EA200701987A1 - Составы из нанодисперсного антагониста лейкотриеновых рецепторов/кортикостероида - Google Patents
Составы из нанодисперсного антагониста лейкотриеновых рецепторов/кортикостероидаInfo
- Publication number
- EA200701987A1 EA200701987A1 EA200701987A EA200701987A EA200701987A1 EA 200701987 A1 EA200701987 A1 EA 200701987A1 EA 200701987 A EA200701987 A EA 200701987A EA 200701987 A EA200701987 A EA 200701987A EA 200701987 A1 EA200701987 A1 EA 200701987A1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- corticosteroid
- antagonist
- receptors
- compositions
- adults
- Prior art date
Links
- 239000003246 corticosteroid Substances 0.000 title abstract 3
- 239000005557 antagonist Substances 0.000 title abstract 2
- 239000000203 mixture Substances 0.000 abstract 5
- 239000003814 drug Substances 0.000 abstract 2
- 229940079593 drug Drugs 0.000 abstract 2
- 239000003199 leukotriene receptor blocking agent Substances 0.000 abstract 2
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 abstract 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 abstract 1
- 208000036284 Rhinitis seasonal Diseases 0.000 abstract 1
- 208000002205 allergic conjunctivitis Diseases 0.000 abstract 1
- 201000010105 allergic rhinitis Diseases 0.000 abstract 1
- 208000006673 asthma Diseases 0.000 abstract 1
- 208000024998 atopic conjunctivitis Diseases 0.000 abstract 1
- 239000002552 dosage form Substances 0.000 abstract 1
- 238000009472 formulation Methods 0.000 abstract 1
- 230000002440 hepatic effect Effects 0.000 abstract 1
- 102000003835 leukotriene receptors Human genes 0.000 abstract 1
- 108090000146 leukotriene receptors Proteins 0.000 abstract 1
- 210000004185 liver Anatomy 0.000 abstract 1
- 238000011866 long-term treatment Methods 0.000 abstract 1
- 239000002245 particle Substances 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 208000017022 seasonal allergic rhinitis Diseases 0.000 abstract 1
- 208000024891 symptom Diseases 0.000 abstract 1
- 238000011200 topical administration Methods 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
- 238000011269 treatment regimen Methods 0.000 abstract 1
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
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- 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
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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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
- A61K9/145—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 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
- A61K9/146—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- 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
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Otolaryngology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Описываются нанодисперсные композиции, содержащие кортикостероид и антагонист лейкотриеновых рецепторов. Композиции являются пригодными для профилактики и длительного лечения астмы у взрослых и детей и для купирования аллергического конъюнктивита, симптомов сезонного аллергического ринита у взрослых и детей. Сочетание антагониста лейкотриеновых рецепторов с кортикостероидом с размером частиц менее чем 2000 нм в отдельном составе приводит к повышенной эффективности. В дополнение, соблюдение больным режима и схемы лечения улучшается, поскольку только одна лекарственная форма требуется для применения. Кроме того, местное применение антагониста лейкотриеновых рецепторов является результатом снижения печеночной токсичности, поскольку печень подвергается воздействию меньших количеств лекарственного средства, чем это происходит при введении пероральным путем. Лекарственные композиции изобретения могут быть в виде составов для ингаляционного, назального или офтальмологического применения.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US66233905P | 2005-03-16 | 2005-03-16 | |
PCT/US2006/009837 WO2006099591A1 (en) | 2005-03-16 | 2006-03-16 | Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations |
Publications (1)
Publication Number | Publication Date |
---|---|
EA200701987A1 true EA200701987A1 (ru) | 2008-02-28 |
Family
ID=36615692
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EA200701987A EA200701987A1 (ru) | 2005-03-16 | 2006-03-16 | Составы из нанодисперсного антагониста лейкотриеновых рецепторов/кортикостероида |
Country Status (14)
Country | Link |
---|---|
US (1) | US20070065374A1 (ru) |
EP (1) | EP1863450A1 (ru) |
JP (1) | JP2008533174A (ru) |
KR (1) | KR20070118258A (ru) |
CN (1) | CN101175480A (ru) |
AU (1) | AU2006225117A1 (ru) |
BR (1) | BRPI0606283A2 (ru) |
CA (1) | CA2601179A1 (ru) |
EA (1) | EA200701987A1 (ru) |
IL (1) | IL185951A0 (ru) |
MX (1) | MX2007011502A (ru) |
NO (1) | NO20075291L (ru) |
WO (1) | WO2006099591A1 (ru) |
ZA (1) | ZA200708456B (ru) |
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US20090317476A1 (en) * | 2003-07-31 | 2009-12-24 | Robinson Cynthia B | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease |
US8497258B2 (en) | 2005-11-12 | 2013-07-30 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
US8324192B2 (en) | 2005-11-12 | 2012-12-04 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
US8679545B2 (en) | 2005-11-12 | 2014-03-25 | The Regents Of The University Of California | Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract |
JP2009516003A (ja) * | 2005-11-15 | 2009-04-16 | バクスター・インターナショナル・インコーポレイテッド | リポキシゲナーゼ阻害剤の組成物 |
JP2009538927A (ja) * | 2006-05-30 | 2009-11-12 | エラン ファーマ インターナショナル,リミティド | ナノ粒子状のポサコナゾール製剤 |
JP2009543797A (ja) * | 2006-07-10 | 2009-12-10 | エラン ファーマ インターナショナル,リミティド | ナノ粒子ソラフェニブ製剤 |
WO2008079834A2 (en) * | 2006-12-21 | 2008-07-03 | Lantheus Medical Imaging, Inc. | Preparation of paramagnetic nanoparticles conjugated to leukotriene b4 (ltb4) receptor antagonists, and their use as mri contrast agents for the detection of infection and inflammation |
JP5443979B2 (ja) * | 2007-05-11 | 2014-03-19 | 備前化成株式会社 | 新規のロイコトリエン受容体アンタゴニスト |
DE112008001135A5 (de) * | 2007-06-08 | 2010-04-15 | Bayer Consumer Care Ag | Antiinflammatorische Wirkstoffkombinationen zur Behandlung von Erkrankungen der Haut und Schleimhäute |
GB0712454D0 (en) * | 2007-06-27 | 2007-08-08 | Generics Uk Ltd | Pharmaceutical compositions |
RU2470639C2 (ru) * | 2007-10-25 | 2012-12-27 | Мерк Фросст Кэнада Лтд. | Композиции для ингаляции, содержащие кислоту монтелукаст и ингибитор pde-4 или ингаляционный кортикостероид |
DK2214677T3 (da) | 2007-11-13 | 2017-11-20 | Meritage Pharma Inc | Sammensætninger til behandling af inflammation i mavetarmkanalen |
US8865692B2 (en) | 2007-11-13 | 2014-10-21 | Meritage Pharma, Inc | Compositions for the treatment of gastrointestinal inflammation |
WO2009137555A1 (en) * | 2008-05-06 | 2009-11-12 | Schlesinger S Larry | Topical and injectable formulations comprising leukotriene receptor antagonist and uses thereof |
CA2723458C (en) | 2008-05-14 | 2014-01-28 | Otonomy, Inc. | Controlled release corticosteroid compositions and methods for the treatment of otic disorders |
US20100016450A1 (en) * | 2008-07-21 | 2010-01-21 | Otonomy, Inc. | Controlled release delivery devices for the treatment of otic disorders |
WO2010021636A1 (en) * | 2008-08-20 | 2010-02-25 | The Regents Of The University Of California | Corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract |
EP2221048A1 (en) * | 2009-02-18 | 2010-08-25 | Siegfried Generics International AG | Pharmaceutical composition for inhalation |
CA2763456C (en) * | 2009-05-27 | 2017-10-24 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
CA2872845C (en) | 2012-05-08 | 2021-11-09 | Aciex Therapeutics, Inc. | Preparation of nanocrystals of fluticasone propionate |
US8765725B2 (en) | 2012-05-08 | 2014-07-01 | Aciex Therapeutics, Inc. | Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof |
CA3189252A1 (en) | 2012-05-16 | 2013-11-21 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions |
US9815865B2 (en) | 2013-01-07 | 2017-11-14 | Nicox Ophthalmics, Inc. | Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof |
WO2014175253A1 (ja) * | 2013-04-22 | 2014-10-30 | 株式会社栃木臨床病理研究所 | 抗腫瘍剤 |
WO2014203210A1 (en) * | 2013-06-20 | 2014-12-24 | Glenmark Pharmaceuticals S.A. | Nanoparticulate formulation comprising a trpa1 antagonist |
WO2015009776A1 (en) * | 2013-07-19 | 2015-01-22 | Merck Sharp & Dohme Corp. | Low dose corticosteroid microemulsion compositions and methods of treatments thereof |
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-
2006
- 2006-03-16 BR BRPI0606283-0A patent/BRPI0606283A2/pt not_active IP Right Cessation
- 2006-03-16 MX MX2007011502A patent/MX2007011502A/es not_active Application Discontinuation
- 2006-03-16 CA CA002601179A patent/CA2601179A1/en not_active Abandoned
- 2006-03-16 KR KR1020077023439A patent/KR20070118258A/ko not_active Application Discontinuation
- 2006-03-16 AU AU2006225117A patent/AU2006225117A1/en not_active Abandoned
- 2006-03-16 US US11/376,553 patent/US20070065374A1/en not_active Abandoned
- 2006-03-16 EA EA200701987A patent/EA200701987A1/ru unknown
- 2006-03-16 CN CNA2006800170773A patent/CN101175480A/zh active Pending
- 2006-03-16 WO PCT/US2006/009837 patent/WO2006099591A1/en active Application Filing
- 2006-03-16 JP JP2008502115A patent/JP2008533174A/ja not_active Withdrawn
- 2006-03-16 EP EP06738842A patent/EP1863450A1/en not_active Withdrawn
-
2007
- 2007-09-16 IL IL185951A patent/IL185951A0/en unknown
- 2007-10-03 ZA ZA200708456A patent/ZA200708456B/xx unknown
- 2007-10-16 NO NO20075291A patent/NO20075291L/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
JP2008533174A (ja) | 2008-08-21 |
EP1863450A1 (en) | 2007-12-12 |
ZA200708456B (en) | 2009-05-27 |
WO2006099591A1 (en) | 2006-09-21 |
CA2601179A1 (en) | 2006-09-21 |
MX2007011502A (es) | 2007-12-07 |
IL185951A0 (en) | 2008-01-06 |
AU2006225117A1 (en) | 2006-09-21 |
NO20075291L (no) | 2007-11-21 |
KR20070118258A (ko) | 2007-12-14 |
CN101175480A (zh) | 2008-05-07 |
BRPI0606283A2 (pt) | 2009-06-09 |
US20070065374A1 (en) | 2007-03-22 |
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