EP1603538A2 - Poudre impregnee ameliorant la biodisponibilite et/ou la solubilite et procede de fabrication - Google Patents
Poudre impregnee ameliorant la biodisponibilite et/ou la solubilite et procede de fabricationInfo
- Publication number
- EP1603538A2 EP1603538A2 EP04717669A EP04717669A EP1603538A2 EP 1603538 A2 EP1603538 A2 EP 1603538A2 EP 04717669 A EP04717669 A EP 04717669A EP 04717669 A EP04717669 A EP 04717669A EP 1603538 A2 EP1603538 A2 EP 1603538A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- impregnated
- powder
- tablets
- liquid medium
- impregnated powder
- 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.)
- Withdrawn
Links
Classifications
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- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2991—Coated
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2991—Coated
- Y10T428/2993—Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2991—Coated
- Y10T428/2993—Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
- Y10T428/2995—Silane, siloxane or silicone coating
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2991—Coated
- Y10T428/2993—Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
- Y10T428/2996—Glass particles or spheres
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2991—Coated
- Y10T428/2998—Coated including synthetic resin or polymer
Definitions
- Impregnated powder improving bioavailability and / or solubility and method of making
- the present invention relates to a process for the manufacture of an impregnated powder which increases the bioavailability and / or the solubilization of one or more active principle (s) or facilitates its mode of administration, which is inexpensive to manufacture and easy to implement.
- the active principle (s) can belong to the pharmaceutical, parapharmaceutical, cosmetic, personal hygiene of food supplements or agri-food, liposoluble and / or water-soluble fields.
- This powder is impregnated with a liquid based on one or more active principle (s). This liquid can be in the form of a solution and a dispersed system.
- Bioavailability corresponds to the quantity of active ingredient administered which reaches the systemic circulation. The effectiveness of an active ingredient depends on its bioavailability.
- active ingredients suffer from low bioavailability orally. Before reaching the vena cava, an active ingredient is transported through the gastrointestinal tract and crosses the intestinal wall and the liver. It is in the liver that the active ingredients can be metabolized in an inactive form and undergo the first pass liver effect before reaching the systemic circulation. This first pass liver effect is responsible for the low oral bioavailability of most of the active ingredients.
- the short residence time in the gastrointestinal tract can also cause poor bioavailability. If the active ingredient does not dissolve quickly or cannot penetrate the epithelial membrane (in the case of a highly ionized or polar active ingredient) absorption may be insufficient. In this case, the bioavailability is variable and very low.
- Another cause of low bioavailability is attributed to competitive reactions of the absorption phenomenon, namely the formation of complex, hydrolysis by gastric acid or digestive enzymes, conjugation in the intestinal wall, absorption of other active ingredients, metabolism by luminal microflora.
- the physico-chemical properties of the active ingredients govern its absorption potential, however the properties of the dosage form used largely determine the bioavailability and / or solubility of the active ingredient.
- the subject of the invention is therefore an impregnated powder increasing the bioavailability and / or the solubility as defined above and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability), of easy and inexpensive manufacture, in contrast to the lyophilization and atomization process generally used in the prior art for the adsorption of fatty substances on a solid support.
- the invention therefore relates to a powder increasing the bioavailability and / or the solubility of at least one active principle comprising a solid, inert support, in particulate form impregnated with a liquid medium comprising a hydrophobic phase and a hydrophilic phase, at least a surfactant and at least one active principle, characterized in that the active principle (s) is (are) dissolved in one of said hydrophilic or hydrophobic phases and in the form of a suspension in the other of said phases .
- Another object of the present invention is to provide a process for manufacturing an impregnated powder making it possible to increase the bioavailability and / or the solubility and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability) and in which the integrity of the active principles is preserved.
- the present invention finally also relates to the use of the impregnated powder increasing the bioavailability and / or the solubility as defined above and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability) for the formulation of various preparations.
- an impregnated powder increasing the bioavailability and / or the solubility of at least one active principle comprising a solid, inert support, in particulate form impregnated with a liquid medium comprising a hydrophobic phase, and optionally a hydrophilic phase at least one surfactant and at least one active principle dissolved in at least one of said phases, characterized in that the said active principle (s) is (are) also present ( s) in at least one of said phases in the form of a suspension.
- suspension is meant a dispersion of solid particles in a liquid medium.
- one of the hydrophobic or hydrophilic phases is in dispersed form in the other of the phases.
- the liquid medium can also optionally comprise one or more cosurfactant (s), or any other adjuvant necessary for the preparation such as a penetration adjuvant, a mucoadhesive agent, a preservative, a colorant, a flavor, etc. mixtures of these.
- the phase in which the active principle (s) is (are) dissolved constitutes a saturated solution.
- the impregnated powder can be obtained by a process comprising the following steps: - obtaining a liquid medium comprising a hydrophobic phase, and optionally a hydrophilic phase, at least a surfactant and at least one active principle dissolved in at least one of said phases and present in at least one of said phases in the form of a suspension; - the mixture d 5 an appropriate amount of the liquid medium and an appropriate amount of an inert solid support in particulate form able to adsorb the liquid medium; and recovering an impregnated powder.
- the dissolved active ingredient and the active ingredient in suspension form are in separate phases.
