WO2007113356A2 - Peptidos sintéticos útiles en el tratamiento de la piel y su uso en composiciones cosméticas o dermofarmacéuticas - Google Patents
Peptidos sintéticos útiles en el tratamiento de la piel y su uso en composiciones cosméticas o dermofarmacéuticas Download PDFInfo
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- WO2007113356A2 WO2007113356A2 PCT/ES2007/000180 ES2007000180W WO2007113356A2 WO 2007113356 A2 WO2007113356 A2 WO 2007113356A2 ES 2007000180 W ES2007000180 W ES 2007000180W WO 2007113356 A2 WO2007113356 A2 WO 2007113356A2
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- peptide
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- skin
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Definitions
- the present invention relates to synthetic peptides that regulate fibrinogenesis and cosmetic or dermopharmaceutical compositions containing said peptides useful in the treatment of the skin, preferably for the treatment of those skin conditions that require a regulation of fibrinogenesis such as treatment of aged skin (either intrinsic aging due to the passage of time and genetic factors, or extrinsic due to prolonged exposure to the sun and / or environmental pollutants such as ultraviolet (UV) radiation from sunlight, chemical contaminants, smoke of cigarettes and pollution), or as adjuvants in healing processes to soften the appearance of scars.
- UV ultraviolet
- the skin is composed of two layers: the epidermis and the dermis.
- the outermost layer is the epidermis, which is mainly composed of keratinocytes, melanocytes and Langerhans cells, and its basic function is to retain water from the body, act as a barrier mechanism against harmful chemical agents as well as against pathogenic organisms and carry Out the cell renewal processes.
- the innermost layer, the dermis, formed by fibroblasts, adipocytes and macrophages, is strongly linked to the epidermis through the basement membrane, and contains numerous nerve endings that provide sensations of touch and temperature. It also houses the hair follicles, sweat glands, sebaceous glands, apocrine glands and blood vessels, and one of its main functions is to maintain the elasticity and appearance of the skin.
- extracellular matrix In the dermis is also the extracellular matrix, formed by a set of extracellular proteins (fibrous proteins, glycoproteins and proteoglycans) whose key function is to maintain the structure of the skin, and the proper functioning and development of tissues depends on that its training and regulation is correct [Wiberg C, Klatt AR, Wagener R., Paulsson M., Bateman JF, Heinegard D. and Morgelin M. (2003) "Complexes of matrilin-1 and biglycan or decorin connect collagen Vl microfibrils to both collagen Il and aggrecan" J . BIoI. Chem. 278, 37698-37704].
- extracellular proteins fibrous proteins, glycoproteins and proteoglycans
- the two most important fibrous proteins of the extracellular matrix are collagen and elastin, responsible for the mechanical properties of the tissues, such as the ability to resist tension, compression, extensibility and torsion.
- Proteoglycans have a structural and metabolic function, while glycoproteins, together with proteoglycans, serve as bridges between the components of the matrix and cells [Aumailley M. and Gayraud B. (1998) "Structure and biological! Activity of the extracellular matr ⁇ x "J. Mol. Med. 76, 253-265; Culav EM, Clark CH. and Merrilees MJ. (1999) "Connective tissues: matr ⁇ x composition and its relevance to physical therapy” Phys. Ther. 79, 308-319; Scott JE (2003) "Elasticity in extracellular matrices 'shape modules' of tendon, cartilage, etc. A sliding proteoglycanning model" J. Physiol. 553, 335-343].
- the collagens are a family of extracellular matrix fibrous proteins that constitute 25% of the total protein mass in mammals. They have been classified in more than 20 families, all with individual characteristics that fulfill specific functions in different tissues.
- the main characteristic of collagen is its helical structure formed by association of three polypeptide chains, rich in glycine and proline. Alterations in its amino acid composition cause dysfunction and loss of its mechanical properties [Culav EM, Clark CH. and Merrilees MJ. (1999) "Connective tissues: matr ⁇ x composition and its relevance to physical therapy” Phys. Ther. 79, 308-319].
- These polypeptide chains can be associated with each other forming the fibrils, which have a diameter of 10-300 nm and a length of up to several hundred micrometers in mature tissues. These fibrils often aggregate into larger structures, such as cable bundles, which can be seen by electron microscopy as collagen fibers several micrometers in diameter.
- fibrilogenesis This process is known as fibrilogenesis [Aumailley M. and Gayraud B. (1998) "Structure and biological / activity of the extracellular matrix” J. Mol. Med. 76, 253-265]. Not all collagens have the ability to form fibrils; only type I, II, III, V and Xl collagens, which are known as fibrillar collagens. The dermis of an adult is basically formed by fibrillar collagen type I (80-90%), III, and V. Generally, type I collagen fibers have a larger diameter, a characteristic that correlates with their ability to withstand a greater mechanical load.
- Type III collagen plays a role in tissue extensibility, and over the years it is replaced by type I collagen molecules, a process partially responsible for mature skins being less extensible than infant ones.
- Type V collagen is associated with type I and III by regulating the diameter of the fibrils ['The Biology of the Skin ", Freinkel RK and Woodley DJ., Eds. The Parthenon Publishing Group, 2001; C ⁇ lav EM, Clark CH . and Merrilees MJ. (1999) "Connective tissues: matrix composition and / te relevance to physical therapy” Phys. Ther. 79, 308-319].
- the damage to the collagen architecture can lead to the deposition of disorganized collagen during repair processes, as in the processes of liver cirrhosis, pulmonary fibrosis or dermal scar formation.
- the regulation of the organization of collagen can be potentially useful not only for cosmetic or dermopharmaceutical treatments but also for treating various clinical conditions.
- Proteoglycans constitute one of the major components of the extracellular matrix and are characterized by having a protein heart covalently linked to carbohydrates called glycosaminoglycans (GAGs). They are involved in many of the cellular processes that take place through molecular interactions on the surface of the cells, such as extracellular matrix-cell, cell-cell and receptor-ligand interactions, since they avidly bind to proteins, and are very abundant in these regions [Perrimon N. and Bernfield M. (2001) "Cellular functions of proteoglycans- an overview "Semin. CeII Dev. Biol. 12, 65-67].
- GAGs glycosaminoglycans
- Proteoglycans act as tissue organizers, facilitate cell growth and maturation of specialized tissues, play a fundamental role as biological filters and regulate the activity of growth factors [lozzo RV (1998) "Matrix proteoglycans: from molecular design to cellular function” Annu. Rev. Biochem. 67, 609-652; Ruoslahti E. (1989) "Proteoglycans in cell regulation” J. Biol. Chem. 264, 13369-13372].
