JP2008501802A - 医薬組成物 - Google Patents

医薬組成物 Download PDF

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Publication number
JP2008501802A
JP2008501802A JP2007527639A JP2007527639A JP2008501802A JP 2008501802 A JP2008501802 A JP 2008501802A JP 2007527639 A JP2007527639 A JP 2007527639A JP 2007527639 A JP2007527639 A JP 2007527639A JP 2008501802 A JP2008501802 A JP 2008501802A
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JP
Japan
Prior art keywords
solid dispersion
polymer
pharmaceutical composition
amorphous
surfactant
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Pending
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JP2007527639A
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English (en)
Japanese (ja)
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JP2008501802A5 (enExample
Inventor
マウラ・マーフィー
カーク・ダインハート
パトリシア・ハーター
パトリック・コネリー
クイ・ヨン
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Publication date
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of JP2008501802A publication Critical patent/JP2008501802A/ja
Publication of JP2008501802A5 publication Critical patent/JP2008501802A5/ja
Pending legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07Tetrapeptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965Non-condensed pyrazines
    • A61K31/497Non-condensed pyrazines containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate 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
    • A61K9/145Intimate 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate 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
    • A61K9/146Intimate 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Mechanical Treatment Of Semiconductor (AREA)
JP2007527639A 2004-06-08 2005-06-08 医薬組成物 Pending JP2008501802A (ja)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57804304P 2004-06-08 2004-06-08
PCT/US2005/019929 WO2005123076A2 (en) 2004-06-08 2005-06-08 Pharmaceutical compositions

Related Child Applications (1)

Application Number Title Priority Date Filing Date
JP2012000814A Division JP5337262B2 (ja) 2004-06-08 2012-01-05 医薬組成物

Publications (2)

Publication Number Publication Date
JP2008501802A true JP2008501802A (ja) 2008-01-24
JP2008501802A5 JP2008501802A5 (enExample) 2008-07-24

Family

ID=35510250

Family Applications (2)

Application Number Title Priority Date Filing Date
JP2007527639A Pending JP2008501802A (ja) 2004-06-08 2005-06-08 医薬組成物
JP2012000814A Expired - Fee Related JP5337262B2 (ja) 2004-06-08 2012-01-05 医薬組成物

Family Applications After (1)

Application Number Title Priority Date Filing Date
JP2012000814A Expired - Fee Related JP5337262B2 (ja) 2004-06-08 2012-01-05 医薬組成物

Country Status (18)

Country Link
US (2) US20060089385A1 (enExample)
EP (1) EP1765283A4 (enExample)
JP (2) JP2008501802A (enExample)
KR (2) KR101370580B1 (enExample)
CN (2) CN102512372A (enExample)
AR (1) AR049297A1 (enExample)
AU (1) AU2005253957B2 (enExample)
BR (1) BRPI0511900A (enExample)
CA (1) CA2569310A1 (enExample)
IL (2) IL179809A (enExample)
MX (1) MXPA06014253A (enExample)
NO (1) NO20070130L (enExample)
NZ (1) NZ588471A (enExample)
RU (1) RU2373923C2 (enExample)
SG (1) SG153800A1 (enExample)
TW (1) TWI389688B (enExample)
WO (1) WO2005123076A2 (enExample)
ZA (2) ZA200700030B (enExample)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012503669A (ja) * 2008-09-24 2012-02-09 バーテックス ファーマシューティカルズ インコーポレイテッド 肝炎を治療するためのpeg−インターフェロン、リバビリンおよびvx−950を含む治療レジメ
JP2014507424A (ja) * 2011-03-08 2014-03-27 ザリカス ファーマスーティカルズ リミテッド 固体分散物製剤およびその使用方法
JP2015503560A (ja) * 2011-12-29 2015-02-02 アッヴィ・インコーポレイテッド Hcv阻害剤を含む固体組成物

