EP2155154A2 - Pharmaceutical or cosmetic preparations for topical and/or parenteral application, preparation methods thereof and use of same - Google Patents

Pharmaceutical or cosmetic preparations for topical and/or parenteral application, preparation methods thereof and use of same

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Publication number
EP2155154A2
EP2155154A2 EP08788213A EP08788213A EP2155154A2 EP 2155154 A2 EP2155154 A2 EP 2155154A2 EP 08788213 A EP08788213 A EP 08788213A EP 08788213 A EP08788213 A EP 08788213A EP 2155154 A2 EP2155154 A2 EP 2155154A2
Authority
EP
European Patent Office
Prior art keywords
hyaluronic acid
inhibitor
degradation
pharmaceutical
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP08788213A
Other languages
German (de)
French (fr)
Inventor
Marc Moutet
Jean-Claude Yadan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galderma Research and Development SNC
Original Assignee
Galderma Research and Development SNC
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Filing date
Publication date
Application filed by Galderma Research and Development SNC filed Critical Galderma Research and Development SNC
Publication of EP2155154A2 publication Critical patent/EP2155154A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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

Definitions

  • compositions for topical and / or parenteral application comprising, in a physiologically acceptable medium, at least one inhibitor of the degradation of hyaluronic acid and an oligosaccharide, processes for the production of such compositions, and their uses.
  • pharmaceutical compositions in particular of pharmaceutical or cosmetic compositions.
  • Said compositions are intended for the treatment of dermatological conditions, in particular, the filling treatment of wrinkles, fine lines, fibroblastic depletions and any scarring.
  • the aging of the skin is one of the most visible changes in the senescence process.
  • the skin is exposed to many factors that can accelerate this physiological process.
  • intrinsic aging which is easier to evaluate in areas that are normally not exposed to the sun and, on the other hand, extrinsic aging, caused by the interaction of environmental factors, in particular UV rays. These environmental factors have a much more marked effect on sun-exposed body parts, especially in light-skinned people.
  • actinic aging Other factors such as eating habits, smoking, excessive alcohol consumption, Chronic diseases and dysfunctions of the endocrine glands also contribute to this aging.
  • the stratum corneum is little modified.
  • the epidermis is atrophic and the dermal-epidermal junction is flattened, so that adhesion to the dermis is less good, facilitating the formation of bubbles.
  • the thickness of the dermis is significantly reduced; there are fewer blood vessels. There are also fewer fibroblasts and their biosynthesis and proliferation abilities are diminished.
  • the elastic fibers undergo modifications first, and then disappear.
  • Wrinkles are the most visible signs of aging. We can distinguish it from several natures, in particular superficial and deep wrinkles. Deep wrinkles may be due to dermo-hypodermic changes, while superficial wrinkles could be explained by dermal and possibly epidermal changes. Wrinkles are mainly due to the loss of elasticity of the skin. The reaching of the network elastic subepidermal gives rise to a superficial laxity of the aged skin and a fold of its surface. The destruction of elastic fibers in the reticular dermis is responsible for the loss of elasticity and the ability of the skin to regain its shape after stretching. Depending on the type, intensity and topography, a suitable treatment will be possible.
  • dermal implants that is to say as substances injected directly into the skin, in order to remedy the skin changes resulting from aging. , trauma or disease.
  • Botulinum toxin inactivated (Botox®) or the use of laser techniques. These different types of treatment are not exclusive and their combination has even been recommended.
  • collagen and hyaluronic acid are the ones that are at the origin of the majority of the products available on the market.
  • Hyaluronic acid is a ubiquitous natural polysaccharide that exists in the same form from the simplest bacterium to humans. It is a polysaccharide composed alternately of D-glucuronic acid and N- acetylglucosamine, linked together by alternating glycosidic bonds beta-1,4 and beta-1,3. According to Saari H et al. Differential effects of reactive oxygen species on a native synovial fluid and purified human umbilical cord hyaluronate.
  • the polymers of this repeating unit can have a size between 10 2 and 10 4 kDa m vivo, the hyaluronic acid taken from the umbilical cord having a weight of 2500 kDa.
  • Hyaluronic acid is a natural component of the dermis where it plays an important role in the hydration and elasticity of the skin. However, it decreases in quantity and quality with age, resulting in drying of the skin that wrinkles. It is highly water soluble and forms high viscosity solutions in water. Because of these particular properties, hyaluronic acid is one of the most widely used pharmaceutical products.
  • hyaluronic acid is very quickly eliminated from plasma by degradation. Its plasma half-life after intravenous injection is very short, between 2.5 and 5.5 minutes, while in the skin, its half-life is 0.5 to 2 days depending on its concentration. Its urogenic excretion is low, less than 1% of total clearance.
  • the rate of elimination in the skin was measured (Reed RK, Laurent UB, JR Fraser, Laurent TC.) Removal rate of [3H] hyaluronan injected subcutaneously m rabbits Am J Physiol 1990 Aug; 259 (2Pt 2): H532-5). It is non-exponential with a half-life of 0.5 to 1 day when its concentration is 5 mg / ml. The tolerance of hyaluronic acid is very good and no immunogenicity has been associated with this substance. This has a very low incidence of side effects.
  • hyaluronic acid alone or in combination
  • injectable compositions such as, for example, hyaluronic acid alone, collagen alone or the combination "hyaluronic acid and collagen" have already been used in reconstructive surgery, as part of treatment by filling wrinkles, fine lines, fibroblastic depletions and all scars.
  • hyaluronic acid because of its low bioavailability after injection and its too high injection frequency, can not be used as such.
  • compositions based on hyaluronic acid having a very good bioavailability and likely to better withstand the action of degradation enzymes. This allows, in particular, to space interventions and reduce their number.
  • compositions used as a dermal implant are all composed of stabilized hyaluronic acid and a large number of them comprise hyaluronic acid chemically modified for this purpose.
  • hyaluronic acid included in these products is predominantly of non-human origin such as for example of avian or bacterial origin.
  • compositions there are numerous hyaluronic acid derivatives chemically modified in the form, in particular of esters, of amides, as well as derivatives having "intra and / or interchain bridges".
  • a problem to be solved by the invention is to provide compositions which make it possible to provide hyaluronic acid with better bioavailability while retaining its physico-chemical characteristics and its biological properties, as well as a method of manufacturing such compositions.
  • the solution of the invention to this problem has for first object a pharmaceutical or cosmetic composition, especially for topical and / or parenteral application comprising, in a physiologically acceptable medium, as sole active ingredients:
  • this composition does not comprise retinoid nor its salts nor its derivatives.
  • Its second object is a process for producing such a composition, comprising a step of mixing at least one oligosaccharide and at least one inhibitor of the degradation of hyaluronic acid with a physiologically acceptable medium.
  • the method according to the invention also comprises a step of preparing a physiologically acceptable medium, in which the active ingredients are mixed.
  • its third object is the use of at least one inhibitor of the degradation of hyaluronic acid and of at least one oligosaccharide chosen from oligomers of hyaluronic acid, or a composition according to the invention. , for the manufacture of a medicament for the treatment and / or prevention of dermatological conditions.
  • a composition according to the invention significantly increases the bioavailability of a hyaluronic acid, which is furthermore included in said composition, or which is administered separately.
  • the composition according to the invention makes it possible to space the applications of hyaluronic acid and to reduce the number thereof and it has a significant effectiveness in the filling of wrinkles, fine lines, fibroblastic depletions and all scars.
  • the Applicant has also demonstrated a decrease in catabolism of hyaluronic acid in vivo human keratinocytes to which hyaluronic acid, an oligosaccharide and an inhibitor of the degradation of hyaluronic acid are applied, in the absence of rétmoide.
  • the absence of retinoid in a composition comprising an oligosaccharide and an inhibitor of the degradation of hyaluronic acid gives the hyaluronic acid also applied a better stability, a better bioavailability.
  • compositions of the prior art are therefore more effective than the compositions of the prior art, and in particular compositions comprising retinoids, in the filling of wrinkles, fine lines, fibroblastic depletions and all scars, as well as in the hydration of the skin.
  • Figure 1 shows in a semi-logarithmic the results of a study to assess the inhibitory effect of glycyrrhizin on bovine hyaluronidase activity.
  • composition according to the invention comprises, in a physiologically acceptable medium, at least one oligosaccharide, and at least one inhibitor of the degradation of hyaluronic acid.
  • a physiologically acceptable medium at least one oligosaccharide, and at least one inhibitor of the degradation of hyaluronic acid.
  • it does not include retinoid nor its salts or drifts.
  • composition according to the invention may further comprise hyaluronic acid.
  • the composition according to the invention may be administered to a subject to whom hyaluronic acid is independently administered.
  • the hyaluronic acid may be included in a separate composition, which may be administered simultaneously or in a different time from that of the administration of the composition according to the invention.
  • the distinct composition comprising hyaluronic acid can be administered topically, orally or parenterally, for example by injection.
  • Physiologically acceptable medium means a medium compatible with the skin and optionally with its integuments (eyelashes, nails, hair) and / or mucous membranes.
  • compositions according to the invention the oligosaccharide and the inhibitor of the degradation of hyaluronic acid and, where appropriate, hyaluronic acid, are present in proportions ranging from 0.0000001% to 10%, preferably from 0.00001% to 1% by weight, relative to the total weight of the composition. In the present description, and unless otherwise specified, it is understood that when concentration ranges are given, they include the upper and lower limits of said range.