- GAGs are polymers formed by repetitions of disaccharides, usually an acetylated amino sugar ( ⁇ / -acetylglucosamine or ⁇ / -acetylgalactosamine) alternating with uric acid (glucuronate or iduronate), and have a high index of sulfate groups, except hyaluronic acid. Due to their richness in acidic groups, they are negatively charged and tend to attract cations such as Na + and, being osmotically active, attract water and allow to maintain tissue hydration.
- GAGs The most common GAGs are hyaluronic acid, chondroitinsulfate, dermatan sulfate, heparan sulfate and queratan sulfate [Sugahara K. and Kitagawa H. (2000) "Recent advances in the study of the biosynthesis and functions of sulfated glycosaminoglycans" Curr. Opin. Struct. Biol. 10, 518-527; Zamfir A., Seidler DG, Kresse H. and Peter-Katalinic J. (2003) "Str ⁇ ctural investigation of chondroitin / dermatan sulfated oligosaccharides from human skin fibroblast decorin" Glycobiology 13, 733-742].
- proteoglycans are the so-called “leucine-rich proteoglycans", which do not exhibit interaction with hyaluronic acid, and which are involved in the structuring of extracellular matrices, in the modulation of the activity of growth factors as well as in the regulation of cell growth properties [lozzo RV (1997) 'The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth "Crit. Rev. Biochem. Mol. Biol. 32, 141-174].
- the biglican is found in differentiating keratinocytes in the epidermis and in the vascular endothelium [Bianco P., Fisher LW., Yo ⁇ ng MF, Termine JD and Robey PG (1990) "Expression and localization of the two small proteoglycans biglycan and decorin in developing human skeletal and non-skeletal tissues" J. Histochem. Cytochem.
- Decorin is considered one of the key proteoglycans in the regulation of the structuring and function of many of the elements of the extracellular matrix.
- Decorin binds to growth factors, including proliferation transformation beta factor (TGF- ⁇ ), to other proteins of the extracellular matrix such as fibronectin and thrombospondin, to cell membrane receptors (endocytosis receptor of decorin ), and can also directly interfere with the cell cycle through the induction of p21, a potent inhibitor of cyclin-dependent kinases (CDKs) [Stander M., Naumann U., Wick W. and Weller M. (1999) 'Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth "CeII Tissue Res. 296, 221-227].
- CDKs cyclin-dependent kinases
- Decorin binds to two adjacent parallel molecules of collagen of the fibril, helping to stabilize The fibril and orienting the fibrinogenesis, being attached to the surface of the collagen fibrils, the lateral interaction between the triple collagen helices becomes more difficult, since it acts as a spacer, and the diameter of the fibrils decreases, thus controlling the dimensions of the fibrils, in particular the uniformity of their diameter and the regular distance between them, thus allowing it to maintain the shape of the tissue / Te ⁇ n / R., Viola M., Welser F., Sini P., Giudici C, Rossi A . and Tira ME (2002) "Interaction of decorin with CNBr peptides from collagens I and II.
- transgenic animals also exhibit increased collagen degradation, which contributes to the poor quality of their skin [Schaefer L, Macakova K, Raslik I., Micegova M., Gr ⁇ ne HJ., Schonherr E., Robenek H., Echtermeyer FG, Grássel S., Bruckner P., Schaefer RM, lozzo RV and Kresse H. (2002) "Absence of decorin adversely influences tubulointerstitial fibrosis of the obstructed kidney by enhanced apoptosis and increased inflammatory reaction" Am. J. Pathol. 160, 1181-1191].
- Babies' skin is smooth and soft, with a thick layer of fat and a very thin protective layer of keratin, while the skin of the elderly is very thin and has many wrinkles, with a very small layer of fat.
- the extracellular matrix also undergoes changes with age, and these contribute to the set of changes in the physical properties of Aging-related skin [Wiberg C, Klatt AR, Wagener R., Paulsson M., Bateman JF, Heinegard D. and Morgelin M. (2003) "Complexes of matrilin- 1 and biglycan or decorin connect collagen Vl microfibrils to both collagen Il and aggrecan "J.
- the cosmetic industry has made significant efforts to counteract this loss of the functionality of the components of the extracellular matrix with age.
- the balance between the production and the degradation of essential biomolecules of the skin is decanted with aging towards the degradation processes, and this leads to a progressive thinning and disorganization of the dermis that causes a flaccidity in the dermis with the consequent wrinkle formation.
- the collagen of the aged skins both chronologically - mature skin - and by prolonged exposure to the sun or environmental pollutants
- the dermal extracellular matrix also contains proteoglycans that are involved in the properties of tissues and that are altered with aging.
- decorin is catabolized into a fragment known as decorunt, which corresponds to a version of decorin to Ia that the carboxy-terminal fragment is missing.
- the skins of fetal origin do not show detectable levels of decorunt, while the maximum levels of decorunt are determined from the age of 30, which is the age from which the signs of aging begin to manifest.
- decorin influences the processes of fibrinogenesis of the collagen and regulates the diameter of the fibrils
- the appearance of decorunt can have an important effect on the elasticity and morphological differences between the collagen fibers of young skins and those of aged skins [ Canino DA, Sorrell JM and Captan AA. (2000) "Age-related changes in the proteoglycans of human skin” Arch. Biochem. Biophys 373, 91-101].
- decorin synthesis is diminished in skin aged by prolonged exposure to the sun or environmental contaminants [Bernstein EF, Fisher LW., Li K., LeBaron RG, Tan EM. and Uitto J.
- Wound healing in adults is a complicated reparative process.
- the healing process begins with the recruitment of a variety of specialized cells for transfer to the site of the wound, and involves the deposition of extracellular matrix and basement membrane, angiogenesis, selective protease activity and reepithelialization.
- An important component of the healing process in adult mammals is the stimulation of fibroblasts to generate the extracellular matrix.
- This matrix Extracellular is a main component of connective tissue that develops to repair the area of the wound.
- a scar is an abnormal morphological structure resulting from a previous injury or injury (such as an incision, excision or trauma) and consists of a connective tissue, which is predominantly a matrix of collagen types I and III and fibronectin .
- the scar consists of collagen fibers in an abnormal organization as well as an excess deposition of collagen.
- mammals when the scar rises on the skin, presenting a bulky appearance, it is because they contain excessly arranged collagen irregularly, and are classified as hypertrophic scars.
- a keloid is another form of pathological healing that not only remains elevated on the surface of the skin, but also extends beyond the limits of the original lesion, and also has an excessive amount of connective tissue that is organized so abnormally forming predominantly vortex bands of collagen tissue.
