PL2459176T3 - Sposób krystalizacji i biodostępność - Google Patents

Sposób krystalizacji i biodostępność

Info

Publication number
PL2459176T3
PL2459176T3 PL10805109T PL10805109T PL2459176T3 PL 2459176 T3 PL2459176 T3 PL 2459176T3 PL 10805109 T PL10805109 T PL 10805109T PL 10805109 T PL10805109 T PL 10805109T PL 2459176 T3 PL2459176 T3 PL 2459176T3
Authority
PL
Poland
Prior art keywords
bioavailability
crystallization method
crystallization
Prior art date
Application number
PL10805109T
Other languages
English (en)
Polish (pl)
Inventor
Mazen Hanna
Ning Shan
Miranda Cheney
David Weyna
Raymond K. Houck
Original Assignee
Grünenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Publication of PL2459176T3 publication Critical patent/PL2459176T3/pl

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/675Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/375Ascorbic acid, i.e. vitamin C; Salts thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503Five-membered rings
    • C07F9/6506Five-membered rings having the nitrogen atoms in positions 1 and 3
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00Preparations for use in therapy
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
PL10805109T 2009-07-31 2010-07-30 Sposób krystalizacji i biodostępność PL2459176T3 (pl)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US23022209P 2009-07-31 2009-07-31
US28803609P 2009-12-18 2009-12-18
US30211010P 2010-02-06 2010-02-06
US31287910P 2010-03-11 2010-03-11
US31850310P 2010-03-29 2010-03-29
US35954410P 2010-06-29 2010-06-29
EP10805109.5A EP2459176B1 (en) 2009-07-31 2010-07-30 Crystallization method and bioavailability
PCT/US2010/043892 WO2011014766A2 (en) 2009-07-31 2010-07-30 Crystallization method and bioavailability

Publications (1)

Publication Number Publication Date
PL2459176T3 true PL2459176T3 (pl) 2018-02-28

Family

ID=43527595

Family Applications (1)

Application Number Title Priority Date Filing Date
PL10805109T PL2459176T3 (pl) 2009-07-31 2010-07-30 Sposób krystalizacji i biodostępność

Country Status (20)

Country Link
US (5) US8399023B2 (enExample)
EP (2) EP2459176B1 (enExample)
JP (1) JP5852569B2 (enExample)
KR (1) KR101813728B1 (enExample)
CN (1) CN102573809B (enExample)
AU (2) AU2010278860B2 (enExample)
CA (1) CA2769633C (enExample)
CY (1) CY1121952T1 (enExample)
DK (1) DK2459176T3 (enExample)
ES (1) ES2650665T3 (enExample)
HR (1) HRP20171755T1 (enExample)
HU (1) HUE034784T2 (enExample)
IL (1) IL217828B (enExample)
IN (1) IN2012DN01216A (enExample)
LT (1) LT2459176T (enExample)
NO (1) NO2459176T3 (enExample)
PL (1) PL2459176T3 (enExample)
PT (1) PT2459176T (enExample)
SI (1) SI2459176T1 (enExample)
WO (1) WO2011014766A2 (enExample)

