No. 2 vis-à-vis dermal fibroblasts subjected to oxidative stress caused by UVB radiation. To evaluate the oxidative damage to cells, protein carbonylation assays were performed. The carbonylation of proteins results from the oxidative cleavage of proteins or from the oxidation of arginine, lysine, proline or threonine residues. The determination of protein carbonylation is carried out by an EIA (Enzyme Immuno Assay) technique.
Protocole :Protocol:
Des fibroblastes en culture ont été mis en présence du peptide SEQ ID n°2 à 1 %, à partir d'une solution mère à 50 ppm, 72 heures avant, pendant, et encore 24 heures après l'irradiation aux UVB à 100 mJ/cm2. Des contrôles non traités sont réalisés.Fibroblasts in culture were brought into contact with the peptide SEQ ID No. 2 at 1%, from a stock solution at 50 ppm, 72 hours before, during, and another 24 hours after UVB irradiation at 100 mJ. / cm 2 . Untreated controls are performed.
La mesure de la carbonylation consiste à utiliser du DNP (dinitrophényl) qui a la propriété de se fixer spécifiquement sur les groupements carbonyles des protéines. Le DNP fixé sera ensuite dosé par une méthode ELISA, grâce à un anticorps anti-DNP biotinylé (DNP-KLH, Molecular Probes). Une gamme de BSA (bovine sérum albumine) oxydée (dont on connaît la concentration en groupements carbonyles) est utilisée pour l'étalonnage. Résultats :The measurement of carbonylation consists in using DNP (dinitrophenyl) which has the property of binding specifically on the carbonyl groups of the proteins. The fixed DNP will then be assayed by an ELISA method, using a biotinylated anti-DNP antibody (DNP-KLH, Molecular Probes). A range of oxidized BSA (bovine serum albumin) (whose concentration in carbonyl groups is known) is used for calibration. Results:
Les résultats obtenus montrent une diminution de 39% de la carbonylation des protéines lorsque les cellules sont traitées avec le peptide SEQ ID n°2 selon l'invention, en comparaison avec les cellules non traitées. On observe plus particulièrement une diminution de 21 % de la carbonylation lorsque les cellules traitées avec le peptide SEQ ID n°2 sont soumises à une irradiation par les UVB, par comparaison aux cellules irradiées mais non traitées avec l'agent actif.The results obtained show a 39% decrease in carbonylation of the proteins when the cells are treated with the peptide SEQ ID No. 2 according to the invention, compared with the untreated cells. More particularly, a 21% decrease in carbonylation is observed when the cells treated with the peptide SEQ ID No. 2 are subjected to irradiation with UVB, compared to cells irradiated but not treated with the active agent.
Conclusions :Conclusions:
Le peptide SEQ ID n°2 limite la carbonylation de cellules non stressées et protège efficacement les cellules cutanées contre les dommages oxydatifs provoqués par des rayonnements UVB.Peptide SEQ ID No. 2 limits the carbonylation of unstressed cells and effectively protects the skin cells against oxidative damage caused by UVB radiation.
Exemple 2 : Evaluation de l'effet protecteur du peptide SEQ ID n°2 vis-à-vis d'un stress induit par la glycation Le but de cette étude est de déterminer l'effet protecteur du peptide SEQ ED n°2, vis- à-vis de culture d'épiderme ex vivo soumises à un stress par un agent glycant.EXAMPLE 2 Evaluation of the Protective Effect of the Peptide SEQ ID No. 2 on a Stress Induced by Glycation The aim of this study is to determine the protective effect of the peptide SEQ ED No. 2, screw with respect to ex vivo epidermis culture subjected to stress by a glycating agent.
Protocole :Protocol:
Des biopsies de peau humaine sont maintenues en culture ex vivo, traitées avec une solution à 1 %, d'une solution mère à 50 ppm de peptide SEQ ID n°2, 24 heures avant, et encore 24 heures après la mise en présence avec un agent glycant (méthyl glyoxal à 5 ouHuman skin biopsies are maintained in culture ex vivo, treated with a 1% solution, a stock solution at 50 ppm of peptide SEQ ID No. 2, 24 hours before, and another 24 hours after contacting with a glycating agent (methyl glyoxal 5 or
10 raM). Des coupes et des colorations histologiques hématoxyline-éosine (H&E) permettent d'évaluer la qualité des structures cutanées.10 raM). Hematoxylin-Eosin (H & E) histological sections and stainings are used to evaluate the quality of cutaneous structures.