- An analysis of decorin content in hypertrophic scars shows that the concentration of this is only 25% of that found in healthy tissues [Scott P.G., Dodd C.M., Ghahary A., Shen J. and Tredget E.E. (1998) "Fibroblasts from post-burn hypertrophic scar tissue synthesize less decorin than normal dermal fibroblasts" Clin. ScL (Lond). 94, 541-547), a fact that explains the irregular organization of the collagen present in hypertrophic scars.
- cosmetic or dermopharmaceutical compositions containing molecules that mimic the activity of decorin interacting with the fibrils or collagen fibers, regulating the fibrinogenesis process are potential candidates for use as anti-aging products in order to increase The elasticity, firmness, structuring and flexibility of the skin, or as adjuvants in post-surgical treatments in order to soften the appearance of the scars.
- the applicant of the present invention has determined that the synthetic peptides of the invention are effective in the regulation of fibrinogenesis, thus mimicking the function of decorin.
- the sequence of the peptides of the invention is not contained in the native sequence of the decorin, so that they can be considered as mimetic peptides of the activity of the decorin. It has been postulated in the literature that for its binding to collagen, and consequently the regulation of fibrinogenesis, the peptide sequences must have four amino acids with a pattern of charges [+, -, 0, +] [Scott JE (1996) "Proteodermatan and proteokeratan sulfate (decorin, lumican / fibromodulin) proteins are horseshoe shaped.
- the patent RU2,181,728 describes a synthetic 10 amino acid peptide linked by a disulfide bridge to a 12 amino acid peptide that has a sequence that encompasses the sequence Lys-Glu-Leu-Cit, which is based on the interleukin-8 molecule and stimulates Ia neutrophil migration.
- said peptide meets the load pattern [+, - > u] and has a contiguous citrulline residue, it is not included within the family of the peptides of the present invention, since it has a total of 22 amino acids .
- said patent does not give any indication or suggest that the peptide described is capable of inhibiting fibrinogenesis.
- citrulline is a necessary residue for the regulation of fibrinogenesis, so that an expert in the field could not deduce the nature of the peptides that regulate fibrinogenesis.
- the peptides of the present invention may be useful in the treatment of those skin conditions that require regulation of fibrinogenesis, such as the treatment of aged skin (either due to the passage of age or exposure to sun and / or environmental pollutants) or as adjuvants in healing processes to soften the appearance of scars.
- the present invention provides a simple, effective and risk-free solution for the treatment of skin conditions that require regulation of fibrinogenesis, such as aging or scarring, comprising the application on the skin of a cosmetic or dermopharmaceutical composition. containing at least one peptide of general formula (I).
- treatment refers to the reduction, delay and / or prevention of the signs of aging or to the softening of the appearance of the scars.
- aging refers to the changes experienced by the skin with the passage of age (chrono-aging) or by exposure to the sun (photo-aging) or to environmental agents such as tobacco smoke, extreme cold or wind weather conditions, chemical pollutants or pollution, and includes all visible external changes and as well as perceptible by touch, such as and without limitation, the development of discontinuities in the skin such as wrinkles, fine lines, cracks, irregularities or roughness, increase in size of the pores, loss of elasticity, loss of firmness, loss of smoothness, loss of capacity recovery of the deformation, sagging of the skin such as the sagging of the cheeks, the appearance of bags under the eyes or the appearance of jowls among others, changes in the color of the skin such as spots, redness, dark circles or appearance of hyperpigmented areas such as age spots or freckles among others, abnormal differentiation, hyperkeratinization, elastosis, keratosis, hair loss, loss of collagen structuring and other histological changes of the stratum corneum, the dermis
- a first aspect of this invention refers to a peptide capable of regulating fibrinogenesis, according to the general formula (I):
- Z is selected from the group consisting of alanyl, a // o-isoleucil, glycyl, isoleucil, isoseril, isovalil, leucil, norleucil, norvalil, prolil, seril, threonyl, a // o-threonyl or valil;
- n and m can vary independently from each other between 1 and 5;
- AA is selected from the group consisting of the natural amino acids encoded in their L- or D- form or uncoded amino acids;
- x e y can vary independently from each other between O and 2;
- R 1 is selected from the group consisting of H or alkyl, aryl, aralkyl or acyl group; Y
- R 2 is selected from the group consisting of amino, hydroxyl or thiol, substituted or not with aliphatic or cyclic groups.
- the preferred structures of the peptides represented in the general formula (I) are those where: Z can be: isoleucyl, threonyl or valile;
- R 1 can be: H or C 2 to C 24 linear, branched or cyclic, saturated or unsaturated acyl; Y
- R 2 can be: amino or hydroxyl, substituted or not with linear, branched or cyclic, saturated or unsaturated C 1 to C 24 aliphatic groups.
- the peptides of the present invention may exist as stereoisomers or mixtures of stereoisomers; for example, the amino acids that compose them can have an L-, D-, or be racemic configuration independently of each other. Therefore, it is possible to obtain isomeric mixtures as well as racemic or diastereomeric mixtures, or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and which isomers or isomeric mixtures are present.
- Preferred structures of the peptides of general formula (I) are pure isomers, that is, enantiomers or diastereomers.
- uncoded amino acids refers to those amino acids not encoded by the genetic code, natural or not, such as, for example, and without limitation, citrulline, ornithine, sarcosine, desmosin, norvaline, 4-aminobutyric acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 6-aminohexanoic acid, 1-naphthylalanine, 2-naphthylalanine, 2-aminobenzoic acid, 4- aminobenzoic acid, 4-chlorophenylalanine, 2,3-diaminopropionic acid, acid 2,4-diaminobutyric acid, cycloserine, carnitine, cystine, penicillamine, pyroglutamic acid, thienylalanine, hydroxyproline, a // o-isoleucine, a // o-threonine, isonipecotic acid,
- aliphatic group refers to a saturated or unsaturated, linear or cyclic hydrocarbon group.
- hydrocarbon group is used in the present invention to cover, for example, the alkyl, alkenyl and alkynyl groups.
- alkyl group refers to a saturated linear or branched hydrocarbon group, including, for example, methyl, ethyl, isopropyl, isobutyl, ⁇ -butyl, heptyl, dodecyl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2- methylbutyl, 5-methylhexyl and the like.
- alkenyl group refers to an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon double bonds, such as the vinyl group.
- alkynyl group refers to an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon triple bonds.
- cyclic group refers to a closed hydrocarbon ring, which can be classified as an alicyclic, aromatic or heterocyclic group.
- alicyclic group refers to a cyclic hydrocarbon group with properties similar to aliphatic groups.
- aromatic group or the “aryl group” refers to a mono or polycyclic aromatic hydrocarbon group.