Families Citing this family (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2650665T3 (es) 2009-07-31 2018-01-19 Grünenthal GmbH Método de cristalización y biodisponibilidad
US20160016982A1 (en) 2009-07-31 2016-01-21 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
WO2011014781A1 (en) 2009-07-31 2011-02-03 Thar Pharmaceuticals, Inc. Novel oral forms of a phosphonic acid derivative
HRP20171201T1 (hr) * 2010-02-06 2017-10-06 Grünenthal GmbH Postupak kristalizacije i biodostupnost
WO2012071517A2 (en) * 2010-11-24 2012-05-31 Thar Pharmaceuticals, Inc. Novel crystalline forms
US9999629B2 (en) 2012-05-14 2018-06-19 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US10173986B2 (en) 2012-05-14 2019-01-08 Antecip Bioventures Ii Llc Methods for the safe administration of imidazole or imidazolium compounds
US9956238B2 (en) 2014-05-15 2018-05-01 Antecip Bioventures Ii Llc Compositions for administration of zoledronic acid or related compounds for treating low back pain
US9782421B1 (en) 2012-05-14 2017-10-10 Antecip Bioventures Ii Llc Neridronic acid molecular complex for treating complex regional pain syndrome
US10016445B2 (en) 2012-05-14 2018-07-10 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9694023B2 (en) 2012-05-14 2017-07-04 Antecip Bioventures Ii Llc Methods for the safe administration of imidazole or imidazolium compounds
US10004756B2 (en) 2014-05-15 2018-06-26 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US8802658B2 (en) 2012-05-14 2014-08-12 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating disease
US9707247B2 (en) 2012-05-14 2017-07-18 Antecip Bioventures Ii Llc Compositions for administration of zoledronic acid or related compounds for treating low back pain
US10034890B2 (en) 2012-05-14 2018-07-31 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US20140349974A1 (en) * 2014-08-12 2014-11-27 Antecip Bioventures Ii Llc Zoledronic acid dosage forms for the treatment of pain
US9211257B2 (en) 2012-05-14 2015-12-15 Antecip Bioventures Ii Llc Osteoclast inhibitors for knee conditions
US9795622B2 (en) 2012-05-14 2017-10-24 Antecip Bioventures Ii Llc Neridronic acid for treating pain associated with a joint
US9770457B2 (en) 2012-05-14 2017-09-26 Antecip Bioventures Ii Llc Neridronic acid for treating bone marrow lesion
US9789128B2 (en) 2012-05-14 2017-10-17 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9861648B2 (en) 2012-05-14 2018-01-09 Antecip Boiventures Ii Llc Osteoclast inhibitors for knee conditions
US10080765B2 (en) 2012-05-14 2018-09-25 Antecip Bioventures Ii Llc Neridronic acid for treating complex regional pain syndrome
US9655908B2 (en) 2012-05-14 2017-05-23 Antecip Bioventures Ii Llc Neridronic acid molecular complex for treating complex regional pain syndrome
US9901589B2 (en) 2012-05-14 2018-02-27 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9662343B2 (en) 2012-05-14 2017-05-30 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9827256B2 (en) 2014-05-27 2017-11-28 Antecip Bioventures Ii Llc Compositions for administration of zoledronic acid or related compounds for treating lower back pain
US9943531B2 (en) 2014-08-08 2018-04-17 Antecip Bioventures Ii Llc Osteoclast inhibitors such as zoledronic acid for low back pain treatment
US10039773B2 (en) 2012-05-14 2018-08-07 Antecip Bioventures Ii Llc Neridronic acid for treating arthritis
US9895383B2 (en) 2012-05-14 2018-02-20 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9949993B2 (en) 2012-05-14 2018-04-24 Antecip Bioventures Ii Llc Compositions for administration of zoledronic acid or related compounds for treating low back pain
US9675626B2 (en) 2012-05-14 2017-06-13 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9616078B2 (en) 2012-05-14 2017-04-11 Antecip Bioventures Ii Llc Dosage forms for oral administration of zoledronic acid or related compounds for treating disease
US9956237B2 (en) 2012-05-14 2018-05-01 Antecip Bioventures Ii Llc Osteoclast inhibitors for knee conditions
US10463682B2 (en) 2012-05-14 2019-11-05 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating low back pain
