Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/65—Tetracyclines
• • 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
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
  • A61P23/02—Local anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • 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
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

• New pharmaceutical system for the transport of active ingredients, preparation process and use.
• the present invention relates to a new galenic system allowing the protection of an active, particularly of a drug, against its degradation during transit in the stomach during an oral absorption,
• the galenical system according to the invention also allows the masking of the taste of an active agent possibly contained in the galenic system, the stabilization of said active ingredient, the modulation of the release properties of said active ingredient, the masking of the effects of mucosal irritability and the toxicity certain active ingredients.
• the simplest and most practical route of therapeutic administration remains the oral route. In France, it constitutes 75% of the medication taken (Pharmacie galénique, A. Le Hir - Editions Masson.).
• the dosage forms intended for the oral route come essentially in two forms, liquid and dry. They have the enormous advantage of not requiring a medical procedure when taking it.
• the pH of the stomach is between 2 and 6.
• the acidic nature of the stomach medium can lead to the degradation of the active ingredients contained in the ingested compositions, before these reach the intestine, where they are theoretically absorbed through from the intestinal lining to get into the circulation.
• Such a deleterious effect of stomach transit can go against the desired objective, namely the absorption by the body of said active ingredient in its most effective form for the desired effect. This drawback is all the more serious when one addresses pharmaceutical compositions.
• Compliance is a key factor on which the effectiveness of therapeutic treatment directly depends. Compliance, we also speak of good use of the drug, is defined as being the action of following a drug treatment in accordance with the indications of the prescription: respect for the duration of treatment, the number and schedules of taking. Taken at an insufficient dose or frequency, a medicine may to be inactive or ineffective. In the case of transient conditions, poor adherence to treatment only delays the time of healing and leads to relapses, sometimes responsible for serious complications. In the case of chronic diseases, poor compliance can be responsible for irreversible damage. The main difficulties encountered during oral administration vary depending on the presentation.
• This property involves obtaining a stable galenic system in an acid medium, that is to say resistant to an acid pH.
• the coating techniques consist in placing a layer of insulating compounds, polymers or mixtures, around the active principle to isolate it from the external medium.
• Many polymeric, natural or synthetic compounds have been used for the constitution of this outer layer.
• cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), ethylcellulose, carboxymethylcelluloses, hydroxypropylmethylcellulose phthalate or mixtures of these products.
• HPMC hydroxypropylmethylcellulose
• ethylcellulose carboxymethylcelluloses
• hydroxypropylmethylcellulose phthalate or mixtures of these products.
• the immediate release at the level of the digestive tract is conditioned by the use of polymer pH dependent very sensitive to the pH higher than 7 of the oral cavity or the stomach, which implies the addition of acid to the final formulation.
• These coating technologies have a certain number of disadvantages: the gastroprotection is not total the masking of the taste is not total and in the case of compounds with strong bitterness, the taste is still too unpleasant - the kinetics of release are modified the coating particles have a size of a few hundred microns, and are noticeable during absorption. In this case their rupture can lead to a bad taste. the coating processes are complex, involve numerous stages and have a high cost. These technologies are not compatible with the preparation of long-term stable syrups. These technologies are therefore not yet fully satisfactory.
• the present invention provides a new galenic system allowing: gastroprotection, - masking of taste, protection of the active principle, particularly in an acid medium, the possibility of modulation of the release properties, masking of the effects of mucosal irritability and of the toxicity of certain active ingredients, - the preparation of aqueous forms, with a masked taste, stable and independent pH.
• the dosage system according to the invention is characterized in that it consists of a mixture of hydrophobic compounds insoluble in water, in that it is in solid form at room temperature and that it is completely devoid of surfactant compounds , solvent and water residues which can cause hydrolysis or oxidation reactions of an active ingredient that it may contain.
• This galenical system has the capacity to incorporate compounds of hydrophilic, hydrophobic or mineral nature.
• the subject of the invention is a galenic system, in the form of solid lipid particles, strictly hydrophobic, containing strictly no water, no surfactants, no emulsifying agents nor traces of solvents, characterized in that it comprises at least one hydrophobic wax and at least one non-neutralized fatty acid.
• galenic system in the form of solid lipid particles, strictly hydrophobic, containing strictly no water, no surfactants, no emulsifying agents nor traces of solvents, characterized in that it comprises at least one hydrophobic wax and at least one non-neutralized fatty acid.
• the galenical system is also devoid of talc.
• the lipid particles are solid at a temperature which can range up to 45 ° C., preferably up to 37.5 ° C.
• the lipid particles are in a spherical form.
