WO2014044808A2 - Charge dermique à usage cosmétique et à pénétration rapide pour application topique - Google Patents

Charge dermique à usage cosmétique et à pénétration rapide pour application topique Download PDF

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Publication number
WO2014044808A2
WO2014044808A2 PCT/EP2013/069597 EP2013069597W WO2014044808A2 WO 2014044808 A2 WO2014044808 A2 WO 2014044808A2 EP 2013069597 W EP2013069597 W EP 2013069597W WO 2014044808 A2 WO2014044808 A2 WO 2014044808A2
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Prior art keywords
hyaluronic acid
cosmetic
skin
molecular weight
dalton
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PCT/EP2013/069597
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English (en)
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WO2014044808A3 (fr
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Daniela Montanari
Manuela Guglielmo
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Labo Cosprophar Ag
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Publication of WO2014044808A3 publication Critical patent/WO2014044808A3/fr

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    • 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
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/59—Mixtures
    • A61K2800/592—Mixtures of compounds complementing their respective functions
    • A61K2800/5922—At least two compounds being classified in the same subclass of A61K8/18

Definitions

  • the present invention relates to a fast-penetration cosmetic dermal filler for external application.
  • the present invention relates to a cosmetic dermal composition for topical use for filling and relaxing wrinkles, depressions or microreliefs of the epidermis of the face or body or for increasing the volume of the lips or of the tissues close to the cheekbones.
  • the cosmetic dermal composition of the invention is particularly suitable for application to epidermis of the face.
  • the present invention origins from the area of cosmetic preparations for external use, in particular for application to the epidermis of the face.
  • Wrinkles are folds or furrows, of variable depth, present on the surface of the skin which are considered a sign of skin ageing. They involve a failure in the skin structures and stretching or repeated extension of some areas of the skin, especially of the face.
  • the causes which lead to the formation of wrinkles are manifold and are mainly attributable to the combined action of the following factors: ageing of the skin, the force of gravity, degradation of collagen fibres accompanied by loss of elasticity, the action of external agents, predominantly sunlight, and repeated movements of muscles and joints.
  • ageing of the skin the force of gravity
  • degradation of collagen fibres accompanied by loss of elasticity
  • the action of external agents predominantly sunlight
  • repeated movements of muscles and joints The combined action of internal and external factors leads to more fast ageing of the skin and to the appearance, even prematurely, of wrinkles.
  • the internal factors are related to the physiological process of ageing of the tissues which contribute progressively to keratinisation of the epidermis, relaxation of the dermis, hypotonia of the "mimic" muscle groups and decreased hydration.
  • hyaluronic acid plays an important role because of its plasticity features and because of its capacity for filling the wrinkle and maintaining the correction for a long period of time, without any side effects.
  • Hyaluronic acid is a disaccharide present in living organisms as a component of the extracellular space.
  • This molecule is essential for the formation of the collagen matrix and elastic fibres and for maintaining skin hydration.
  • hyaluronic acid is a linear polymer of N- acetyl-glucosamine and glucuronic acid in alternating sequences, and the carboxyl groups thereof are strongly ionised at the prevailing pH of the skin surface.
  • glycosaminoglycans - which contain sulphate groups, are small in size (on average 80 sugar residues, with an MW of 1 .5-2 x 10 4 Da) and form glycoprotein complexes (proteoglycans) - hyaluronic acid contains no sulphur, does not have a polypeptide component and reaches MWs up to a thousand times greater (even 2 ⁇ 10 7 Da), containing over 25,000 disaccharides; in linear terms, the macromolecule can reach an extension of 25 ⁇ (three times the diameter of a red blood cell).
  • hyaluronic acid Unlike protein chains, which often tend to wrap themselves in globular conformations, polymer sequences of hyaluronic acid, which are more rigid, take on an extended arrangement.
  • the carboxyl groups brought about by the glucuronic acid give the polyglucide an acidic nature (pKa approximately 3): at physiological tissue pH, they are fully dissociated. Therefore, hyaluronic acid expresses a strong anionic valence, able to attract a swarm of cations (mainly Na + ): the high expression of charges, contributed to by the presence of numerous hydroxyl groups, exerts a strong attraction on bipolar water molecules and makes it possible to trap a huge hydration cloud.
  • Hyaluronic acid is present in all human connective tissues, in the dermis and in the epidermis. It is produced by both fibroblasts and keratinocytes. It plays a vital role in providing firmness and compactness to the skin, since by binding to collagen, fibronectin and proteoglycans in the dermis it forms macromolecular complexes which provide a type of support structure. Moreover, the hyaluronic acid molecule has a high capacity to bind water, thus ensuring increased hydration and skin firmness.
  • the stratum corneum also contains HA, which plays a key role against dehydration. It interacts with lipids in the lamellar structures of the stratum corneum, adjusting the mechanical properties thereof.
  • Hyaluronic acid has the same chemical structure whether it is in bacteria, in animals or in humans. Since it is thus chemically identical in all species and in all types of tissue, hyaluronic acid has total biocompatibility.
  • hyaluronic acid is well documented not only in cosmetic medicine but also in other areas of medicine such as ophthalmic surgery and orthopaedics.
  • the hyaluronic acid used in cosmetic medicine is a sterile viscoelastic, colourless and transparent gel, composed of cross-linked hyaluronate molecules.
  • the medical / cosmetic treatment based on hyaluronic acid gives vitality to the skin and is indicated for correction of the lips (fullness and firmness, volume and contour), folds (for example nasolabial), remodelling facial contours (for example cheeks and chin), wrinkles (for example glabellar, periorbital), post-acne scarring, and remodelling the breast and body.