US9877977B2 (en) 2012-05-14 2018-01-30 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US10413560B2 (en) 2012-05-14 2019-09-17 Antecip Bioventures Ii Llc Dosage forms for oral administration of zoledronic acid or related compounds for treating disease
US8865757B1 (en) 2014-05-28 2014-10-21 Antecip Bioventures Ii Llp Therapeutic compositions comprising imidazole and imidazolium compounds
US9669040B2 (en) 2012-05-14 2017-06-06 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9867840B2 (en) 2014-05-27 2018-01-16 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9956234B2 (en) 2012-05-14 2018-05-01 Antecip Bioventures Ii Llc Osteoclast inhibitors for joint conditions
US9999628B2 (en) 2012-05-14 2018-06-19 Antecip Bioventures Ii Llc Neridronic acid for treating complex regional pain syndrome
US9827192B2 (en) 2012-05-14 2017-11-28 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9289441B2 (en) 2014-08-08 2016-03-22 Antecip Bioventures Ii Llc Osteoclast inhibitors such as zoledronic acid for low back pain treatment
US10493085B2 (en) 2012-05-14 2019-12-03 Antecip Bioventures Ii Llc Neridronic acid and other bisphosphonates for treating complex regional pain syndrome and other diseases
US10016446B2 (en) 2012-05-14 2018-07-10 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating Paget's disease of bone
US9700570B2 (en) 2014-05-27 2017-07-11 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9707245B2 (en) 2012-05-14 2017-07-18 Antecip Bioventures Ii Llc Neridronic acid for treating complex regional pain syndrome
US9427403B2 (en) * 2012-05-14 2016-08-30 Antecip Bioventures Ii Llc Methods for the safe administration of imidazole or imidazolium compounds
US10413561B2 (en) 2012-05-14 2019-09-17 Antecip Bioventures Ii Llc Neridronic acid and other bisphosphonates for treating complex regional pain syndrome and other diseases
US11654152B2 (en) 2012-05-14 2023-05-23 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating disease
US9820999B2 (en) 2012-05-14 2017-11-21 Antecip Bioventures Ii Llc Neridronic acid for treating complex regional pain syndrome
US10350227B2 (en) 2012-05-14 2019-07-16 Antecip Bioventures Ii Llc Neridronic acid for treating complex regional pain syndrome
US10028969B2 (en) 2012-05-14 2018-07-24 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US9925203B2 (en) 2012-05-14 2018-03-27 Antecip Bioventures Ii Llc Compositions for administration of zoledronic acid or related compounds for treating low back pain
US9844559B2 (en) 2012-05-14 2017-12-19 Antecip Bioventures Ii Llc Neridronic acid for treating bone marrow lesions
US9867839B2 (en) 2012-05-14 2018-01-16 Antecip Bioventures Ii Llc Osteoclast inhibitors for joint conditions
US9717747B2 (en) 2012-05-14 2017-08-01 Antecip Bioventures Ii Llc Osteoclast inhibitors for knee conditions
US10028908B2 (en) 2012-05-14 2018-07-24 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome
US10111837B2 (en) 2012-05-14 2018-10-30 Antecip Bioventures Ii Llc Dosage forms for oral administration of zoledronic acid or related compounds
US10092581B2 (en) 2014-05-15 2018-10-09 Antecip Bioventures Ii Llc Osteoclast inhibitors such as zoledronic acid for low back pain treatment
MY176246A (en) * 2013-10-25 2020-07-24 Antecip Bioventures Ii Llc Compositions for oral administration of zoledronic acid or related compounds for treating disease
US9127069B1 (en) 2014-06-11 2015-09-08 Antecip Bioventures LLC Compositions comprising rank/rankl antagonists and related compounds for treating pain
US9079927B1 (en) 2014-05-27 2015-07-14 Antecip Bioventures Ii Llc Substituted imidazolium compounds for treating disease
US9688765B2 (en) 2014-06-11 2017-06-27 Antecip Bioventures Ii Llc Methods using RANK/RANKL antagonist antibodies for treating pain
EP3362071A4 (en) * 2015-09-18 2019-07-17 Grünenthal GmbH CRYSTALLIZATION PROCESS AND BIOVERABILITY
WO2017208070A1 (en) 2016-05-31 2017-12-07 Grünenthal GmbH Bisphosphonic acid and coformers with lysin, glycin, nicotinamide for treating psoriatic arthritis
CN112778365A (zh) * 2020-12-30 2021-05-11 华南理工大学 一种唑来膦酸钙配合物及其制备方法