- the liquid medium is obtained by dissolving an amount of active principle (s) in one of said phases, mixing with the phase containing the active principle (s) dissolved in the other of said phases, adding an additional quantity of active principle (s) to the mixture of the two phases to form a suspension of the active principle (s).
- the liquid medium is obtained by mixing the two phases and by adding a quantity of active principle (s) sufficient to obtain a dissolution of the active principle (s) in the at least one of the phases and a suspension of the active principle (s) in at least the other of the phases.
- the active principle (s) can be dissolved or dispersed in the hydrophobic phase or in the hydrophilic phase or in both.
- the process of manufacturing the impregnated powder increasing the bioavailability and / or solubility has the advantage of being easy and inexpensive to implement. All liquid and powder agitation processes known to those skilled in the art can be used.
- An important advantage of the impregnated powder according to the invention is the increase in the bioavailability and / or solubility of the active principle (s) which are contained therein.
- the impregnated powder increasing the bioavailability and / or solubility according to the invention can be used as it is or be included in various formulations.
- another advantage of the impregnated powder increasing the bioavailability and / or solubility of the invention is to allow the realization of various dosage forms, particularly orally administrable or mucosal route (oral, nasal, vaginal 5) or by cutaneous for local or systemic action.
- the dosage forms are generally dry forms such as bare or dandruff tablets, coated tablets, coated tablets (soluble coating, pH-dependent or independent coating, with gastric, intestinal or other release), matrix tablets, osmotic tablets , multilayer tablets, effervescent tablets, double-core tablets, floating tablets, gastric and / or floating forms, mucoadhesive forms, capsules, powders, multiparticulate forms such as granules, coated microgranules (coated , soluble coating, pH-dependent) or not, mucoadhesive, solid sprays.
- This impregnated powder can also be applied to fabric-type supports (wipe) to be applied to the body surface, etc.
- the dosage forms obtained can be in any form of packaging.
- the impregnated powder increasing the bioavailability and / or solubility according to the invention also has the advantage of allowing high contents of active materials.
- a liquid medium, saturated or unsaturated and dispersed with active materials, is thus obtained.
- the liquid medium thus obtained can be impregnated on an inert support.
- FIG. 1 to 4 flow diagrams of the main steps of different methods of manufacturing the impregnated powder increasing the bioavailability and / or solubility according to the invention.
- Figures 9 and 12 particle size curves of an impregnated powder according to the invention.
- the hydrophobic phase of the impregnated powder increasing the bioavailability and / or solubility can consist of any non-toxic compounds conventionally used to form an oily phase.
- the hydrophobic phase can be chosen from vegetable, animal, mineral or synthetic or semi-synthetic oils, mono, di or tri glycerides, fatty alcohols and their derivatives, polyol esters, liquid paraffin, hydrocarbons long chain such as squalane and squalene, tocopherol and its derivatives, aliphatic fatty acids, fatty acid esters, silicone oils, phospholipid compounds and their derivatives, and mixtures of these compounds.
- the hydrophobic phase includes aliphatic hydrocarbons, aromatic hydrocarbons, phosphatidylcholine, sterols, cholesterol, lecithin.
- the oils constituting the oily phase can be polar or nonpolar oils.
- vegetable oils there may be mentioned the refined oils of sunflower, olive, soya, corn, sesame, sweet almond, peanut, rapeseed as well as avocado oils, wheat germ , castor, coconut, etc ...
- cod liver oil Among animal oils, mention may be made of cod liver oil, shark liver oil and lanolin oil.
- paraffin oil Among the mineral oils, mention may be made of paraffin oil.
- aliphatic fatty acids mention may be made of isostearic acid, lauric acid, linoleic acid and oleic acid.
- fatty esters mention may be made of dibutyl adipate, dibutyl sebacate, diketyl adipate, diethyl sebacate, dihexyl adipate, diisocetyl adipate, diisopropyl, diisopropyl dimerate, diisopropyl sebaçate, diisostearyl adipate, dioctyl adipate, dioctyl sebaçate and dioctyl succinate, branched chain fatty esters such as 2-ethylhexyl isononanoate, 2 - 5 ethylhexyl myristate, 2-ethylhexyl oxystearate, 2-ethylhexyl palmitate, 2-ethylhexyl pelargonate, 2-ethylhexyl stearate, isocetyl isodecanoate, isocet
- caprilic / capric triglycerides mention may be made of caprilic / capric triglycerides, triisononanoin, triisostearine, trilaurin, trilinoline and triolein.
- silicone oils mention may be made of volatile or non-volatile polyorganosiloxane, in particular of polydimethylsiloxane oils, such as cyclic polydimethylsiloxane oils having 3 to 6 silicon atoms, for example cyclomethicone, as well as linear polydimethylsiloxanes .
- the hydrophobic phase represents from 0.1 to
- the hydrophilic phase of the impregnated powder increasing the bioavailability and / or solubility can be any non-toxic aqueous phase conventionally used by those skilled in the art.
- the hydrophilic phase can consist of water (distilled or deionized), a hydroalcoholic mixture, in particular a water / alkanol mixture such as ethanol, an aqueous buffered solution, an aqueous saline solution, an aqueous glucose solution. , and a mixture of water-polyethylene glycol, water-propylene glycol and water-glycerol.