  • hyaluronic acid is injected in small doses in the regions concerned by means of a syringe comprising a thin needle. Once administered, it stimulates cell function and returns the lost compactness to the skin.
  • the filler effect resulting from administering hyaluronic acid depends on the type of skin and the quality and amount injected.
  • Hyaluronic acid also stimulates the proliferation of fibroblasts, thus promoting the synthesis of new collagen and other extracellular matrix components.
  • the progressive reduction of the size of the hyaluronic acid polymer in the skin is another feature of advanced age. With age, changes also occur in the concentrations and types of protein molecules which bind to hyaluronic acid polymers. Each of these phenomena contributes to the apparent dehydration, atrophy and loss of volume that characterise aged skin.
  • the process of ageing in the face is also linked to more complex alterations affecting the anatomical structures of the face at every depth.
  • the bone resorption at the jaw bone and gums leads to a reduced ability to support bone structures, which is associated with gradual muscular hypotonia and reduction and redistribution of subcutaneous fat. All of this, combined with the thinning of the dermis and the reduced ability to support the elastic fibres and collagen, leads to a gradual modification of even the morphological appearance of the face, with a loss of the natural youthful convexities.
  • the complex relationship between hyaluronic acid and skin has been documented in the Journal of Investigative Dermatology. In a 1999 study, T.J. Brown et al.
  • the deepest portion of the stratum corneum has a "cemented wall” structure, in which the bricks are represented by the corneocytes, nonviable cells, filled in with keratin filaments and wrapped in a rigid shell protein; the cement is formed by intercorneocyte lipids, which are highly hydrophobic.
  • This organisation provides, at a thickness of a fraction of a millimetre, an efficient barrier which is almost completely impervious to hydrophilic substances and to those having a high steric hindrance: both features are peculiar to hyaluronic acid and make this polymer a paradigm of compounds for which it seems reasonable to exclude the possibility of transcutaneous absorption.
  • hyaluronic acid smeared on the skin of hairless mice and human volunteers, in areas subsequently protected from contact and chafing, disappears shortly from the epidermal surface, suggesting fast absorption; a few hours later the autoradiography examination shows radioactive granules dispersed throughout the thickness of the stratum corneum and, to a lesser extent, in the vital layers of the epidermis, especially at the basal element; in the vital layers of the epidermis, the treatment with hyaluronidase leads to the disappearance of the radioactive speckling; this does not take place in the stratum corneum, where, probably, hyaluronic acid stabilises with the lipid tissue components, an intimate bond which protects against lysis; autoradiography grains which mark the presence of tritiated glycosaminoglycan soon become evident even in the dermis.
  • T.J. Brown et al. favour the hypothesis of permeation through the intercorneocyte lipid phase, made possible by hydrophobic patches scattered along the hydrophilic chain of hyaluronic acid.
  • Another theory predicts an "active transport" functionality, triggered by the binding of hyaluronic acid to specific membrane receptors (although not expressed by corneocytes).
  • the simplest conjecture attributes the transport to a momentary increase in the permeability of the barrier as a result of the hyperhydration produced by the same hyaluronic acid.
  • the gel based on glycosaminoglycan initially has a film- forming activity, stratifying on the corneal surface and pouring down in this part of its liquid phase; imbibition would lead to disruption of the ordered arrangement of lamellar lipids, giving rise to the opening of hydrophilic channels, which hyaluronic acid would make use of so as to penetrate.
  • the study demonstrates, by autoradiography and radiochemical analysis, that hyaluronic acid applied to the surface of the skin penetrates the normal epidermis and is subsequently deposited, at least for a brief period of time, in the dermis, before disposal and degradation through known metabolic pathways.
  • One of the purposes of the present invention is to provide a cosmetic dermal composition having fast-penetration, based on different types of hyaluronic acid, which when externally applied to the skin leads to an effective filling effect on the signs of sagging of the face and makes it possible to avoid or reduce resorting to cosmetic surgery or invasive techniques for administering hyaluronic acid and / or collagen.
  • the Applicant has found that by combining hyaluronic acid having different selected molecular weight, a mixture or complex is obtained which acts as a filler in the deeper layers of the epidermis, even when it is applied topically to the skin.
  • the present invention provides a cosmetic dermal composition having a filler effect or dermal filler for topical application, comprising a mixture based on hyaluronic acid or salts thereof of different molecular weights comprising
  • hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 800 to 1200 Dalton
  • hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 4000 to 6000 Dalton having a molecular weight from 4000 to 6000 Dalton
  • hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 20,000 to 70,000 Dalton
  • hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 1 ,800,000 to 2,200,000 Dalton,
  • hyaluronic acid refers to a linear glycosaminoglycan comprising repeated units of D- glucuronic acid and N-acetyl-D-glucosamine.
  • the Applicant has also found that if a mixture of hyaluronic acid having 6 different molecular weights is combined with two selected peptides, the resulting composition fastly and effectively penetrates the epidermis by way of topical application and reaches the deeper skin layers where it has a filling effect leading to modelling of the treated areas and relaxation of wrinkles.
  • the present invention relates to a cosmetic composition having a filler effect for topical application in which the mixture of hyaluronic acid having different molecular weights a) - f) is associated with the peptides palmitoyl-lysyl-dioxymethionyl-lysine and acetyl hexapeptide-37 (INCI name).
