Classifications

• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors

Definitions

• the invention relates to a kit comprising a pharmaceutical composition containing repinotan or a physiologically acceptable salt of repinotan, and a means for determining the concentration of repinotan or its
• Metabolites in body fluids, as well as new pharmaceutical compositions containing repinotan or a physiologically acceptable salt of repinotan, and process for their preparation are described.
• Subarachnoid hemorrhage does not yet have any medicinal approaches that take sufficient account of the pathophysiological cascade.
• EP-A-0 352 613 discloses 2- [4 - ( ⁇ [(2R) -chroman-2-yl] methyl ⁇ amino) butyl] -l, 2-benzisothiazol-3 (2H) -one 1,1- dioxide (generic name: Repinotan) and Repinotan
• DE-A-195 43 476 describes the suitability of repinotan and its salts for the treatment of traumatic brain injury.
• kits according to the invention which comprises a pharmaceutical composition containing repinotan or a physiologically acceptable salt of repinotan and an agent for determining the concentration of repinotan or its metabolites in body fluids.
• kit according to the invention makes it possible to use a medicinal product as
• the kit according to the invention therefore represents a significant advance in the acute therapy of neurodegenerative diseases, in particular of stroke and traumatic brain injury.
• the pharmaceutical compositions included in the kit according to the invention can be present, for example, as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions, solutions or lyophilisates, which can be reconstituted to form a solution.
• the pharmaceutical compositions contain repinotan or a physiologically acceptable salt of repinotan as the active ingredient.
• the active ingredient should be present in a concentration of about 0.05 to 95
• compositions preferably from about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the stated dosage range.
• pharmaceutical compositions additionally contain inert, non-toxic, pharmaceutically suitable auxiliaries.
• Repinotan has the following structural formula:
• Physiologically acceptable salts of repinotan can be salts of repinotan with mineral acids, carboxylic acids or sulfonic acids. Salts of are preferred
• Repinotan with hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
• Repinotan hydrochloride is particularly preferred.
• auxiliaries include water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerol), carriers such as e.g. natural stone powder (e.g.
• synthetic rock flours e.g. highly disperse silica, silicates
• sugar e.g. cane, milk and glucose
• emulsifiers e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers
• dispersants e.g. Lignin, lye, methyl cellulose, starch and polyvinyl pyrrolidone
• lubricants
• the kit according to the invention preferably comprises an infusion solution containing the active ingredient or a solid pharmaceutical composition, from which this infusion solution can then be added by adding
• Water or isotonic electrolyte solution can be made.
• a preferred solid pharmaceutical formulation is the lyophilisate, which can be reconstituted by adding water or an isotonic electrolyte solution to, for example, an infusion solution.
• the active ingredient has an increased storage stability, and the lyophilisate can be easily and quickly prepared under sterile conditions to produce a particle-free solution that is used directly
• the lyophilisate advantageously contains further pharmaceutically suitable auxiliaries, in particular scaffold formers.
• Scaffolders in the sense of the invention are amino acids such as glycine, alanine or
• Aspartic acid peptides such as gelatin, collagen or albumin, monosaccharides such as glucose or lactose, disaccharides such as maltose, sucrose or trehalose, oligosaccharides such as cyclodextrins or maltodextrins, polysaccharides such as starch and starch derivatives or cellulose and cellulose derivatives, polymeric skeletal formers such as polyvinyl methylene chloride, such as polyvinyl methylene chloride such as polyvinyl methylene chloride or calcium carbonate, sugar alcohols such as mannitol, sorbitol or xylitol. Mannitol, common salt, glycine, sucrose, maltose or lactose are preferred. Mannitol is very particularly preferred.
• the lyophilisate is reconstituted into a solution for infusion, this is advantageously isotonic. This can be achieved in that the lyophilisate already contains sufficient amounts of electrolyte, such as, for example, table salt, mannitol or glucose, or in that an isotonic electrolyte solution is used to reconstitute and dilute the solution.
• electrolyte such as, for example, table salt, mannitol or glucose
• Isotonic electrolyte solutions are, for example, aqueous 0.9% by weight saline solutions or 5% by weight glucose solutions.
• the proportion of the active ingredient in the infusion solution should be about 0.1 ⁇ g / ml to 1 mg / ml, preferably about 0.5 to 5 ⁇ g / ml.