  • the compositions according to the invention may comprise hyaluronic acid.
  • hyaluronic acid is meant a ubiquitous natural polysaccharide existing in the same form from the simplest bacterium to humans. It is a polysaccharide composed alternately of D-glucuronic acid and N-acetylglucosamine, linked together by alternating glycoside bonds beta-1,4 and beta-1,3. According to Saari H et al. Differential effects of reactive oxygen species on a native synovial fluid and pu ⁇ fied human umbilical cord hyaluronate.
  • the polymers of this repeating unit can have a size between 10 2 and 10 4 kDa in vivo, the hyaluronic acid taken from the umbilical cord having a weight of 2500 kDa.
  • hyaluronic acid is natural.
  • hyaluronic acid By natural hyaluronic acid is meant a non-stabilized hyaluronic acid, not chemically modified in the form, especially of esters, amides, or in the form of derivatives having "intra and / or interchain bridges" (cross linked), such modifications affecting the physico-chemical characteristics and the biological properties of said hyaluronic acid, as well as its fate after administration.
  • compositions according to the invention comprise an oligosaccharide.
  • oligosaccharide polymers formed of a number n (with n less than or equal to 100) of monosaccharides by glycosidic bonding, in particular any oligosaccharide limiting the penetration of hyaluronic acid into the cells of the skin, in particular keratinocytes and fibroblasts.
  • the oligomers of hyaluronic acid preferentially the di-dodecamers of hyaluronic acid, will be chosen, said dimer comprising a disaccharide unit. component of hyaluronic acid, and the dodecamere comprising six of these disaccharide units, more preferably the tetra- to hexamers of hyaluronic acid, more preferably the pentamere of hyaluronic acid.
  • the molecular weight of a disaccharide unit of hyaluronic acid is about 400 Da.
  • An oligomer of one to six disaccharide units of hyaluronic acid therefore has a molecular weight of between 400 and 2400 Da.
  • Oligomer means, according to IUPAC in Pure Appl. Chem., Vol. 68, No.12, pp. 2287-2311, 1996, a molecule of intermediate molecular weight, the structure of which comprises a small amount of molecules having a lower molecular weight.
  • a molecule having an intermediate molecular mass we will speak of a molecule having an intermediate molecular mass, when the removal of one or a few constituent units will significantly modify the properties of the molecule.
  • the oligosaccharides used in the compositions according to the invention are compounds that exist naturally in the human body.
  • one oligosaccharide is used at concentrations of between 10 -9 M and 10 -3 M, preferably between 10 -8 M and 10 -5 M.
  • compositions according to the invention comprise an inhibitor of the degradation of hyaluronic acid.
  • inhibitor of the degradation of hyaluronic acid is meant a compound capable of reducing, or even blocking, the catabolism either extracellular or intracellular of hyaluronic acid, preferably a compound capable of reducing or even blocking the extracellular catabolism of hyaluronic acid, more preferably a compound capable of inhibiting extracellular hyaluronidase present in the skin.
  • 1,2,3,4,6-penta-O-galloylglucose will be chosen in particular.
  • the inhibitors of the degradation of hyaluronic acid used in the compositions according to the invention are natural.
  • the inhibitor is used at concentrations of between 10 -9 M and 10 -2 M, preferentially between 10 -6 M and 10 -3 M.
  • derivatives of glycyrrhizin or glycyrrhetinic acid is meant in particular salts, substituted derivatives, enantiomers and racemates of said compounds.
  • salts of said compounds there may be mentioned the salts obtained by adding said compounds with a base inorganic, chosen in particular from hydroxides of sodium, lithium, calcium, potassium, magnesium, ammonium or zinc, alkali or alkaline earth metal carbonates such as sodium carbonates, sodium bicarbonates, calcium, potassium, magnesium, ammonium or zinc, or with an organic base, chosen in particular from methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris ( hydroxymethyl) ammomethane, ethanolamine, pyrimidine, picolme, dicyclohexylamine, morpholine, process, lysine, arginine, histidine, N-methylglucamine or phosphonium salts such as alkylphosphonium, arylphosphonium salts, alkylarylphosphonium salts, alkenylarylphosphonium salts or quaternary ammonium salts such as tetra-
  • Such salts are in particular the potassium salt of glycyrrhetinic acid, the sodium salt of glycyrrhetinic acid, or the monoammonium salt of glycyrrhetinic acid (ammonium glycyrrhetmate).
  • analogue is intended to mean, in particular, the enzymatic or biomimetic analogs of said compounds, capable of binding to the catalytic or non-catalytic site of hyaluronidases and of thus inhibiting their activation.
  • Such analogs can be selected in vitro by hyaluronidase binding or inhibition tests according to conventionally used techniques.
  • the derivatives and / or analogues must be of natural origin.
  • the compounds and their derivatives and / or analogues of natural origin are compounds in the pure state or in solution at different concentrations, obtained by various processes for extracting or hydrolyzing biological material of natural origin.
  • compositions according to the invention may also contain the usual adjuvants well known to those skilled in the art.
  • compositions according to the invention are preferably formulated for topical and / or parenteral application.
  • topical means an external application on the skin or mucous membranes.
  • compositions may be in any of the galenic forms normally used for topical administration.
  • topical compositions mention may be made of compositions in liquid, pasty or solid form and, more particularly, in the form of ointments, aqueous, hydroalcoholic or oily solutions, and optionally two-phase lotion-type dispersions.
  • serum, aqueous, anhydrous or lipophilic gels powders, soaked swabs, syndets, wipes, sprays, foams, sticks, shampoos, compresses, washing bases, emulsions of liquid consistency or semi-liquid of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O), a microemulsion, suspensions or emulsions of soft consistency, semi-liquid liquid or solid white or colored cream, gel or ointment, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, or microcapsules, microparticles or nanoparticles or polymeric or gelled patches for controlled release.
  • compositions according to the invention can be applied subcutaneously or intradermally.
  • parenteral compositions mention may be made of compositions in the form of solutions or suspensions for infusion or injection.
  • hyaluronic acid may be administered in the form of an injectable aqueous solution, the pentamere of acid hyaluronic acid and glycyrrhizin being administered in the form of a cream.
  • the administration frequencies may be identical or different.
  • the frequency of administration of hyaluronic acid injected in the form of an aqueous solution for injection may vary from 4 to 24 months, preferably from 4 to 16 months, while those of composition according to the invention, administered topically, for example in cream form, can vary from 1 to 7 days, preferably from 1 to 3 days.
  • the process for manufacturing a composition comprises the steps of preparing a physiologically acceptable medium and mixing an effective amount of pentamer of hyaluronic acid, and glycyrrhizin and / or its derivatives and / or analogues.
  • the invention also relates to the use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid, or of a composition as described previously for the manufacture of a medicament for the treatment, improvement and / or prevention of dermatological conditions.
  • the invention relates to the use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid, or of a composition such as as described above, for the manufacture of a cosmetic or pharmaceutical composition for the treatment, improvement and / or prevention of skin aging.
  • Skin aging is understood to mean wrinkles, fine lines, fibroblastic depletions and scars.
  • Such a composition is adapted to the treatment of wrinkled and / or aged skin, and is intended in particular to prevent and / or reduce the effects thereof.
  • the treatment of wrinkles, fine lines, Fibroblastic depletions and all scarring is done by filling.
  • composition according to the invention can be applied to the areas of the face or forehead marked by expression lines.
  • the invention also relates to the use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid, or of a composition as described previously, for the manufacture of a cosmetic or pharmaceutical composition for use in reconstructive surgery.
  • GLZ at different concentrations, is pre-incubated or not for 20 minutes at 37 ° C in the presence of the enzyme.
  • the enzymatic reaction is triggered by adding the hyaluronic acid solution (TO time). After 20 minutes of incubation, the unhydrolysed hyaluronic acid is precipitated by addition of the acid solution of bovine albumin.
  • TO time the time of incubation
  • bovine albumin the acid solution of bovine albumin
  • the turbidimetry of the solutions is determined on a spectrophotometer at a wavelength of 600 nm.
  • the optical density (OD) of these solutions is deduced from the OD of a control solution of hyaluronic acid (of the same concentration) not hydrolyzed by the enzyme. This difference in OD, which is inversely proportional to the concentration of hyaluronic acid, is used to measure the activity of hyaluronidase.
  • Example 2 Inhibitory effect of pentameric bindmg (NAC-Glucuronic acid) on the CD44 receptor of hyaluronic acid
  • hyaluronic acid labeled with fluoresceinamine (according to DeBelder et al., 1975, Carbohydrate Res., 44, 251-257) and then increasing concentrations of pentamer (NAC-Glucuronic acid) 5.
  • the measurement of the displacement of fluorescent hyaluronic acid by the pentamer (NAC-Glucuronic acid) is carried out.
  • composition is prepared in a conventional manner for the person skilled in the art:
  • Example 4 Composition No. 2

Abstract

The invention relates to a pharmaceutical or cosmetic composition for topical and/or parenteral application, containing, in a physiologically acceptable medium, at least one oligosaccharide and at least one inhibitor of hyaluronic acid degradation. The invention is particularly suitable for use in human dermatology and plastic surgery.