  • the hyaluronic acids a) - f) are individually conveyed by suitable cosmetically acceptable vehicles, in particular cyclodextrins, which increase the ability thereof to penetrate into the skin layers. It is observed that delivering each of the components based on hyaluronic acid a) - f) with cyclodextrins increases the stability and resistance to cellular oxidation of hyaluronic acid cell.
  • the cosmetic composition having filling effect or dermal filler of the invention is useful in the cosmetic treatment of wrinkles, or other beauty flaw such as skin depressions, corrugations, stretch marks of any body areas for example face, breasts or gluteus.
  • Fig. 1 is a table showing the percentages of absorption into the epidermis of 6 samples of hyaluronic acid, of which 5 have increasing molecular weights and 1 as cross-linked sodium hyaluronate, at different times;
  • Fig. 2 is a graphical representation of the absorption curves in the epidermis, with respect to time, of 6 samples of hyaluronic acid of which 5 have increasing molecular weights and 1 has cross-linked sodium hyaluronate;
  • Fig. 3 is a table showing the percentages of absorption into the dermis of 6 samples of hyaluronic acid, of which 5 have increasing molecular weights and 1 as cross-linked sodium hyaluronate, at different times;
  • Fig. 4 is a graphical representation of the absorption curves in the dermis, with respect to time, of 6 samples of hyaluronic acid of which 5 have increasing molecular weights and 1 has cross-linked sodium hyaluronate
  • Fig. 5 is a table showing the combined percentages of absorption into the epidermis and dermis of 6 samples of hyaluronic acid, of which 5 have increasing molecular weights and 1 as cross-linked sodium hyaluronate, at different times;
  • Fig. 6 is a graphical representation of the combined absorption curves in the epidermis and dermis, with respect to time, of 6 samples of hyaluronic acid of which 5 have increasing molecular weights and 1 has cross-linked sodium hyaluronate.
  • the Applicant has found that by combining six types of hyaluronic acid, each having molecular weights selected so as to be progressively increasing, a dermal filler is obtained which, when applied topically, penetrates the deeper layers of the skin resulting in the treated skin areas being filled.
  • the filling of the skin areas relaxes the corrugations or roughness of the skin and / or leads to a filling effect which leads to an increase in volume of the treated skin areas, for example in the vicinity of the cheekbones or lips.
  • the invention therefore relates to a cosmetic composition or dermal filler comprising a mixture of hyaluronic acid and/or salts thereof comprising
  • hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 800 to 1200 Dalton
  • hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 4000 to 6000 Dalton
  • hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 20,000 to 70,000 Dalton
  • hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 1 ,800,000 to 2,200,000 Dalton,
  • cosmetic composition with filler effect dermal filler or dermo- cosmetic filler as used herein are interchangeable and substantially have the same meanings.
  • physiologically acceptable salt of hyaluronic acid means the sodium and potassium salts and other suitable salts and mixtures thereof.
  • the salt of hyaluronic acid is the sodium salt.
  • the components a) - e) of the mixture of hyaluronic acids of the invention are in free form or in the form of one of the physiologically acceptable salts of hyaluronic acid, whilst the component f) is in the form of a cross-linked gel.
  • hyaluronic acid in free form means hyaluronic acid which is not in form of a salt.
  • the cross-linked hyaluronic acid is a polymeric matrix which contains, within the three-dimensional structure thereof, the components a) - e) based on hyaluronic acid in free form or in the form of a physiologically acceptable salt. These components a) - e) are released gradually from the three-dimensional matrix of cross-linked hyaluronic acid by passive diffusion for degradation of the matrix by the hyaluronidase present on the epidermal surface.
  • the mixture of the components of hyaluronic acid a) - f) of the invention is in the form of a gel or hydrogel.
  • the components a - f) of the mixture of hyaluronic acid may be present in varying quantities in the compositions of the invention.
  • the hyaluronic acid of component a) may be present in an amount from 0.0001 to 30 % by weight, more preferably from 0.1 to 10 %, even more preferably from 1 to 5 % by weight; the hyaluronic acid of component b) may be present from 0.0001 to 30 % by weight, more preferably from 0.01 to 10 %, even more preferably 1 to 5 % by weight; the hyaluronic acid of component c) may be present from 0.0001 to 30 % by weight, more preferably from 0.01 to 10 %, even more preferably 1 to 5 % by weight; the hyaluronic acid of component d) may be present from 0.0001 to 30 % by weight, more preferably from 0.01 to 10 %, even more preferably 1 to 5 % by weight; the hyaluronic acid of component e) may be present from 0.0001 to 30 % by weight, more preferably from 0.01 to 10 %, even more preferably 1 to 5 % by weight;
  • the mixture of hyaluronic acid having different molecular weights a) - f) is present in concentrations ranging from 0.01 to 50% by weight with respect the total weight of the cosmetic composition.
  • the component a) of the mixture of hyaluronic acid of the invention is a hyaluronic acid of low molecular weight, with a range from 800 to 1200 Da, or a physiologically acceptable salt thereof.
  • the component a) is a mixture of hyaluronic acid having a molecular weight from 1000 to 1200 Dalton, for example obtained by a process of acid hydrolysis of sodium hyaluronate of high molecular weight, originally obtained by bacterial fermentation.
  • the reduced average molecule size of the hyaluronic acid of the component a) improves the intradermal penetration and makes possible the physiological formation in-situ of hyaluronic acid of medium molecular weight.