- the aqueous phase represents from 0.1 to 99.9% by weight, preferably 5 to 60% of the total weight of the liquid medium containing active principle (s).
- the liquid medium containing in principle active ingredient (s) comprises at least one non-toxic surfactant.
- the surfactant can be non-ionic, anionic, cationic or amphiphilic. This liquid medium may possibly be neutral or negatively charged depending on the functionality sought.
- Non-ionic surfactants are also well known compounds per se (see in particular in this regard "Handbook of Surfactants” by MR PORTER, Editions Blackie & Son (Glasgow and London), 1991, pp 116-178) and their nature is not, in the context of the present invention, of a critical nature.
- alcohols can in particular be chosen from (nonlimiting list) alcohols, alpha-diols, alkylphenols or polyethoxylated, polypropoxylated or polyglycerolated fatty acids, having a fatty chain comprising for example 8 to 18 carbon atoms, the number of ethylene oxide or propylene oxide groups which can range in particular from 2 to 50 and the number of glycerol groups which can range in particular from 2 to 30.
- polyethoxylated fatty amides preferably having from 2 to 30 moles of ethylene oxide, polyglycerolated fatty amides comprising on average 1 to 5 glycerol groups
- esters of polyoxyethylenated fatty acids sucrose esters, sucroglycerides, lauryl ether and derivatives, polysorbate, sorbitan ester, dioctyl sodium sulfosuccinate, bis-2-ethylhexyl sodium sulfosuccinate and derivatives, all sorbitan derivatives, polyoxyethylenated glycol alkyl ether.
- anionic surfactants which can be used, alone or in mixtures, in the context of the present invention, mention may be made in particular (non-limiting list) of the salts (in particular alkaline, in particular sodium, ammonium salts , amine salts, amino alcohol salts or alkaline earth (magnesium) salts of the following compounds: alkyl sulfates, alkyl ether sulfates, alkylamidoethersulfates, alkylarylpolyethersulfates, monoglycerides sulfates; alkylsulfonates, alkylphosphates, alkylamidesulfonates, alkylarylsulfonates, ⁇ -olefins paraffme-sulfonates; alkylsulfosuccinates, alkylethersulfosuccinates, alkylamidesulfosuccinates; alkylsulfosuccinamates; alkyls
- anionic surfactants which can still be used, mention may also be made of the salts of fatty acids such as the salts of oleic, ricinoleic, palmitic, stearic acids, coconut oil or hydrogenated coconut oil acids; acyl-lactylates whose acyl radical contains 8 to 20 carbon atoms.
- Weakly anionic surfactants can also be used, such as uronic alkyl D galactoside acids and their salts and also the polyoxyalkylenated (C 6 -C 24 ) alkyl ether carboxylic acids, the polyoxyalkylenated (C 6 -C 24 ) aryl ether carboxylic acids, polyoxyalkylenated alkyl (C6-C24) amido ether acids and their salts, in particular those comprising from 2 to 50 ethylene oxide groups, and their mixtures.
- uronic alkyl D galactoside acids and their salts and also the polyoxyalkylenated (C 6 -C 24 ) alkyl ether carboxylic acids, the polyoxyalkylenated (C 6 -C 24 ) aryl ether carboxylic acids, polyoxyalkylenated alkyl (C6-C24) amido ether acids and their salts, in particular those comprising from 2 to 50 ethylene oxide groups, and their mixtures.
- Anionic surfactants also include: petroleum sulfonate, sulfonated glycerides, alpha sulfonate and soaps.
- anionic surfactants it is preferred to use according to the invention the salts of alkyl sulphates (for example sodium lauryl sulphate) and of alkyl ether sulphates and their mixtures.
- alkyl sulphates for example sodium lauryl sulphate
- alkyl ether sulphates and their mixtures.
- amphoteric surfactants may in particular be (non-limiting list) derivatives of aliphatic secondary or tertiary amines, in which the aliphatic radical is a linear chain or branched having 8 to 22 carbon atoms and containing at least one water-soluble anionic group (for example carboxylate, sulfonate, sulfate, phosphate or phosphanate); Mention may also be made of (C 8 -C 2 o) alkyl betaines, sulfobetaines, (C 8 -C 2 o) alkyl amidoalkyl (C ⁇ -C 6 ) betaines or (C 8 -C 20 ) alkyl amidoalkyl (C ⁇ -C 6 ) sulfobetaines.
- Amphoteric surfactants also include phospholipids of natural, modified natural, semi-synthetic, synthetic origin, with grafts (lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phytoglycolipid, lysophosphatide, sphyngomyelin), alkylaminocarboxylic acids
- Cationic surfactants can be in particular (nonlimiting list) alkylated quaternary ammoniums, alkylamine salts and amine oxides.
- Cationic surfactants include cetrimide, primary amines, acetates and hydrochloride of fatty amines, quaternary ammonium salts, amides of substituted and derived diamines, amides of diethylenetriamine.
- the amount of surfactant present is at least 1% by weight relative to the total weight of the liquid medium, generally from 2 to 70% by weight, and preferably from 10 to 60% by weight.
