JP6188021B2 - グリブリドおよび他の薬剤の静脈内投与方法 - Google Patents

グリブリドおよび他の薬剤の静脈内投与方法 Download PDF

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JP6188021B2
JP6188021B2 JP2013520785A JP2013520785A JP6188021B2 JP 6188021 B2 JP6188021 B2 JP 6188021B2 JP 2013520785 A JP2013520785 A JP 2013520785A JP 2013520785 A JP2013520785 A JP 2013520785A JP 6188021 B2 JP6188021 B2 JP 6188021B2
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glyburide
administration
period
continuous infusion
hours
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JP2013532658A5 (enExample
JP2013532658A (ja
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スヴェン マーティン ジェイコブソン，
スヴェン マーティン ジェイコブソン，
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バイオジェン チェサピーク エルエルシー
バイオジェン チェサピーク エルエルシー
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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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • 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
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • A61P9/06—Antiarrhythmics
    • 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

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Anesthesiology (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
  • Medicinal Preparation (AREA)
JP2013520785A 2010-07-19 2011-07-18 グリブリドおよび他の薬剤の静脈内投与方法 Active JP6188021B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US36568910P 2010-07-19 2010-07-19
US61/365,689 2010-07-19
PCT/US2011/044397 WO2012012347A2 (en) 2010-07-19 2011-07-18 Methods of intravenous administration of glyburide and other drugs

Related Child Applications (2)

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JP2015212868A Division JP6179574B2 (ja) 2010-07-19 2015-10-29 グリブリドおよび他の薬剤の静脈内投与方法
JP2017051153A Division JP6506335B2 (ja) 2010-07-19 2017-03-16 グリブリドおよび他の薬剤の静脈内投与方法

Publications (3)

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JP2013532658A JP2013532658A (ja) 2013-08-19
JP2013532658A5 JP2013532658A5 (enExample) 2015-05-28
JP6188021B2 true JP6188021B2 (ja) 2017-08-30

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JP2013520785A Active JP6188021B2 (ja) 2010-07-19 2011-07-18 グリブリドおよび他の薬剤の静脈内投与方法
JP2015212868A Active JP6179574B2 (ja) 2010-07-19 2015-10-29 グリブリドおよび他の薬剤の静脈内投与方法
JP2017051153A Active JP6506335B2 (ja) 2010-07-19 2017-03-16 グリブリドおよび他の薬剤の静脈内投与方法
JP2018230763A Active JP6795571B2 (ja) 2010-07-19 2018-12-10 グリブリドおよび他の薬剤の静脈内投与方法
JP2020019464A Pending JP2020073595A (ja) 2010-07-19 2020-02-07 グリブリドおよび他の薬剤の静脈内投与方法

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JP2015212868A Active JP6179574B2 (ja) 2010-07-19 2015-10-29 グリブリドおよび他の薬剤の静脈内投与方法
JP2017051153A Active JP6506335B2 (ja) 2010-07-19 2017-03-16 グリブリドおよび他の薬剤の静脈内投与方法
JP2018230763A Active JP6795571B2 (ja) 2010-07-19 2018-12-10 グリブリドおよび他の薬剤の静脈内投与方法
JP2020019464A Pending JP2020073595A (ja) 2010-07-19 2020-02-07 グリブリドおよび他の薬剤の静脈内投与方法

Country Status (7)