  • This type of very low molecular weight hyaluronic acid is particularly suitable for retaining water in the connective tissue; it is thus responsible for intense hydration and resulting tissue swelling, both in the lower and in the upper layers of the skin, where it reduces transdermal water loss (TEWL). It also acts on the fibroblasts, stimulating them to produce endogenous hyaluronic acid of medium molecular weight. It promotes the filling of wrinkles and fleshing-out of the empty tissue areas of the face.
  • the component a) of the mixture has a molecular weight of substantially 1000 Da.
  • the component b) of the mixture of hyaluronic acid is hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 4000 to 6000 Dalton. In some embodiments, the hyaluronic acid has a molecular weight of 5000 Da
  • biotechnological derivative prepared by acid hydrolysis of sodium hyaluronate of a higher molecular weight, obtained by bacterial fermentation.
  • the component c) of the mixture of hyaluronic acid is hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 20,000 to 70,000 Dalton. In some embodiments, this hyaluronic acid has a molecular weight of approximately 50,000 Da
  • this hyaluronic acid may be obtained by biotechnological fermentation of the bacterium Bacillus subtilis.
  • This component of the mixture of hyaluronic acid is found to be particularly active in bringing about wrinkle reduction after topical application.
  • the reduction in deep wrinkles was determined by image analysis of the replicas at the experimental times of 4 and 8 weeks.
  • the increase in elasticity was determined by the use of a cutometer at experimental times of 4 and 8 weeks.
  • the increase in skin hydration is determined by the use of a corneometer to experimental times 4 and 8 weeks.
  • the component d) of the mixture of hyaluronic acid is a hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 150,000 to 250,000 Dalton. According to some embodiments, it is a hydrolysed hyaluronic acid, in particular having a molecular weight of ca. 200,000 Da.
  • the component d) of hyaluronic acid can be produced by a process comprising the fermentation of bacterial strains of Streptococcus zooepidemicus on plant substrates.
  • the biosynthesis involves the following steps:
  • the cells of the bacterial strains are grown on a substrate consisting of peptides of wheat and glucose,
  • the component e) of the mixture of hyaluronic acid is a hyaluronic acid or a physiologically acceptable salt thereof having a molecular weight from 1 ,800,000 to 2,200,000 Da.
  • the hyaluronic acid having an MW of approximately 2,000,000 Da is used in an amount 11 times greater than that indicated by the manufacturer of hyaluronic acid itself.
  • the component e) is obtained by fermentation of strains of Streptococcus zooepidemicus.
  • the raw materials used in the fermentation include glucose, peptone, yeast extract and other raw materials derived from animal sources.
  • the component e) of hyaluronic acid has a molecular rigidity and a high capacity to bind water molecules so as to form a gel which is resistant to mechanical pressure.
  • This gel once it has passed into the deep layers of the skin, behaves like a sponge and can mobilise an amount of water molecules up to 20 times its own weight.
  • the component f) of the mixture of hyaluronic acid is cross-linked hyaluronic acid in free form or a physiologically acceptable salt thereof.
  • the component f) is a cross-linked polymer of sodium hyaluronate, namely a sodium salt of the cross-linked polymer hyaluronic acid which typically is derived from non-animal sources.
  • the component f) has a high capacity to bind water molecules thereto, resulting in an excellent moisturiser.
  • hyaluronic acid is chemically modified by cross-linking.
  • the glycosidic linkages ⁇ -1 , 4, the breakup of which is catalysed by hyaluronidase are better protected, and therefore the process of degradation of the polysaccharide chain is slowed down.
  • the cross-linked hyaluronic acid remains intact on the skin surface for a prolonged time.
  • the hyaluronic acid can be cross-linked by attaching thiols, methacrylates or tyramine, or the hyaluronic acid can be cross-linked directly using formaldehyde or using divinylsulphone
  • the hyaluronic acid is cross-linked using divinylsulphone or 1 ,4-butanediol diglycidyl ether as a cross-linking agent, the former being the preferred agent.
  • cross-linked hyaluronic acid has the ability to bind 50 times more water than a linear HA. In addition, it is approximately 5 times more hydrating after 24 hours than a non-cross-linked hyaluronic acid.
  • the degree of hydration of the skin achieved by applying of cross-linked hyaluronic acid has been verified by using confocal Raman spectroscopy. For this analysis, solutions containing 0.1 % linear (non-cross-linked) hyaluronic acid (HA) or cross-linked HA are applied to skin biopsies.
  • the instrument measures a water content of the treated skin, with the following results: in the stratum corneum 5 times greater, in the entire skin (entire biopsy) 6 times greater for the skin treated with the cross-linked HA than for that treated with the linear HA.
  • the mixture of hyaluronic acids a) - f) present in the composition of the invention is of the following composition:
  • composition comprising a mixture of hyaluronic acid a) - f) in a synergistic combination with two selected peptides, palmitoyl-lysyl-dioxymethionyl-lysine and acetyl hexapeptide-37 (INCI name).
  • the Applicant has surprisingly found that combining the mixture of hyaluronic acid having different molecular weights a) - f) with the two selected peptides, palmitoyl-lysyl-dioxymethionyl-lysine and acetyl hexapeptide-37, increases the synthesis of the main components of the skin matrix and the dermal-epidermal junction and increases the hydration of the deep layers of the skin, resulting in a filling and anti-wrinkle effect which is unexpected from a composition for topical application.
  • Palmitoyl-lysyl-dioxymethionyl-lysine is a deoxygenated lipopeptide which stimulates the synthesis of collagen I, III, IV, fibronectin, hyaluronic acid and laminin-5, which are the main components of the skin matrix and the dermal-epidermal junction.