• the preparation of repinotan and repinotan salts is described in EP-A-0 352 613.
• Repinotan hydrochloride corresponds to example 92H there.
• the salts according to the invention can also be obtained by reacting the free base repinotan in suitable solvents with stoichiometric or excess stoichiometric amounts of the acid on which the salt is based in a temperature range from 0 ° C. to the boiling point of the solvent.
• suitable solvents are, for example, water, aliphatic alcohols such as methanol, ethanol or 2-propanol, aliphatic open-chain or cyclic ethers such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran or aliphatic ketones such as 2-
• compositions of the kit according to the invention can also contain mixtures of repinotan and its salts or of various repinotane salts.
• Repinotan or its physiologically acceptable salts can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
• Active substance solutions or solid pharmaceutical compositions which can be converted into a solution, such as, for example, lyophilisates, are preferred.
• the therapeutically active substance should be present in a concentration of about 0.05 to 95% by weight, preferably about 0.5 to 90% by weight, of the total mixture, that is to say in amounts which are sufficient for the stated Achieve dosage range.
• the formulations are prepared, for example, by stretching the active compounds with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, it being possible, for example if organic solvents to be used as diluents, to use organic solvents as auxiliary solvents.
• kit according to the invention comprises means for determining the concentration of repinotan or its metabolites in body fluids.
• Body fluids in the sense of the invention are, for example, urine, blood and fractions derived from blood, such as serum or plasma. Blood and fractions obtained from blood are preferred, blood plasma being particularly preferred.
• the concentration of repinotan is determined in blood or in fractions obtained from blood, preferably in blood plasma.
• Suitable means for determining the concentration are, for example, chromatographic devices such as liquid or gas chromatography, which can optionally be coupled to a mass spectrometer (LC-MS or GC-MS). Also suitable are agents that work according to immunological methods, such as ELISAs (enzyme linked immunosorbent assays). Means of this kind are known.
• Agents that can be used at the treatment site are particularly suitable, since they can be used to make the dose adjustments required for optimal therapy without delay.
• Preferred devices in the kit according to the invention are the devices for determining the concentration of analytes disclosed in WO-A-99/46591. These devices can be manufactured and used according to the methods described therein and allow the dose adjustments that may be necessary for optimal therapy to be made without delay and with little effort in terms of personnel and equipment.
• the kit according to the invention is particularly suitable for the acute treatment of neurodegenerative diseases, in particular stroke or traumatic brain injury.
• composition according to the invention is applied in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.
• tablets can of course, in addition to the carriers mentioned, also additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as
• Starch preferably potato starch, gelatin and the like.
• Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
• the active ingredients can be mixed with various flavor enhancers or colorants.
• parenteral in the case of parenteral
• Solutions of the active ingredients can be used using suitable liquid carrier materials.
• the active ingredient in amounts of about 0.01 ⁇ g / kg / h to 10 ⁇ g / kg / h ( ⁇ g or mg per kg
• Body weight per hour preferably about 0.05 ug / kg / h to 2 ug / kg / h to achieve effective results.
• the administration can take place in the form of individual doses.
• the daily dose of the active ingredient is 0.001 to 0.2 mg / kg, preferably 10 to 100 ⁇ g / kg body weight. Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place , In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses over the day.
• the patient is administered a defined starting dose of repinotan, the concentration of repinotan is checked with the agents according to the invention after fixed, predetermined times and then the further
• patients are infused with a solution containing repinotan hydrochloride at a rate of 1.25 mg repinotan / day.
• the agent according to the invention is used to determine whether the repinotan plasma concentration is above or below about 17 ⁇ g / l. If the repinotan plasma concentration is below the specified limit, the infusion will continue at the specified rate. On the other hand, if the repinotan plasma concentration exceeds the specified limit concentration, the infusion rate is reduced to 0.5 mg repinotan / day. The repinotan plasma concentration is checked again 12 hours after the start of the infusion.
• the infusion rate is maintained when the repinotan plasma concentration is below about 17 ⁇ g / l and reduced to 0.625 or 0.25 mg repinotan / day when the repinotan plasma concentration exceeds about 17 ⁇ g / l.