- heterocyclic group refers to a closed hydrocarbon ring, in which one or more of one of the ring atoms is an element other than carbon (for example, nitrogen, oxygen, sulfur, etc.).
- group and “block” will be used to differentiate between chemical species that allow substitution or that can be substituted ("group"), and those that do not allow substitution or that cannot be substituted (“block”).
- group when used to describe a chemical substituent, the chemical material described includes both the unsubstituted group and the one containing the atoms of O, N or S.
- alkyl group will include not only saturated open chain alkyl substituents, such as methyl, ethyl, propyl, isobutyl and the like, but also alkyl substituents containing other substituents known in the state of the art, such as hydroxy , alkoxy, amino, carboxyl, carboxamido, halogen atoms, cyano, nitro, alkylsulfonyl, and others.
- alkyl group includes ether, haloalkyl, alcohol, thiol, carboxyls, amines, hydroxyalkyl, sulfoalkyl, guanidine, and other groups.
- alkyl block is limited only to the inclusion of saturated open chain alkyl substituents, such as methyl, ethyl, propyl, isobutyl and the like.
- cosmetically or dermopharmaceutically acceptable salts of the peptides of formula (I) provided by this invention.
- the term "cosmetically or dermopharmaceutically acceptable salts” includes salts commonly used to form metal salts or acid addition salts, whether organic (such as, for example and without limitation, acetate, citrate, oleate, oxalate or gluconate) or inorganic (such as for example and without limitation chloride, sulfate, borate or carbonate).
- the nature of the salt is not critical, as long as it is cosmetically or dermopharmaceutically acceptable.
- Cosmetically or dermopharmaceutically acceptable salts of the peptides of formula (I) can be obtained by conventional methods, well known in the state of the art.
- the synthesis of the peptides of the general formula (I) can be carried out according to conventional methods, known in the state of the art, such as for example the adaptation of solid phase peptide synthesis methods [Stewart JM and Young JD (1984) " Solid Phase Peptide Synthesis ", 2nd edition, Pierce Chemical Company, Rockford, Illinois; Bodanzsky M. and Bodanzsky A. (1984) 'The practice of Peptide Synthesis ", Springer Verlag, New York; Lloyd-Williams P., Albericio F. and Giralt E. (1997) Chemical Approaches to the Synthesis of Peptides and Proteins.
- Peptides can also be obtained by fermentation of a bacterial strain, modified or not by genetic engineering in order to produce the desired sequences.
- a method of obtaining the peptides of general formula (I) is that in which a fragment of the peptide of general formula (I) having a free carboxyl group or a reactive derivative thereof, is reacted with a fragment complementary, which has an amino group, with at least one free hydrogen atom, with the consequent formation of an amide type bond, and where said fragments present the functional groups that do not participate in the formation of the amide type bond, if any, conveniently protected, with temporary or permanent protective groups.
- Another example of a method for obtaining the peptides of the general formula (I) is that in which a fragment of the peptide of the general formula (I) having a leaving group is reacted, such as the tosyl group, the mesyl group and halogen groups among others, with a complementary fragment that possesses an amino group with at least one free hydrogen atom by means of a nucleophilic substitution reaction, and where said fragments present the functional groups that do not participate in the formation of the NC bond, if any , conveniently protected, with temporary or permanent protective groups.
- protective groups their introduction and their elimination, can be found described in the literature [Greene T. W.
- protecting groups also includes the polymeric supports used in solid phase synthesis.
- the polystyrene supports polyethylene glycol grafted in polystyrene and the like, such as for example p-methylbenzhydrylamine (MBHA) resins [MBHA] [ Matsueda GR and Stewart JM. (1981) "A p-methylbenzhydrylamine resin for improved solid-phase synthesis o ⁇ peptide amides" Peptides 2, 45-50], 2-chlorotrityl resins [Barios K., Cats D., Kallitsis J., Papaphotiu G., Sotiriu P ., Wenqing Y. and Scháfer W.
- MBHA p-methylbenzhydrylamine
- TentaGel ® resins and the like which may or may not include a labile spacer, such as 5- (4-aminomethyl-3 acid), 5-Dimethoxyphenoxy) valeric (PAL) [Albericio F., Kneib-Cordonier N., Biancalana S., Gera L, Masada RI, Hudson D. and Barany G. (1990) "Prepared and application of the 5- (4- (9-fluorenylmethyloxycarbonyl) aminomethyl- 3,5-dimethoxyphenoxy) -valeric acid (PAL) handle for the solid-phase synthesis of C-terminal peptide amides under mild conditions "J. Org. Chem.
- the peptides according to the invention can be part of various types of compositions for external application in the body of a mammal, preferably humans.
- the invention provides a cosmetic or dermopharmaceutical composition comprising at least one peptide of general formula (I).
- Said compositions can be prepared by conventional methods known to those skilled in the art.
- the peptides of the invention have a variable water solubility, depending on the nature of the groups R 1 , R 2 , AA and Z and the values of n, m, x and y.
- Those that are not soluble in water can be solubilized in conventional cosmetically or dermopharmaceutically acceptable solvents such as, for example and without limitation, water, ethanol, propanol or isopropanol, propylene glycol, glycerin, butylene glycol or polyethylene glycol or any combination thereof.
- the peptides can also be previously incorporated into vehiculization systems and / or cosmetic or dermopharmaceutical sustained release systems such as liposomes, miliparticles, microparticles and nanoparticles as well as in sponges, vesicles, micelles, microspheres, microspheres and nanospheres, lipospheres, millicapsules, microcapsules and nanocapsules, in order to achieve greater penetration of the active substance.
- the peptides of the present invention can also be adsorbed on solid organic polymers or mineral supports such as talc, bentonite, silica, starch or maltodextrin among others.
- compositions such as creams, oil and / or silicone emulsions in water, water emulsions in oil and / or silicone, oils, milks, balms, foams, lotions, gels, liniments, serums, soaps, ointments, mousses, ointments, sticks, pencils or vaporizers ("sprays"), including permanence (“leave on”) and rinse (“rinse-off”) formulations, as well as can be incorporated by known techniques by experts in the field to different types of solid accessories such as, for example, wipes, hydrogels, adhesive patches (or non-adhesives) or face masks, or they can be incorporated into different makeup line products such as dark circles, makeup funds, Cleansing lotions or milks, eyeshadows and lipsticks among others.
- the peptides can also be incorporated into tissues for making garments that are in direct contact with the skin of the body, so that they release the peptides of the invention either by biodegradation of the tissue anchoring system or by friction of the garment with the body, by the body moisture, by the pH of the skin or by the body temperature.