• hydrophobic wax it is meant that the galenical system can consist of one or more waxes, vegetable, animal or mineral, or of a mixture of one or more waxes and at least one non-amphiphilic oil.
• the dosage system can also comprise at least one hydrophobic compound making it possible to adjust the melting point and the physicochemical properties such as the hardness.
• a hydrophobic compound mention may be made of beeswax or palm oil ...
• compositions should be chosen, compatible in terms of toxicity, biocompatibility, non immunogenicity and biodegradability with absorption by the oral route or any other mode of administration.
• the components will be chosen from among the components already used for oral administration, such as those defined in the GRAS list published by the Food and Drug Administration, and so that the particles formed retain their properties of incorporation, taste masking and stabilization of the active components.
• the wax can be chosen from any known wax compatible with the requirements of the invention.
• the wax can in particular be chosen from triglycerides and palm oil derivatives - Carnauba wax Candellila wax Alfa wax cocoa butter ozo erites vegetable waxes such as olive wax, rice wax, hydrogenated jojoba wax or absolute flower waxes, beeswax and modified beeswax. According to a particular form of the invention, the wax can be a mixture of waxes.
• the melting point of which can be between 15 ° C. and 75 ° C., preferably between 30 ° C. and 45 ° C.
• the wax can be in an amount between 0.5% and 99%, preferably between and 1% and 50%
• the non-neutralized fatty acid can be any non-neutralized fatty acid compatible with the requirements of the invention.
• the non-neutralized fatty acid can be chosen from fatty acids with straight chains having a number of carbon atoms between 4 and 18, such as for example myristic acid, lauric acid, palmitic acid or else oleic acid.
• the non-neutralized fatty acid can consist of a mixture of non-neutralized fatty acids
• the non-neutralized fatty acid can be used at a fatty acid level of between 0.5% and 75% by mass and preferably between 1% and 30%.
• the galenical system according to the invention can also contain oily, pasty or solid additives, liposoluble or water-soluble active ingredients.
• high molecular weight fatty alcohols preferably linear and even saturated fatty acids having from 12 to 30 carbon atoms
• esters of acids and alcohols with high molecular weight in particular the esters of linear and saturated even acids having from 4 to 20 carbon atoms and linear and saturated alcohols having from 14 to 32 carbon atoms.
• the mixture obtained must be characterized by a final melting point of between 15 ° C and 75 ° C, by the absence of surfactant compounds, by hydrophobic behavior and non-wettability by water.
• the composition according to the invention may contain an oil or a mixture chosen from: hydrophobic silicone oils with a viscosity of between 5 and 9000 centistocks, cyclomethicones, lipophilic organofluorinated oils, perhydrosqualene.
• oily compounds such as oleic alcohol, lanolin, sunflower oil, palm oil, olive oil, fatty acids and fatty alcohols can be used, but the oily mixture obtained must be characterized by hydrophobic behavior, an absence of miscibility with water and a melting point of between 15 ° C and 75 ° C, preferably between 30 ° C and 45 ° C.
• the lipid particles according to the invention can have a size between
• microns and 1500 microns preferably between 10 microns and 250 microns.
• the lipid particles according to the invention have the advantage of allowing the delayed release of an active which they could contain, a very great stability at acid pH, particularly in acidic aqueous formulation, thus allowing the protection of the active when they are in contact with a medium having an acidic pH such as for example the gastric medium, and a total masking of the taste.
• the invention also relates to a galenical system according to the invention further comprising an active ingredient.
• the active term is used to denote any substance usable in cosmetics, pharmacy, biotechnology, in the veterinary field or even in food.
• the active can be an active therapeutic substance which can advantageously be administered to humans or other animals to diagnose, treat, reduce, treat or prevent disease.
• the active agent can be any compound of hydrophilic, hydrophobic or mineral nature.
• the active ingredient can be dissolved or dispersed in the galenical system.
• the active can be a mixture of active.
• the active ingredient can be chosen from essential oils, flavors, pigments, fillers, dyes, enzymes and coenzymes and other active substances.
• vitamins or provitamins A, B, C, D, E, PP and their esters mention may be made of vitamins or provitamins A, B, C, D, E, PP and their esters, carotenoids, anti-radical substances, hydroxy acids, antiseptics, molecules acting on pigmentation, on inflammation, biological extracts.
• the active can also be chosen from preservatives, antioxidants, dyes and pigments, cells and cellular organelles or even pharmaceutical components intended to treat pathologies, particularly cutaneous or mucosal pathologies.