• the invention relates to solid pharmaceutical compositions containing repinotan or its physiologically acceptable salt and a physiologically acceptable acid.
• Physiologically acceptable acids in the sense of the invention are, for example
• Malic acid, pyruvic acid, citric acid, fumaric acid, maleic acid, lactic acid and tartaric acid are preferred.
• Citric acid and tartaric acid are particularly preferred.
• the effect according to the invention is achieved in particular with solid pharmaceutical compositions in which the active ingredient, i.e. Repinotan or its physiologically acceptable salts, 0.01 - 15 wt .-% and the physiologically acceptable acid make up 0.5 - 15 wt .-% of the total weight of the composition.
• the active ingredient i.e. Repinotan or its physiologically acceptable salts
• 0.01 - 15 wt .-% and the physiologically acceptable acid make up 0.5 - 15 wt .-% of the total weight of the composition.
• compositions containing repinotan hydrochloride and citric acid or tartaric acid are very particularly preferred.
• the solid pharmaceutical compositions according to the invention can be prepared by customary processes.
• Another aspect of the invention relates to lyophilisates containing repinotan or its physiologically tolerable salts, and a physiologically acceptable Acid, with repinotan hydrochloride as the active ingredient, malic acid, pyruvic acid, citric acid, fumaric acid, maleic acid, lactic acid and tartaric acid, in particular citric acid and tartaric acid, being preferred as acids.
• the lyophilisates can advantageously contain pharmaceutical auxiliaries such as the above-mentioned scaffolders.
• the abovementioned amounts of the repinotane or repinotan salt, the physiologically acceptable acid and, if appropriate, further pharmaceutical auxiliaries are dissolved in water and / or other suitable solvents, made sterile, filled into suitable containers and freeze-dried.
• Suitable solvents for the purposes of the invention are, for example, glacial acetic acid or tert-butanol.
• the solution can usually be prepared at temperatures from 5 to 35 ° C., preferably at 20 to 25 ° C.
• Sterilizing the solution in the sense of the invention means converting the solution into the sterile state, for example by sterile filtration through filters with a maximum pore size of 0.2 ⁇ m from suitable filter materials such as e.g. Polyether sulfone or nylon 6.6.
• Suitable containers for freeze-drying are, for example, cottage glass or tubular glass bottles.
• the filling volume of the solution is between 0.2 ml and 20 ml, preferably 0.5 ml to 5 ml, particularly preferably 0.7 ml to 3.0 ml.
• the solution is freeze-dried in the containers.
• the containers with the solution are placed on pre-cooled or non-pre-cooled shelves and frozen.
• the subsequent main drying is carried out in vacuum at chamber pressures from 0.05 mbar to 1.8 mbar with shelf temperatures from -40 ° C to + 60 ° C.
• Post-drying is carried out at chamber pressures from 1 ⁇ bar to 1.8 mbar with shelf temperatures from -20 ° C to + 70 ° C.
• the freeze-drying process can be carried out according to the process described in the international application PCT / EP00 / 07034. Freeze drying produces the storage-stable lyophilizate of the above-mentioned compositions.
• the infusion solutions according to the invention show an unexpectedly high storage stability.
• An infusion solution in the sense of the invention is a solution which predominantly contains water as the solvent and normally has an osmolality in the range from 250 to 500 mOsmol / kg, preferably 280 to 350 mOsmol / kg.
• the above-mentioned osmolality of the infusion solution can be achieved by already having the necessary amounts of, for example, table salt, mannitol or glucose
• the repinotan concentration of the infusion solution is usually 0.1 to 500 ⁇ g repinotan / ml solution, preferably 0.5 to 5 ⁇ g / ml.
• the infusion solution contains so much acid that at 20 ° C the pH is 3.5 to 5, preferably about 4.
• Example 1 Lyophilisate of a composition containing repinotan hydrochloride
• a mixture of 55 mg repinotan hydrochloride (corresponds to 50 mg repinotan), 20 g mannitol and 3.7 g citric acid was made up to 1000 ml with water.
• This aqueous solution was sterile filtered through filters with a maximum pore size of 0.2 ⁇ m from polyethersulfone and filled into tubular glass bottles. The filling volume of the solution was 1 ml.
• the solution was freeze-dried in the tubular glass bottles.
• the tube glass bottles with the solution were placed on the freezer dryer plates at room temperature and frozen at - 0 ° C.
