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
  • A61K9/14—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
  • A61P9/12—Antihypertensives

Definitions

• the present invention is directed to nanoparticulate formulations of a drug having at least one copolymer of vinyl pyrrolidone and vinyl acetate adsorbed on the surface of the drug as a surface stabilizer, and methods of making and using such compositions.
• Nanoparticulate compositions are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto the surface thereof a non-crosslinked surface stabilizer.
• the '684 patent describes the use of a variety of surface stabilizers for nanoparticulate compositions.
• the use of a copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer for nanoparticulate compositions, or any other component of such compositions, is not described by the '684 patent.
• the '684 patent describes a method of screening drugs to identify useful surface stabilizers that enable the production of a nanoparticulate composition. Not all surface stabilizers will function to produce a stable, non-agglomerated nanoparticulate composition for all drugs. Moreover, known surface stabilizers may be unable to produce a stable, non-agglomerated nanoparticulate composition for certain drugs. Thus, there is a need in the art to identify new surface stabilizers useful in making nanoparticulate compositions. Additionally, such new surface stabilizers may have superior properties over prior known surface stabilizers.
• the present invention is directed to nanoparticulate compositions comprising a poorly soluble drug and at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer adsorbed to the surface of the drug.
• compositions comprising a nanoparticulate composition of the invention.
• the pharmaceutical composition preferably comprises a poorly soluble drug, at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer adsorbed to the surface of the drug, and a pharmaceutically acceptable carrier, as well as any desired excipients.
• This invention further discloses a method of making a nanoparticulate composition having at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer adsorbed on the surface of the drug.
• a method comprises contacting a poorly soluble nanoparticulate drug with at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer for a time and under conditions sufficient to provide a nanoparticle/copolymer composition.
• the copolymer surface stabilizers can be contacted with the drug either before, during, or after size reduction of the drug.
• the present invention is further directed to a method of treatment comprising administering to a mammal in need a therapeutically effective amount of a nanoparticulate drug/copolymer composition according to the invention.
• the present invention is directed to a composition
• a composition comprising nanoparticulate drug having at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer adsorbed on the surface thereof, and methods of making and using such nanoparticulate compositions.
• compositions A. Compositions
• compositions of the invention comprise nanoparticulate drag and at least one copolymer of vinyl pyrrohdone and vinyl acetate as a surface stabiHzer adsorbed to the surface of the drag.
• Surface stabilizers useful herein physically adhere to the surface of the nanoparticulate drag, but do not chemically react with the drug or itself. Individually adsorbed molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.
• the present invention also includes nanoparticulate compositions having at least one copolymer of vinyl pyrrohdone and vinyl acetate as a surface stabilizer adsorbed on the surface thereof, formulated into compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers.
• the compositions can be formulated for parenteral injection, oral administration in solid or liquid form, rectal or topical administration, and the like.
• the nanoparticles of the invention comprise a therapeutic or diagnostic agent, collectively referred to as a "drug.”
• a therapeutic agent can be a pharmaceutical agent, including biologies such as proteins, peptides, and nucleotides, or a diagnostic agent, such as a contrast agent, including x-ray contrast agents.
• the drag exists either as a discrete, crystalline phase, or as an amorphous phase. The crystalline phase differs from a non-crystalline or amorphous phase which results from precipitation techniques, such as those described in EP Patent No. 275,796.
• the invention can be practiced with a wide variety of drags.
• the drag is preferably present in an essentially pure form, is poorly soluble, and is dispersible in at least one liquid medium.
• “poorly soluble” it is meant that the drag has a solubility in the liquid dispersion medium of less than about 10 mg/mL, and preferably of less than about 1 mg/mL.
• the drag can be selected from a variety of known classes of drags, including, for example, proteins, peptides, nucleotides, anti-obesity drags, nutriceuticals, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti- emetics, analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti- a ⁇ hythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antMstamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cortico
• the drugs are commercially available and or can be prepared by techniques known in the art.
• copolymers of vinyl pyrrolidone and vinyl acetate are Plasdone ® S630 (ISP) and Kollidon ® VA 64 (BASF), which contain vinyl pyrrolidone and vinyl acetate in a 60:40 ratio.