Résultats :Results:
L'observation des coupes de peau montrent une nette diminution des signes de stress cellulaire et une meilleure préservation des structures cutanées dans les biopsies de peau traitées par le peptide SEQ ED n°2, comparées aux biopsies de peau non traitées.The observation of the skin sections shows a clear decrease of the signs of cell stress and a better preservation of the cutaneous structures in the skin biopsies treated with the peptide SEQ ED n ° 2, compared to the untreated skin biopsies.
Conclusions :Conclusions:
Le peptide SEQ ED n°2 protège efficacement la peau du stress induit par la glycation. - -Peptide SEQ ED No. 2 effectively protects the skin from the stress induced by glycation. - -
Exemple 3 : Evaluation de l'effet protecteur et anti-apoptotique du peptide SEQ ID n°2 sur les cellules cutanées soumises à un stress oxydatif ou à une irradiation UVBExample 3 Evaluation of the Protective and Anti-Apoptotic Effect of Peptide SEQ ID No. 2 on Cutaneous Cells Under Oxidative Stress or UVB Irradiation
Le but de cette étude est de déterminer l'effet protecteur du peptide SEQ ID n°2 vis-à- vis de fibroblastes dermiques soumis à un stress oxydatif, provoqué par de l'eau oxygénée (H2O2) ou à une irradiation UVB. On utilise pour ce test l'annexine V, un marqueur des modifications de la membrane cellulaire qui apparaissent précocement dans l'apoptose : l'asymétrie des lipides membranaires est perturbée et la phosphatidyl-sérine se retrouve exposée à la surface de la cellule. L'annexine V fluorée peut alors se fixer sur la phosphatidyl serine et marquer les cellules apoptotiques. Protocole :The aim of this study is to determine the protective effect of peptide SEQ ID No. 2 vis-à-vis dermal fibroblasts subjected to oxidative stress, caused by oxygenated water (H 2 O 2 ) or irradiation. UVB. Annexin V, a marker of changes in the cell membrane that occurs early in apoptosis, is used for this test: the asymmetry of membrane lipids is disturbed and the phosphatidyl serine is exposed on the surface of the cell. The fluorinated annexin V can then bind to the phosphatidyl serine and mark the apoptotic cells. Protocol:
Les fibroblastes dermiques humains sont traités avec une solution à 1 %, d'une solution mère à 50 ppm de peptide SEQ ID n°2, pendant 72 heures, puis soumis à un stress oxydatif provoqué par de l'H2O2 à 2 mM, pendant 30 minutes ou à une irradiation UVB à 50 mJ/cm2. Des contrôles non traités par le peptide ou par de l'H2O2. ou non irradiés, ainsi que des contrôles traités seulement par le peptide, sont réalisés dans les mêmes conditions. A la fin de l'expérimentation, les cellules sont lavées, fixées et soumises à un marquage par de l'annexine V fluorée, afin de révéler la perturbation des membranes, signe précoce de l'apoptose.The human dermal fibroblasts are treated with a 1% solution of a 50 ppm stock solution of peptide SEQ ID No. 2 for 72 hours and then subjected to oxidative stress caused by H 2 O 2 to 2 mM for 30 minutes or at UVB irradiation at 50 mJ / cm 2 . Controls not treated with peptide or H 2 O 2 . or non-irradiated, as well as controls treated only by the peptide, are carried out under the same conditions. At the end of the experiment, the cells are washed, fixed and labeled with fluorinated annexin V to reveal membrane disruption, an early sign of apoptosis.
Résultats : Dans les conditions de contrôle, les fibroblastes non irradiés ou non soumis à un stress oxydatif, présentent une fluorescence très faible. Dans les conditions de stress (UVB et H2O2) la fluorescence est nettement visible dans une majorité de fibroblastes. Au contraire, dans les mêmes conditions de stress, les fibroblastes traités par le peptide SEQ ID n°2 présentent une fluorescence très inférieure. Conclusions :Results: Under control conditions, non-irradiated or non-oxidatively stressed fibroblasts exhibit very low fluorescence. Under stress conditions (UVB and H 2 O 2 ) the fluorescence is clearly visible in a majority of fibroblasts. In contrast, under the same stress conditions, the fibroblasts treated with peptide SEQ ID No. 2 have a much lower fluorescence. Conclusions:
Le peptide SEQ ID n°2, protège les cellules cutanées vis-à-vis des stress oxydatifs et de l'irradiation par des UVB et diminue sensiblement le nombre de cellules apoptotiques.Peptide SEQ ID No. 2 protects cutaneous cells against oxidative stress and irradiation with UVB and appreciably decreases the number of apoptotic cells.
