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
  • A61K9/20—Pills, tablets, discs, rods
• • 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
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives 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
  • A61K9/20—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
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • 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
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to a water dispersible multilayer pharmaceutical composition comprising an antimalarial agent in combination with at least one other antimalarial agent.
• the present invention also includes a method for producing such a pharmaceutical composition.
• Multidrug-resistant P. falciparum malaria is widespread in South-East Asia and South America.
• the African continent which bears the heaviest burden of malaria morbidity and mortality, is now also reached.
• Resistance to cheap monotherapies such as chloroquine and sulfadoxine-pyrimethamine is gaining ground, leading to increased mortality.
• the current situation is partly the result of the misuse of antimalarials in the last century: antimalarials have been used massively, always as monotherapy, one after the other, and generally in violation of the rules of drug use since they have have been maintained despite unacceptable levels of resistance.
• a new group of antimalarials - artemisinin derivatives in particular artesunate, artemether and dihydroartemisinin - has been used more and more for ten years. These compounds have a very fast therapeutic action (decrease in parasite count and resolution of symptoms), they are effective against multidrug-resistant P. falciparum malaria, they are well tolerated by patients and they reduce the carrying of gametocytes (and can therefore reduce the transmission of malaria).
• Artemisinin is a sesquiterpenic lactone with two oxygen atoms linked by a peroxide bridge over a seven-carbon ring. It is mainly artemisinin derivatives which are used in therapy, such as, for example, artemether, artesunate, arteether, or dihydroartemisinin.
• ferroquine the structural formula of which is shown below, which is described in WO96 / 35698.
• WO 2006/111647 further describes the association between ferroquine and an artemisinin derivative, and in particular Artesunate.
• a combination of two active ingredients is carried out by mixing the powders containing the active ingredients and the excipients, or by granulating them.
• the most conventional method is to manufacture the pharmaceutical composition corresponding to an active ingredient, and to add the second active ingredient during the mixing or the granulation step.
• ferroquine is understood to mean ferroquine in the form of base, salt, hydrate or solvate.
• artemisinin means artemisinin or a derivative thereof, for example artemether, artesunate, arteether, or dihydroartemisinin, artemisinin or its derivative being basic form, salt, hydrate or solvate.
• An object of the present invention is a multilayer pharmaceutical composition characterized in that it comprises at least two layers and a minimum of two active ingredients per pharmaceutical composition, said composition being dispersible in water and comprising: ferroquine in the form of base, salt, hydrate or solvate as the first active ingredient,
• the pharmaceutical composition is in the form of a tablet.
• the pharmaceutical composition according to the invention is a multilayer pharmaceutical composition comprising at least two layers.
• this pharmaceutical composition is a bilayer pharmaceutical composition.
• this pharmaceutical composition is a three-layer pharmaceutical composition.
• such a pharmaceutical composition contains therapeutically effective doses of ferroquine, or a pharmaceutically acceptable salt, hydrate or solvate of ferroquine, and at least one artemisinin derivative or one of its derivatives, or a pharmaceutically acceptable salt, a hydrate or a solvate of artemisinin or a derivative thereof, and at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• Ferroquine may especially be in the form of L-tartrate salt, di-hydrochloride salt, hydrochloride salt, or base.
• An example of a salt / base ratio for ferroquine L-tartrate salt is 1.69
• an example of a salt / base ratio for ferroquine di-hydrochloride salt is 1.17.
• the pharmaceutical composition also contains a therapeutically effective dose of artemisinin or a derivative thereof selected from artemether, artesunate, arteether, and dihydroartemisinin.
• the artemisinin derivative used is artesunate. It is important that the pharmaceutical composition according to the invention can be ingested as a conventional tablet and not dissolve in the oral cavity during its passage to the esophagus, even if the passage is facilitated by the simultaneous deglutition of liquid .
• malaria also affects infants and young children on immature swallowing, and it is also important that these young patients have access to antimalarial treatment.
• the pharmaceutical composition according to the invention is available in the form of tablets developed according to different sizes depending on the dosage and specifically adapted to the age of the patient.
• the tablet size or compression format (width x length) is expressed in millimeters (1 * L mm). Since the thickness of the tablets obtained is a function of the compression format used, the amount of powder to be compressed and the compression force applied, it is variable.
• the pharmaceutical composition according to the invention is also dispersible in water, making it suitable for pediatric use.
• water-dispersible pharmaceutical composition is meant a pharmaceutical composition of high hardness, limited friability and rapid disintegration.
• water dispersible does not limit the scope of the invention to a dispersion of the pharmaceutical composition in water, but should be understood as being the dispersion of the pharmaceutical composition in an aqueous liquid vehicle, such as water, fruit juice, milk, or soda.
• the hardness of the present composition is between 50 and 160 N, preferably between 60 and 150 N, and even more preferably between 70 and 150 N. 140N, for example 93, 8N.
• the hardness of the present composition is between 100 and 175N, preferably between 110 and 165N, and even more preferably between 115 and 160N, for example 132N.
• the hardness of the present composition is between 110 and 230N, preferably between 120 and 220N, and even more preferably between 130 and 210N, for example 169N.