- the liquid medium also contains at least one co-surfactant.
- the co-surfactant is a compound whose molecule is generally considerably smaller than that of the surfactant and whose role is to act on the molecular stacking at the interface of the droplets, so that the formation of the liquid medium is energetically favored.
- alkanols in particular from C 3 to C 6 , glycol ethers, glycol and its derivatives, propylene glycol and its derivatives, lauric esters of propylene glycol , polyglycerol and its derivatives, oleic esters of polyglycerole and ethyldiglycol.
- Co-surfactants include polyoxylated castor oil, hydrogenated polyoxylated castor oil, polyglyceryls and derivatives, organic acids (oleic acid, naphthalenic acid, resinic acid, diacid alcohols (tartaric acid %), triacids alcohols (citric acid), diacids (malonic acid, maleic acid, succinic acid, adipic acid)) alcohols with hydrophilic and / or lipophilic tendency (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, iso-amyl alcohol , hexanol, heptanol, octanol Among, glycols with a hydrophilic and / or hydrophobic tendency (ethylene glycol, propylene glycol, isopropyiene glycol, butylene glycol, butanediol 2-3, isobutene glycol, butanediol
- fatty acids and their derivatives lauric, palmitic, oleic, stearic acid
- polyols glycerol, trimethylolpropane, pentane triol 2-3-4
- amines and polyamines and their derivatives dimethylamine, ethylene diamine, diet hylene triamine, triethylene tretramine, tetra-ethylene pentamine Certainly, amino alcohols (ethanolamine, diethanolamine, triethanolamine, diethyl amino ethanol .
- the co-surfactant when used, generally represents from 0.01 to 60% by weight of the total weight of the liquid medium containing at least one active principle.
- the active material (s) included in the liquid medium can be any active principle having an activity in the pharmaceutical, parapharmaceutical, cosmetic, food or agri-food supplements, in particular in the cosmetic fields and / or therapeutic, preferably therapeutic.
- These active ingredients can be soluble and / or dispersible in one or other of the components of the liquid medium.
- the active ingredients can be water-soluble, liposoluble or amphiphilic.
- the active principles of chemical, natural or biological origin, used according to the invention can be selected from those conventionally used in the following pharmacotherapeutic families: allergology, anesthesia / resuscitation, oncology and hematology, cardiology and angiology, contraception and termination of pregnancy, dermatology, endocrinology, gastroenterohepathology, gynecology and obstetrics, immunology and transplantation drugs, infectiology and parasitology, metabolism diabetes and nutrition, neurology / psychiatry, ophthalmology, otolaryngology, pneumology, rheumatology, stomatology, toxicology, urology / nephrology, as well as analgesics / anti-pyretics and antispasmodics, anti-inflammatories, contrast agents used in radiology, hemostats and blood treatment products and derivatives.
- the active ingredients can be selected from the group consisting of active ingredients passing through the mucosal barrier and reaching the systemic circulation, such as cyproterone acetate, ⁇ -4-androstenedione, 3-keto-desogestrel, desogestrel. .
- ⁇ -3 adrenergic agonist the ⁇ -3 adrenergic agonist, growth hormone, oxybutinin, buprenorphine, pergolide, nestorone, 7 ⁇ -methyl-19-nortesterone, mecamylamine, salbutamol, selegiline, buspirone, ketotifen, lidocaine, ketorolac, eptazocin, insulin, interferon ⁇ , prostaglandins, 5-aminolevulinic acid, benzodiazepine alprozolam, diclofenac, fenoprofen , flubiprofen, ketoprofen, methylphenidate, miconazole, piroxicam, buprenorphine, alprozolam, dexmedetomidine, prazosin (adrenergic antagonist), alprostadil, tulobuterol ( ⁇ adrenergic agonist) 9 thinylestradin + norelgestol nororostoline + nore
- Esomeprazole Esomeprazole
- Melagatran in case of thrombosis
- Rosuvastatin Ezetimide
- Pitavastatin hyperlipidemia
- Mitiglinide type II diabetes
- Cilomilast Viozan
- Omapatrilat hypertensive
- Orzel oncology
- Caspofongin acetate Voriconazole (infections)
- new COX inhibitors such as Etoricoxib (inflammation), Valdecoxib (arthritis) and Parecoxib
- Substance P antagonist depression
- Darifenacine urology
- Eletriptan migraine
- Alosetron Tegaserod
- Capravirine HAV
- vitamin A for example isotretinoin, coenzyme Q10
- antivirals for example acyclovir
- analgesics for example indometacin, naproxen
- antiulcers e.g. omeprazole, lansoprazole
- antisporiasics e.g. Cyclosporine
- antibiotics cefaclor, amoxicillin, cloxaciline
- sex hormones antiestrogens, e.g. raloxifene; estrogens, e.g.
- the active ingredients can also be chosen from those conventionally used in cosmetics, parapharmacy and for food supplements.
- the contents of these active ingredients are those conventionally used in the fields considered.
- cosmetic and parapharmaceutical active agents there may be mentioned emollients, humectants, pigments and dyes, anti-wrinkle agents (retinol), anti-fungal agents, anti-acne agents, softeners, perfumes and vitamins.