- tissue anchoring system or by friction of the garment with the body
- body moisture by the body moisture
- body temperature by the pH of the skin or by the body temperature.
- Examples of garments, tissues and means of immobilization of the peptides to the tissues, among which are microencapsulation can be found described in the literature and are known in the state of the art [Schaab CK. (1986) "Impregnating Fabrics With Microcapsules", HAPPI May 1986; Nelson G. (2002) “Application of microencaps ⁇ lation in textiles” Int. J. Pharm. 242, 55-62].
- Preferred garments are bandages, girdles, stockings, socks, panties,
- the cosmetic or dermopharmaceutical composition object of the present invention can also be applied in areas of the body that require treatment by subcutaneous injection, intradermal injection, occlusive cure or by iontophoresis, in order to achieve greater penetration of the active ingredient.
- the preferred areas for application are face, neck, forearms, chest, buttocks, abdomen and thighs.
- compositions mentioned in the present invention may contain additional ingredients commonly used in compositions for the care and treatment of the skin, such as, for example, and without limitation, emulsifying agents, emollients, organic solvents, skin conditioners such as humectants , alpha hydroxy acids, moisturizers, vitamins, pigments or dyes, gelling polymers, thickeners, softeners, anti-wrinkle agents, agents capable of reducing or treating the bags under the eyes, bleaching or depigmenting agents, exfoliating agents, anti-aging agents, free radical scavenging agents and / or anti-air pollution, NO-synthase inhibitors, antioxidant agents, anti-aging agents glycation, agents that stimulate the synthesis of dermal or epidermal macromolecules and / or capable of inhibiting their degradation, such as agents that stimulate collagen synthesis, agents that stimulate elastin synthesis, agents that stimulate laminin synthesis, agents stimulators of decorin synthesis, agents that inhibit collagen degradation, agents that inhibit elast
- compositions of the present invention can contain or can be co-administered with analgesic compounds and / or anti-inflammatory compounds in order to reduce swelling and irritation associated with both sensitive skin and healing processes or to treat hypertrophic scars. or keloid.
- analgesic compounds and / or anti-inflammatory compounds in order to reduce swelling and irritation associated with both sensitive skin and healing processes or to treat hypertrophic scars. or keloid.
- steroidal-type compounds such as hydrocortisone, non-steroidal-type such as paracetamol or acetylsalicylic acid or natural extracts or essential oils with intrinsic analgesic and anti-inflammatory activity can be highlighted.
- a further aspect of the present invention relates to a cosmetic or dermopharmaceutical composition
- a cosmetically or dermopharmaceutically effective amount of at least one peptide according to the general formula (I) and also a cosmetically or dermopharmaceutically effective amount of at least one extract with anti-wrinkle and / or anti-aging activity such as, for example and without limitation, the extracts of Vitis vinifera, Rosa canina, Turmeric longa, Iris paluda, Theobroma cacao, Ginkgo biloba, or Dunaliella salina among others or in addition to at least one synthetic compound, extract or biofermentation product with anti-wrinkle and / or anti-aging activity such as, for example and without limitation, Matrixyl ® marketed by Sederma, Vialox ® or Syn-ake ® marketed by Pentapharm, Myoxinol TM marketed by Cognis, Algisum C ® or Hydroxyprolisilane CN ®
- a further aspect of the present invention relates to a cosmetic or dermopharmaceutical composition
- a cosmetic or dermopharmaceutical composition comprising a cosmetically or dermopharmaceutically effective amount of at least one peptide according to the general formula (I), and also a cosmetically or dermopharmaceutically effective amount of at least one extract or combination of extracts with firming, redensifying and / or restructuring activity such as, for example and without limitation, the extracts of Malpighia punicitolia, Cynara scolymus, Gossypium herbaceum, Aloe Barbadensis, Panicum miliaceum, Morus nigra, Sesamum indicum, Glycine soja, Tr ⁇ ticum vulgare, Tr ⁇ ticum vulgare ® Refirming HSC or Polyplan ® Refirming marketed by Provital, Lanablue ® marketed by Atrium, Pepha ® -Nutrix marketed by Pentapharm, or plant extracts
- a further aspect of the present invention relates to a cosmetic or dermopharmaceutical composition
- a cosmetic or dermopharmaceutically effective amount of at least one peptide according to the general formula (I) and also a cosmetically or dermopharmaceutically effective amount of at least one extract or combination of extracts with healing or re-epithelial activity or effectively as adjuvants in healing or re-epithelialization processes
- the peptides of the general formula (I) are used in the cosmetic or dermopharmaceutical compositions of the present invention at cosmetically or dermopharmaceutically effective concentrations to achieve the desired effect; preferably between 0.000001% (by weight) and 20% (by weight); more preferably between 0.00001% (by weight) and 10% (by weight) and even more preferably between 0.0001% (by weight) and 5% (by weight).
- a further aspect of this invention refers to the use of at least one peptide of general formula (I) in the preparation of a cosmetic or dermopharmaceutical composition for application in the skin, preferably for the treatment of those skin conditions that require a regulation of fibrinogenesis such as the treatment of aged skin (either due to the passage of age or exposure to the sun and / or environmental pollutants) or as adjuvants in healing processes to soften the appearance of scars
- Preferred applications are applications on thighs, abdomen, buttocks, chest, forearms, neck and face, or on those areas of the body that have scars.
- the present invention also provides a cosmetic or dermopharmaceutical method for treating those skin conditions that require a regulation of fibrinogenesis, preferably the skin of humans, which comprises the administration of an effective amount of peptides of general formula (I ), preferably in the form of a cosmetic or dermopharmaceutical composition containing them.
- the frequency of the application on the skin can vary widely, depending on the needs of each subject, suggesting a range of application from once a month to 10 times a day, preferably from once a week to 4 times a day, more preferably from three times a week to twice a day, even more preferably once a day.
- Preferred cosmetic or dermopharmaceutical method is one in which the regulation of fibrinogenesis aims to reduce, delay and / or prevent the signs of aging or soften the appearance of scars.
- HPLC chromatographic analysis is carried out in a Shimadzu device (Kyoto, Japan) using a thermostated reverse phase column at 3O 0 C (250 x 4.0 mm, Kromasil C 8 , 5 ⁇ m, Akzo Nobel, Sweden). Elution is performed by a gradient of acetonitrile (+ 0.07% TFA) in water (+ 0.1% TFA) at a flow of 1 mL / min and the detection is performed at 220 nm.
- the Fmoc ⁇ / -terminal group is deprotected as described in the general methods, and 22.5 g of palmitic acid (88 mmol, 10 equiv) pre-dissolved in DMF (10 mL) are incorporated, in the presence of 13.55 g of HOBt (88 mmol , 10 equiv) and 13.55 ml_ of DIPCDI (88 mmol, 10 equiv).