• the subsequent main drying was carried out under vacuum at a chamber pressure of 0.2 mbar and a shelf temperature of 0 ° C.
• the overnight drying was carried out at one
• freeze drying can be carried out according to the method described in the international application PCT / EP00 / 07034.
• Example 2 Analogously to the process described in Example 1, the amounts of mannitol, citric acid and water used in Example 1 were used to lyophilisates containing 0.27 g, 0.681 g, 1.36 g and 2.73 g of repinotan hydrochloride, corresponding to 0.25 g, 0.625 g, 1, 25 g and 2.5 g repinotan, respectively.
• Example 2 Infusion solution containing repinotan hydrochloride
• a ready-to-use infusion solution is prepared from the freeze-dried product according to Example 1 by using a 0.9% by weight ⁇ aCl-
• Solution reconstituted and then with this solution to a total volume of 500 ml is diluted.
• the ready-to-use solution is chemically stable for at least 30 h at room temperature, ie the solution then contains at least 90% unchanged repinotan.
• Example 3 Determination of repinotan using an ELISA on a microtiter plate
• the test is carried out on the basis of a competitive ELISA.
• the protein conjugate of a hapten analogous to repinotan is reacted in a constant amount with a constant amount of monoclonal or polyclonal antibody Fab or Fab2 fragment, specifically against the chemical structure of repinotan, and a constant volume of sample containing repinotan.
• the concentration of repinotan can then be determined from the ratio of bound to free protein conjugate using a calibration curve to be established in parallel with known concentrations of repinotan in the sample to be examined.
• Goat IgG is chemically linked to the repinotan analog mentioned below in a molar ratio of 1: 7.5.
• the competitive test can now be carried out on the plate prepared in this way.
• 100 ⁇ l sample are placed in a microtiter well and 100 ⁇ l antibody solution (mouse anti-repinotan antibody 10 ng / ml in phosphate-buffered saline solution) is added. Incubate for 1 h at room temperature. After washing three times with washing buffer (see above), secondary antibodies, coupled to Horseradish peroxidase (1: 1; Zymed goat anti-mouse IgG; diluted 1: 1000), are pipetted into the microtiter well in a further reaction. This binds to the repinotan-specific mouse antibody, which is bound to the repinotan-analogous hapten conjugate that is.
• the amount of repinotan-specific mouse antibody bound in this way is indirectly proportional to the amount of free repinotan in the sample. Excess antibody-enzyme conjugate is washed out by washing three times and, after addition of enzyme substrate (TMB), the remaining bound amount is determined photometrically by means of a kinetic measurement. With the protocol shown, repinotane concentrations between 1 and 100 ng / ml can be determined using appropriate calibrators.
• This repino test is intended for use in the area of intensive care and other hospital areas for the determination of repino concentrations above and below a defined limit concentration of approximately 17 ng / ml in whole blood, serum or plasma. This is a one-time test with a visual readout.
• test is based on the competitive immunological method described above
• the reflective signal of colloidal gold particles is used as the readout mechanism.
• All necessary test components and mechanical manipulations, which are necessary to carry out conventional immunoassays, are housed in a plastic device. This includes a mechanism for separating the blood cells from the serum and a mechanism for the exact measurement of a certain amount of the separated serum.
• Buffer reservoir contains the liquid phase necessary for the reaction, which enables capillary movement within the system.
• Anti-repinotan antibodies and hapten-goat-IgG-gold conjugate are lyophilized in a reaction cell of the plastic device.
• a mixing chamber at the end of a capillary and an immunochromatographic test strip complete the system.
• On the Test strips are applied to stationary reaction zones: a donkey anti-mouse antibody and a rabbit anti-goat antibody.
• the donkey anti-mouse antibody captures most of the gold conjugate and forms a red color zone.
• the duration of the test is approximately 15 minutes, from the application of the sample to the
• the test can be carried out with 100 - 150 ⁇ l whole blood, which guarantees the generation of approx. 15 ⁇ l serum.
• This compound is new and can be prepared by the processes described in EP-A-0 352 613, for example by reaction of repinotane with 6-bromo-hexanecarboxylic acid tert-butyl ester in the presence of a base in suitable solvents and subsequent acidic ester cleavage.

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