• Other copolymers of vinyl pyrrolidone and vinyl acetate can also be used in the invention.
• the copolymer contains at least 40% vinyl pyrrolidone, although smaller amounts of vinyl pyrrolidone can also be utilized.
• Other useful copolymers contain vinyl pyrrohdone and vinyl acetate in ratios of, for example, 90:10, 80:20, 70:30, and 50:50.
• the amount of vinyl pyrrolidone can range from about 40% up to about 99.9%, and the amount of vinyl acetate can range from about 0.1% up to about 60%.
• Two or more surface stabilizers can be used in combination.
• compositions of the invention can also include one or more auxiliary surface stabilizers in addition to the at least one copolymer of vinyl pyrrolidone and vinyl acetate.
• Suitable auxiliary surface stabilizers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface stabilizers include nonionic and ionic surfactants. Two or more surface auxiliary stabilizers can be used in combination.
• auxiliary surface stabilizers include cetyl pyridiniurn chloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens ® such as e.g., Tween 20 ® and Tween 80 ® (ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxes 3350 ® and 1450 ® , and Carbopol 934 ® (Union Carbide
• a charged phospholipid such as dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic 1508 ® (T- 1508) (BASF Wyandotte Corporation ), dialkylesters of sodium sulfosuccinic acid (e.g., Aerosol OT ® , which is a dioctyl ester of sodium sulfosuccinic acid (Cytec Industries, West Paterson, NJ)); Duponol P ® , which is a sodium lauryl sulfate (DuPont); Triton X-200 ® , which is an alkyl aryl polyether sulfonate (Union Carbide); Crodestas F-l 10 ® , which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol)
• the compositions of the invention contain nanoparticles which have an effective average particle size of less than about 2000 nm (i.e., 2 microns), more preferably less than about 1500 nm, less than about 1000 nm, less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods.
• an effective average particle size of less than about 2000 nm (i.e., 2 microns), more preferably less than about 1500 nm, less than about 1000 nm, less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods
• an effective average particle size of less than about 2000 nm it is meant that at least 50% of the drag particles have a particle size of less than about 2000 nm when measured by light scattering techniques.
• at least 70% of the drug particles have a particle size of less than about 2000 nm, more preferably at least 90% of the drag particles have a particle size of less than about 2000 nm, and even more preferably at least about 95% of the particles have a particle size of less than about 2000 nm.
• the relative amount of drag and one or more surface stabilizers can vary widely.
• the optimal amount of the surface stabilizers can depend, for example, upon the particular active agent selected, the hydrophilic lipophilic balance (HLB), melting point, and water solubility of the copolymer, and the surface tension of water solutions of the stabilizer, etc.
• the concentration of the one or more surface stabilizers can vary from about 0.01 to about 90%, from about 1 to about 75%, from about 10 to about 60%, and from about 10 to about 55% by weight based on the total combined weight of the drag substance and surface stabilizer, not including other excipients.
• the concentration of the drag can vary from about 99.9% to about 0.1%, from about 80% to about 5.0%, or from about 50% to about 10%, by weight based on the total combined weight of the drag substance and surface stabilizer, not including other excipients.
• the nanoparticulate drag compositions can be made using, for example, milling or precipitation techniques. Exemplary methods of making nanoparticulate compositions are described in the '684 patent. Methods of making nanoparticulate compositions are also described in U.S. Patent No. 5,518,187, for "Method of Grinding Pharmaceutical Substances;” U.S. Patent No. 5,718,388, for "Continuous Method of Grinding Pharmaceutical Substances;” U.S. Patent No. 5,862,999, for "Method of Grinding Pharmaceutical Substances;” U.S. Patent No. 5,665,331, for "Co- Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No.
• Milling of aqueous drug to obtain a nanoparticulate dispersion comprises dispersing drag particles in a liquid dispersion medium in which the drag is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of the drag to the desired effective average particle size.
• the dispersion medium can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol.