Exemple 4 : Préparation de compositionsExample 4: Preparation of compositions
1 - Crème protection solaire: - -1 - Sun protection cream: - -
Figure imgf000016_0001
Figure imgf000016_0001
Les constituants de la phase A et de la phase B sont chauffés séparément entre 700C et 75°C. La phase B est émulsionnée dans la phase A sous agitation. La phase C est ajoutée, à 45°C, en augmentant l'agitation. La phase D est ensuite additionnée lorsque la température se situe en dessous de 400C. Le refroidissement est poursuivi jusqu'à 25°C sous vive agitation.The constituents of phase A and phase B are separately heated between 70 ° C. and 75 ° C. Phase B is emulsified in phase 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.
2 -Lait après-soleil : - -2 -After-sun milk: - -
Figure imgf000017_0001
Figure imgf000017_0001
Préparer la phase A sous agitation. Incorporer la gomme xanthane progressivement, sous agitation défloculeuse. Les phases C et D seront incorporées une fois le gel terminé. La - -Prepare phase A with stirring. Incorporate the xanthan gum gradually, with deflocculating stirring. Phases C and D will be incorporated once the gel is complete. The - -
phase E, préparée préalablement jusqu'à parfaite dissolution de la DHA, sera rajoutée ensuite. Ajuster le pH si nécessaire à 4 - 4,5. Colorer et parfumer.phase E, previously prepared until perfect dissolution of the DHA, will be added later. Adjust the pH if necessary to 4 - 4.5. Color and perfume.
3 -Crème anti-âge :3 -Anti-age cream:
Figure imgf000018_0001
- -
Figure imgf000018_0001
- -
Figure imgf000019_0001
Figure imgf000019_0001
Préparer et fondre la phase A à 65-700C. Chauffer la phase C à 65-700C. La phase B est ajoutée à la phase A juste avant d'émulsionner A dans B. A environ 45°C, le carbomer est neutralisé par addition de la phase D. La phase E est ensuite additionnée sous légère agitation et le refroidissement est poursuivi jusqu'à 25°C. La phase F est alors additionnée si souhaité.Prepare and melt phase A at 65-70 ° C. Heat phase C at 65-70 ° C. Phase B is added to phase A just before emulsifying A in B. At about 45 ° C, the carbomer is neutralized by addition of phase D. Phase E is then added with gentle stirring and cooling is continued to 25 ° C. Phase F is then added if desired.
4 -Crème protectrice de jour :4 -Protective protector of day:
Figure imgf000019_0002
- -
Figure imgf000019_0002
- -
Figure imgf000020_0001
Figure imgf000020_0001
Préparer la phase A et chauffer à 75°C sous agitation. Préparer la phase B en dispersant le carbopol, puis la gomme xanthane sous agitation. Laisser reposer. Chauffer à 75°C. A température, émulsionner A dans B sous agitation rotor-stator. Neutraliser avec la phase C sous agitation rapide. Après refroidissement à 400C, additionner la phase D, puis la phase E. Le refroidissement est poursuivi sous agitation légère et la phase F rajoutée. Prepare phase A and heat to 75 ° C with stirring. Prepare phase B by dispersing the carbopol, then the xanthan gum with stirring. Let rest. Heat to 75 ° C. At temperature, emulsify A in B with rotor-stator stirring. Neutralize with phase C with rapid stirring. After cooling to 40 ° C., add phase D and then phase E. Cooling is continued with gentle stirring and phase F added.