Description

PREPARATIONS PHARMACEUTIQUES OU COSMETIQUES POUR PHARMACEUTICAL OR COSMETIC PREPARATIONS FOR
APPLICATION TOPIQUE ET/OU PARENTERALE, LEURS PROCEDES DETOPICAL AND / OR PARENTERAL APPLICATION, THEIR METHODS OF
PREPARATION, ET LEURS UTILISATIONSPREPARATION AND USES THEREOF
La présente invention se rapporte a des compositions pour application topique et/ou parentérale comprenant, dans un milieu physiologiquement acceptable, au moins un inhibiteur de la dégradation de l'acide hyaluronique et un oligosacchaπde, des procédés de fabrication de telles compositions, et leurs utilisations en tant que compositions pharmaceutiques, notamment de médicament, ou cosmétiques. Lesdites compositions sont destinées au traitement des affections dermatologiques, en particulier, au traitement par comblement des rides, ridules, déplétions fibroblastiques et toutes cicatrices.The present invention relates to compositions for topical and / or parenteral application comprising, in a physiologically acceptable medium, at least one inhibitor of the degradation of hyaluronic acid and an oligosaccharide, processes for the production of such compositions, and their uses. as pharmaceutical compositions, in particular of pharmaceutical or cosmetic compositions. Said compositions are intended for the treatment of dermatological conditions, in particular, the filling treatment of wrinkles, fine lines, fibroblastic depletions and any scarring.
Le vieillissement de la peau est une des modifications les plus visibles du processus de sénescence. De plus, la peau se retrouve exposée à de nombreux facteurs susceptibles d'accélérer ce processus physiologique. On distingue deux types différents de vieillissement cutané. D'une part, le vieillissement intrinsèque, qu'il est plus facile d'évaluer sur des zones qui normalement ne sont pas exposées au soleil et, d'autre part, le vieillissement extrinsèque, provoqué par l'interaction de facteurs environnementaux, notamment les rayons UV. Ces facteurs environnementaux ont un effet beaucoup plus marque sur les parties du corps exposées au soleil, surtout chez les personnes de phototype clair. On parle alors également de vieillissement actinique. D'autres facteurs tels que les habitudes alimentaires, le tabagisme, la consommation excessive d'alcool, les maladies chroniques et les dysfonctionnements des glandes endocrines contribuent également a ce vieillissement.The aging of the skin is one of the most visible changes in the senescence process. In addition, the skin is exposed to many factors that can accelerate this physiological process. There are two different types of skin aging. On the one hand, intrinsic aging, which is easier to evaluate in areas that are normally not exposed to the sun and, on the other hand, extrinsic aging, caused by the interaction of environmental factors, in particular UV rays. These environmental factors have a much more marked effect on sun-exposed body parts, especially in light-skinned people. We also speak of actinic aging. Other factors such as eating habits, smoking, excessive alcohol consumption, Chronic diseases and dysfunctions of the endocrine glands also contribute to this aging.
Lors du vieillissement intrinsèque de la peau, la couche cornée est peu modifiée. L'épiderme est atrophique et la jonction dermo-épidermique est aplatie, de sorte que l'adhésion au derme est moins bonne, facilitant la formation de bulles. L'épaisseur du derme est nettement réduite ; il y a moins de vaisseaux sanguins. On observe aussi moins de fibroblastes et leurs capacités de biosynthèse et de prolifération sont diminuées. Les fibres élastiques subissent d'abord des modifications, pour disparaître par la suite.During the intrinsic aging of the skin, the stratum corneum is little modified. The epidermis is atrophic and the dermal-epidermal junction is flattened, so that adhesion to the dermis is less good, facilitating the formation of bubbles. The thickness of the dermis is significantly reduced; there are fewer blood vessels. There are also fewer fibroblasts and their biosynthesis and proliferation abilities are diminished. The elastic fibers undergo modifications first, and then disappear.
En ce qui concerne le vieillissement extrinsèque, on observe un épiderme irrégulier, parfois atrophique, parfois hyperplasique, avec des signes de desorganisation et de dysplasie. Les mélanocytes sont plus nombreux à certains endroits, et en nombre réduit à d'autres. Il y a aussi une irrégularité de la distribution de la mélanine dans l'épiderme, suite a des problèmes de transfert des melanosomes. Le nombre de cellules de Langerhans diminue. Les petits vaisseaux sanguins sont d'abord dilates, pour ensuite s'amincir et s'atrophier.As far as extrinsic aging is concerned, there is an irregular epidermis, sometimes atrophic, sometimes hyperplastic, with signs of disorganization and dysplasia. Melanocytes are more numerous in some places, and fewer in number. There is also an irregular distribution of melanin in the epidermis, due to problems of melanosome transfer. The number of Langerhans cells decreases. The small blood vessels are first dilated, then thin and atrophy.
Les rides sont les signes les plus visibles du vieillissement. On en distingue de plusieurs natures, notamment les rides superficielles et profondes. Les rides profondes seraient dues aux modifications dermo- hypodermiques, tandis que les rides superficielles pourraient s'expliquer par des modifications dermiques et éventuellement épidermiques . Les rides sont surtout dues à la perte d'élasticité de la peau. L'atteinte du réseau élastique sous-épidermique donne lieu à une laxité superficielle de la peau vieillie et à un plissement de sa surface. La destruction des fibres élastiques dans le derme réticulaire est responsable de la perte d'élasticité et de la capacité de la peau à reprendre sa forme après étirement. Selon le type, l'intensité et la topographie, un traitement adapté sera possible.Wrinkles are the most visible signs of aging. We can distinguish it from several natures, in particular superficial and deep wrinkles. Deep wrinkles may be due to dermo-hypodermic changes, while superficial wrinkles could be explained by dermal and possibly epidermal changes. Wrinkles are mainly due to the loss of elasticity of the skin. The reaching of the network elastic subepidermal gives rise to a superficial laxity of the aged skin and a fold of its surface. The destruction of elastic fibers in the reticular dermis is responsible for the loss of elasticity and the ability of the skin to regain its shape after stretching. Depending on the type, intensity and topography, a suitable treatment will be possible.
Le traitement des modifications cutanées inesthétiques liées au vieillissement a fait d'énormes progrès ces dernières années.The treatment of unsightly skin changes related to aging has made tremendous progress in recent years.
Un nombre relativement important de substances naturelles ou synthétiques ont d'ores et déjà été décrites en tant qu'implants dermiques, c' est-a-dire en tant que substances injectées directement dans la peau, afin de remédier aux altérations cutanées résultant du vieillissement, de traumatismes ou de maladies.A relatively large number of natural or synthetic substances have already been described as dermal implants, that is to say as substances injected directly into the skin, in order to remedy the skin changes resulting from aging. , trauma or disease.
D'autres alternatives thérapeutiques pour ces applications sont notamment l'injection locale de la toxine botulique désactivée (Botox®) ou l'utilisation de techniques laser. Ces différents types de traitement ne sont pas exclusifs et leur combinaison a même été recommandée. Parmi les substances naturelles d'origine humaine, le collagene et l'acide hyaluronique sont celles qui sont à l'origine de la majorité des produits disponibles sur le marché.Other therapeutic alternatives for these applications include local injection of botulinum toxin inactivated (Botox®) or the use of laser techniques. These different types of treatment are not exclusive and their combination has even been recommended. Among the natural substances of human origin, collagen and hyaluronic acid are the ones that are at the origin of the majority of the products available on the market.
L' acide hyaluronique est un polysaccharide naturel ubiquitaire qui existe sous la même forme de la plus simple bactérie a l'Homme. C'est un polysaccharide composé alternativement d'acide D-glucuronique et de N- acétylglucosamine, liés entre eux par des liaisons glycosidiques alternées beta-1,4 et beta-1,3. Selon Saari H et al. Differential effects of reactive oxygen species on native synovial fluid and purified human umbilical cord hyaluronate. Inflammation 17 ( 1993) : 403-415, les polymères de cette unité récurrente peuvent avoir une taille entre 102 et 104 kDa m vivo, l'acide hyaluronique prélevé dans le cordon ombilical présentant un poids de 2500 kDa.Hyaluronic acid is a ubiquitous natural polysaccharide that exists in the same form from the simplest bacterium to humans. It is a polysaccharide composed alternately of D-glucuronic acid and N- acetylglucosamine, linked together by alternating glycosidic bonds beta-1,4 and beta-1,3. According to Saari H et al. Differential effects of reactive oxygen species on a native synovial fluid and purified human umbilical cord hyaluronate. Inflammation 17 (1993): 403-415, the polymers of this repeating unit can have a size between 10 2 and 10 4 kDa m vivo, the hyaluronic acid taken from the umbilical cord having a weight of 2500 kDa.
L'acide hyaluronique représente notamment un constituant naturel du derme où il joue un rôle important dans l'hydratation et l'élasticité de la peau. Il diminue cependant en quantité et en qualité avec l'âge, entraînant un dessèchement de la peau qui se ride. Il est très hydrosoluble et forme des solutions à haute viscosité dans l'eau. Du fait de ces propriétés particulières, l'acide hyaluronique fait partie des produits pharmaceutiques les plus utilisés.Hyaluronic acid is a natural component of the dermis where it plays an important role in the hydration and elasticity of the skin. However, it decreases in quantity and quality with age, resulting in drying of the skin that wrinkles. It is highly water soluble and forms high viscosity solutions in water. Because of these particular properties, hyaluronic acid is one of the most widely used pharmaceutical products.