• the particles can be reduced in size in the presence of at least one copolymer of vinyl pyrrolidone and vinyl acetate surface stabilizer. Alternatively, the particles can be contacted with one or more surface stabilizers after attrition. Other compounds, such as a diluent, can be added to the drag/surface stabilizer composition during the size reduction process. Dispersions can be manufactured continuously or in a batch mode. The resultant nanoparticulate drag dispersion can be utilized in solid or liquid dosage formulations.
• Another method of forming the desired nanoparticulate composition is by microprecipitation.
• This is a method of preparing stable dispersions of poorly soluble drugs in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
• Such a method comprises, for example: (1) dissolving the poorly soluble drag in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one copolymer surface stabilizer to form a clear solution; and (3) precipitating the formulation from step (2) using an appropriate non-solvent.
• the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
• the resultant nanoparticulate drug dispersion can be utilized in solid or liquid dosage formulations.
• Formulations Comprisin One or More Surface Stabilizers
• nanoparticulate compositions of the present invention can be achninistered to humans and animals via any conventional means, including but not limited to orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), intracisternally, pulmonary, intravaginally, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray.
• compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene- glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• the nanoparticulate compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
• Solid dosage.forms for oral aclministration include capsules, tablets, pills, powders, and granules.
• the active compound is admixed with at least one of the following: (a) one or more inert excipients (or carrier), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
• Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tefrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
• oils such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil
• glycerol tefrahydrofurfuryl alcohol
• polyethyleneglycols fatty acid esters of sorbitan, or mixtures of these substances, and the like.
• composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• Actual dosage levels of active ingredients in the nanoparticulate compositions of the invention may be varied to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
• the selected dosage level therefore depends upon the desired therapeutic effect, the route of administration, the potency of the administered drag, the desired duration of treatment, and other factors.
• the total daily dose of the compounds of this invention administered to a host in single or divided dose may be in amounts of, for example, from about 1 nanomol to about 50 micromoles per kilogram of body weight. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose.
• Naproxen is a non-steroidal anti-inflammatory drag (NSAID) used in the treatment of rheumatoid conditions.
• Plasdone ® S-630 (60% vinyl pyrrolidone, 40% vinyl acetate) (ISP Technologies, Inc.) was milled using a Dyno ® Mill (Type: KDL; Mfg.: Willy A Bachofen AG, Basel Switzerland) equipped with a 150 cc batch chamber using a 500 ⁇ m milling media (PolyMill ® 500; Dow Chemical) for 2 hrs at ca. 10°C Following milling, the nanoparticulate naproxen dispersion had a mean particle size of 96 nm, with 90% of the particles having a size of less than 141 nm.
• Example 2 The purpose of this example was to prepare a nanoparticulate dispersion of a mfedipine composition comprising a copolymer of vinyl pyrrohdone and vinyl acetate.
• Nifedipine is a poorly water-soluble calcium channel blocking agent. The drag affects the movement of calcium into heart and blood vessel cells, and causes a relaxing effect of the muscles to allow an increased amount of blood flow into the heart. Nifedipine is useful in treating angina pectoris (chest pain), and to help reduce blood pressure (antihypertensive).
• Plasdone® S-630 (60% vinyl pyrrolidone and 40% vinyl acetate) (ISP Technologies, Inc.) and 0.05% sodium lauryl sulfate (SLS) (Spectrum) was prepared by dissolving 0.85 g of polymer and 4.59 g of a 1% SLS solution in 75.66 g of deionized water.
• the stabilizer solution was mixed with 4.25 g of nifedipine (5% w/w) and charged into the chamber of a DYNO ® -Mill Type KDL media mill (Willy Bachofen AG, Basel, Switzerland) along with 500 micron polymeric media (PolyMill ® 500; Dow Chemical). The mill was operated for 2 hours and yielded a stable colloidal dispersion of drag substance having a mean particle size of 132 nm, with 90% of the particles having a size of less than 193 nm.
• Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID) effective in treating fever, pain, and inflammation in the body.
• NSAID nonsteroidal anti-inflammatory drug
• Plasdone® S-630 (60% vinyl pyrrolidone and 40% vinyl acetate) (ISP Technologies, Inc.) and 0.05% sodium lauryl sulfate (SLS) (Spectrum) was prepared by dissolving 0.85 g of polymer and 4.26 g of a 1% SLS solution in 75.71 g of deionized water.