- vitamins A, B, E, C, Bl, B2, B3, B6, B9, B12, B8H, B5 .
- minerals calcium, phosphorus, iron, magnesium, zinc, iodine ...)
- carotenoids alpha-carotene, beta-carotene, gamma cartene, lutein, zeaxanthin, cryptoxanthin, lycopene ...)
- phytoestrogens isoflavones (genistein, diadzein, biochanin A , formononetin ...), lignans (enterolactone, enterodiol %), coumestanes (coumestrol)), plant extracts (fennel, heather, blackcurrant, grape seed extract, fucus, ginjseng, green coffee, ginger. ..), oils (evening primrose, wheat germ, borage, pumpkin seeds ...), clays (diosm
- the content of active material (s) in the impregnated powder increasing the bioavailability and / or the solubility according to the invention is from 0.001 to 70% by weight, preferably from 0.5 to 60% by weight, relative to the total weight of the liquid medium, depending on the nature of the active material.
- the liquid medium can also contain a penetration adjuvant or a mixture of adjuvants, intended to promote the passage of the active molecules through the membrane concerned.
- a penetration adjuvant or a mixture of adjuvants, intended to promote the passage of the active molecules through the membrane concerned.
- the penetration adjuvants mention may be made of the group consisting of esters of aliphatic fatty acids such as isopropyl myristate, fatty acids such as oleic acid; alcohols or polyols such as ethanol, propylene glycol and polyethylene glycol; components of essential oils and terpene derivatives (such as eugenol, geraniol, nerol, eucalyptol, menthol); preferably nonionic surfactants, such as polyoxyethylene sorbitan (fatty acid ester), polyoxyethylene alkyl ether, polyoxyethylene derived from castor oil as well as their mixtures; moisturizers such as glycerin, urea; kerato
- the liquid medium can also comprise an adhesive agent (mucous membrane, skin), so as to finally obtain an impregnated powder increasing the bioavailability and / or the solubility.
- adhesive agents mention may be made of carbomers, polyoxyethylenes, methylcelluloses, carboxymethylcelluloses, sodium carboxymethylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses, polyvinylpyrrolidone, polyvinyl alcohol, polyisobutylene, polyisobutylene xanthan, Carob gum, chitosan, polycarboxylates, acrylic / methacrylic acid copolymers, acrylic acid / acrylamide copolymers, acrylic acid / methylmethacrylate copolymers, acrylic acid / polyethylene glycol copolymers, polyacrylic acid / butyl acrylate copolymers , 2-hydroxyethylmethacrylate (HEMA), the compound sold under the name CYDOT ®
- the amount of adhesive agents present in the liquid medium represents from 0.01 to 70% by weight of the total weight of the liquid medium.
- thermoreversible polymers such as the compounds marketed under the names LUTROL ® ® xyloglucan and, particularly for the mucosal or dermal administration.
- the powder impregnated according to the invention can gel on contact with the mucosa or the epidermis.
- these polymers are present in an amount of 0.01 to 70% by weight of the total weight of the liquid medium.
- the invention also has the advantage of allowing high contents of active principles.
- the liquid medium generally represents from 1 to 99%, preferably 20 to 90%, better 40 to 90% and even better 50 to 80% of the total weight of the impregnated powder increasing the bioavailability and / or solubility.
- the inert support in particulate form can be any non-toxic support that is chemically inert with respect to the liquid medium containing the active principle and its constituents, suitable for the intended application and capable of being impregnated with the liquid medium. without damaging its integrity.
- particulate inert supports Among the particulate inert supports recommended, mention may be made of natural silicas, silica gels, fumed silicas, precipitated silicas, clays, talc, magnesium hydroxide, aluminum hydroxide, magnesium oxide, maltodextrins, cyclodextrins, cellulose derivatives such as cellulose powder and their mixtures.
- the preferred particulate inert supports are silicas.
- the silicas can be hydrophilic, hydrophobic, or amphiphilic. Suitable silicas are marketed under the names AEROSIL ®
- montmorillonites and bentonites.
- Maltodextrins are marketed under the brand LYCATAB ® . 0
- the average particle size of the inert particulate supports according to the invention is generally between 0.001 and 300 ⁇ m, preferably between 1 and 100 ⁇ m.
- the particulate inert support represents from 1 to 90%, preferably 10 to 80%, better 10 to 60%, and better still 20 to 5 50% by weight of the total weight of the impregnated powder increasing the bioavailability and / or solubility.
- the impregnated powder can also include any other adjuvant necessary for the preparation such as (non-exhaustive list) flavorings, perfumes, essential oils, colorings, 0 antioxidants, preservatives, sweeteners, fillers, etc. or mixture thereof
- the particle size of the impregnated powder increasing the bioavailability and / or solubility according to the invention varies from 1 ⁇ m to 100 ⁇ m, preferably from 20 to 50 ⁇ m.
- the impregnated powder increasing the bioavailability and / or solubility according to the invention can be easily produced by proceeding in the following general manner: firstly, a liquid medium containing at least one active principle is obtained in both dissolved and suspension form. The liquid medium o containing at least one active principle is gradually impregnated with stirring on the inert particulate support. After homogenization of the mixture, the formulation is recovered in the form of an impregnated powder increasing the bioavailability and / or the solubility.