  • collagen I together with collagen II I, is the most abundant collagen in the tissues, and in the dermis reaches 80 % by weight.
  • the collagen molecules secreted by fibroblasts will self-assemble, forming the characteristic fibres. In this way, they form the characteristic cross-linked structure which can resist the various physical stresses to which the skin is subjected.
  • Collagen III is produced by young fibroblasts, but also by fibroblasts stimulated by the wound healing process. It is less resistant than collagen I and is partially responsible for the smoothness of the skin.
  • Collagen IV is a part of the proteins of the basement membrane anchoring.
  • Laminin-5 is an adhesion glycoprotein. It helps with cell migration and anchoring.
  • Fibronectins are extracellular matrix proteins, which together with the integrins make it possible for the cells to bind to the collagen. They also play an important role in cell migration and differentiation.
  • acetyl hexapeptide-37 one of the two selected peptides according to some aspects of the invention, in the composition of the invention leads to an increase in the expression of aquaporins 3, improving the exchange of water between the basal layer of the epidermis and the stratum corneum.
  • This hexapeptide in combination with the tripeptide described above and the mixture of hyaluronic acids a) - f), leads to surprising skin hydration.
  • Aquaporins are integral membrane proteins involved in the transport of water through the different cell layers, acting as pores which are selective for water.
  • the AQP3 is the most abundant aquaglyceroporin in the human epidermis which facilitates the transport of water, glycerol and other small solutes. Therefore, the AQP3 improves the transepidermal permeability, increasing the water content in the skin and helping the barrier function.
  • the activity of hexapeptide as promoter of AQP3 has been demonstrated by way of specific tests.
  • the luciferase enzyme assay in the analysis of gene expression in keratinocytes.
  • This assay makes it possible to understand how the hexapeptide-37 is capable of positively or negatively regulating the activity of the specific promoter for the AQP3.
  • cells are incubated with different concentrations of the active ingredient, and the light signal produced by the reaction between the luciferase and its substrate is quantified using a luminometer.
  • the increase in the activity of the promoter of the human AQP3 is: 0.5 mg / ml hexapeptide-37: + 62 % with respect to the negative control, 1 mg / ml hexapeptide-37: + 96 % with respect to the negative control.
  • the behaviour is dose-dependent.
  • one or more of components a) - f) of the mixture of hyaluronic acid is conveyed by a suitable cosmetically acceptable vehicles which increase the ability thereof to penetrate skin layers and so as to obtain visible aesthetic results with relatively brief periods of treatment.
  • cosmetically acceptable vehicles which can be used in the composition of the invention include cyclodextrins, liposomes, nanospheres and others.
  • Suitable cosmetically acceptable vehicles are hollow in shape and internally enclose the polymer component based on hyaluronic acids a - f, forming a complex species in which the HAs act as "guests" and the vehicle acts as a host.
  • a suitable class of compounds which can function as a "guest" for many organic molecules such as HAs is the class of the cyclodextrins, cyclic molecules consisting of different units (6-8 in the more common cyclodextrins) of one of the most common sugars, D-glucose, held together by alpha-1 ,4-glycosidic bonds.
  • Cyclodextrins have a three-dimensional truncated cone shape, having an internal cavity which can accommodate low-polarity organic molecules.
  • the use of cyclodextrins makes the hyaluronic acids of the composition more stable and resistant to oxidation, air degradation and temperature.
  • cyclodextrins by releasing in a controlled manner the molecules which they incorporate, increase the bioavailability of the molecules of HA contained in the composition, causing an increase in the activity.
  • the delivery of the mixture containing the components a - f having cyclodextrins improves the skin bioavailability, making them usable on the skin surface for a longer period of time.
  • the cyclodextrins also form a completely transparent and invisible film on the skin and are able to bring about a very good skin lifting action; this protective, lifting and moisturising action is very useful in all products having an immediate action and in products which need to be transparent for marketing reasons.
  • the reduced average molecular size of cyclodextrins improves the intradermal penetration of hyaluronic acid and gives the components a - f the role of a precursor suitable for in situ physiological formation of medium molecular weight hyaluronic acid, which retains water in the connective tissue leading to intense hydration and tissue swelling, both in the deep and in the upper layers of the skin, where it reduces transdermal water loss (TEWL).
  • TEWL transdermal water loss
  • the cosmetically acceptable vehicles are beta-cyclodextrins, in particular HP-beta-cyclodextrins specific for hyaluronic acids having a very low molecular weight, such as those of the components a), b) and c) described above.
  • Another aspect of the invention provides the cosmetic use of a composition for topical application according to any one of the above- disclosed embodiments for filling in wrinkles or corrugations and / or maintaining the mechanical properties and elasticity of the skin.
  • Another aspect provides the use of one of the above-disclosed cosmetic compositions for stretching and / or reducing or mitigating wrinkles, particularly of the face.
  • the cosmetic composition of the invention provides increased amounts of hyaluronic acid at depth to reduce wrinkles, furrows and loss of volume in the face and body and/or increasing the volume of areas of the human body affected by aging such as face, lips, breasts, gluteus, thighs.
  • a cosmetic dermal composition according to one of the above-disclosed embodiments is provided, such as dermal filler by topical application on the facial and/or body epidermis.
  • the invention concerns with the cosmetic use of a composition or dermal filler according to anyone of the above mentioned embodiments as filler or a cosmetic method for volumizing any parts of the human body for example buttocks, calf, breasts.