Country Link
US (9) US8946293B2 (enExample)
EP (3) EP2595633A4 (enExample)
JP (5) JP6188021B2 (enExample)
KR (8) KR20230165363A (enExample)
CN (2) CN109172363A (enExample)
CA (3) CA3225438A1 (enExample)
WO (1) WO2012012347A2 (enExample)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10519504B2 (en) 2009-05-11 2019-12-31 Berg Llc Methods for treatment of oncological disorders using epimetabolic shifters, multidimensional intracellular molecules, or environmental influencers
EP2595633A4 (en) 2010-07-19 2014-01-22 Remedy Pharmaceuticals Inc METHOD FOR INTRAVENOUS ADMINISTRATION OF GLYBURID AND OTHER MEDICAMENTS
WO2012054831A2 (en) * 2010-10-21 2012-04-26 Rtu Pharmaceuticals, Llc Ready to use ketorolac formulations
EP2694463B8 (en) 2011-04-04 2019-10-09 Berg LLC Treating central nervous system tumors with coenzyme q10
WO2013169939A2 (en) 2012-05-08 2013-11-14 Aeromics, Llc New methods
EA032775B1 (ru) 2013-04-08 2019-07-31 Берг Ллк Способы лечения злокачественной опухоли с использованием комбинированной терапии с коферментом q10
WO2015035094A1 (en) * 2013-09-04 2015-03-12 Berg Llc Methods of treatment of cancer by continuous infusion of coenzyme q10
KR20160079109A (ko) 2013-11-06 2016-07-05 에어로믹스, 인코포레이티드 새로운 조성물
WO2016196113A1 (en) 2015-05-29 2016-12-08 University Of Maryland, Baltimore Methods of reducing or preventing intimal damage caused by mechanical stimulation of endothelial cells
BR112018006925A2 (pt) * 2015-10-07 2018-10-16 Biogen Chesapeake Llc métodos de tratamento de lesões ou patologias associadas com um edema do snc
WO2017087576A1 (en) 2015-11-16 2017-05-26 Berg Llc Methods of treatment of temozolomide-resistant glioma using coenzyme q10
CA3032294C (en) 2016-07-29 2025-03-11 Biogen Chesapeake Llc MEDICAL TREATMENT METHODS WITH SUR1-TRPM4 CHANNEL INHIBITORS
AU2018261756B2 (en) 2017-05-05 2022-01-20 Nino Sorgente Methods and compositions for improving eye health
US11382881B2 (en) 2017-05-05 2022-07-12 Nino Sorgente Methods and compositions for diagnosing and treating glaucoma
CN108078999B (zh) * 2017-12-22 2020-08-14 沈阳药科大学 用于防治缺血性脑卒中的药物组合物及其制备方法和用途
TW202214561A (zh) 2020-07-17 2022-04-16 大陸商上海森輝醫藥有限公司 磺醯脲類衍生物及其醫藥用途
US12251388B1 (en) 2024-05-09 2025-03-18 Remedy Pharmaceuticals, Inc. Methods of treating ischemic stroke at risk for cerebral or cerebellar edema
US12251389B1 (en) 2024-04-22 2025-03-18 Remedy Pharmaceuticals, Inc. Methods of treating ischemic stroke at risk for cerebral or cerebellar edema