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EA001915B1 (ru) * 1996-10-18 2001-10-22 Вертекс Фармасьютикалз Инкорпорейтед Ингибиторы серин-протеаз, в частности ns3 протеазы вируса гепатита c (hvc)
SV2003000617A (es) * 2000-08-31 2003-01-13 Lilly Co Eli Inhibidores de la proteasa peptidomimetica ref. x-14912m
MY169670A (en) 2003-09-03 2019-05-08 Tibotec Pharm Ltd Combinations of a pyrimidine containing nnrti with rt inhibitors
TW201127828A (en) * 2003-09-05 2011-08-16 Vertex Pharma Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
TW201424733A (zh) 2004-10-29 2014-07-01 Vertex Pharma 劑量型式
AU2006252519B2 (en) 2005-06-02 2012-08-30 Merck Sharp & Dohme Corp. HCV protease inhibitors in combination with food
PE20070011A1 (es) * 2005-06-02 2007-03-08 Schering Corp Formulaciones farmaceuticas de compuestos inhibidores de proteasa del vhc o catepsina
CN101277950B (zh) 2005-08-02 2013-03-27 弗特克斯药品有限公司 丝氨酸蛋白酶抑制剂
US8399615B2 (en) 2005-08-19 2013-03-19 Vertex Pharmaceuticals Incorporated Processes and intermediates
AR055395A1 (es) * 2005-08-26 2007-08-22 Vertex Pharma Compuestos inhibidores de la actividad de la serina proteasa ns3-ns4a del virus de la hepatitis c
US7964624B1 (en) * 2005-08-26 2011-06-21 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases
US8039475B2 (en) * 2006-02-27 2011-10-18 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical compositions comprising the same
CN101460166B (zh) 2006-03-06 2014-11-19 Abbvie公司 用于治疗c型肝炎病毒的利托那韦组合物及其用途
KR20080112303A (ko) 2006-03-16 2008-12-24 버텍스 파마슈티칼스 인코포레이티드 중수소화 c형 간염 프로테아제 억제제
AU2007226983A1 (en) * 2006-03-20 2007-09-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions
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WO2007120595A2 (en) * 2006-04-11 2007-10-25 Novartis Ag Amines for the treatment of hcv
KR101059593B1 (ko) 2006-04-11 2011-08-25 노파르티스 아게 Hcv/hiv 억제제 및 이들의 용도
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NZ579295A (en) * 2007-02-27 2012-03-30 Vertex Pharma Inhibitors of serine proteases
EA200970806A1 (ru) * 2007-02-27 2010-08-30 Вертекс Фармасьютикалз Инкорпорейтед Сокристаллы и содержащие их фармацевтические композиции
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PT2305263E (pt) * 2007-06-07 2012-10-22 Novartis Ag Formas amorfas estabilizadas de mesilato de imatinib
WO2009032198A1 (en) * 2007-08-30 2009-03-12 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical compositions comprising the same
JP5161528B2 (ja) * 2007-10-02 2013-03-13 浜松ホトニクス株式会社 パクリタキセル微粒子、パクリタキセル微粒子分散液、および、これらの製造方法
JP5149585B2 (ja) * 2007-10-02 2013-02-20 浜松ホトニクス株式会社 微粒子分散液製造方法
MX2010003916A (es) 2007-10-10 2010-05-05 Novartis Ag Espiro-pirrolidinas y su uso contra infeccion por el virus de hepatitis c (hcv) y por el virus de inmunodeficiencia humana (vih).
AR068916A1 (es) * 2007-10-19 2009-12-16 Abbott Gmbh & Co Kg Producto de dispersion solida que contiene un compuesto a base de n- aril urea
WO2009061395A2 (en) * 2007-11-05 2009-05-14 Vertex Pharmaceuticals Incorporated Hcv combination therapies
US12458635B2 (en) 2008-08-13 2025-11-04 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
EP2396028A2 (en) 2009-02-12 2011-12-21 Vertex Pharmceuticals Incorporated Hcv combination therapies comprising pegylated interferon, ribavirin and telaprevir
AU2010232670B2 (en) 2009-04-03 2015-07-09 F. Hoffmann-La Roche Ag Propane- I-sulfonic acid {3- [5- (4 -chloro-phenyl) -1H-pyrrolo [2, 3-b] pyridine-3-carbonyl] -2, 4-difluoro-pheny l } -amide compositions and uses thereof
US8512690B2 (en) 2009-04-10 2013-08-20 Novartis Ag Derivatised proline containing peptide compounds as protease inhibitors
WO2011014882A1 (en) 2009-07-31 2011-02-03 Medtronic, Inc. CONTINUOUS SUBCUTANEOUS ADMINISTRATION OF INTERFERON-α TO HEPATITIS C INFECTED PATIENTS
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WO2012009503A1 (en) 2010-07-14 2012-01-19 Vertex Pharmaceuticals Incorporated Palatable pharmaceutical composition comprising vx-950
WO2012109646A1 (en) 2011-02-11 2012-08-16 Vertex Pharmaceuticals Incorporated Treatment of hcv in hiv infection patients
US8409560B2 (en) 2011-03-08 2013-04-02 Zalicus Pharmaceuticals Ltd. Solid dispersion formulations and methods of use thereof
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
AU2013201406B2 (en) 2011-10-21 2014-10-02 Abbvie Ireland Unlimited Company Methods for treating HCV
AR088408A1 (es) 2011-10-21 2014-05-28 Abbvie Inc Metodos para el tratamiento de hcv
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US9034832B2 (en) 2011-12-29 2015-05-19 Abbvie Inc. Solid compositions
WO2013116339A1 (en) 2012-01-31 2013-08-08 Vertex Pharmaceuticals Incorporated High potency formulations of vx-950
HK1203840A1 (en) 2012-02-27 2015-11-06 沃泰克斯药物股份有限公司 Pharmaceutical composition and administration thereof
ITMI20120608A1 (it) 2012-04-13 2013-10-14 Dipharma Francis Srl Procedimento per la preparazione di un inibitore delle proteasi virali in forma amorfa
WO2013178031A1 (en) * 2012-06-01 2013-12-05 Sunshine Lake Pharma Co., Ltd. New forms of telaprevir and preparation methods thereof
WO2014096343A1 (en) * 2012-12-21 2014-06-26 Sandoz Ag Novel forms of telaprevir
EP3650013A1 (en) 2013-01-31 2020-05-13 Gilead Pharmasset LLC Combination formulation of two antiviral compounds
KR20150129005A (ko) 2013-03-15 2015-11-18 베링거 인겔하임 인터내셔날 게엠베하 무정형 상태의 hcv 억제제의 고체 경구 투여 제형
SI3038601T1 (sl) 2013-08-27 2020-07-31 Gilead Pharmasset Llc Formulacija kombinacije dveh protivirusnih spojin
EA201892448A1 (ru) 2016-04-28 2019-06-28 Эмори Юниверсити Алкинсодержащие нуклеотидные и нуклеозидные терапевтические композиции и связанные с ними способы применения
CN110193013B (zh) * 2019-07-02 2022-02-08 力品药业(厦门)股份有限公司 一种去乙酰真菌环氧乙酯固体分散体及其制备方法
CN119546305A (zh) * 2022-05-16 2025-02-28 首日生物制药公司 泛raf激酶抑制剂的口服液体悬浮液
JPWO2024080308A1 (enExample) * 2022-10-12 2024-04-18