- FIG. 1 to 4 are flow diagrams of the main steps of variant methods of manufacturing the impregnated powder increasing the bioavailability and / or the solubility according to the invention. s Referring to FIG. 1, there is shown the main steps for manufacturing an impregnated powder increasing the bioavailability and / or the solubility according to the invention including a hydrophobic active principle.
- the hydrophobic active principle is dissolved, with stirring, in this hydrophobic medium.
- the active principle is solubilized at saturation, but we can consider the 5 case where it is not at saturation.
- the aqueous medium is introduced with stirring. Obtaining a liquid containing the active principle (s) at saturation or not depending on the case. At this stage, an additional quantity of the hydrophobic active ingredient is added, with stirring, until the desired active ingredient content is obtained. A suspension is thus obtained, in general in a semi-solid creamy and opaque form.
- FIG. 2 relates to a variant of the method of FIG. 1 which differs from the latter in that the hydrophilic medium is first added with stirring to the hydrophobic medium, then the desired quantity of hydrophobic active principle is added with stirring up to 0 get the suspension. We can therefore obtain the desired amount of active ingredient. As in the previous case, the suspension is then impregnated on the inert support by simple stirring.
- FIGS. 3 and 4 are similar to those of FIGS. 1 and 2, respectively, but relate to the incorporation of a hydrophilic active principle, and for which the order of preparation and incorporation of the hydrophobic medium and the aqueous medium.
- the impregnated powder increasing the bioavailability and / or solubility according to the invention can be used for making various presentations, in particular dosage forms which can be administered orally or mucosally, presentations used in the cosmetic industry, food and agrifood supplements in the parapharmaceutical industry.
- the manufacturing process remains the same as those described above.
- impregnated powder increasing the bioavailability and / or the solubility can also be used alone as such and in various presentations in (non-limitative list of the invention) sachets, stick-packs, pressurized bottles or not with or without applicators, wipes, etc.
- the impregnation support selected from inert powders, the dosage form chosen various release profiles are then accessible such as immediate, modified, delayed, bimodal, pulsed release.
- the impregnated powder increasing the bioavailability of the invention can also be put in the form of capsules, stick packs (and remain in the form of powder), in sachets, in powder sprayers for nasal, buccal or vaginal route in powder sprayers. with special applicator, etc.
- diluents for example: microcrystalline cellulose, lactose, cellulose powder, dicalcium phosphate, sucrose, starch, bicarbonate, mannitol .
- lubricants for example magnesium stearate, sodium stearyl fumarate .
- binders for example: polyvinylpy ⁇ Olidone-vinyl acetate, povidone .
- disintegrating agent starch and derivatives, sodium glycolate starch, alginate, microcrystalline cellulose, croscarmellose sodium, crosspovidone ?” or other excipients necessary for the production of tablets.
- the tablets can be obtained by direct compression, by wet granulation, by dry granulation, or any other technique known to those skilled in the art.
- Example 1_ making rapid release progesterone fease tablet.
- solution A saturated with active ingredient
- the sunflower oil solution (Lesieur) is saturated with progesterone.
- the surfactant / co-surfactant ratio is fixed at 75/25.
- the co-surfactant is Transcutol ® (Gattefossé), it also plays the role of absorption promoter and promotes passage through the mucosa.
- a translucent phase is obtained in which progesterone is incorporated so as to saturate the mixture.
- progesterone is incorporated so as to saturate the mixture.
- At temperature ambient with mechanical stirring with the Heidolph Bioblock RZR 2051 agitator: 700 rpm for 4 minutes, it is possible to pass the solution to the ultrasonic bath for a few minutes (6 minutes 30 seconds) in order to speed up the process of solubilization of the active ingredient.
- Progesterone is added to 62.5% by weight of the previous solution, so as to obtain a suspension dosed at 40% in active principle.
- progesterone is added to solution A with mechanical stirring with the Heidolph Bioblock RZR 2051 agitator, at 700 rpm for 5 minutes.
- This suspension B which is generally a semi-solid creamy and opaque form, has the following composition:
- this suspension B is obtained, it is impregnated on silica such as Sipernat ® 50 (Degussa).
- silica such as Sipernat ® 50 (Degussa).
- a Zanchetta mixer-granulator-dryer is used for this manipulation.
- the B progesterone suspension is gradually incorporated into the device to be impregnated on the silica.
- the impregnated powder increasing the bioavailability and / or the solubility then has the following composition:
- Dissolution profile of the impregnated powder increasing the bioavailability and / or the solubility above compared to a pharmaceutical form marketed: Utrogestan ®100mg (Besins.
- the in vitro dissolution test was carried out with a Sotax AT7 dissolutest, with glass dissolution beakers.
- the dissolution medium used is 1% kleptose.
- the temperature of the bath is maintained at 37 ° C., and the speed of rotation of the blades is 150 rpm.
- the assay is carried out online by UV spectrometry.
- Apparent volume at V0 122 ml.
- Apparent volume at V10 114 ml o
- Apparent volume at V500 104 ml
- the diluent used is a mixture of Vivapur ® 102 (Rettenma ⁇ er) and Encompress ® (Penwest).