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856360A (en) * 1996-05-03 1999-01-05 Children's Hospital Medical Center Pharmaceutical method for the treatment of severe blood loss and for the inhibition or treatment of hemorrhagic shock
DE10300323A1 (de) * 2003-01-09 2004-10-14 Baxter Healthcare S.A. Sicherheitsbehälter mit erhöhter Bruch und Splitterfestigkeit sowie kontaminationsfreier Außenfläche für biologisch aktive Substanzen und Verfahren zu deren Herstellung
US20080220441A1 (en) 2001-05-16 2008-09-11 Birnbaum Eva R Advanced drug development and manufacturing
US7872048B2 (en) 2004-09-18 2011-01-18 University Of Maryland, Baltimore Methods for treating spinal cord injury with a compound that inhibits a NCCa-ATP channel
PT2438913T (pt) 2002-03-20 2020-05-27 Us Veterans Affairs Canal de catiões não seletivos em células neurais e compostos que bloqueiam o canal para utilização no tratamento de edema cerebral
US8980952B2 (en) * 2002-03-20 2015-03-17 University Of Maryland, Baltimore Methods for treating brain swelling with a compound that blocks a non-selective cation channel
US20040073192A1 (en) * 2002-10-15 2004-04-15 Flament-Garcia Mary Jane Intravenous fluid delivery set
US20050148928A1 (en) * 2003-12-31 2005-07-07 Medtronic Minimed, Inc. Multiple layer tubing and method of making same
JP5000493B2 (ja) * 2004-05-20 2012-08-15 ディアメディカ インコーポレイテッド インスリン抵抗性を治療するための製薬組成物、同製薬組成物の調製においてベタネコール及びｎ−アセチルシステインを使用する方法及び同製薬組成物を含むキット
EP2359832A3 (en) * 2004-09-18 2011-11-23 University of Maryland, Baltimore Therapeutic agents targeting the NCCA-ATP channel and methods of use thereof
EP1833734A4 (en) * 2004-12-23 2012-06-20 Hospira Inc ORIFICE CLOSURE SYSTEM FOR INTRAVENOUS FLUID CONTAINER
CA2663610C (en) * 2006-09-29 2015-11-03 Infa S.A. Packaging system for pharmaceutical compositions and kit for intravenous administration
CA2974689C (en) * 2007-06-22 2020-02-25 The United States Of America As Represented By The Department Of Veters Affairs Inhibitors of ncca-atp channels for therapy
US20110034560A1 (en) * 2008-01-29 2011-02-10 Sven Jacobson Liquid formulations of compounds active at sulfonylurea receptors
CN101229316B (zh) * 2008-01-31 2010-08-25 广东药学院 一种知母提取物
EP2595633A4 (en) 2010-07-19 2014-01-22 Remedy Pharmaceuticals Inc METHOD FOR INTRAVENOUS ADMINISTRATION OF GLYBURID AND OTHER MEDICAMENTS

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WO2012012347A2 (en) 2012-01-26
US20190328653A1 (en) 2019-10-31
KR20200054319A (ko) 2020-05-19
JP6795571B2 (ja) 2020-12-02
EP3339190A1 (en) 2018-06-27
CA3101711C (en) 2024-02-13
KR20130133165A (ko) 2013-12-06
CA3225438A1 (en) 2012-01-26
US20150157560A1 (en) 2015-06-11
EP2595633A2 (en) 2013-05-29
CN109172363A (zh) 2019-01-11
CN103108637B (zh) 2018-09-14
US10786445B2 (en) 2020-09-29
US20250221924A1 (en) 2025-07-10
JP2017105846A (ja) 2017-06-15
JP2016020393A (ja) 2016-02-04
WO2012012347A3 (en) 2012-05-10
KR20180123176A (ko) 2018-11-14
US9561176B2 (en) 2017-02-07
US10391053B2 (en) 2019-08-27
US20210154135A1 (en) 2021-05-27
US20130203853A1 (en) 2013-08-08
KR20250026419A (ko) 2025-02-25
US10052280B2 (en) 2018-08-21
JP6179574B2 (ja) 2017-08-16
US12226521B2 (en) 2025-02-18
EP3586850A1 (en) 2020-01-01
EP2595633A4 (en) 2014-01-22
CN103108637A (zh) 2013-05-15
KR20190031592A (ko) 2019-03-26
KR101917975B1 (ko) 2018-11-13
US8946293B2 (en) 2015-02-03
US11559481B2 (en) 2023-01-24
AU2011279878A1 (en) 2013-03-07
KR20220000943A (ko) 2022-01-04
JP2019038855A (ja) 2019-03-14
US20160030370A1 (en) 2016-02-04
JP2013532658A (ja) 2013-08-19
CA2806069C (en) 2021-01-19
KR20170118960A (ko) 2017-10-25
US20170348227A1 (en) 2017-12-07
US9254259B2 (en) 2016-02-09
CA3101711A1 (en) 2012-01-26
US20170333340A1 (en) 2017-11-23
CA2806069A1 (en) 2012-01-26
US20230414489A1 (en) 2023-12-28
JP2020073595A (ja) 2020-05-14
JP6506335B2 (ja) 2019-04-24
KR20230165363A (ko) 2023-12-05

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