Family Cites Families (142)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3959361A (en) 1970-03-20 1976-05-25 Joh. A. Benckiser Gmbh Process of producing amino methylene phosphonic acids
US3961934A (en) 1974-12-19 1976-06-08 Monsanto Company Method for increasing the sucrose content of growing plants
EP0275821B1 (de) * 1986-11-21 1992-02-26 Ciba-Geigy Ag Neue substituierte Alkandiphosphonsäuren
IE912115A1 (en) * 1990-06-25 1992-01-01 Takeda Chemical Industries Ltd Bisphosphonic acid derivatives, their production and use
SK90093A3 (en) 1991-02-26 1994-09-07 Norwich Eaton Pharma Mixture of phosphonite and estrogene for treatment of osteoporosis
US5431920A (en) 1993-09-21 1995-07-11 Merck Frosst, Canada, Inc. Enteric coated oral compositions containing bisphosphonic acid antihypercalcemic agents
EP0779812A4 (en) 1994-09-09 1997-09-10 Procter & Gamble METHOD FOR TREATING OSTEOPOROSIS USING BONE-ACTIVE PHOSPHONATES AND PARATHORMONE
US6541454B1 (en) * 1995-04-04 2003-04-01 Yissum Research Development Company Of The Hebrew University Jerusalem Phosphonates, biphosphonates and pharmaceutical compositions containing them
GB9516268D0 (en) 1995-08-08 1995-10-11 Danbiosyst Uk Compositiion for enhanced uptake of polar drugs from the colon
GB9710699D0 (en) 1997-05-24 1997-07-16 Danbiosyst Uk Gastro-retentive controlled release system
RU2193880C2 (ru) 1997-06-11 2002-12-10 Дзе Проктер Энд Гэмбл Компани Покрытая пленкой таблетка улучшенной безопасности для верхних отделов желудочно-кишечного тракта
EP0998933A1 (de) 1998-10-09 2000-05-10 Boehringer Mannheim Gmbh Verfahren zur Herstellung von bisphosphonathaltigen pharmazeutischen Zusammensetzungen zur oralen Applikation
US7658938B2 (en) * 1999-02-22 2010-02-09 Merrion Reasearch III Limited Solid oral dosage form containing an enhancer
US8119159B2 (en) * 1999-02-22 2012-02-21 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
WO2000050012A1 (en) 1999-02-22 2000-08-31 Elan Corporation, Plc Solid oral dosage form containing an enhancer
SE9901272D0 (sv) 1999-04-09 1999-04-09 Astra Ab New improved formulation
AU4652100A (en) 1999-04-22 2000-11-10 Hydromed Sciences A Division Of Gp Strategies Corporation Controlled delivery of bisphosphonates
IL146520A0 (en) * 1999-05-21 2002-07-25 Novartis Ag Use of bisphosphonic acids for treating angiogenesis
AR021347A1 (es) * 1999-10-20 2002-07-17 Cipla Ltd Una composicion farmaceutica que contiene acido(s) bisfosfoncio o sal(es) del mismo y un proceso de preparacion de la misma
US6936275B2 (en) * 1999-12-20 2005-08-30 Scolr, Inc. Amino acid modulated extended release dosage form
US6677320B2 (en) 2000-01-20 2004-01-13 Hoffmann-La Roches Inc. Parenteral bisphosphonate composition with improved local tolerance
AU2001251432A1 (en) * 2000-04-07 2001-10-23 The Board Of Regents Of The University Of Texas System Unique compositions of zwitterionic phospholipids and bisphosphonates and use ofthe compositions as bisphosphate delivery systems with reduced gi toxicity
US6468559B1 (en) 2000-04-28 2002-10-22 Lipocine, Inc. Enteric coated formulation of bishosphonic acid compounds and associated therapeutic methods
JP3923800B2 (ja) * 2000-05-05 2007-06-06 エフ.ホフマン−ラ ロシュ アーゲー ビスホスホン酸またはそれらの塩を含む、皮下投与のためのゲル様医薬組成物
DK1591122T3 (da) 2000-06-20 2013-02-25 Novartis Ag Fremgangsmåde til indgivelse af bisphosphonater
DE60113537T3 (de) * 2000-06-20 2013-05-29 Novartis Ag Methode zur verabreichung von biphosphonaten
US6476006B2 (en) * 2000-06-23 2002-11-05 Teva Pharmaceutical Industries, Ltd. Composition and dosage form for delayed gastric release of alendronate and/or other bis-phosphonates
AU2001271055B2 (en) * 2000-07-17 2005-07-07 Astellas Pharma Inc. Pharmaceutical composition improved in peroral absorbability
MXPA03007029A (es) * 2001-02-06 2004-10-15 Royal Alexandra Hosp Children Un farmaco para el tratamiento de osteonecrosis y para el manejo de pacientes en riesgo de desarrollar osteonecrosis.
AU2002254082B2 (en) * 2001-03-01 2007-05-24 Emisphere Technologies, Inc. Compositions for delivering bisphosphonates