- Fmoc-L-Val-OH (2.5 mmol, 5 equiv)
- 1.03 g of Fmoc-L-Asp (OtBu) -OH (2.5 mmol, 5 equiv)
- 1.17 g of Fmoc-L-Lys (Boc) -OH (2.5 mmol, 5 equiv) in the presence at each coupling of 385 mg of HOBt (2.5 mmol, 5 equiv) and 385 ⁇ l_ of DIPCDI (2.5 mmol, 5 equiv).
- the Fmoc ⁇ / -terminal group is deprotected as described in the general methods, washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.
- the amino terminal Fmoc group is deprotected as described in the general methods and 1.99 g of Fmoc-L-Thr (tBu) -OH (5 mmol, 5 equiv) are incorporated in the presence of DIPCDI (770 ⁇ L, 5 mmol, 5 equiv) and HOBt (770 mg, 5 mmol, 5 equiv) using DMF as solvent for 1 h.
- DIPCDI 770 ⁇ L, 5 mmol, 5 equiv
- HOBt 770 mg, 5 mmol, 5 equiv
- the Fmoc ⁇ / -terminal group is deprotected as described in the general methods, the peptidyl resin is treated for 30 min with 2.36 ml_ of acetic anhydride (25 mmol, 25 equiv) in the presence of 4.28 ml_ of DIEA (25 mmol, 25 equiv) using DMF as solvent, wash with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dry in vacuo.
- the fully protected peptide [Ac-L-Orn (Boc) -L-Asp (OtBu) -L-Thr (tBu) -L-Cit-OH] is obtained by treatment for 5 minutes of the peptidyl resin, previously dried at vacuum in the presence of KOH, with a solution of 3% TFA in DCM. The filtrates are collected on cold diethyl ether and the treatment is repeated three times. The ethereal solutions are rotavaporated to dryness and at room temperature, the precipitate is resuspended in 50% MeCN in H 2 O and lyophilized.
- tissues are treated with H-Lys-Asp-lle-Cit-NH 2 and with H-Lys-Asp-Val-Cit-NH 2 at a 0.1 mg / mL concentration in culture medium. This is changed daily for 14 days, adding peptide at the same concentration at each change. On day 14, the tissues are fixed with a solution of 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 M phosphate buffer pH 7.4 for a minimum of 2h at 4 0 C. Then, post-fixation is performed with 1% osmium tetraoxide containing 0.8% potassium ferricyanide for 1 hour at 4 0 C.
- the tissues are dehydrated in alcohols and Slowly include epoxy resin (Spurr).
- the samples are cut and oriented correctly in the block, allowing them to polymerize for 48 hours at 6O 0 C. They are subsequently sectioned with an Ultracut E ultramicrotome (Reichert-Jung) and the obtained cuts, once contrasted, are observed with a Microscope Transmission Electronic Jeol JEM 1010, determining the diameter of the fibers observed with the AxioVision.AC (Cari Zeiss Vision) program.
- the average of the diameters of the collagen fibrils observed was 6,825 nm for the untreated tissue and 5,774 nm for H-Lys-Asp-Val-Cit-NH 2 and 5,791 nm for H-Lys-Asp-lle-Cit -NH 2 , which means a decrease in the diameter of the collagen fibers by 15.5% for the tissue treated with H-Lys-Asp- VaI-Qt-NH 2 and 15.1% for the treated with H-Lys- Asp-lle-Cit-NH 2 .
- Phase A In a sufficiently large reactor components of Phase A are weighed and the mixture is heated to 80 0 C to melt the waxes. In a suitable container for the entire content, the components of Phase B are weighed and heated to 70 0 C. Phase A is added over Phase B slowly and under intense agitation, and then Phase C is added to the previous mixture under agitation Once the addition is finished, it is allowed to cool with gentle stirring and when the mixture is at room temperature an aqueous solution of Palm-Lys-Asp-lle-Cit-NH 2 and the lecithin is added, the pH is homogenized and corrected with triethanolamine if necessary.
- the cream obtained has a pH between 6 and 7 and a viscosity of 10,000-15,000 cps (6/50).
- Palm-Lys-Asp-lle-Cit-NH 2 (0.05%) 5.0 LECITINE 0.4
- DPPC Dipalmitoylphosphatidylcholine
- chloroform aqueous solution containing the peptide at the desired concentration (containing Phenonip ®), obtaining the MLV liposomes.
- ULV liposomes are obtained the submerging the MLV liposomes in an ultrasonic bath at 55 0 C for 8 cycles of 2 min in 5 min intervals.
- the present invention relates to a peptide of general formula (I):
- Z is selected from the group consisting of alanyl, a // o-isoleucil, glycyl, isoleucil, isoseril, isovalil, leucil, norleucil, norvalil, prolil, seril, threonyl, a // o-threonyl or valil;
- n and m can vary independently from each other between 1 and 5;
- AA is selected from the group consisting of the natural amino acids encoded in their L- or D- form or uncoded amino acids;
- x e y can vary independently from each other between 0 and 2;
- R 1 is selected from the group consisting of H or alkyl, aryl, aralkyl or acyl group; Y
- R 2 is selected from the group consisting of amino, hydroxyl or thiol, substituted or not with aliphatic or cyclic groups.
- R 1 is H or linear, branched or cyclic, saturated or unsaturated C 2 to C 24 acyl.
- R 2 is preferably amino or hydroxy, substituted or not with linear, branched or cyclic, saturated or unsaturated C 1 to C 24 aliphatic groups.
- Z is preferably L-isoleucil, L-threonyl or L-valil.
- Z is preferably L-isoleucil, n is 4, m is 1, R 1 is H or acetyl or palmitoyl and R 2 is amino or hydroxyl, substituted or not with methyl or ethyl or hexyl or dodecyl or hexadecyl groups.
- Z is L-threonyl, n is 4, m is 1, R 1 is H or acetyl or palmitoyl and R 2 is amino or hydroxyl, substituted or not with methyl or ethyl or hexyl or dodecyl or hexadecyl groups.
- Z is L-Valyl, n is 4, m is 1, Ri is H or acetyl or palmitoyl and R 2 is amino or hydroxyl, substituted or not with methyl or ethyl or hexyl or dodecyl or hexadecyl groups.
- Z is preferably L-isoleucil, n is 4, m is 1, x and 0, R 1 is H or acetyl or palmitoyl and R 2 is amino or hydroxyl, substituted or not with methyl or ethyl or hexyl or dodecyl or hexadecyl groups.
