Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/07—Retinol compounds, e.g. vitamin A
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/203—Retinoic acids ; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7016—Disaccharides, e.g. lactose, lactulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/728—Hyaluronic acid
• • 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
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
  • A61K8/347—Phenols
• • 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
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides 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
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/60—Sugars; 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
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/67—Vitamins
  • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to compositions for topical and / or parenteral application comprising, in a physiologically acceptable medium, a retinoid and / or its salts and / or derivatives, and an oligomer of hyaluronic acid consisting of 1 to 6 disaccharide units methods of making such compositions, and their uses as pharmaceutical, especially drug, or cosmetic compositions.
• the said compositions being intended for the treatment of dermatological conditions, in particular, the treatment by filling wrinkles, fine lines, fibroblastic depletions and all scars.
• 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 greater 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. 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.
• 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 the 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. Urinary 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 in 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, in the context 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 many of them comprise chemically modified hyaluronic acid for this purpose.
• the hyaluronic acid included in these products is predominantly of non-human origin such as for example of avian or bacterial origin.
• compositions there are thus in these compositions 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 ensure that hyaluronic acid has a 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 as its first object a pharmaceutical or cosmetic composition, especially for topical and / or parenteral application comprising, as sole active ingredients, in a physiologically acceptable medium:
• At least one compound chosen from retinoids, their salts and their derivatives at least one compound chosen from retinoids, their salts and their derivatives
• At least one oligomer of hyaluronic acid chosen from compounds containing from 1 to 6 disaccharide units.
• the composition does not comprise an inhibitor of the degradation of hyaluronic acid.
• composition according to the invention indeed contains as active ingredients only the retinoid (s) and the (e) oligomer of hyaluronic acid; any other active ingredient is excluded.
• Its second object is a process for manufacturing such a pharmaceutical or cosmetic composition, comprising a step of mixing at least one compound chosen from retinoids, their salts and derivatives and at least one selected hyaluronic acid oligomer. among compounds containing from 1 to 6 disaccharide units 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.
• composition according to the invention for the manufacture of a medicament for the treatment and / or prevention of dermatological conditions.
• a pharmaceutical or cosmetic composition according to the invention significantly increases the bioavailability of a hyaluronic acid, which is further 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 demonstrated a decrease in the catabolism of hyaluronic acid in human keratinocytes in vivo to which hyaluronic acid, a hyaluronic acid oligomer chosen from compounds containing from 1 to 6 disaccharide units, and a retinoid, in the absence of an inhibitor of hyaluronic acid degradation.
• the composition comprising a hyaluronic acid oligomer chosen from compounds containing from 1 to 6 disaccharide units and a retinoid confers on hyaluronic acid also applied a better stability and a better bioavailability.
• a composition is more effective than the compositions of the prior art, and in particular compositions comprising inhibitors of the degradation of hyaluronic acid, in the filling of wrinkles, fine lines, fibroblastic depletions and all scars, as well as in hydration. skin.
• the invention will be better understood on reading the nonlimiting description which follows.
• composition according to the invention comprises, in a physiologically acceptable medium, at least one retinoid and / or its salts and / or derivatives and a hyaluronic acid oligomer chosen from compounds containing from 1 to 6 disaccharide units. In particular, it does not include an inhibitor of the degradation of hyaluronic acid.
• 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 retinoid and / or its salts and / or its derivatives, and
• the oligomer of hyaluronic acid selected from compounds containing from 1 to 6 disaccharide units 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.
• concentration ranges are given, they include the upper and lower limits of said range.
• 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.
• 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.
• natural hyaluronic acid is meant an unstabilized hyaluronic acid, not chemically modified in the form, in particular 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 a retinoid and / or its salts and / or its derivatives, taken alone or as a mixture.
• retinoids that may be used in the compositions according to the invention, retinol, retinal, retinoic acid, adapalene or their salts and derivatives, taken alone or as a mixture, more preferably retinol, will preferably be chosen.
• retinoid salt is meant in particular an alkali metal salt, or an alkaline earth salt, or an organic amine salt.
• retinoid derivative is meant in particular the esters, such as retinyl palmitate, retinyl acetate, retinyl stearate, retinyl oleate, retinyl propionate or retinyl linoleate.
• the retinoids used in the compositions according to the invention are retinoids naturally occurring in the human body.
• Oligosaccharide is understood to mean polymers formed of a number n (with n less than or equal to 100) of monosaccharides by glycosidic bond, in particular any oligosaccharide limiting the penetration of hyaluronic acid into skin cells, which are in particular keratinocytes. and fibroblasts.
• n n
• 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- to dodecamers of hyaluronic acid, will be chosen, said dimer comprising a disaccharide unit.
• 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 oligomers of hyaluronic acid taken alone or as a mixture, capable of entering into the compositions according to the invention, are the dimers and four-mers of hyaluronic acid, said dimer comprising a disaccharide unit component of hyaluronic acid. , and the four-mer comprising two of these disaccharide units.
• the molecular weight of a disaccharide unit of hyaluronic acid is about 400 Da.
• An oligomer of one or two disaccharide units of hyaluronic acid therefore has a molecular weight of 400 to 800 Da, respectively.
• the oligomers used in the compositions according to the invention are compounds naturally occurring in the human body.
• one oligomer 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 do not 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.
• compositions according to the invention may also contain the usual adjuvants well known to those skilled in the art.
• compositions according to the invention may be formulated for topical and / or parenteral application.
• topical means an external application on the skin or mucous membranes.
• compositions may be in any dosage form 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, semi-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 allowing release n controlled.
• 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 for injection.
• hyaluronic acid may be administered in the form of an injectable aqueous solution and a composition according to the invention.
• invention comprising a dimer of hyaluronic acid is 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, may vary from 1 to 7 days, preferably from 1 to 3 days.
• the method of manufacturing a composition comprises the steps of preparing a physiologically acceptable medium and mixing an effective amount of a four-mer of hyaluronic acid.
• the invention also relates to the use of at least one compound chosen from retinoids, their salts and derivatives and at least one hyaluronic acid oligomer chosen from compounds containing from 1 to 6 disaccharide units or from 'a composition such as described above, 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 compound chosen from retinoids, their salts and derivatives and at least one oligomer of hyaluronic acid chosen from compounds containing from 1 to 6 disaccharide units. , or a composition 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 scars 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 compound chosen from retinoids, their salts and derivatives and at least one oligomer of hyaluronic acid chosen from compounds containing from 1 to 6 disaccharide units, or of a composition as described above, for the manufacture of a cosmetic or pharmaceutical composition for use in reconstructive surgery.
• the present invention will now be illustrated by the following examples.
• composition is prepared in a conventional manner for the person skilled in the art:
• Example 2 Composition No. 2
• Stearic acid 3.00% mixture of glyceryl monostearate and PEG stearate (100 EO) 2.5%

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• 2008
  • 2008-04-22 WO PCT/FR2008/050728 patent/WO2008148967A2/fr not_active Ceased
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  • 2008-04-22 US US12/599,510 patent/US20100298259A1/en not_active Abandoned
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