AU2002244520B2 (en) 2001-04-03 2007-05-24 The Royal Alexandra Hospital For Children A drug for use in bone grafting
CZ20033271A3 (en) 2001-04-30 2004-06-16 Novologix Gmbh Antibacterial agent
PL363507A1 (en) * 2001-05-02 2004-11-29 Novartis Ag Pharmaceutical uses of bisphosphonates
BR0209360A (pt) * 2001-05-02 2004-06-08 Novartis Ag Método de administração de bisfosfonatos por inalação no tratamento ou prevenção de reabsorção óssea e osteoporose
WO2002092069A1 (en) * 2001-05-11 2002-11-21 Elan Corporation, Plc Permeation enhancers
EP1416919A1 (en) 2001-07-17 2004-05-12 Teva Pharmaceutical Industries Ltd. Dosage forms for immediate gastric release of a calcium transport stimulator coupled with delayed gastric release of a bis-phosphonate
CA2461085A1 (en) * 2001-10-19 2003-05-01 Novartis Ag Pharmaceutical composition for use for the treatment of malignancies comprising in combination a bisphosphonates, a cox-2 inhibitor and a taxol
CA2468687A1 (en) 2001-12-13 2003-06-26 Merck & Co., Inc. Liquid bisphosphonate formulations for bone disorders
WO2004078163A2 (en) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
ITMI20020908A1 (it) * 2002-04-29 2003-10-29 Chemi Spa Processo di preparazione di sodio alendronato
CA2481142C (en) * 2002-05-10 2012-11-13 F.Hoffmann-La Roche Ag Bisphosphonic acids for the treatment and prevention of osteoporosis
EP1476451B1 (en) * 2002-05-17 2010-03-17 Teva Pharmaceutical Industries Ltd. Use of certain diluents for making bisphosphonic acids
US20040047835A1 (en) * 2002-09-06 2004-03-11 Cell Therapeutics, Inc. Combinatorial drug therapy using polymer drug conjugates
GB0220885D0 (en) 2002-09-09 2002-10-16 Novartis Ag Organic compounds
US20040138180A1 (en) * 2002-10-03 2004-07-15 Barr Laboratories, Inc. Bisphosphonate composition and process for the preparation thereof
JP2006506365A (ja) 2002-10-15 2006-02-23 ノバルティス アクチエンゲゼルシャフト ビスホスホネートの投与方法
NZ555514A (en) 2002-12-20 2008-12-24 Hoffmann La Roche High dose ibandronate formulation
CA2517387A1 (en) 2003-02-27 2004-09-10 Teva Pharmaceutical Industries Ltd Process for purification of zoledronic acid
ATE550022T1 (de) 2003-02-28 2012-04-15 Mcneil Ppc Inc Pharmazeutische mischkristalle von celecoxib- nicotinamid
US20040220264A1 (en) * 2003-03-17 2004-11-04 Yu Ruey J Bioavailability and improved delivery of acidic pharmaceutical drugs
GB0310919D0 (en) 2003-05-13 2003-06-18 West Pharm Serv Drug Res Ltd Pharmaceutical compositions
WO2005000404A2 (en) 2003-05-29 2005-01-06 Synta Pharmaceuticals, Corp. Heterocyclic compounds for preventing and treating disorders associated with excessive bone loss
JPWO2005002590A1 (ja) * 2003-07-01 2006-08-10 アステラス製薬株式会社 骨量増加誘導剤
WO2005005447A2 (en) * 2003-07-03 2005-01-20 Teva Pharmaceutical Industries Ltd. Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
DK1656386T3 (da) * 2003-08-21 2010-04-19 Sun Pharmaceuticals Ind Ltd Fremgangsmåde til fremstilling af bisphosphonsyreforbindelser
MY141763A (en) * 2003-09-18 2010-06-30 Novartis Ag Pharmaceutical products comprising bisphosphonates
US20050119230A1 (en) * 2003-09-18 2005-06-02 Alexandra Glausch Pharmaceutical products comprising bisphosphonated
AU2004273672A1 (en) * 2003-09-19 2005-03-31 Wisconsin Alumni Research Foundation Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a bisphosphonate
WO2005048979A2 (en) 2003-10-06 2005-06-02 Torrent Pharmaceuticals Limited Pharmaceutical composition having casing with multiple micro tablets
WO2005037157A1 (en) 2003-10-14 2005-04-28 Dermatrends, Inc. Enhancing transdermal administration of hydrophilic drugs
AR046773A1 (es) * 2003-12-23 2005-12-21 Novartis Ag Formulaciones farmaceuticas de bisfosfonatos
WO2005063717A1 (en) 2003-12-26 2005-07-14 Natco Pharma Limited An improved process for the preparation of zoledronic acid
WO2005099676A2 (en) 2004-04-07 2005-10-27 Dermatrends, Inc. Transdermal delivery system for use with basic permeation enhancers
US7645460B2 (en) * 2004-05-24 2010-01-12 The Procter & Gamble Company Dosage forms of risedronate
US20080286359A1 (en) * 2004-05-24 2008-11-20 Richard John Dansereau Low Dosage Forms Of Risedronate Or Its Salts