Toutefois, chez l'Homme, l'acide hyaluronique est très rapidement élimine du plasma par dégradation. Sa demi-vie plasmatique après injection intraveineuse est très courte, entre 2,5 et 5,5 minutes, alors que dans la peau, sa demi-vie est de 0,5 à 2 jours selon sa concentration. Son excrétion uπnaire est faible, inférieure a 1% de la clairance totale. Chez le lapin, la vitesse d'élimination, dans la peau, a été mesurée (Reed RK, Laurent UB, Fraser JR, Laurent TC. Removal rate of [3H] hyaluronan injected subcutaneously m rabbits. Am J Physiol. 1990 Aug;259(2 Pt 2):H532-5). Elle est non exponentielle avec une demi-vie de 0,5 a 1 jour quand sa concentration est de 5 mg/ml. La tolérance de l'acide hyaluronique est très bonne et aucune îmmunogénicité n'a ete associée a cette substance. On retrouve ainsi une incidence d'effets secondaires très faible.However, in humans, hyaluronic acid is very quickly eliminated from plasma by degradation. Its plasma half-life after intravenous injection is very short, between 2.5 and 5.5 minutes, while in the skin, its half-life is 0.5 to 2 days depending on its concentration. Its urogenic excretion is low, less than 1% of total clearance. In rabbits, the rate of elimination in the skin was measured (Reed RK, Laurent UB, JR Fraser, Laurent TC.) Removal rate of [3H] hyaluronan injected subcutaneously m rabbits Am J Physiol 1990 Aug; 259 (2Pt 2): H532-5). It is non-exponential with a half-life of 0.5 to 1 day when its concentration is 5 mg / ml. The tolerance of hyaluronic acid is very good and no immunogenicity has been associated with this substance. This has a very low incidence of side effects.
L'utilisation de l'acide hyaluronique, seul ou en association, a ainsi été décrite pour plusieurs applications médicales, telles que par exemple le traitement de l' ostéoarthrite ainsi que l'arthrite rhumatoide. Des compositions injectables telles que par exemple l'acide hyaluronique seul, le collagène seul ou l'association « acide hyaluronique et collagène » ont déjà ete utilisées en chirurgie réparatrice, dans le cadre de traitement par comblement des rides, ridules, déplétions fibroblastiques et toutes cicatrices.The use of hyaluronic acid, alone or in combination, has thus been described for several medical applications, such as, for example, the treatment of osteoarthritis as well as rheumatoid arthritis. Injectable compositions such as, for example, hyaluronic acid alone, collagen alone or the combination "hyaluronic acid and collagen" have already been used in reconstructive surgery, as part of treatment by filling wrinkles, fine lines, fibroblastic depletions and all scars.
Actuellement, de nombreux implants dermiques sont utilisés mais aucun n'a encore été considéré comme idéal dans le cadre d'une augmentation tissulaire sûre et saineCurrently, many dermal implants are used but none has yet been considered ideal for safe and healthy tissue augmentation.
(Naoum C, Dasiou-Plakida D. Dermal filler materials and botulm toxm Int J Dermatol. 2001 Oct; 40 (10) : 609-21) .(Naoum C, Dasiou-Plakida D. Dermal filler materials and botulinum toxin Int J Dermatol 2001 Oct; 40 (10): 609-21).
Cependant, l'acide hyaluronique, en raison de sa biodisponibilité trop faible après injection et sa fréquence d'injection trop élevée, ne peut être utilisé en tant que tel.However, hyaluronic acid, because of its low bioavailability after injection and its too high injection frequency, can not be used as such.
Bien sûr, on a cherché à développer des compositions à base d'acide hyaluronique possédant une très bonne biodisponibilité et susceptibles de mieux résister à l'action des enzymes de dégradation. Ceci permet, notamment, d'espacer les interventions et d'en réduire le nombre .Of course, attempts have been made to develop compositions based on hyaluronic acid having a very good bioavailability and likely to better withstand the action of degradation enzymes. This allows, in particular, to space interventions and reduce their number.
Ces compositions utilisées en tant qu'implant dermique sont toutes composées d'acide hyaluronique stabilisé et un grand nombre d'entre elles comprennent de l'acide hyaluronique modifie chimiquement dans ce but. En outre, l'acide hyaluronique inclus dans ces produits est majoritairement d'origine non humaine telle que par exemple d'origine aviaire ou bactérienne.These compositions used as a dermal implant are all composed of stabilized hyaluronic acid and a large number of them comprise hyaluronic acid chemically modified for this purpose. In addition, the hyaluronic acid included in these products is predominantly of non-human origin such as for example of avian or bacterial origin.
On retrouve ainsi dans ces compositions de nombreux dérivés d'acide hyaluronique modifies chimiquement sous forme, notamment d'esters, d'amides, ainsi que des dérivés possédant des « ponts intra et/ou interchaînes »Thus, in these compositions, there are numerous hyaluronic acid derivatives chemically modified in the form, in particular of esters, of amides, as well as derivatives having "intra and / or interchain bridges".
(cross-linked) .(cross-linked).
Cependant, ces modifications affectent les caractéristiques physico-chimiques et les propriétés biologiques de l'acide hyaluronique, son immunogénicité potentielle ainsi que son devenir après administration. Ces modifications structurelles de l'acide hyaluronique peuvent entraîner des réactions inflammatoires comme le reporte Sopaar CNS, Patrinely JR Ophtalmie plastic and reconstructive surgery 2005 Mar ; 21(2) :151-53.However, these modifications affect the physico-chemical characteristics and the biological properties of hyaluronic acid, its potential immunogenicity and its fate after administration. These structural modifications of hyaluronic acid can lead to inflammatory reactions as reported by Sopaar CNS, Patrinely JR Ophthalmic Plastic and Reconstructive Surgery 2005 Mar; 21 (2): 151-53.
Compte tenu de ce qui précède, un problème que se propose de résoudre l'invention est de réaliser des compositions permettant d'assurer à l'acide hyaluronique une meilleure biodisponibilite tout en conservant ses caractéristiques physico-chimiques et ses propriétés biologiques, ainsi qu'un procède de fabrication de telles compositions . La solution de l'invention à ce problème pose a pour premier objet une composition pharmaceutique ou cosmétique, notamment pour application topique et/ou parentérale comprenant, dans un milieu physiologiquement acceptable, à titre de seuls principes actifs :In view of the foregoing, a problem to be solved by the invention is to provide compositions which make it possible to provide hyaluronic acid with better bioavailability while retaining its physico-chemical characteristics and its biological properties, as well as a method of manufacturing such compositions. The solution of the invention to this problem has for first object a pharmaceutical or cosmetic composition, especially for topical and / or parenteral application comprising, in a physiologically acceptable medium, as sole active ingredients:
- au moins un oligosacchaπde, etat least one oligosaccharide, and
- au moins un inhibiteur de la dégradation de l'acide hyaluronique . Tout autre principe actif est exclu de la présente composition. De préférence, cette composition ne comprend pas de rétinoide ni ses sels ni ses dérivés.at least one inhibitor of the degradation of hyaluronic acid. Any other active ingredient is excluded from the present composition. Preferably, this composition does not comprise retinoid nor its salts nor its derivatives.
Elle a pour deuxième objet un procède de fabrication d'une telle composition, comprenant une étape de mélange d'au moins un oligosaccharide et d'au moins un inhibiteur de la dégradation de l'acide hyaluronique avec un milieu physiologiquement acceptable. De préférence, le procédé selon l'invention comprend également une étape de préparation d'un milieu physiologiquement acceptable, dans lequel les actifs sont mélangés.Its second object is a process for producing such a composition, comprising a step of mixing at least one oligosaccharide and at least one inhibitor of the degradation of hyaluronic acid with a physiologically acceptable medium. Preferably, the method according to the invention also comprises a step of preparing a physiologically acceptable medium, in which the active ingredients are mixed.
Enfin, elle a pour troisième objet l'utilisation d'au moins un inhibiteur de la dégradation de l'acide hyaluronique et d'au moins un oligosaccharide choisi parmi les oligomères de l'acide hyaluronique, ou d'une composition selon l'invention, pour la fabrication d'un médicament destiné au traitement et/ou à la prévention des affections dermatologiques.Finally, its third object is the use of at least one inhibitor of the degradation of hyaluronic acid and of at least one oligosaccharide chosen from oligomers of hyaluronic acid, or a composition according to the invention. , for the manufacture of a medicament for the treatment and / or prevention of dermatological conditions.
Une composition selon l'invention augmente nettement la biodisponibilité d'un acide hyaluronique, qui est compris en outre dans ladite composition, ou bien qui est administré séparément. La composition selon l'invention permet d'espacer les applications d'acide hyaluronique et d'en réduire le nombre et elle présente une efficacité importante dans le comblement des rides, ridules, déplétions fibroblastiques et toutes cicatrices.A composition according to the invention significantly increases the bioavailability of a hyaluronic acid, which is furthermore included in said composition, or which is administered separately. The composition according to the invention makes it possible to space the applications of hyaluronic acid and to reduce the number thereof and it has a significant effectiveness in the filling of wrinkles, fine lines, fibroblastic depletions and all scars.