• antibiotics As an example of a therapeutic active agent which can be incorporated into the galenical system according to the invention, mention may be made of antibiotics, antifungals, antiparasitics, antimalarials, adsorbents, hormones and derivatives, nicotine, antihistamines, steroidal and nonsteroidal anti-inflammatory drugs, antiallergic agents, analgesics, local anesthetics, antivirals, antibodies and molecules acting on the immune system, cytostatic and anticancer drugs, analgesics, lipid-lowering agents, vasodilators, vasoconstrictors, angiotensin converting enzyme inhibitors and phosphodiesterase, nitrates and antianguines, beta blockers, calcium channel blockers, antidiuretics and diuretics, bronchodilators, opiates and derivatives, barbiturates, benzodiazepines, molecules acting on the central nervous system, nucleic acids ues, peptides, anthracene compounds, paraffin
• the lipid particles further comprising an active agent have a melting temperature, after incorporation of the active principle, of between 15 ° C and 75 ° C, preferably between 30 and 45 ° C.
• the active ingredient loading capacity can range from 0.02% to 75% relative to the weight of particles, particularly from 5% to 50%.
• an appropriate lipid composition should be chosen so that the particles are solid at the temperature of use with a size preferably between 0.5 microns and 1500 microns and preferably between 0.5 microns and 100 microns, allow a total masking of the taste to be obtained without modifying the release properties and having very great stability in aqueous formulation even at high pH.
• the galenical system further comprising an active ingredient can be prepared according to the method described in patent WO 99/65448.
• the particles are obtained by mixing under moderate heating. More precisely, these compositions are obtained by a process characterized in that the wax, the wax and the oil are mixed at the melting point until a mixture characterized by a melting point below the temperature of wax melting.
• the initial ratio between the wax and the oil can be modulated so that the melting temperature of the final mixture is lower than the degradation temperature of the compound to be incorporated, the most sensitive to heat.
• the final mixture must be solid at use temperature and must have, in one of these preferred forms, a melting point of 37.5 ° C.
• the mixture is then cooled with suitable stirring, to a temperature 2 ° C or 3 ° C above its melting point, to allow the inclusion of pharmaceutical active ingredients.
• the mixture is then shaped to give spherical hydrophobic particles called particles.
• the process of the present invention does not involve emulsifying agents or amphiphilic products in the composition, to allow a stable dispersion during the solidification phase by cooling.
• this comprises a step of washing said particles obtained with a washing mixture comprising ethanol.
• a washing mixture comprising ethanol.
• the presence of ethanol in the washing mixture is essential to the process because the ethanol allows complete washing of any active residues that may be present on the surface of the lipid particles which could generate an unpleasant taste.
• the mixing of the various components of the galenical system (wax and non-neutralized fatty acid among others) and of the active agent is carried out in a first step of the method.
• This mixing is carried out hot at 2 ° C or 3 ° C above the melting point of the compound having the highest melting point.
• Those skilled in the art know that it is necessary to apply an appropriate agitation method to the dispersion of all the components.
• lipid droplets comprising the active agent are formed by dispersing the mixture obtained in the first step in a gel prepared with a gelling, shear-thinning and non-surfactant agent, with which said mixture is immiscible, previously brought to the same temperature, and gelling agent concentration between 0.1 g / 1 and 30 g / 1, preferably between 0.2 g / 1 and 20 g / 1 sufficiently high to freeze the dispersion. . It may be preferable to inject the composition into the gel, for example through an orifice located at the base of a reactor.
• the agitation which must be maintained throughout the injection has the characteristic of presenting a blade equipped with an anchor, intended to disperse the composition and a second axial blade equipped with a three-blade propeller intended to form the droplets of dispersion. desired size. This last step is extremely rapid since the droplets are obtained as the composition is injected. Agitation does not need to be continued after the injection is complete, as the droplets are frozen in the gel.
• the droplets are immediately cooled, below the solidification temperature of the mixture, and then washed.
• the washing phase is very important because it makes it possible to have no residue on the surface of the particles, which could generate an unpleasant taste.
• the washing of the particles can be carried out using a washing mixture consisting of water and ethanol in a proportion of between 0% and 25% d ethanol.
• the washed particles are then recovered by sieving and then dried. The particles obtained have a large homogeneity in size and can be handled industrially without special precautions.
• shear-thinning and non-surfactant gelling agents suitable for the formation of the gel used as a dispersion medium according to the process mention may be made of carboxyvinyl polymers such as polyacrylic polymers not modified by hydrophobic or surfactant groups, carrageenans, thickeners and gelling agents polysaccharides such as xanthans, guar and locust bean gums, alginates, cellulose derivatives, pectins, agar, or a mixture thereof.