- composition of the tablets is as follows:
- Example 2 production of an impregnated powder increasing the bioavailability and / or the solubility based on quick-release fenofibrate.
- the suspension Al is performed based on DC Labrafac ® (Gattefosse), ® Montanox 85 (Seppic), propylene glycol (Copper), and distilled water.
- the first 3 components are mixed using a Heidolph Bioblock RZR2051 agitator at 700 rpm.
- the active ingredient is added to the previous mixture, the formulation is passed through ultrasonic baths for 5 minutes. Then mechanical agitation in the Bioblock at 1200 rpm for 45 minutes.
- the wording is as follows
- the formulation loaded with fenofibrate is gradually incorporated into the device to be impregnated on silica.
- the in vitro dissolution test was carried out with a Sotax AT7 dissolutest, with rotating paddles.
- the dissolution medium used is from SLS to O.IM.
- the temperature of the bath is maintained at 37 ° C., and the speed of rotation of the blades is 75 rpm.
- the assay is carried out online by UV spectrometry. The results are shown graphically in Figure 6.
- the impregnated powder increasing the bioavailability and / or solubility of the invention permits release of active principle much more rapidly than Lipanthyl ® 160mg in the first 10 minutes.
- Example 3 ⁇ realization cAn impregnated powder attempting bioavailability and / or care! has a quick release 9 acydov! r case.
- the last 3 components are mixed using a Heidolph Bioblock RZR2051 agitator at 500 rpm.
- the active ingredient is added to the previous mixture, the formulation is passed through ultrasonic baths for 5 minutes. Then mechanical agitation in the Bioblock at 900 rpm for 20 minutes.
- the wording is as follows:
- the formulation loaded with acyclovir is gradually incorporated into the apparatus to be impregnated on the silica.
- Example 4 Production of rapid release progesterone tablet.
- Saturated solution of active ingredient, solution A The hydrophobic phase based on sunflower oil (Lesieur) is saturated with progesterone.
- the surfactant / co-surfactant ratio is fixed at 75/25.
- a mixture of surfactants is used: Tween® 80 (Seppic) and Montane® 80 (Seppic).
- the co-surfactant is Transcutol® (Gattefossé), it also plays the role of promoter of absorption and promotes the passage through the gastrointestinal mucosa.
- Sunflower oil, montane 80, Tween 80 and Transcutol are mixed using a Heidolph Bioblock RZE2051 agitator, at 500 rpm for 6 min, at room temperature. A translucent phase is obtained in which the progesterone is incorporated until saturation, with stirring at 700 rpm for 4 min.
- the hydrophilic phase (purified water) is added.
- the whole is homogenized with the Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min.
- Progesterone is dispersed in solution A, until a suspension dosed at 45.28% in Progesterone is obtained, with stirring at 700 rpm for 5 min using a Heidolph Bioblock RZR 2051 agitator.
- the suspension obtained is slightly viscous and white.
- the suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
- Adsorption is carried out using a Rotolab mixer-granulator, Zan peu.
- the impregnation parameters are as follows:
- the dissolution profile of the progesterone-impregnated powder improving bioavailability and solubility is compared to that of the commercial form Utrogestran®.
- the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
- the dissolution medium used is a 1% Kleptose solution.
- the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 150 RPM.
- the assay is carried out online by UV spectrophotometry.
- FIG. 7 illustrates a comparison of the dissolution profile (Kleptose 1%, 150 rpm) of the progesterone-based impregnated powder dosed at 100 mg according to the invention with a commercial formulation. After 1 hour, the entire dose is released with the impregnated powder while only 10% of progesterone is released from the commercial form.
- the mixture is then compressed with an alternative Frogerais tableting machine.
- the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
- the dissolution medium used is a 1% Kleptose solution.
- the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 150 RPM.
- the assay is carried out online by UV spectrophotometry.
- FIG. 8 illustrates a comparison of the dissolution profile (Kleptose 1%, 150 rpm, 37 ° C), between, respectively, (i) a powder impregnated according to the invention, (ii) a powder tablet impregnated according to the invention and (iii), a commercial formulation, dosed at 100 mg of progesterone.
- the tablets based on the impregnated powder release approximately 95% of progesterone while only 10% of progesterone are released from the commercial form.
- Acyclovir Acyclovir is dissolved in the hydrophilic phase (HCl buffer, pH 2), at 500 rpm for 10 min, at room temperature. Solution A obtained is clear and fluid.
- the hydrophobic phase (Captex® 300, Abitec), the surfactant (Acconon® CC6, Abitec) and the co-surfactant (Plural oleic, Gattefossé) are mixed for 5 min, at 500 RPM, at room temperature. Solution B obtained is slightly yellowish and fluid.
- Solution A sutured in Acyclovir and solution B are mixed, 5 min 500 rpm.
- the mixture C obtained is fluid and slightly yellowish.
- PAcyclovir The remainder of PAcyclovir is suspended, with stirring 700RPM, for 10 min.
- Suspension D obtained at 65% Acyclovir is white and creamy.
- the suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
- Adsorption is carried out using a Rotolab mixer-granulator, Zanchetta.
- the dissolution profile of the impregnated powder based on Acyclovir improving the bioavailability and the solubility is compared with that of the commercial form Zovirax®.