La Demanderesse a également mis en évidence une diminution du catabolisme de l'acide hyaluronique dans des kératinocytes humains m vivo sur lesquels sont appliqués de l'acide hyaluronique, un oligosaccharide et un inhibiteur de la dégradation d'acide hyaluronique, en l'absence de rétmoide. Ainsi, de manière surprenante, l'absence de rétinoide dans une composition comprenant un oligosaccharide et un inhibiteur de la dégradation de l'acide hyaluronique, confère à l'acide hyaluronique également appliqué une meilleure stabilité, une meilleure biodisponibilité. Une telle composition est donc plus efficace que les compositions de l'art antérieur, et notamment des compositions comprenant des retinoides, dans le comblement des rides, ridules, déplétions fibroblastiques et toutes cicatrices, ainsi que dans l'hydratation de la peau.The Applicant has also demonstrated a decrease in catabolism of hyaluronic acid in vivo human keratinocytes to which hyaluronic acid, an oligosaccharide and an inhibitor of the degradation of hyaluronic acid are applied, in the absence of rétmoide. Thus, surprisingly, the absence of retinoid in a composition comprising an oligosaccharide and an inhibitor of the degradation of hyaluronic acid, gives the hyaluronic acid also applied a better stability, a better bioavailability. Such a composition is therefore more effective than the compositions of the prior art, and in particular compositions comprising retinoids, in the filling of wrinkles, fine lines, fibroblastic depletions and all scars, as well as in the hydration of the skin.
L'invention sera mieux comprise à la lecture de la description non limitative qui va suivre, notamment au regard du dessin annexé, dans lequel :The invention will be better understood on reading the nonlimiting description which follows, in particular with reference to the appended drawing, in which:
- La figure 1 présente sous une représentation semi- logarithmique les résultats d'une étude ayant pour but d'évaluer l'effet inhibiteur de la glycyrrhizine sur l'activité hyaluronidase d'origine bovine.- Figure 1 shows in a semi-logarithmic the results of a study to assess the inhibitory effect of glycyrrhizin on bovine hyaluronidase activity.
La composition selon l'invention comprend, dans un milieu physiologiquement acceptable, au moins un oligosaccharide, et au moins un inhibiteur de la dégradation de l'acide hyaluronique . En particulier, elle ne comprend pas de rétinoide ni ses sels ni ses dérives.The composition according to the invention comprises, in a physiologically acceptable medium, at least one oligosaccharide, and at least one inhibitor of the degradation of hyaluronic acid. In particular, it does not include retinoid nor its salts or drifts.
La composition selon l'invention peut comprendre en outre de l'acide hyaluronique. Ou bien, la composition selon l'invention peut être administrée chez un sujet auquel de l'acide hyaluronique est administré de manière indépendante. Dans ce cas, l'acide hyaluronique peut être compris dans une composition distincte, qui peut être administrée de manière simultanée ou bien en un temps différent de celui de l'administration de la composition selon l'invention. La composition distincte comprenant de l'acide hyaluronique peut être administrée de façon topique, orale ou parentérale, par exemple par injection.The composition according to the invention may further comprise hyaluronic acid. Alternatively, the composition according to the invention may be administered to a subject to whom hyaluronic acid is independently administered. In this case, the hyaluronic acid may be included in a separate composition, which may be administered simultaneously or in a different time from that of the administration of the composition according to the invention. The distinct composition comprising hyaluronic acid can be administered topically, orally or parenterally, for example by injection.
Par milieu physiologiquement acceptable selon l'invention, on entend un milieu compatible avec la peau et éventuellement avec ses phanères (cils, ongles, cheveux) et/ou les muqueuses.Physiologically acceptable medium according to the invention means a medium compatible with the skin and optionally with its integuments (eyelashes, nails, hair) and / or mucous membranes.
Dans les compositions selon l'invention, 1' oligosaccharide et l'inhibiteur de la dégradation de l'acide hyaluronique et, le cas échéant, l'acide hyaluronique, sont présents en proportions pouvant aller de 0,0000001% à 10%, préférentiellement de 0,00001% a 1% en poids, par rapport au poids total de la composition. Dans la présente description, et à moins qu'il ne soit spécifié autrement, il est entendu que, lorsque des intervalles de concentrations sont donnes, ils incluent les bornes supérieures et inférieures dudit intervalle. Les compositions selon l'invention peuvent comprendre de l'acide hyaluronique .In the compositions according to the invention, the oligosaccharide and the inhibitor of the degradation of hyaluronic acid and, where appropriate, hyaluronic acid, are present in proportions ranging from 0.0000001% to 10%, preferably from 0.00001% to 1% by weight, relative to the total weight of the composition. In the present description, and unless otherwise specified, it is understood that when concentration ranges are given, they include the upper and lower limits of said range. The compositions according to the invention may comprise hyaluronic acid.
Par acide hyaluronique, on entend un polysaccharide naturel ubiquitaire existant sous la même forme de la plus simple bactérie à l'Homme. C'est un polysaccharide composé alternativement d'acide D-glucuronique et de N- acétylglucosamine, liés entre eux par des liaisons glycosidiques alternées beta-1,4 et beta-1,3. Selon Saari H et al. Differential effects of reactive oxygen species on native synovial fluid and puπfied human umbilical cord hyaluronate. Inflammation 17 ( 1993) : 403-415, les polymères de cette unité récurrente peuvent avoir une taille entre 102 et 104 kDa in vivo, l'acide hyaluronique prélevé dans le cordon ombilical présentant un poids de 2500 kDa.By hyaluronic acid is meant a ubiquitous natural polysaccharide existing in the same form from the simplest bacterium to humans. It is a polysaccharide composed alternately of D-glucuronic acid and N-acetylglucosamine, linked together by alternating glycoside bonds beta-1,4 and beta-1,3. According to Saari H et al. Differential effects of reactive oxygen species on a native synovial fluid and puπfied human umbilical cord hyaluronate. Inflammation 17 (1993): 403-415, the polymers of this repeating unit can have a size between 10 2 and 10 4 kDa in vivo, the hyaluronic acid taken from the umbilical cord having a weight of 2500 kDa.
De façon avantageuse, l'acide hyaluronique est naturel .Advantageously, hyaluronic acid is natural.
Par acide hyaluronique naturel, on entend un acide hyaluronique non stabilise, non modifié chimiquement sous forme, notamment d'esters, d'amides, ou sous forme de dérivés possédant des « ponts intra et/ou interchaines » (cross linked) , de telles modifications affectant les caractéristiques physico-chimiques et les propriétés biologiques dudit acide hyaluronique, ainsi que son devenir après administration.By natural hyaluronic acid is meant a non-stabilized hyaluronic acid, not chemically modified in the form, especially of esters, amides, or in the form of derivatives having "intra and / or interchain bridges" (cross linked), such modifications affecting the physico-chemical characteristics and the biological properties of said hyaluronic acid, as well as its fate after administration.
Les compositions selon l'invention comprennent un oligosaccharide . Par oligosaccharide, on entend des polymères formes d'un nombre n (avec n inférieur ou égal à 100) de monosaccharides par liaison glycosidique notamment tout oligosaccharide limitant la pénétration de l'acide hyaluronique dans les cellules de la peau, notamment les kératinocytes et les fibroblastes .The compositions according to the invention comprise an oligosaccharide. By oligosaccharide is meant polymers formed of a number n (with n less than or equal to 100) of monosaccharides by glycosidic bonding, in particular any oligosaccharide limiting the penetration of hyaluronic acid into the cells of the skin, in particular keratinocytes and fibroblasts.
Parmi les oligosaccharides, pris seuls ou en mélange, susceptibles d'entrer dans les compositions selon l'invention, on choisira les oligomères de l'acide hyaluronique, préférentiellement les di- a dodécamères de l'acide hyaluronique, ledit dimère comprenant une unité disaccharidique composante de l'acide hyaluronique, et le dodecamere comprenant six de ces unîtes disaccharidiques, plus préférentiellement les tetra- à hexamères de l'acide hyaluronique, plus préférentiellement le pentamere de l'acide hyaluronique. Le poids moléculaire d'une unité disaccharidique d'acide hyaluronique est d'environ 400 Da. Un oligomère de une à six unités disaccharidiques d' acide hyaluronique a donc un poids moléculaire compris entre 400 à 2400 Da.Among the oligosaccharides, taken alone or as a mixture, capable of entering into the compositions according to the invention, the oligomers of hyaluronic acid, preferentially the di-dodecamers of hyaluronic acid, will be chosen, said dimer comprising a disaccharide unit. component of hyaluronic acid, and the dodecamere comprising six of these disaccharide units, more preferably the tetra- to hexamers of hyaluronic acid, more preferably the pentamere of hyaluronic acid. The molecular weight of a disaccharide unit of hyaluronic acid is about 400 Da. An oligomer of one to six disaccharide units of hyaluronic acid therefore has a molecular weight of between 400 and 2400 Da.
Par oligomère on entend, selon l' IUPAC dans Pure Appl. Chem., Vol. 68, No.12, pp. 2287-2311, 1996, une molécule de masse moléculaire intermédiaire, dont la structure comprend une petite quantité de molécules ayant une masse moléculaire plus faible. On parlera de molécule ayant une masse moléculaire intermédiaire, lorsque le retrait d'une ou de quelques unités constituantes modifiera significativement les propriétés de la molécule . De façon avantageuse, les oligosaccharides utilises dans les compositions selon l'invention sont des composes existant de façon naturelle dans l'organisme humain.Oligomer means, according to IUPAC in Pure Appl. Chem., Vol. 68, No.12, pp. 2287-2311, 1996, a molecule of intermediate molecular weight, the structure of which comprises a small amount of molecules having a lower molecular weight. We will speak of a molecule having an intermediate molecular mass, when the removal of one or a few constituent units will significantly modify the properties of the molecule. Advantageously, the oligosaccharides used in the compositions according to the invention are compounds that exist naturally in the human body.