• the hardness of the present composition is between 140 and 260N, preferably between 160 and 240N, and even more preferably between 170 and 230N, for example 198N.
• the hardness is measured according to the method described below: the tablet is placed against the fixed jaw of a durometer.
• the other jaw, mobile, moves by means of a motorized drive system and applies on the tablet a pressure which increases constantly.
• the increase in pressure is electronically monitored by the durometer and continues to be applied to the sample until an equal value or higher is measured.
• the resistance of the tablet to the applied pressure decreases.
• the measurement system detects this decrease and the highest resistance value is then displayed and is validated as the breaking strength value of the tablet.
• the friability of the pharmaceutical composition is also dependent on the size of the tablet (compression format) and the compressive force applied, having an impact on the disintegration time of the tablets obtained.
• the friability of the pharmaceutical composition after 4 minutes is, according to one aspect of the invention, between 0 and 0.3%, preferably between 0 and 0.2%, even more preferably between 0 and 0.15%, for example 0.11%.
• the friability of the pharmaceutical composition after 4 minutes is, according to one aspect of the invention, between 0 and 0.3% and even more preferably between 0 and 0.2%, for example 0.11%.
• the friability of the pharmaceutical composition after 4 minutes is, according to one aspect of the invention, between 0 and 0.3% and even more preferably between 0 and 0.2%, for example 0, 17%.
• the friability of the composition after 4 minutes is, according to one aspect of the invention, between 0 and 0.5%, preferably between 0 and 0.4%, even more preferably between 0 and 0.3%, for example 0.21%.
• the friability of the tablets is measured after 100 rotations according to the method described in the European Pharmacopoeia 6th Edition 2010 chapter 2.9.7.
• the disintegration is measured according to the method described in the European Pharmacopoeia 6th Edition 2010, chapter 2.9.1.
• the fineness of dispersion is also, in one embodiment, in accordance with the following definition: two tablets are placed in 100 ml of purified water and stirred until total dispersion.
• the dispersion obtained is homogeneous and passes through a sieve with a nominal mesh size of 710 ⁇ m.
• the fineness of dispersion is measured according to the method described in the European Pharmacopoeia 6th Edition 2010 Chapter 7, relating to the definition of dispersible tablets.
• the tablet according to the invention comprises two layers, one comprising ferroquine in the form of base, salt, hydrate or solvate, and the other comprising artesunate in the form of base, salt, hydrate or solvate.
• the tablet according to the invention comprises three layers, one comprising ferroquine in the form of base, salt, hydrate or solvate, and the other comprising artesunate in the form of base, salt, hydrate or solvate, these two layers being separated by an insulating layer containing no active ingredient (neutral).
• the layers can be the same or different in weight or volume, and they can all be visible from the outside or not.
• Artemisinin or one of its derivatives the two halves being of the same color and appearance, and therefore indistinguishable by the patient.
• the two halves may alternatively be colored and / or of different appearance.
• the two layers containing the two active ingredients will be separated by an insulating layer being of the same color and the same appearance as one of the two layers comprising one of the active ingredients, said layers remaining therefore indistinguishable by the patient.
• the neutral insulating layer separates the two layers containing the incompatible active ingredients. It therefore limits the degradation of the active ingredients within the tablet and thus makes it possible to obtain greater stability of the formulation.
• the two halves as well as the intermediate insulating layer may alternatively be colored and / or of different appearance.
• the tablet is a "sandwich" of layers comprising different active principles, for example a layer of artemisinin or one of its derivatives, between two layers of ferroquine, or vice versa.
• the invention consists of a multilayer pharmaceutical composition dispersible in water comprising at most two active ingredients per pharmaceutical composition, said composition comprising ferroquine as the first active ingredient,
• the level of disintegrating agent being less than 5% by weight of the tablet, expressed relative to the total mass of the tablet.
• the level of disintegrating agents of the pharmaceutical composition in particular of the tablet, is less than 5%, and in particular less than 3.5% relative to the total mass of the tablet.
• the level of disintegrating agent in each of the layers is less than 2.5% relative to the total mass of the tablet, for example less than 2%.
• the pharmaceutical composition according to the invention has a disintegration time of 120 ⁇ 15 seconds; friability less than 0.5%;
• a level of disintegrating agent in each of the layers of less than 2.5% relative to the mass
• composition according to the invention has:
• a level of disintegrating agent in each of the layers of less than 2% relative to the mass
• the pharmaceutical composition according to the invention despite high tablet hardnesses, very low friabilities, and a disintegrating agent level of less than 5 "6 ⁇ ⁇ ⁇ . ⁇ . ⁇ less than 3 , 5% relative to the total mass of the tablet, are nevertheless hydrodispersible.
• Hydrodispersible or water-dispersible means the definition of the European Pharmacopoeia, which states that the dispersible tablets are uncoated tablets or film-coated tablets intended to be dispersed in water prior to administration, giving a homogeneous dispersion.
• the pharmaceutical composition comprises:
• binding agent between 0.5 and 2% of binding agent
• phase compounds for the artemisinin layer or one of its derivatives:
• compositions o between 0 and 2% of disintegrating agent, it being understood that if the pharmaceutical composition does not comprise an external phase, it must contain from 0.5 to 2% of lubricating agent.