• carboxyvinyl polymers such as polyacrylic polymers not modified by hydrophobic or surfactant groups, carrageenans, thickeners and gelling agents polysaccharides such as xanthans, guar and locust bean gums, alginates, cellulose derivatives, pectins, agar, or a mixture thereof.
• the lipid particles comprising an active agent can be incorporated into any composition, particularly into any cosmetic, pharmaceutical, veterinary or food composition.
• the subject of the invention is also a composition comprising at least one lipid particle containing an active ingredient.
• composition according to the invention may also comprise any additive intended to modify the appearance or the rheology thereof.
• lubricants can be added which improve the fluidity of particles such as talc, starches, silica powders, antistatic agents.
• the composition according to the invention can be in the form of any suitable pharmaceutical formulation.
• the particles of the invention are used in aqueous suspensions, syrups and sachets.
• the particles can be used in conventional galenical formulations of the capsules, capsules, granules, oral powders, dispersible powders, tablets, hydrodispersible and orodispersible tablets.
• the compositions can be used for administration by injectable route and in particular for the preparation of sustained-release forms.
• the lipid particles according to the invention are prepared to have a size preferably between 0.5 ⁇ m and 5 ⁇ m. It is preferable to sift them to obtain a size distribution in accordance with the mode of administration. Their waxy composition is chosen to be in accordance with the needs of the injectable route.
• This dosage form eliminates the toxicity problems encountered by the polymer particles obtained with the emulsion polymerization processes, linked to the use of solvents and surfactant compounds.
• the particles according to the invention make it possible to obtain loading rates of active principle of between 0.10 and 2 grams / gram of waxy matrix. Those skilled in the art know that encapsulation technologies do not allow these rates to be achieved. Finally, the degradation of the particles does not cause an inflammatory reaction as can be encountered with injectable particles based on polylactic-glycolic polymer.
• Example 1 Particles containing erythromycin Example given for the manufacture of 120 g of particles containing erythromycin:
• the stirring speed of the three-bladed propeller is 110 revolutions / min. Stirring is continued for 30 seconds after the end of the addition of the composition, then stopped.
• the dispersion is then cooled to 15 ° C.
• the particles are recovered by, then washed with distilled water, then by a mixture of distilled water with 15% ethanol, then recovered and dried.
• the particles thus obtained have an average size of 62 microns. These particles are totally devoid of active ingredient on their surface.
• compositions containing erythromycin have a pronounced taste.
• the taste masking test carried out on the particles obtained does not give any detection of the active principle.
• Particles according to example 1 100 g - Aroma 7 g
• the taste masking test carried out on the particles gives no detection of the active principle.
• the particles are obtained by the dispersion of the lipid phase in the gelled aqueous phase with stirring.
• the carbopol concentration of the aqueous phase is 0.05%.
• the stirring is carried out using an axial turbo stirring rod, at a speed of 300 revolutions / min. Stirring is continued for 60 seconds after the end of the addition of the composition, then stopped.
• the dispersion is then cooled to 15 ° C.
• the particles are recovered by sieving, then washed with distilled water, then by a mixture distilled water with 15% ethanol, then collected and dried.
• the particles thus obtained have an average size of 1.2 microns.

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• Health & Medical Sciences (AREA)
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• 2003
  • 2003-03-24 FR FR0303568A patent/FR2852843B1/fr not_active Expired - Lifetime
• 2004
  • 2004-03-24 JP JP2006505750A patent/JP5072355B2/ja not_active Expired - Fee Related
  • 2004-03-24 CA CA2519962A patent/CA2519962C/fr not_active Expired - Fee Related
  • 2004-03-24 EP EP04742337.1A patent/EP1605918B1/fr not_active Expired - Lifetime
  • 2004-03-24 KR KR1020057017992A patent/KR20060012576A/ko not_active Ceased
  • 2004-03-24 WO PCT/FR2004/000729 patent/WO2004084856A2/fr not_active Ceased
  • 2004-03-24 AU AU2004224601A patent/AU2004224601A1/en not_active Abandoned
  • 2004-03-24 US US10/550,027 patent/US20070116728A1/en not_active Abandoned
  • 2004-03-24 MX MXPA05010217A patent/MXPA05010217A/es active IP Right Grant
  • 2004-03-24 NZ NZ542590A patent/NZ542590A/en unknown
• 2010
  • 2010-04-26 US US12/767,248 patent/US8911788B2/en not_active Expired - Lifetime
• 2014
  • 2014-10-27 US US14/523,999 patent/US9192679B2/en not_active Expired - Fee Related

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