Dans les compositions selon l'invention, 1' oligosaccharide est utilisé à des concentrations comprises entre 10-9 M et 10-3 M, preferentiellement entre 10-8 M et 10-5 M.In the compositions according to the invention, one oligosaccharide is used at concentrations of between 10 -9 M and 10 -3 M, preferably between 10 -8 M and 10 -5 M.
Les compositions selon l'invention comprennent un inhibiteur de la dégradation de l'acide hyaluronique .The compositions according to the invention comprise an inhibitor of the degradation of hyaluronic acid.
Par inhibiteur de la dégradation de l'acide hyaluronique, on entend un composé capable de diminuer, voire de bloquer, le catabolisme soit extracellulaire soit intracellulaire de l'acide hyaluronique, préferentiellement un composé capable de diminuer, voire de bloquer, le catabolisme extracellulaire de l'acide hyaluronique, plus préferentiellement un composé capable d' inhiber la hyaluronidase extracellulaire présente dans la peau.By inhibitor of the degradation of hyaluronic acid is meant a compound capable of reducing, or even blocking, the catabolism either extracellular or intracellular of hyaluronic acid, preferably a compound capable of reducing or even blocking the extracellular catabolism of hyaluronic acid, more preferably a compound capable of inhibiting extracellular hyaluronidase present in the skin.
Parmi les inhibiteurs de la dégradation de l'acide hyaluronique, pris seuls ou en mélange, susceptibles d'entrer dans les compositions selon l'invention, on choisira notamment le 1 , 2 , 3, 4 , 6-Penta-O-galloylglucose, l'apigénine, la beta-escin, la caltrin, le cis- Hinokiresinol (CHR), l'echinacin, l'acide eicosatrienoique (C20:3), le fenoprofen, , le GoId sodium thiomalate, le gossypol, l'héparine, l'Hespeπdine phosphate, l' Indométhacme, l'acide L-ascorbique, l'acide L-ascorbique 6-hexadecanoate, la L-carnitine, la L-aminocarnitme, la myocrisine (sodium aurothiomalate) , la N-tosyl-L-phenyl-alanine-chloromethyl ketone (TPCK) et la cetone N-alpha-p-tosyl-L-lysine chlorométhyle (TLCK) , l'hespéπdine phosphorylee, le poly (sodium 4- styrenesulfonate) (T-PSS) , le polyestradiol phosphate, le Polyphloretine phosphate, le PS53 (un polymère hydroquinone-acide suifonique-formaldéhyde) , le sodium polystyrène sulfonate (N-PSS) , le 2-hydroxyphenyl monolactobioside sulphaté, l'hydroquinone digalactoside sulphaté, les oligosaccharides sulphatés verbascose, plantéose et néomycine, le tétradecyl sodium sulfate (TDSS), un acide gras insaturé C14:l a C24:l avec une double liaison, l'inhibiteur urinaire de la trypsine (UTI), l'urolithine B, la WSG, la glycyrrhizine et l'acide glycyrrhétinique, leurs dérives et/ou analogues. La glycyrrhizine, l'acide glycyrrhétinique, leurs dérives et/ou analogues sont préférés.Among the inhibitors of the degradation of hyaluronic acid, taken alone or as a mixture, which may be used in the compositions according to the invention, 1,2,3,4,6-penta-O-galloylglucose will be chosen in particular. apigenin, beta-escin, caltrin, cis-Hinokiresinol (CHR), echinacin, eicosatrienoic acid (C20: 3), fenoprofen, GoId sodium thiomalate, gossypol, heparin, Hespeπdine phosphate, indomethacin, L-ascorbic acid, L-ascorbic acid 6-hexadecanoate, L-carnitine, L-aminocarnitme, myocrisine (sodium aurothiomalate), N-tosyl-L-phenyl-alanine-chloromethyl ketone (TPCK) and N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), hespéπdine phosphorylee, poly (sodium-4-styrenesulfonate) (T -PSS), polyestradiol phosphate, polyphloretin phosphate, PS53 (a hydroquinone-sulfonic acid-formaldehyde polymer), sodium polystyrene sulfonate (N-PSS), 2-hydroxyphenyl monolactobioside sulphate, hydroquinone digalactoside sulphate, oligosaccharides sulphate verbastosis, planting and neomycin, tetradecyl sodium sulfate (TDSS), an unsaturated fatty acid C14: C24: 1 with a double bond, urinary trypsin inhibitor (UTI), urolithin B, WSG, glycyrrhizin and glycyrrhetinic acid, their derivatives and / or analogues. Glycyrrhizin, glycyrrhetinic acid, their derivatives and / or analogues are preferred.
De façon avantageuse, les inhibiteurs de la dégradation de l'acide hyaluronique utilisés dans les compositions selon l'invention sont naturels.Advantageously, the inhibitors of the degradation of hyaluronic acid used in the compositions according to the invention are natural.
Dans les compositions selon l'invention, l'inhibiteur est utilisé à des concentrations comprises entre 10-9 M et 10-2 M, préférentiellement entre 10-6 M et 10-3 M.In the compositions according to the invention, the inhibitor is used at concentrations of between 10 -9 M and 10 -2 M, preferentially between 10 -6 M and 10 -3 M.
Par dérives de la glycyrrhizine ou de l'acide glycyrrhétinique, on entend notamment les sels, les dérivés substitués, les énantiomères et les racemates desdits composés.By derivatives of glycyrrhizin or glycyrrhetinic acid is meant in particular salts, substituted derivatives, enantiomers and racemates of said compounds.
Comme sels desdits composés, on peut citer les sels obtenus par addition desdits composés avec une base inorganique, choisie notamment parmi les hydroxydes de sodium, de lithium, de calcium, de potassium, de magnésium, d'ammonium ou de zinc, les carbonates de métaux alcalins ou alcalino-terreux tels que les carbonates et bicarbonates de sodium, de lithium, de calcium, de potassium, de magnésium, d'ammonium ou de zinc, ou avec une base organique, choisie notamment parmi la méthylamme, la propylamme, la trimethylamine, la diéthylamine, la triethylamine, la N, N- diméthyléthanolamine, le tris (hydroxyméthyl) - ammométhane, l' ethanolamme, la pyπdme, la picolme, la dicyclohexylamine, la morpholine, la proceme, la lysine, l'arginine, l'histidme, la N-méthylglucamine ou encore les sels de phosphonium tels que les sels d'alkyl- phosphonium, les sels d' aryl-phosphonium, les sels d' alkyl-arylphosphonium, les alkènyl-arylphosphonium ou les sels d'ammonium quaternaires tels que les sels de tetra-n-butyl-ammonium. De tels sels sont notamment le sel de potassium de l'acide glycyrrhétinique, le sel de sodium de l'acide glycyrrhétinique, ou encore le sel monoammonium de l'acide glycyrrhétinique (ammonium glycyrrhétmate) .As salts of said compounds, there may be mentioned the salts obtained by adding said compounds with a base inorganic, chosen in particular from hydroxides of sodium, lithium, calcium, potassium, magnesium, ammonium or zinc, alkali or alkaline earth metal carbonates such as sodium carbonates, sodium bicarbonates, calcium, potassium, magnesium, ammonium or zinc, or with an organic base, chosen in particular from methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris ( hydroxymethyl) ammomethane, ethanolamine, pyrimidine, picolme, dicyclohexylamine, morpholine, process, lysine, arginine, histidine, N-methylglucamine or phosphonium salts such as alkylphosphonium, arylphosphonium salts, alkylarylphosphonium salts, alkenylarylphosphonium salts or quaternary ammonium salts such as tetra-n-butylammonium salts. Such salts are in particular the potassium salt of glycyrrhetinic acid, the sodium salt of glycyrrhetinic acid, or the monoammonium salt of glycyrrhetinic acid (ammonium glycyrrhetmate).
Par analogue, on entend notamment les analogues enzymatiques ou biomimetiques desdits composés, capables de se fixer au site catalytique ou non des hyaluronidases et d'inhiber ainsi leur activation. De tels analogues peuvent être sélectionnés m vitro par des tests de liaison ou d' inhibition des hyaluronidases selon les techniques classiquement utilisées.The term "analogue" is intended to mean, in particular, the enzymatic or biomimetic analogs of said compounds, capable of binding to the catalytic or non-catalytic site of hyaluronidases and of thus inhibiting their activation. Such analogs can be selected in vitro by hyaluronidase binding or inhibition tests according to conventionally used techniques.
De façon avantageuse, les dérivés et/ou analogues doivent être d'origine naturelle. Les composés et leurs dérivés et/ou analogues d'origine naturelle sont des composés à l'état pur ou en solution à différentes concentrations, obtenus par différents procèdes d'extraction ou d'hydrolyse de matériel biologique d'origine naturelle.Advantageously, the derivatives and / or analogues must be of natural origin. The compounds and their derivatives and / or analogues of natural origin are compounds in the pure state or in solution at different concentrations, obtained by various processes for extracting or hydrolyzing biological material of natural origin.