  • the present invention relates to a cosmetic method for relaxing wrinkles or for filling cutaneous or subcutaneous regions, comprising external application to the epidermis of a cosmetically effective amount of a cosmetic dermal composition according to any one of the above-disclosed embodiments.
  • the cosmetic method of the invention comprises the external application of the composition or dermal filler of the invention wherein the external application is carried out using an applicator / dispenser provided with cannula with one end cut off.
  • Hyaluronic acid binding water promotes filling-out of the depressions or sagging of the face or deep or large wrinkles and / or an increase in the volume of the skin near the cheekbones and lips and or body areas subjected to structural failure of skin such as breasts, gluteus and surrounding body areas.
  • combining the mixture of hyaluronic acids a) - f) with the two selected peptides stimulates fibroblasts to produce the extracellular matrix of the dermis and regulates the transcutaneous passage of water, further increasing the prolonged filling action on the skin tissue.
  • One or more excipients typically used in the conventional formulation of cosmetic products such as oils, glycerin, emollients, emulsifiers or dispersants may be incorporated into the cosmetic dermal composition of the invention, in amounts typical for cosmetic compositions.
  • the formulation of the cosmetic composition of the invention may further include one or more cosmetically active ingredients such as vitamins, vegetal extracts, mineral salts, or lecithin.
  • the cosmetically active ingredients include one or more substances selected from vitamins, for example vitamin A, vitamin E and the derivatives thereof, or other cosmetically active substances such as lecithins, coenzyme Q, plant extracts or mineral salts.
  • composition of the invention contains substances or lipophilic excipients such as oils and butters, such as shea butter or coconut oil.
  • composition of the invention may be in a solid, semi-liquid or liquid form.
  • Typical formulations in solid form include creams, ointments, pastes, sticks for application for example to the lips, trans-dermal patches, or make-up such as foundation, powder, blush, eye shadow, mascara, eye pencil, lip pencil, etc.
  • composition or dermal filler of the invention is in the form of a cream for the application on the body especially on the face, breasts, buttocks or thighs.
  • Typical formulations in liquid form include solutions, suspensions, aqueous or hydroalcoholic lotion, serum, cosmetic milk, oleolites, shampoos, bath foam, and oil-in-water or water-in-oil emulsion.
  • water is present as a diluent or solvent, optionally mixed with other liquids used for the formulation of cosmetic compositions such as alcohols, typically ethyl alcohol, and glycols, such as ethylene or propylene glycol.
  • alcohols typically ethyl alcohol
  • glycols such as ethylene or propylene glycol.
  • Typical formulations in semi-liquid form are gels or hydrogels.
  • the composition of the invention is in the form of monophase hydrogel, that is to say a gel in a single homogeneous phase.
  • the composition of the invention is in the form of a transparent hydrophilic gel, obtained without the aid of gel- forming polymers such as carbomer, xanthan gum etc.
  • the composition of the invention can be applied with a suitable applicator / dispenser equipped with a cannula with an end cut off, which makes it possible to release the gel precisely to the body areas in need of treatment.
  • composition of the invention After the cosmetic treatment with the composition of the invention it is possible to apply a nourishing cosmetic preparation which brings in nutrients to provide comfort to the skin, in particular of the face, neck or other parts of the body.
  • the cosmetic composition further comprises one or more out of cosmetically acceptable thickeners, solubilisers, preservatives, water, alcohols, glycerin, stabilisers, antioxidants, and antibacterials, in quantities in line with those provided for common cosmetic formulations.
  • Cosmetic composition in the form of a gel for facial treatment having the following formulation:
  • Cosmetic composition in the form of a face cream having the following formulation:
  • hyaluronic acid having six selected molecular weights, as described in the table below.
  • the 6 hyaluronic acids were prepared individually in solution by dilution in phosphate buffer (PBS), as reported in the following table:
  • the purpose of the study was to investigate the ability of hyaluronic acid, in various chemical forms and at different molecular weights, to penetrate and be absorbed through the skin, quantifying over 24 hours the amounts available in the epidermis and in the dermis.
  • the experimental model used was pig skin, which is the most similar to human skin (retrieved once the animal has been slaughtered for food purposes).
  • the absorption system employed consists of the Franz diffusion cell.
  • the anatomical portions of skin employed in this test were: epidermis and epidermis + dermis.
  • the epidermis is obtained from whole skin by subjecting the tissue to a heat treatment (60 °C for 45 minutes) followed by chemical peeling with 80 % lactic acid until no "frosting" is observed.
  • the epidermis + dermis is obtained by removing the hypodermis using surgical instruments, and once the treatments are complete, the dermis is separated from the epidermis using surgical instruments.
  • the hyaluronic acids of very low molecular weight can cross the stratum corneum and the epidermis upon arrival, thanks to the low steric hindrance as far as the dermis.
  • the 200,000 Da hyaluronic acid is evenly distributed between the epidermis and dermis: 27 % absorption for both regions at 24 hours, for a total of 55.65 % absorption.
  • the 2,000,000 Da hyaluronic acid of high weight has better absorption into the epidermis, at 29.9 % at 24 hours and 10 % in the dermis at the same experimental time, for a total of 39.9 % absorption.
  • the cross-linked hyaluronic acid appears to have a poor affinity for the skin, but reaches approximately 20 % penetration into the dermis after 24 hours, a sign that after this time the hyaluronidase starts to degrade the molecule and make the penetration possible.
  • the study/trial confirms, the temporal progression of the penetration of hyaluronic acids as far as the deeper layers of the skin, this penetration being quantitatively greater the smaller the molecules used.