• pharmaceutically acceptable excipients include a disintegrant which may be selected from sodium carboxymethyl starch, croscarmellose sodium, sodium or calcium carboxymethylcellulose, pregelatinized starch, crospovidone or alginic acid or a derivative thereof.
• binding agents examples include polyethylene glycol, pregelatinized starch, copovidone, maltodextrins, hydroxypropyl cellulose, guar gum, alginates, for example sodium alginates, povidone (PVP K30 polyvinylpyrrolidone), carbomers, methylcellulose, dextrins, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polydextrose, gelatin, propylene glycol, or polymethacrylates.
• PVP K30 polyvinylpyrrolidone povidone
• carbomers methylcellulose, dextrins, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polydextrose, gelatin, propylene glycol, or polymethacrylates.
• the diluting agent may be chosen from microcrystalline cellulose PH 112, starch (maize, rice, potato, in particular), pregelatinized starch, maltose, mannitol, maltitol, xylitol, lactitol, sorbitol, fructose, lactose (whether anhydrous, monohydrate or atomised), dextrin or any of its derivatives, calcium carbonate, calcium lactate, calcium phosphate, calcium sulphate, or sucrose, for example.
• lubricating agents examples include magnesium stearate, hydrogenated castor oil, glyceryl palmitostearate, polyoxyethylene stearates, glyceryl behenate, sodium lauryl sulfate, calcium stearate, leucine, sodium stearyl fumarate, poloxamer, glyceryl monostearate, or polyethylene glycol.
• Sweetening agent may be chosen from acesulfame potassium, sucrose, sucralose, aspartame, neohesperine dihydrochalcone, thaumatin, neotame, tagatose, saccharin sodium, sodium cyclamate, maltose, mannitol, maltitol, xylitol, lactitol, sorbitol, fructose, lactose (whether anhydrous, monohydrate or atomized), or else trehalose.
• the flow agent may be selected from colloidal silica, talc, magnesium silicate, calcium stearate, or calcium phosphate, for example.
• the pharmaceutical composition comprises:
• the daily doses in each of the two active ingredients of the combination according to the invention may be the following:
• ferroquine between 1 and 10 mg / kg / day, for example 2, 4 or 6 mg / kg / day;
• artemisininin derivative between 1 and 10 mg / kg / day, for example between 2 and 6 mg / kg / day, or about 4 mg / kg / day.
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the pharmaceutical composition according to the invention is intended to be administered for 3 consecutive days, in one or more daily doses of each of the two active ingredients, preferably a single dose per day.
• This treatment time limited to 3 days is particularly advantageous, in comparison with the 7 days recommended for monotherapy with artemisinin derivatives, in that it allows a better observation of the treatment by the patients, thus avoiding premature discontinuation of the treatment. which induce long-term parasite resistance.
• Such a tablet is compressed for example by respecting the following parameters:
• Such a tablet is compressed for example by respecting the following parameters:
• Such a tablet is compressed for example by respecting the following parameters:
• Such a tablet is compressed for example by respecting the following parameters:
• the invention consists of a method of manufacturing the pharmaceutical composition.
• the compression grains of the ferroquine layer are prepared separately from the compression grains of the artemisinin layer or its derivatives and grains of the neutral layer.
• the grain for compression of the ferroquine layer is prepared in
• the grain for compression of the artemisinin layer or its derivatives is prepared by mixing the active ingredient and the internal and external phase excipients.
• the grain of the neutral layer is, meanwhile, prepared by a simple mixture of all its constituents.
• the compression step is performed on a multilayer compressing machine, for example Fette type P102i or Hata HT45.
• the grain for compression of the ferroquine layer is prepared by following the steps of:
• the grain for compression of the neutral layer is prepared according to the following operational mode:
• a6) optionally, mixing a lubricating agent and, secondarily, a sweetening agent, and then calibrating this ingredient or these two ingredients on a rotary sizer with a 1 mm grid,
• step a6) if step a6) has taken place, mixing the compounds resulting from step a6) and the compounds resulting from step a5),
• b1) weighing the active ingredient (artemisinin or a derivative thereof), a diluent, a disintegrating agent, a binding agent, and a co-diluent,
• a multilayer compressing machine for example Fette type P102i or Hata HT45.
• the agents cited in the following steps are respectively:
• step a6) or, if appropriate, in the last step carried out in a): magnesium stearate and acesulfame potassium,
• step b1) calcium carbonate, croscarmellose sodium, povidone (PVP K30), and microcrystalline cellulose PH112, step b4): magnesium stearate and anhydrous colloidal silica.
• step c1) microcrystalline cellulose, calcium carbonate, sodium carboxymethyl starch, magnesium stearate.
• a pharmaceutical composition according to the invention having the composition mentioned in the table and manufactured according to the above-mentioned method has the following characteristics:
• Disintegration time according to the European Pharmacopoeia (n 6) in purified water at room temperature: 123 seconds Conformity of dispersion fineness according to European Pharmacopoeia: in conformity.

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