De façon connue, les compositions selon l'invention peuvent contenir également les adjuvants habituels bien connus de l'homme de l'art.In known manner, the compositions according to the invention may also contain the usual adjuvants well known to those skilled in the art.
Les compositions selon l'invention sont de préférence formulées pour une application par voie topique et/ou parentérale.The compositions according to the invention are preferably formulated for topical and / or parenteral application.
Par voie topique, on entend une application externe sur la peau ou les muqueuses.By topical means an external application on the skin or mucous membranes.
Par voie topique, les compositions peuvent se présenter sous toutes les formes galeniques normalement utilisées pour une administration par voie topique. A titre d'exemple non limitatif de compositions topiques, on peut citer des compositions sous forme liquide, pâteuse, ou solide et, plus particulièrement, sous forme d'onguents, de solutions aqueuses, hydroalcooliques ou huileuses, de dispersions du type lotion éventuellement biphasée, de sérum, de gels aqueux, anhydres ou lipophiles, de poudres, de tampons imbibés, de syndets, de lingettes, de sprays, de mousses, de sticks, de shampoings, de compresses, de bases lavantes, d'émulsions de consistance liquide ou semi-liquide du type lait, obtenues par dispersion d'une phase grasse dans une phase aqueuse (H/E) ou inversement (E/H) , d'une microémulsion, de suspensions ou émulsions de consistance molle, semi- liquide ou solide du type crème blanche ou colorée, gel ou pommade, de suspensions de microsphères ou nanospheres ou de vésicules lipidiques ou polyméπques, ou de microcapsules, micro- ou nanoparticules ou de patchs polymériques ou gélifiés permettant une libération contrôlée .Topically, the compositions may be in any of the galenic forms normally used for topical administration. By way of non-limiting example of topical compositions, mention may be made of compositions in liquid, pasty or solid form and, more particularly, in the form of ointments, aqueous, hydroalcoholic or oily solutions, and optionally two-phase lotion-type dispersions. , serum, aqueous, anhydrous or lipophilic gels, powders, soaked swabs, syndets, wipes, sprays, foams, sticks, shampoos, compresses, washing bases, emulsions of liquid consistency or semi-liquid of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O), a microemulsion, suspensions or emulsions of soft consistency, semi-liquid liquid or solid white or colored cream, gel or ointment, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, or microcapsules, microparticles or nanoparticles or polymeric or gelled patches for controlled release.
Par voie parenterale, les compositions selon l'invention peuvent être appliquées par voie sous-cutanee ou intradermique. A titre d'exemple non limitatif de compositions parenterales, on peut citer des compositions sous forme de solutions ou suspensions pour perfusion ou pour injection.Parenterally, the compositions according to the invention can be applied subcutaneously or intradermally. By way of nonlimiting example of parenteral compositions, mention may be made of compositions in the form of solutions or suspensions for infusion or injection.
A titre d'exemple non limitatif donné simplement à titre d'illustration et qui ne saurait en aucune façon limiter la portée de l'invention, l'acide hyaluronique peut être administré sous forme d'une solution aqueuse injectable, le pentamere d'acide hyaluronique et la glycyrrhizine étant administrés sous forme d'une crème.By way of non-limiting example given merely by way of illustration and which in no way limits the scope of the invention, hyaluronic acid may be administered in the form of an injectable aqueous solution, the pentamere of acid hyaluronic acid and glycyrrhizin being administered in the form of a cream.
Dans le cadre d'une administration combinée d'acide hyaluronique et de la composition selon l'invention, les fréquences d'administration peuvent être identiques ou différentes.In the context of a combined administration of hyaluronic acid and the composition according to the invention, the administration frequencies may be identical or different.
De manière avantageuse dans le cadre de l'invention, la fréquence d'administration de l'acide hyaluronique injecté sous forme d'une solution aqueuse injectable peut varier de 4 à 24 mois, preferentiellement de 4 a 16 mois, alors que celles de la composition selon l'invention, administrée topiquement, par exemple sous forme de crème, peut varier de 1 à 7 jours, préférentiellement de 1 à 3 j ours .Advantageously within the scope of the invention, the frequency of administration of hyaluronic acid injected in the form of an aqueous solution for injection may vary from 4 to 24 months, preferably from 4 to 16 months, while those of composition according to the invention, administered topically, for example in cream form, can vary from 1 to 7 days, preferably from 1 to 3 days.
Selon un mode particulier de l'invention, le procédé de fabrication d'une composition comprend les étapes de préparation d'un milieu physiologiquement acceptable et de mélange d'une quantité efficace de pentamère de l'acide hyaluronique, et de glycyrrhizine et/ou ses dérivés et/ou analogues.According to a particular embodiment of the invention, the process for manufacturing a composition comprises the steps of preparing a physiologically acceptable medium and mixing an effective amount of pentamer of hyaluronic acid, and glycyrrhizin and / or its derivatives and / or analogues.
L'invention se rapporte également à l'utilisation d'au moins un inhibiteur de la dégradation de l'acide hyaluronique, et d'au moins un oligosaccharide choisi parmi les oligomères de l'acide hyaluronique, ou d'une composition telle que décrite précédemment, pour la fabrication d'un médicament destiné au traitement, à l'amélioration et/ou a la prévention des affections dermatologiques .The invention also relates to the use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid, or of a composition as described previously for the manufacture of a medicament for the treatment, improvement and / or prevention of dermatological conditions.
Plus particulièrement, l'invention se rapporte à l'utilisation d'au moins un inhibiteur de la dégradation de l'acide hyaluronique, et d'au moins un oligosaccharide choisi parmi les oligomères de l'acide hyaluronique, ou d'une composition telle que décrite précédemment, pour la fabrication d'une composition cosmétique ou pharmaceutique destinée au traitement, à l'amélioration et/ou à la prévention du vieillissement cutané. Par vieillissement cutané, on entend les rides, les ridules, les déplétions fibroblastiques et les cicatrices. Une telle composition est adaptée au traitement de la peau ridée et/ou âgée, et vise notamment à en prévenir et/ou à en réduire les effets. Le traitement des rides, ridules, déplétions fibroblastiques et toutes cicatrices se fait notamment par comblement.More particularly, the invention relates to the use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid, or of a composition such as as described above, for the manufacture of a cosmetic or pharmaceutical composition for the treatment, improvement and / or prevention of skin aging. Skin aging is understood to mean wrinkles, fine lines, fibroblastic depletions and scars. Such a composition is adapted to the treatment of wrinkled and / or aged skin, and is intended in particular to prevent and / or reduce the effects thereof. The treatment of wrinkles, fine lines, Fibroblastic depletions and all scarring is done by filling.
En particulier, la composition selon l'invention peut être appliquée sur les zones du visage ou du front marquées par des rides d'expression.In particular, the composition according to the invention can be applied to the areas of the face or forehead marked by expression lines.
L'invention se rapporte également à l'utilisation d'au moins un inhibiteur de la dégradation de l'acide hyaluronique, et d'au moins un oligosaccharide choisi parmi les oligomères de l'acide hyaluronique, ou d'une composition telle que décrite précédemment, pour la fabrication d'une composition cosmétique ou pharmaceutique destinée a être utilisée en chirurgie réparatrice.The invention also relates to the use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid, or of a composition as described previously, for the manufacture of a cosmetic or pharmaceutical composition for use in reconstructive surgery.
La présente invention va maintenant être illustrée au moyen des exemples suivants.The present invention will now be illustrated by the following examples.
Exemple 1 : Effet inhibiteur de la qlycyrrhizine (GLZ) sur l'activité hyaluronidase d'origine bovineExample 1 Inhibitory Effect of Qlycyrrhizin (GLZ) on Hyaluronidase Activity of Bovine Origin
Détermination de la CI50 de GLZ, avec ou sans pre- incubation a 37°C :Determination of IC50 of GLZ, with or without pre-incubation at 37 ° C:
La GLZ, a différentes concentrations, est pre- incubée ou non 20 minutes à 37°C en présence de l'enzyme.GLZ, at different concentrations, is pre-incubated or not for 20 minutes at 37 ° C in the presence of the enzyme.
La reaction enzymatique est déclenchée par ajout de la solution d'acide hyaluronique (temps TO) . Apres 20 minutes d'incubation, l'acide hyaluronique non hydrolyse est précipité par ajout de la solution acide d'albumine bovine . Afin de vérifier que l'étape de pre-incubation n'influe pas sur la stabilité de la hyaluronidase, une aliquote d'une solution de l'enzyme est placée à 37°C pendant 20 minutes. Une autre aliquote est conservée dans un bain de glace pendant 19 minutes, puis est incubée àThe enzymatic reaction is triggered by adding the hyaluronic acid solution (TO time). After 20 minutes of incubation, the unhydrolysed hyaluronic acid is precipitated by addition of the acid solution of bovine albumin. In order to verify that the pre-incubation step does not affect the stability of the hyaluronidase, an aliquot of a solution of the enzyme is placed at 37 ° C for 20 minutes. Another aliquot is kept in an ice bath for 19 minutes, then incubated at
370C pendant 1 minute. Une solution d'acide hyaluronique est alors ajoutée dans chaque aliquote (TO). Après 15, 30 ou 45 minutes d'incubation, l'acide hyaluronique non hydrolyse est précipité par ajout de la solution acide d'albumine bovine.37 0 C for 1 minute. A solution of hyaluronic acid is then added to each aliquot (TO). After 15, 30 or 45 minutes of incubation, the unhydrolysed hyaluronic acid is precipitated by addition of the acid solution of bovine albumin.