  • the results obtained make it possible to confirm that the hyaluronic acids of very low molecular weight are able to fill the cutaneous layers quickly, giving the cosmetic preparation containing them an immediate tissue filler effect, whilst the higher molecular weights fill the surface layers of the skin, with a filling-out effect.
  • the ex vivo study also shows a slow and continuous release over time of hyaluronic acid to facilitate the progression of the tissue filling.
  • Example 1 In vivo trial with a composition of Example 1 on a panel of females affected by skin aging.
  • a placebo-controlled, double blind, randomized, clinical-instrumental study was carried out on 40 females (20 subject for each treatment arm) showing the clinical signs of skin ageing (wrinkledness, atony, skin sagging of cheekbones, slightly volumies lips).
  • Example 1 The study show that the dermal filler of Example 1 is effectiveness 3 hours after a single application and 7, 14 and 30 days of treatment on the measured parameters as follows:
  • the treatment with the dermal filler determines a mean statistically significant decrease of the wrinkle depth by -8,4%, -14,5% and -21 ,8% after 7, 14, and 30 days of treatment, respectively.
  • T30 the 95% of the subject participating in the study showed an improvement of the parameter with a maximum variation by 54.8%, compared to its basal value (before product application).
  • the variation of the parameter in the active group are statistically bigger than that obtained in the placebo group.
  • the treatment with the dermal filler determines a mean statistically significant decrease of the wrinkle depth -1 1 .3%, -1 8.4% and -26.3% after 7, 14 and 30 days of treatment, respectively.
  • T30 the 95% of the subjects participating in the study showed an improvement of the parameter with a maximun variation by -48.8% compared to its basal value (before product application).
  • the variation of the parameter in the active group are statistically bigger than that obtained in the placebo group.
  • the treatment with the dermal filler determines a statistically significant reshaping activity of the face contour in all the 5 measured points. This activity is measured in mean variations of -0.443,-1 .124 mm and -1 .326 mm, after 7, 14 and 30 days of treatment, respectively. At the end of the treatment (T30) the 94% of the subjects participating in the study showed an improvement of the parameter indicating a re-modeling activity of the face contour.
  • the variation of the parameter in the active group are statistically bigger than that obtained in the placebo group.
  • the treatment with the dermal filler determines a statistically significant remodeling activity of the cheekbones. This activity was measured as a mean increase, statistically significant at all the experimental monitored times of the distance between a vertical line passing from the nose and the cheekbones (measured in 5 points). In fact the active products determines a mean remodeling activity by + 0.875 mm, +2.186mm, and +2.275mm after 7,14 and 30 days of treatment, respectively. At the end of the treatment (T30) the 100% of the subjects participating at the trial showed an improvement of the parameter indicating a remodeling activity of the face contour.
  • the treatment with the dermal filler determines a lifting activity.
  • the treatment with the dermal filler determines a decrease of the distance between the cheekbones (measured in 3 points) and a line passing for the eyes.
  • the mean variations are -0.989 mm, -2.500 mm and -2.517 mm, after 7, 14 and 30 days of treatment respectively.
  • T30 the 96.6% of the subjects participating in the study showed an improvement of the parameter.
  • the treatment with the active product determines a mean statistically significant improvement of the lips volume by +11 .3%, +12.8% and 14.2% after 7, 14, and 30 days of treatment.
  • T30 the 100% of the subjects participating in the study showed an improvement of parameter with a maximum variation by +44.7% (compared its basal value).

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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Birds (AREA)
  • Epidemiology (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Dermatology (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition ou une charge dermique à usage cosmétique à base d'un mélange d'acides hyaluroniques présentant des masses moléculaires spécifiques. Ladite composition dermique à usage cosmétique est adaptée au remplissage ou à l'atténuation des rides, des dépressions ou des microreliefs de la peau ou à l'accroissement du volume de zones de l'organisme humain affectées par le vieillissement de la peau à l'image du visage, des lèvres, des seins, des fesses et des cuisses.
PCT/EP2013/069597 2012-09-21 2013-09-20 Charge dermique à usage cosmétique et à pénétration rapide pour application topique WO2014044808A2 (fr)

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CH01715/12 2012-09-21
CH17152012A CH705713B1 (de) 2012-09-21 2012-09-21 Dermokosmetische Zusammensetzung zur topischen Anwendung.

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WO2015123115A1 (fr) * 2014-02-11 2015-08-20 Elc Management Llc Procede, compositions, et trousse pour moduler l'aspect de volume de surfaces keratiniques
WO2018122344A1 (fr) * 2016-12-29 2018-07-05 Nestlé Skin Health Sa Composition comprenant un acide hyaluronique (ah) réticulé en combinaison avec un ah de faible poids moléculaire et/ou un agent stimulant la synthèse d'ah endogène
KR20180108132A (ko) 2017-03-24 2018-10-04 박원진 피부 주름 개선 또는 예방용 화장료 조성물
CN109330912A (zh) * 2018-12-10 2019-02-15 安徽徽科生物工程技术有限公司 皮肤美容修复组合物及面膜
CN109965104A (zh) * 2019-03-29 2019-07-05 华熙生物科技股份有限公司 一种含透明质酸钠的组合物及其制备方法和应用
KR20190087642A (ko) * 2016-12-15 2019-07-24 이엘씨 매니지먼트 엘엘씨 화장품 조성물
CN110833516A (zh) * 2019-12-19 2020-02-25 深圳市维琪医药研发有限公司 一种具有补水保湿作用的多肽组合物
WO2019075263A3 (fr) * 2017-10-11 2020-03-26 Illustris Pharmaceuticals, Inc. Procédés et compositions à administration topique
US10959934B2 (en) 2016-12-29 2021-03-30 Galderma Holding SA Micro- or nanoparticular vesicles comprising crosslinked hyaluronic acid, compositions comprising the same and method for their use in skin care
IT201900023349A1 (it) * 2019-12-09 2021-06-09 Unifarco S P A Composizioni cosmetiche per la prevenzione e il trattamento dell’invecchiamento cutaneo.