- Z is L-threonyl
- n is 4
- m is 1
- x and y are 0,
- R 1 is H or acetyl or palmitoyl and
- R 2 is amino or hydroxyl, substituted or not with methyl or ethyl or hexyl or dodecyl or hexadecyl groups.
- Z is preferably L-valil, n is 4, m is 1, x and is 0, R 1 is H or acetyl or palmitoyl and R 2 is amino or hydroxyl, substituted or not with methyl or ethyl or hexyl or dodecyl or hexadecyl groups.
- the present invention relates to a method of obtaining a peptide of general formula (I), which is based on solid phase peptide synthesis.
- the present invention relates to a process for obtaining a peptide of general formula (I), which uses protective groups selected from the group consisting of Fmoc / t-Butyl, Fmoc / trityl and Fmoc / allyl.
- the present invention relates to a cosmetic or dermopharmaceutical composition
- a cosmetic or dermopharmaceutical composition comprising a cosmetic or dermopharmaceutically effective amount of at least one peptide of formula (I) and at least one cosmetic or dermopharmaceutically acceptable excipient or adjuvant.
- the present invention refers to a cosmetic or dermopharmaceutical composition
- a cosmetic or dermopharmaceutical composition comprising at least one peptide of general formula (I) incorporated into a cosmetically or dermopharmaceutically acceptable carrier and / or release system selected from the group formed by liposomes, milliccapsules, microcapsules, nanocapsules, sponges, vesicles, micelles, microspheres, microspheres, nanospheres, lipospheres, miliparticles, microparticles and nanoparticles.
- the present invention refers to a cosmetic or dermopharmaceutical composition
- a cosmetic or dermopharmaceutical composition comprising at least one peptide of general formula (I) adsorbed on a solid organic polymer or mineral support selected from the group consisting of talc, bentonite, silica, starch and maltodextrin
- the present invention relates to a cosmetic or dermopharmaceutical composition in which the peptide of general formula (I) is presented in a formulation selected from the group consisting of creams, oil and / or silicone emulsions in water, emulsions of water in oil and / or silicone, oils, milks, balms, foams, lotions, gels, liniments, serums, soaps, ointments, mousses, ointments, bars, pencils and vaporizers.
- a cosmetic or dermopharmaceutical composition in which the peptide of general formula (I) is presented in a formulation selected from the group consisting of creams, oil and / or silicone emulsions in water, emulsions of water in oil and / or silicone, oils, milks, balms, foams, lotions, gels, liniments, serums, soaps, ointments, mousses, ointments, bars, pencils and vaporizers.
- the present invention refers to a cosmetic or dermopharmaceutical composition in which the peptide of general formula (I) is incorporated in solid supports selected from the group consisting of wipes, hydrogels, adhesive patches, non-adhesive patches and masks facial
- the present invention relates to a cosmetic or dermopharmaceutical composition in which the peptide of general formula (I) is incorporated in tissues selected from the group consisting of bandages, girdles, socks, socks, panties, bras and sleeves for arms and forearms.
- the present invention relates to a cosmetic or dermopharmaceutical composition containing a peptide of general formula (I) incorporated in makeup line products selected from the group consisting of dark circles, makeup funds, lotions and cleansing milks , eyeshadows and lipsticks.
- the present invention refers to a cosmetic or dermopharmaceutical composition containing a peptide of general formula (I) in a concentration between 0.000001% (by weight) and 20% (by weight).
- the present invention relates to the use of a peptide of formula (I) in the preparation of a cosmetic or dermopharmaceutical composition for the treatment of the skin.
- the present invention relates to the use of a peptide of formula (I) in the preparation of a cosmetic or dermopharmaceutical composition for the treatment of the skin in order to reduce, delay and / or prevent the signs of aging .
- the present invention refers to the use of a peptide of formula (I) in the elaboration of a cosmetic or dermopharmaceutical composition for the treatment of the skin of the thighs, abdomen, buttocks, chest, forearms, neck and face .
- the present invention refers to the use of a peptide of formula (I) in the elaboration of a cosmetic or dermopharmaceutical composition for the treatment of the skin in order to soften the appearance of the scars.
- the present invention refers to the use of a peptide of formula (I) in the elaboration of a cosmetic or dermopharmaceutical composition for the treatment of the skin of those areas of the body that present scars.
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Abstract
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0708841A BRPI0708841B1 (pt) | 2006-03-31 | 2007-03-30 | peptídeos úteis no tratamento da pele, procedimento de obtenção, composições cosméticas ou dermofarmacêuticas e usos dos peptídeos |
EP07730420.2A EP2025681B1 (en) | 2006-03-31 | 2007-03-30 | Synthetic peptides used for treating the skin and use thereof in cosmetic or dermopharmaceutical compositions |
CN200780019174.0A CN101990544B (zh) | 2006-03-31 | 2007-03-30 | 用于处理皮肤的合成肽及其在美容或皮肤用药物组合物中的用途 |
ES07730420.2T ES2566493T3 (es) | 2006-03-31 | 2007-03-30 | Péptidos sintéticos utilizados para el tratamiento de la piel y el uso de los mismos en composiciones cosméticas o dermofarmacéuticas |
US12/295,554 US9393186B2 (en) | 2006-03-31 | 2007-03-30 | Synthetic peptides useful in the treatment of the skin and use thereof in cosmetic or dermopharmaceutical compositions |
JP2009502124A JP5247676B2 (ja) | 2006-03-31 | 2007-03-30 | 皮膚のトリートメントにおいて有用な合成ペプチド類および化粧品または皮膚薬剤組成物中でのその用途 |