• the stabilizer solution was mixed with 4.25 g of ketoprofen (Wyckoff; 5% w/w) and charged into the chamber of a DYNO ® -Mill Type KDL media mill (Willy Bachofen AG, Basel, Switzerland) along with 500 micron polymeric media (PolyMill ® 500; Dow Chemical). The mill was operated for 1 hour and yielded a stable colloidal dispersion of drag substance having a mean particle size of 256 nm, with 90% of the particles having a size of less than 355 nm.
• Triamcinolone acetonide is a corticosteroid used as an antiallergic agent.
• An aqueous solution of 1% Plasdone® S-630 (60% vinyl pyrrolidone and
• the purpose of this example was to prepare a nanoparticulate dispersion of a nanoparticulate diagnostic imaging agent, benzoic acid, 3,5-bis(acetylamino) 2,4,6- triodo, 4-(ethyl-3-ethoxy-2-butenoate) ester (WIN 68209) composition comprising a copolymer of vinyl pyrrolidone and vinyl acetate.
• 20% vinyl acetate (Polysciences Inc., Warrington, PA) was prepared by dissolving 0.85 g of polymer in 79.91 g of deionized water.
• the stabilizer solution was mixed with 4.26 g of WIN 68209 (5% drag) and charged into the chamber of a DYNO ® -Mill Type KDL media mill (Willy Bachofen AG, Basel, Switzerland) along with 500 micron polymeric media (PolyMill 500; Dow Chemical).
• the mill was operated for 1 hour and yielded a stable colloidal dispersion of WIN 68209 having a mean particle size of 242 nm, with 90% of the particles having a size of less than 347 nm.
• Example 6 The purpose of this example was to prepare a nanoparticulate dispersion of a nanoparticulate diagnostic imaging agent, WIN 68209, composition comprising a copolymer of vinyl pyrrolidone and vinyl acetate.
• aqueous solution of 1 % of a copolymer of 80% vinyl pyrrolidone and 20% vinyl acetate (Polysciences Inc., Warrington, PA) and 1% SLS was prepared by dissolving 0.85 g of polymer and 4.25 g of a 1% SLS solution in 75.67 g of deionized water.
• the stabilizer solution was mixed with 4.26 g of WIN 68209 (5% drag) and charged into the chamber of a DYNO ® -Mill Type KDL media mill (Willy Bachofen AG, Basel, Switzerland) along with 500 micron polymeric media (PolyMill 500; Dow Chemical). The mill was operated for 1 hour and yielded a stable colloidal dispersion of WTN 68209 having a mean particle size of 188 nm, with 90% of the particles having a size of less than 308 nm.
• the purpose of this example was to prepare a nanoparticulate dispersion of a nanoparticulate diagnostic imaging.
• agent WTN 68209, composition comprising a copolymer of vinyl pyrrohdone and vinyl acetate.
• aqueous solution of 1% of a copolymer of 50% vinyl pyrrolidone and 50% vinyl acetate (Polysciences Inc., Warrington, PA) and 0.05% SLS (Spectrum) was prepared by dissolving 0.85 g of polymer and 0.043 g of SLS in 79.86 g of deionized water.
• the stabilizer solution was mixed with 4.25 g of WIN 68209 (5% drag) and charged into the chamber of a DYNO ® -Mill Type KDL media mill (Willy Bachofen AG, Basel, Switzerland) along with 500 micron polymeric media (PolyMill 500; Dow Chemical). The mill was operated for 2 hours and yielded a stable colloidal dispersion of WIN 68209 having a mean particle size of 96 nm, with 90% of the particles having a size of less than 143 nm.

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• 2001
  • 2001-11-16 AT AT01274072T patent/ATE419834T1/de not_active IP Right Cessation
  • 2001-11-16 ES ES01274072T patent/ES2317874T3/es not_active Expired - Lifetime
  • 2001-11-16 JP JP2002590934A patent/JP4541647B2/ja not_active Expired - Fee Related
  • 2001-11-16 WO PCT/US2001/043111 patent/WO2002094215A2/en not_active Ceased
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  • 2001-11-16 AU AU2001297844A patent/AU2001297844A1/en not_active Abandoned
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