Claims

- -REVENDICATIONS - -REVENDICATIONS
1. Composition caractérisée en ce qu'elle contient en tant qu'agent actif, dans un milieu physiologiquement acceptable, au moins un peptide dérivé du cytochrome c ou un dérivé biologiquement actif de celui-ci, comprenant de 3 à 13 résidus d'acides aminés et dont la séquence répond à la formule générale (I) :1. Composition, characterized in that it contains as active agent, in a physiologically acceptable medium, at least one peptide derived from cytochrome c or a biologically active derivative thereof, comprising from 3 to 13 acid residues amino acids and whose sequence corresponds to the general formula (I):
Ri-(AA)n- X)-X2- X3- X4-X5- (AA)P-R2 Dans laquelleR - (AA) n - X) -X 2 -X 3 -X 4 -X 5 - (AA) P -R 2 wherein
Xi est la tyrosine,Xi is tyrosine,
X2 est la leucine,X 2 is leucine,
X3 est la lysine,X 3 is lysine,
X4 est la thréonine, la serine, la lysine, l'arginine ou aucun acide aminé, X5 est la valine, l'alanine, la tyrosine, la méthionine ou aucun acide aminéX 4 is threonine, serine, lysine, arginine or no amino acid, X 5 is valine, alanine, tyrosine, methionine or no amino acid
AA représente un acide aminé quelconque, ou un de ses dérivés, absent de la séquence du cytochrome c, et n et p sont des nombres entiers compris entre 0 et 4, Ri représente la fonction aminé primaire de l'acide aminé N-terminal, libre ou substituée par un groupement protecteur pouvant être choisi parmi un groupement acétyle, un groupement benzoyle, un groupement tosyle ou un groupement benzyloxycarbonyle.AA represents any amino acid, or a derivative thereof, absent from the cytochrome c sequence, and n and p are integers between 0 and 4, R 1 represents the primary amino function of the N-terminal amino acid, free or substituted by a protective group which may be chosen from an acetyl group, a benzoyl group, a tosyl group or a benzyloxycarbonyl group.
R2 représente la fonction hydroxyle de l'acide carboxyle de l'acide aminé C-terminal, libre ou substituée par un groupement protecteur pouvant être choisi parmi une chaîne alkyle de Ci à C20, ou un groupement NH2, NHY ou NYY avec Y représentant une chaîne alkyle de Ci à C4.R 2 represents the hydroxyl function of the carboxylic acid of the C-terminal amino acid, free or substituted with a protective group that may be chosen from a C 1 to C 20 alkyl chain, or an NH 2 , NHY or NYY group with Y represents an alkyl chain of Ci to C 4 .
2. Composition selon la revendication 1, caractérisée en ce que le peptide de formule générale (I) correspond à une des séquences suivantes :2. Composition according to claim 1, characterized in that the peptide of general formula (I) corresponds to one of the following sequences:
(SEQ ID n°l) Tyr-Leu-Lys-Lys-Ala (SEQ ID n°2) Tyr-Leu-Lys-Lys-Ala -NH2 (SEQ BD n°3) Tyr-Leu-Lys-Lys-NH2 (SEQ ID n°4) Tyr-Leu-Lys(SEQ ID NO: 1) Tyr-Leu-Lys-Lys-Ala (SEQ ID No. 2) Tyr-Leu-Lys-Lys-Ala-NH 2 (SEQ ID No. 3) Tyr-Leu-Lys-Lys- NH 2 (SEQ ID NO: 4) Tyr-Leu-Lys
3. Composition selon la revendication 2 caractérisée en ce que le peptide de formule générale (I) correspond à la séquence SEQ ED n°l. - -3. Composition according to claim 2 characterized in that the peptide of general formula (I) corresponds to the sequence SEQ ED No. 1. - -
4. Composition selon la revendication 2 caractérisée en ce que le peptide de formule générale (I) correspond à la séquence SEQ ID n°2.4. Composition according to claim 2 characterized in that the peptide of general formula (I) corresponds to the sequence SEQ ID No. 2.
5. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce que le peptide de formule générale (I) possède au moins un groupement fonctionnel protégé par un groupement protecteur, ce groupement protecteur étant soit une acylation ou une acétylation de l'extrémité amino-terminale, soit une amidation ou une estérification de l'extrémité carboxy- terminale, soit les deux.5. Composition according to any one of the preceding claims, characterized in that the peptide of general formula (I) has at least one functional group protected by a protective group, this protecting group being either an acylation or an acetylation of the end amino terminus, either amidation or esterification of the carboxy terminus, or both.
6. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce que le peptide de formule générale (I) est présent dans la composition à une concentration comprise entre 0,0005 et 500 ppm environ, et préférentiellement à une concentration comprise entre 0,01 et 5 ppm par rapport au poids total de la composition.6. Composition according to any one of the preceding claims, characterized in that the peptide of general formula (I) is present in the composition at a concentration of between 0.0005 and 500 ppm approximately, and preferably at a concentration between 0 , 01 and 5 ppm relative to the total weight of the composition.
7. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce que le peptide de formule générale (I) est préalablement solubilisé dans un ou plusieurs solvants comme l'eau, le glycérol, l'éthanol, le propylène glycol, le butylène glycol, le dipropylène glycol, les diglycols éthoxylés ou propoxylés, les polyols cycliques, la vaseline, une huile végétale ou tout mélange de ces solvants.7. Composition according to any one of the preceding claims, characterized in that the peptide of general formula (I) is previously solubilized in one or more solvents such as water, glycerol, ethanol, propylene glycol, butylene glycol, dipropylene glycol, ethoxylated or propoxylated diglycols, cyclic polyols, petroleum jelly, a vegetable oil or any mixture of these solvents.
8. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle se présente sous une forme adaptée à l'application par voie topique.8. Composition according to any one of the preceding claims, characterized in that it is in a form suitable for topical application.
9. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle contient, en outre, au moins un autre principe actif favorisant l'action dudit agent actif.9. Composition according to any one of the preceding claims, characterized in that it contains, in addition, at least one other active ingredient promoting the action of said active agent.
10. Composition selon la revendication 9 caractérisée en ce que l'autre agent actif est choisi parmi des agents actifs ayant une action antioxydante, ou encore stimulant la synthèse des macromolécules dermiques, ou encore stimulant le métabolisme énergétique - -10. Composition according to Claim 9, characterized in that the other active agent is chosen from active agents having an antioxidant action, or else stimulating the synthesis of dermal macromolecules, or else stimulating the energetic metabolism. - -
11. Utilisation d'une quantité efficace d'agent actif, tel que défini dans l'une quelconque des revendications 1 à 5, dans une composition cosmétique ou pour la préparation d'une composition pharmaceutique.11. Use of an effective amount of active agent, as defined in any one of claims 1 to 5, in a cosmetic composition or for the preparation of a pharmaceutical composition.
12. Utilisation d'une quantité efficace d'agent actif, tel que défini dans l'une quelconque des revendications 1 à 5, dans une composition cosmétique pour protéger la peau et les phanères contre tous les types d'agressions extérieures.12. Use of an effective amount of active agent, as defined in any one of claims 1 to 5, in a cosmetic composition for protecting the skin and integuments against all types of external aggression.
13. Utilisation d'une quantité efficace d'agent actif, tel que défini dans l'une quelconque des revendications 1 à 5, dans une composition cosmétique pour prévenir ou traiter les dommages causés à la peau et aux phanères par les rayonnements UV.Use of an effective amount of active agent, as defined in any one of claims 1 to 5, in a cosmetic composition for preventing or treating damage to skin and integuments caused by UV radiation.
14. Utilisation d'une quantité efficace d'agent actif, tel que défini dans l'une quelconque des revendications 1 à 5, dans une composition cosmétique pour protéger la peau et les phanères des dommages oxydatifs.14. Use of an effective amount of active agent, as defined in any one of claims 1 to 5, in a cosmetic composition for protecting skin and integuments from oxidative damage.
15. Utilisation d'une quantité efficace d'agent actif, tel que défini dans l'une quelconque des revendications 1 à 5, dans une composition pour prévenir ou traiter les signes cutanés du vieillissement et/ou du photo-vieillissement.15. Use of an effective amount of active agent, as defined in any one of claims 1 to 5, in a composition for preventing or treating cutaneous signs of aging and / or photo-aging.
16. Utilisation d'une quantité efficace d'agent actif, tel que défini dans l'une quelconque des revendications 1 à 5, pour la préparation d'une composition pharmaceutique destinée à prévenir ou à lutter contre les pathologies liées aux processus d'oxydation.16. Use of an effective amount of active agent, as defined in any one of claims 1 to 5, for the preparation of a pharmaceutical composition for preventing or combating pathologies related to oxidation processes. .
17. Procédé de traitement cosmétique destiné à stimuler les défenses et à protéger la peau et les phanères des agressions extérieures, caractérisé en ce que l'on applique topiquement sur la peau ou les phanères à traiter, une composition telle que définie selon l'une quelconque des revendications 1 à 10. 17. A cosmetic treatment method for stimulating the defenses and protecting the skin and the integuments of the external aggressions, characterized in that one applies topically to the skin or integuments to be treated, a composition as defined in one of the any of claims 1 to 10.
PCT/FR2008/000577 2007-04-27 2008-04-23 Pharmaceutical and/or cosmetic composition containing peptides WO2008145854A1 (en)

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