MX2008012444A MX2008012444A (es) | 2006-03-31 | 2007-03-30 | Peptidos sinteticos utiles en el tratamiento de la piel y su uso en composiciones cosmeticas o dermofarmaceuticas. |
CA2647775A CA2647775C (en) | 2006-03-31 | 2007-03-30 | Synthetic peptides useful in the treatment of the skin and use thereof in cosmetic or dermopharmaceutical compositions |
AU2008243084A AU2008243084B2 (en) | 2006-03-31 | 2008-10-31 | Synthetic peptides used for treating the skin and use thereof in cosmetic or dermopharmaceutical compositions |
HK11107273.0A HK1153206A1 (en) | 2006-03-31 | 2011-07-13 | Synthetic peptides used for treating the skin and use thereof in cosmetic or dermopharmaceutical compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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ES200600846A ES2283212B1 (es) | 2006-03-31 | 2006-03-31 | Peptidos sinteticos utiles en el tratamiento de la piel y su uso en composiciones cosmeticas o dermofarmaceuticas. |
ESP200600846 | 2006-03-31 |
Related Child Applications (1)
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AU2008243084A Division AU2008243084B2 (en) | 2006-03-31 | 2008-10-31 | Synthetic peptides used for treating the skin and use thereof in cosmetic or dermopharmaceutical compositions |
Publications (2)
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WO2007113356A2 true WO2007113356A2 (es) | 2007-10-11 |
WO2007113356A3 WO2007113356A3 (es) | 2012-12-20 |
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PCT/ES2007/000180 WO2007113356A2 (es) | 2006-03-31 | 2007-03-30 | Peptidos sintéticos útiles en el tratamiento de la piel y su uso en composiciones cosméticas o dermofarmacéuticas |
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Country | Link |
---|---|
US (1) | US9393186B2 (es) |
EP (1) | EP2025681B1 (es) |
JP (1) | JP5247676B2 (es) |
KR (1) | KR20090014150A (es) |
CN (1) | CN101990544B (es) |
AR (1) | AR060251A1 (es) |
AU (1) | AU2008243084B2 (es) |
BR (1) | BRPI0708841B1 (es) |
CA (1) | CA2647775C (es) |
ES (2) | ES2283212B1 (es) |
HK (1) | HK1153206A1 (es) |
MX (1) | MX2008012444A (es) |
WO (1) | WO2007113356A2 (es) |
Cited By (3)
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WO2010091893A1 (en) * | 2009-02-16 | 2010-08-19 | Lipotec, S.A. | Peptides used in the treatment and/or care of the skin, mucous membranes and/or scalp and their use in cosmetic or pharmaceutical compositions |
US10087221B2 (en) | 2013-03-21 | 2018-10-02 | Sanofi-Aventis Deutschland Gmbh | Synthesis of hydantoin containing peptide products |
US10450343B2 (en) | 2013-03-21 | 2019-10-22 | Sanofi-Aventis Deutschland Gmbh | Synthesis of cyclic imide containing peptide products |
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US20120094919A1 (en) * | 2009-03-16 | 2012-04-19 | Graeub Remo | Use of tripeptides |
DE102009027024A1 (de) * | 2009-06-18 | 2010-12-23 | Henkel Ag & Co. Kgaa | Antifalten-Kosmetikum mit Antioxidantien |
CN103083715A (zh) * | 2011-11-03 | 2013-05-08 | 杭州炬九生物科技有限公司 | 一种软化、淡化疤痕的水凝胶疤痕贴 |
FR3007289B1 (fr) * | 2013-06-24 | 2015-06-19 | Caster | Compositions cosmetiques comprenant des extraits de plantes pour lutter contre le vieillissement cutane |
KR102481341B1 (ko) | 2014-10-31 | 2022-12-23 | 루브리졸 어드밴스드 머티어리얼스, 인코포레이티드 | 피부 표면으로 활성 작용제의 전달을 위한 열가소성 폴리우레탄 필름 |
CN108473652A (zh) | 2015-11-05 | 2018-08-31 | 路博润先进材料公司 | 可热成型的双网络水凝胶组合物 |
KR101895906B1 (ko) * | 2016-07-07 | 2018-10-04 | 주식회사 한국화장품제조 | 펩타이드 리포좀을 포함하는 스틱형 화장료 조성물 |
EP3370178A3 (en) * | 2017-03-03 | 2018-12-19 | Tata Consultancy Services Limited | Method and system for in silico testing of actives on human skin |
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- 2007-03-30 US US12/295,554 patent/US9393186B2/en active Active
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2010091893A1 (en) * | 2009-02-16 | 2010-08-19 | Lipotec, S.A. | Peptides used in the treatment and/or care of the skin, mucous membranes and/or scalp and their use in cosmetic or pharmaceutical compositions |
ES2349972A1 (es) * | 2009-02-16 | 2011-01-13 | Lipotec, S.A. | Péptidos útiles en el tratamiento y/o cuidado de la piel, mucosas y/o cuero cabelludo y su uso en composiciones cosméticas o farmacéuticas. |
CN102317307A (zh) * | 2009-02-16 | 2012-01-11 | 利普泰股份公司 | 用于治疗和/或护理皮肤、粘膜和/或头皮的肽及它们在美容组合物或药物组合物中的用途 |
JP2012519656A (ja) * | 2009-02-16 | 2012-08-30 | リポテック,エセ.ア. | 皮膚、粘膜、および/または頭皮の治療および/またはケアに用いられるペプチド、ならびに、美容または医薬組成物におけるその使用 |
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AU2010213094B2 (en) * | 2009-02-16 | 2014-07-24 | Lipotec, S.A. | Peptides used in the treatment and/or care of the skin, mucous membranes and/or scalp and their use in cosmetic or pharmaceutical compositions |
CN102317307B (zh) * | 2009-02-16 | 2015-04-08 | 利普泰股份公司 | 用于治疗和/或护理皮肤、粘膜和/或头皮的肽及它们在美容组合物或药物组合物中的用途 |
US10087221B2 (en) | 2013-03-21 | 2018-10-02 | Sanofi-Aventis Deutschland Gmbh | Synthesis of hydantoin containing peptide products |
US10450343B2 (en) | 2013-03-21 | 2019-10-22 | Sanofi-Aventis Deutschland Gmbh | Synthesis of cyclic imide containing peptide products |
Also Published As
Publication number | Publication date |
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US9393186B2 (en) | 2016-07-19 |
CA2647775C (en) | 2017-04-18 |
HK1153206A1 (en) | 2012-03-23 |
AU2008243084B2 (en) | 2012-03-08 |
BRPI0708841A2 (pt) | 2011-06-14 |
JP5247676B2 (ja) | 2013-07-24 |
CN101990544A (zh) | 2011-03-23 |
US20130309281A1 (en) | 2013-11-21 |
ES2283212B1 (es) | 2008-08-16 |
EP2025681A2 (en) | 2009-02-18 |
AU2008243084A1 (en) | 2008-11-27 |
KR20090014150A (ko) | 2009-02-06 |
EP2025681A4 (en) | 2015-01-07 |
AR060251A1 (es) | 2008-06-04 |
WO2007113356A3 (es) | 2012-12-20 |
ES2566493T3 (es) | 2016-04-13 |
CA2647775A1 (en) | 2007-10-11 |
MX2008012444A (es) | 2009-03-06 |
CN101990544B (zh) | 2014-09-24 |
EP2025681B1 (en) | 2016-02-17 |
JP2009535297A (ja) | 2009-10-01 |
ES2283212A1 (es) | 2007-10-16 |
BRPI0708841B1 (pt) | 2015-10-27 |
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