Mesure de l'activité hyaluronidase d'origine bovine :Measurement of hyaluronidase activity of bovine origin:
Après l'étape de précipitation, la turbidimétrie des solutions est déterminée au spectrophotomètre a une longueur d'onde de 600 nm. La densité optique (DO) de ces solutions est retranchée de la DO d'une solution témoin d' acide hyaluronique (de même concentration) non hydrolyse par l'enzyme. Cette différence de DO, qui est inversement proportionnelle à la concentration d'acide hyaluronique, est utilisée pour mesurer l'activité de la hyaluronidase .After the precipitation step, the turbidimetry of the solutions is determined on a spectrophotometer at a wavelength of 600 nm. The optical density (OD) of these solutions is deduced from the OD of a control solution of hyaluronic acid (of the same concentration) not hydrolyzed by the enzyme. This difference in OD, which is inversely proportional to the concentration of hyaluronic acid, is used to measure the activity of hyaluronidase.
L'effet inhibiteur de la GLZ sur la hyaluronidase bovine est illustré sur la figure 1 (représentation semi- logarithmique) .The inhibitory effect of GLZ on bovine hyaluronidase is illustrated in Figure 1 (semi-logarithmic representation).
Les résultats obtenus montrent que cet effet est dose-dépendant et que la concentration en GLZ inhibant à 50% (CI50) l'activité hyaluronidase est de 400 μM sans pré-incubation avec l'enzyme. Lorsque la GLZ est pre-incubée 20 minutes à 37°C en présence de l'enzyme, la CI50 est de 350 μM.The results obtained show that this effect is dose-dependent and that the concentration of GLZ inhibiting at 50% (IC50) the hyaluronidase activity is 400 μM without pre-incubation with the enzyme. When the GLZ is preincubated for 20 minutes at 37 ° C. in the presence of the enzyme, the IC50 is 350 μM.
Exemple 2 : Effet inhibiteur du bindmg du pentamère (NAC-Glucuronic acid) 5 sur le récepteur CD44 de l' acide hyaluroniqueExample 2: Inhibitory effect of pentameric bindmg (NAC-Glucuronic acid) on the CD44 receptor of hyaluronic acid
Sur une culture de kératinocytes humains normaux (KHN) est additionné de l'acide hyaluronique marque a la fluoresceinamine (selon DeBelder et al., 1975, Carbohydrate Res., 44, 251-257) puis des concentrations croissantes de pentamère (NAC-Glucuronic acid) 5. La mesure du déplacement de l'acide hyaluronique fluorescent par le pentamère (NAC-Glucuronic acid) 5 est réalisée.On a culture of normal human keratinocytes (KHN) is added hyaluronic acid labeled with fluoresceinamine (according to DeBelder et al., 1975, Carbohydrate Res., 44, 251-257) and then increasing concentrations of pentamer (NAC-Glucuronic acid) 5. The measurement of the displacement of fluorescent hyaluronic acid by the pentamer (NAC-Glucuronic acid) is carried out.
Exemple 3 : Composition n°lExample 3 Composition No. 1
Solution injectable n°lSolution for injection no.
Cette composition est préparée de manière classique pour l'homme du métier:This composition is prepared in a conventional manner for the person skilled in the art:
Glycyrrhizine 0,02% pentamère (NAC-Glucuronic acid) 5 0,002% Eau qsp 100%Glycyrrhizin 0.02% pentamer (NAC-Glucuronic acid) 0.002% Water qs 100%
Exemple 4 : Composition n°2Example 4: Composition No. 2
Solution injectable n°2 d'acide hyaluronique couplée a une crème selon l'inventionInjectable Solution No. 2 Hyaluronic Acid Coupled to a Cream According to the Invention
Solution injectable Acide hyaluronique 2% Eau qsp 100%Injection solution Hyaluronic acid 2% Water qs 100%
CrèmeCream
Glycyrrhizine 0,02% pentamère (NAC-Glucuronic acid) 5 0,002%Glycyrrhizin 0.02% pentamer (NAC-Glucuronic acid) 0.002%
Acide stéarique 3,00% mélange de monostéarate de glycéryle et de stéarate de PEG (100 OE) 2,5% Stéarate de PEG (20 OE) 1,0%Stearic acid 3.00% blend of glyceryl monostearate and PEG stearate (100 EO) 2.5% PEG stearate (20 EO) 1.0%
Cyclopentadiméthylsiloxane 10, 00%Cyclopentadimethylsiloxane 10, 00%
Huiles végétales 7,00%Vegetable oils 7,00%
Huiles synthétiques 6,00%Synthetic oils 6,00%
Gomme de silicone 0,20% Alcool stéarique 1,00%Silicone Gum 0.20% Stearic Alcohol 1.00%
Eau qsp 100% Water qs 100%

Claims

REVENDICATIONS
1. Composition pharmaceutique ou cosmétique comprenant, dans un milieu physiologiquement acceptable, à titre de seuls principes actifs: au moins un inhibiteur de la dégradation de l'acide hyaluronique,1. A pharmaceutical or cosmetic composition comprising, in a physiologically acceptable medium, as sole active ingredients: at least one inhibitor of the degradation of hyaluronic acid,
- et au moins un oligosaccharide choisi parmi les oligomeres de l'acide hyaluronique.and at least one oligosaccharide chosen from oligomers of hyaluronic acid.
2. Composition selon la revendication 1, caractérisée en que l'inhibiteur de la dégradation de l'acide hyaluronique est choisi parmi la glycyrrhizine, l'acide glycyrrhetinique, leurs dérives et leurs analogues.2. Composition according to claim 1, characterized in that the inhibitor of the degradation of hyaluronic acid is selected from glycyrrhizin, glycyrrhetinic acid, their derivatives and their analogues.
3. Composition selon l'une quelconque des revendications 1 ou 2, caractérisée en ce qu'elle est formulée pour une application par voie topique.3. Composition according to any one of claims 1 or 2, characterized in that it is formulated for topical application.
4. Composition selon l'une des revendications 1 ou 2, caractérisée en ce qu'elle est formulée pour une application par voie parentérale.4. Composition according to one of claims 1 or 2, characterized in that it is formulated for parenteral application.
5. Composition selon la revendication 4, caractérisée en ce qu'elle se présente sous forme de solutions ou suspensions pour perfusion ou pour injection .5. Composition according to claim 4, characterized in that it is in the form of solutions or suspensions for infusion or injection.
6. Procédé de fabrication d'une composition selon l'une des revendications 1 à 5, caractérisé en ce qu'il comprend une étape de mélange d'au moins un oligosaccharide et d'au moins un inhibiteur de la dégradation de l'acide hyaluronique avec un milieu physiologiquement acceptable.6. A method of manufacturing a composition according to one of claims 1 to 5, characterized in that it comprises a step of mixing at least one oligosaccharide and at least one inhibitor of the degradation of hyaluronic acid with a physiologically acceptable medium.
7. Utilisation d'au moins un inhibiteur de la dégradation de l'acide hyaluronique, et d'au moins un oligosaccharide choisi parmi les oligomères de l'acide hyaluronique pour la fabrication d'une composition pharmaceutique ou cosmétique destinée au traitement et/ou à la prévention du vieillissement cutané.7. Use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid for the manufacture of a pharmaceutical or cosmetic composition intended for treatment and / or prevention of skin aging.
8. Utilisation d'au moins un inhibiteur de la dégradation de l'acide hyaluronique, et d'au moins un oligosaccharide choisi parmi les oligomères de l'acide hyaluronique pour la fabrication d'une composition pharmaceutique ou cosmétique destinée à être utilisé en chirurgie réparatrice.8. Use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid for the manufacture of a pharmaceutical or cosmetic composition intended for use in surgery restorative.
9. Utilisation d'au moins un inhibiteur de la dégradation de l'acide hyaluronique, et d'au moins un oligosaccharide choisi parmi les oligomères de l'acide hyaluronique pour la fabrication d'une composition pharmaceutique ou cosmétique destinée au traitement par comblement des rides, des ridules, des déplétions fibroblastiques et des cicatrices. 9. Use of at least one inhibitor of the degradation of hyaluronic acid, and of at least one oligosaccharide chosen from oligomers of hyaluronic acid for the manufacture of a pharmaceutical or cosmetic composition intended for the treatment by filling of wrinkles, fine lines, fibroblast depletions and scars.
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FR2939317B1 (en) * 2008-12-08 2010-12-24 Oreal DERMAL TRANS TRANSFER SYSTEM (EPI) COMPRISING VESICULAR DISPERSION, COSMETIC TREATMENT METHOD AND COSMETIC USE
US20110172180A1 (en) 2010-01-13 2011-07-14 Allergan Industrie. Sas Heat stable hyaluronic acid compositions for dermatological use
US9393263B2 (en) 2011-06-03 2016-07-19 Allergan, Inc. Dermal filler compositions including antioxidants
US20130096081A1 (en) 2011-06-03 2013-04-18 Allergan, Inc. Dermal filler compositions
US9408797B2 (en) 2011-06-03 2016-08-09 Allergan, Inc. Dermal filler compositions for fine line treatment
US9149422B2 (en) 2011-06-03 2015-10-06 Allergan, Inc. Dermal filler compositions including antioxidants
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