WO2021171206A1 (fr) * 2020-02-24 2021-09-02 B. G. Negev Technologies And Applications Ltd., At Ben-Gurion University Procédés d'amélioration de l'administration transdermique de glycosaminoglycanes (gags)
EP3991717A1 (fr) * 2020-11-03 2022-05-04 SanderStrothmann GmbH Composition cosmétique antiride
CN114558169A (zh) * 2022-03-02 2022-05-31 北京净嘉生物科技有限公司 一种自体修复营养注射液及其应用方法
WO2023105170A1 (fr) * 2021-12-10 2023-06-15 L V M H Recherche Association d'un acide hyaluronique réticulé, de haut poids moleculaire et d'un acide hyaluronique non reticule, de bas poids moléculaire

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015123115A1 (fr) * 2014-02-11 2015-08-20 Elc Management Llc Procede, compositions, et trousse pour moduler l'aspect de volume de surfaces keratiniques
JP2020502175A (ja) * 2016-12-15 2020-01-23 イーエルシー マネージメント エルエルシー 化粧用組成物
US11291286B2 (en) 2016-12-15 2022-04-05 Elc Management Llc Cosmetic compositions with a micro-mesh structure
KR102251562B1 (ko) 2016-12-15 2021-05-14 이엘씨 매니지먼트 엘엘씨 화장품 조성물
US10660419B2 (en) 2016-12-15 2020-05-26 Elc Management Llc Packaged skin treatment composition and method
KR20190087642A (ko) * 2016-12-15 2019-07-24 이엘씨 매니지먼트 엘엘씨 화장품 조성물
US10660420B2 (en) 2016-12-15 2020-05-26 Elc Management Llc Cosmetic compositions
US10959934B2 (en) 2016-12-29 2021-03-30 Galderma Holding SA Micro- or nanoparticular vesicles comprising crosslinked hyaluronic acid, compositions comprising the same and method for their use in skin care
US20190314263A1 (en) * 2016-12-29 2019-10-17 Nestlé Skin Health Sa Composition comprising a crosslinked hyaluronic acid (ha) in combination with a low-molecular ha and/or an agent stimulating endogenous ha synthesis
WO2018122344A1 (fr) * 2016-12-29 2018-07-05 Nestlé Skin Health Sa Composition comprenant un acide hyaluronique (ah) réticulé en combinaison avec un ah de faible poids moléculaire et/ou un agent stimulant la synthèse d'ah endogène
US11224566B2 (en) * 2016-12-29 2022-01-18 Galderma Holding SA Composition comprising a crosslinked hyaluronic acid (HA) in combination with a low-molecular HA and/or an agent stimulating endogenous HA synthesis
KR20180108132A (ko) 2017-03-24 2018-10-04 박원진 피부 주름 개선 또는 예방용 화장료 조성물
EP3694489A4 (fr) * 2017-10-11 2021-06-30 Illustris Pharmaceuticals, Inc. Procédés et compositions à administration topique
WO2019075263A3 (fr) * 2017-10-11 2020-03-26 Illustris Pharmaceuticals, Inc. Procédés et compositions à administration topique
CN109330912A (zh) * 2018-12-10 2019-02-15 安徽徽科生物工程技术有限公司 皮肤美容修复组合物及面膜
CN109965104A (zh) * 2019-03-29 2019-07-05 华熙生物科技股份有限公司 一种含透明质酸钠的组合物及其制备方法和应用
EP3834813A1 (fr) * 2019-12-09 2021-06-16 Unifarco S.p.A. Compositions cosmétiques pour la prévention et le traitement du vieillissement cutané
IT201900023349A1 (it) * 2019-12-09 2021-06-09 Unifarco S P A Composizioni cosmetiche per la prevenzione e il trattamento dell’invecchiamento cutaneo.
CN110833516A (zh) * 2019-12-19 2020-02-25 深圳市维琪医药研发有限公司 一种具有补水保湿作用的多肽组合物
WO2021171206A1 (fr) * 2020-02-24 2021-09-02 B. G. Negev Technologies And Applications Ltd., At Ben-Gurion University Procédés d'amélioration de l'administration transdermique de glycosaminoglycanes (gags)
EP3991717A1 (fr) * 2020-11-03 2022-05-04 SanderStrothmann GmbH Composition cosmétique antiride
WO2023105170A1 (fr) * 2021-12-10 2023-06-15 L V M H Recherche Association d'un acide hyaluronique réticulé, de haut poids moleculaire et d'un acide hyaluronique non reticule, de bas poids moléculaire
FR3130156A1 (fr) * 2021-12-10 2023-06-16 Lvmh Recherche Association d’un acide hyaluronique réticulé, de haut poids moléculaire et d’un acide hyaluronique non réticulé, de bas poids moléculaire.
CN114558169A (zh) * 2022-03-02 2022-05-31 北京净嘉生物科技有限公司 一种自体修复营养注射液及其应用方法

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