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Patent Citations (3)

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WO1997006781A1 (en) * 1995-08-11 1997-02-27 Nissan Chemical Industries, Ltd. Methods for making hardly soluble medicine amorphous
JPH107558A (ja) * 1996-06-19 1998-01-13 Eisai Co Ltd 溶解性改善製剤
WO2002018369A2 (en) * 2000-08-31 2002-03-07 Eli Lilly And Company Peptidomimetic protease inhibitors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012503669A (ja) * 2008-09-24 2012-02-09 バーテックス ファーマシューティカルズ インコーポレイテッド 肝炎を治療するためのpeg−インターフェロン、リバビリンおよびvx−950を含む治療レジメ
JP2014507424A (ja) * 2011-03-08 2014-03-27 ザリカス ファーマスーティカルズ リミテッド 固体分散物製剤およびその使用方法
JP2015503560A (ja) * 2011-12-29 2015-02-02 アッヴィ・インコーポレイテッド Hcv阻害剤を含む固体組成物
JP2015227352A (ja) * 2011-12-29 2015-12-17 アッヴィ・アイルランド・アンリミテッド・カンパニー Hcv阻害剤を含む固体組成物

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ZA200700030B (en) 2009-06-24
KR20070030270A (ko) 2007-03-15
US20060089385A1 (en) 2006-04-27
WO2005123076A3 (en) 2006-06-15
JP5337262B2 (ja) 2013-11-06
AR049297A1 (es) 2006-07-12
EP1765283A4 (en) 2012-11-28
ZA200802676B (en) 2009-12-30
NZ588471A (en) 2012-02-24
RU2006147247A (ru) 2008-07-20
SG153800A1 (en) 2009-07-29
BRPI0511900A (pt) 2008-01-22
KR101370580B1 (ko) 2014-03-06
NO20070130L (no) 2007-01-25
TWI389688B (zh) 2013-03-21
RU2373923C2 (ru) 2009-11-27
CN102512372A (zh) 2012-06-27
IL179809A (en) 2012-10-31
CN1988885A (zh) 2007-06-27
AU2005253957A1 (en) 2005-12-29
TW200608975A (en) 2006-03-16
MXPA06014253A (es) 2007-07-13
AU2005253957B2 (en) 2011-08-25
CA2569310A1 (en) 2005-12-29
IL222003A0 (en) 2012-12-02
KR20120039763A (ko) 2012-04-25
EP1765283A2 (en) 2007-03-28
JP2012067138A (ja) 2012-04-05
IL179809A0 (en) 2007-05-15
WO2005123076A2 (en) 2005-12-29

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