- the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
- the dissolution medium used is a 0.01 N HCl solution.
- the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM.
- the assay is carried out online by UV specfrophotometry.
- the impregnated powder is mixed with a diluent (Vivapur® 12,
- the mixture is then compressed with an alternative Frogerais tableting machine.
- the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
- the dissolution medium used is a 0.01 N HCl solution.
- the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM.
- the assay is carried out online by UV spectrophotometry.
- the dissolution profile results are represented in FIG. 11 which illustrates a comparison of the dissolution profiles (HCl 0.0 IN; 100 rpm) (i) of an impregnated powder based on Acyclovir according to the invention , (ii) a tablet made from this impregnated powder and (iii) a commercial formulation called ZOVIRAX® dosed at 200 mg.
- FIG. 12 illustrates the curve of distribution of size of the particles of this powder.
- Capryol® 90 (Gattefossé), Acconon® CC6 (Abitec), Transcutol® (Gattefossé) are mixed using a Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min at room temperature.
- a translucent phase is obtained in which the co-micronized fenofibrate is incorporated until saturation, with stirring at 700 rpm for 10 min.
- the hydrophilic phase (purified water) is added.
- the whole is homogenized with the Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min.
- the suspension B obtained is viscous and white.
- the suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
- Adsorption is carried out using a Rotolab mixer-granulator, Zanchetta.
- Co-micronized fenofibrate improving bioavailability and solubility is compared to that of the commercial form Lipanthyl.
- the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
- the dissolution medium used is a 0.1 M sodium lauryl sulfate solution.
- the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM.
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Applications Claiming Priority (3)
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FR0302802A FR2851918B1 (fr) | 2003-03-06 | 2003-03-06 | Poudre impregnee ameliorant la biodisponibilite et/ou la solubilite et procede de fabrication |
FR0302802 | 2003-03-06 | ||
PCT/FR2004/000541 WO2004080381A2 (fr) | 2003-03-06 | 2004-03-05 | Poudre impregnee ameliorant la biodisponibilite et/ou la solubilite et procede de fabrication |
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US (1) | US7569274B2 (no) |
EP (1) | EP1603538A2 (no) |
JP (1) | JP4901469B2 (no) |
AU (1) | AU2004218859B2 (no) |
BR (1) | BRPI0408065A (no) |
CA (1) | CA2518200C (no) |
FR (1) | FR2851918B1 (no) |
MX (1) | MXPA05009440A (no) |
NO (1) | NO20054562L (no) |
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ITMI20011756A1 (it) * | 2001-08-09 | 2003-02-09 | Remedia S R L | Composizione farmaceutica comprendente una microemulsione doppia acqua/olio/acqua incorporata in un supporto solido |
ITMI20012694A1 (it) * | 2001-12-19 | 2003-06-19 | Remedia S R L | Composizione farmaceutica comprendente una microemulsione doppia olio/acqua/olio incorporata in un supporto solido |
-
2003
- 2003-03-06 FR FR0302802A patent/FR2851918B1/fr not_active Expired - Fee Related
-
2004
- 2004-03-05 JP JP2006505704A patent/JP4901469B2/ja not_active Expired - Fee Related
- 2004-03-05 BR BRPI0408065-3A patent/BRPI0408065A/pt not_active IP Right Cessation
- 2004-03-05 WO PCT/FR2004/000541 patent/WO2004080381A2/fr active Application Filing
- 2004-03-05 AU AU2004218859A patent/AU2004218859B2/en not_active Ceased
- 2004-03-05 RU RU2005130989/15A patent/RU2367412C2/ru not_active IP Right Cessation
- 2004-03-05 US US10/547,797 patent/US7569274B2/en not_active Expired - Fee Related
- 2004-03-05 CA CA2518200A patent/CA2518200C/fr not_active Expired - Fee Related
- 2004-03-05 MX MXPA05009440A patent/MXPA05009440A/es active IP Right Grant
- 2004-03-05 EP EP04717669A patent/EP1603538A2/fr not_active Withdrawn
-
2005
- 2005-10-04 NO NO20054562A patent/NO20054562L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO2004080381A3 * |
Also Published As
Publication number | Publication date |
---|---|
JP4901469B2 (ja) | 2012-03-21 |
CA2518200A1 (fr) | 2004-09-23 |
FR2851918A1 (fr) | 2004-09-10 |
US7569274B2 (en) | 2009-08-04 |
US20060182691A1 (en) | 2006-08-17 |
WO2004080381A3 (fr) | 2005-07-28 |
CA2518200C (fr) | 2013-04-30 |
WO2004080381A2 (fr) | 2004-09-23 |
RU2367412C2 (ru) | 2009-09-20 |
JP2006519820A (ja) | 2006-08-31 |
AU2004218859A1 (en) | 2004-09-23 |
AU2004218859B2 (en) | 2009-10-15 |
BRPI0408065A (pt) | 2006-02-14 |
FR2851918B1 (fr) | 2006-06-16 |
NO20054562L (no) | 2005-12-01 |
RU2005130989A (ru) | 2006-08-10 |
MXPA05009440A (es) | 2006-04-07 |
NO20054562D0 (no) | 2005-10-04 |
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