RS51562B (sr) 2004-05-24 2011-08-31 Warner Chilcott Company Llc. Enterični čvrsti oralni dozni oblik bisfosfonata koji sadrži helat
US7645459B2 (en) 2004-05-24 2010-01-12 The Procter & Gamble Company Dosage forms of bisphosphonates
US20080287400A1 (en) * 2004-05-24 2008-11-20 Richard John Dansereau Low Dosage Forms Of Risedronate Or Its Salts
AU2011218625B2 (en) 2004-05-24 2014-03-20 Theramex HQ UK Limited Dosage forms of risedronate
US20050289182A1 (en) 2004-06-15 2005-12-29 Sand Hill Systems Inc. Document management system with enhanced intelligent document recognition capabilities
AU2005275193A1 (en) 2004-07-15 2006-02-23 Nanobac Life Sciences Methods and compositions for the administration of calcium chelators, bisphosphonates and/or citrate compounds and their pharmaceutical uses
WO2006020009A1 (en) 2004-07-23 2006-02-23 The Procter & Gamble Company Solid oral dosage form of a bisphosphonate containing a chelating agent
EP1781258A1 (en) 2004-08-20 2007-05-09 Mepha AG Formulations of bisphosphonates
US20060068010A1 (en) 2004-09-30 2006-03-30 Stephen Turner Method for improving the bioavailability of orally delivered therapeutics
US20060134190A1 (en) * 2004-12-16 2006-06-22 Banner Pharmacaps Inc. Formulations of bisphosphonate drugs with improved bioavailability
US20060178439A1 (en) 2005-01-04 2006-08-10 Mohakhud Pradeep K Crystalline form of zoledronic acid
KR100815040B1 (ko) 2005-01-31 2008-03-18 주식회사종근당 비스포스포네이트계 약물의 경구흡수 개선을 위한약제학적 조성물
CA2597699C (en) * 2005-02-17 2012-07-31 Hadasit Medical Research Services And Development Ltd. Bisphosphonates for treating endometriosis
US8158153B2 (en) * 2005-03-17 2012-04-17 Alkermes Pharma Ireland Limited Nanoparticulate bisphosphonate compositions
EP1883644A2 (en) 2005-05-06 2008-02-06 Medichem, S.A. Process of making geminal bisphosphonic acids and pharmaceutically acceptable salts and/or hydrates thereof
US20070014319A1 (en) 2005-07-15 2007-01-18 Zetetic Institute Continuously Tunable External Cavity Diode Laser Sources With High Tuning And Switching Rates And Extended Tuning Ranges
AR054673A1 (es) * 2005-07-28 2007-07-11 Gador Sa Una forma cristalina del acido zoledronico, un proceso para su obtencion y la composicion farmaceutica que la comprende
US20070049557A1 (en) 2005-08-24 2007-03-01 Hashim Ahmed Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers
US20080255366A1 (en) * 2005-09-12 2008-10-16 Dr. Reddy's Laboratories Limited Crystalline Trihydrate of Zoledronic Acid
JO3006B1 (ar) 2005-09-14 2016-09-05 Janssen Pharmaceutica Nv املاح ليسين مبتكرة من مشتقات حامض 4-((فينوكسي الكيل)ثيو) فينوكسي الخليك
US7473684B2 (en) * 2005-09-16 2009-01-06 Selamine Limited Bisphosphonate formulation
US20070088161A1 (en) * 2005-10-19 2007-04-19 Stockel Richard F Novel chelated bisphosphonates for use as pharmaceutical agents
EP1963345A2 (en) 2005-12-16 2008-09-03 Wockhardt Limited Processes for the preparation of pure zoledronic acid
WO2007083240A2 (en) * 2006-01-20 2007-07-26 Aurobindo Pharma Limited An improved process for the preparation of bisphosphonic acids
AU2007212508A1 (en) * 2006-02-06 2007-08-16 Cypress Bioscience, Inc. Compositions comprising a bisphosphonate and an antifolate
WO2007096896A1 (en) * 2006-02-20 2007-08-30 Alembic Limited An improved process for the preparation of biphosphonic derivatives
US20090137808A1 (en) * 2006-03-21 2009-05-28 Albemarle Corporation Process for manufacturing bisphosphonic acids
CA2648594C (en) 2006-04-07 2012-10-16 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
US20090075941A1 (en) * 2006-04-21 2009-03-19 The Uab Research Foundation Treating neoplasms
WO2007125521A2 (en) 2006-05-02 2007-11-08 Ranbaxy Laboratories Limited Polymorphic form of zoledronic acid and processes for their preparation
CA2654566A1 (en) 2006-06-09 2007-12-21 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
WO2008040763A1 (en) 2006-10-05 2008-04-10 Novartis Ag Pharmaceutical compositions comprising bisphosphonates
EP1923394A1 (en) 2006-11-16 2008-05-21 Sandoz A/S Reagent and use thereof for the production of bisphosphonates
JP2010510195A (ja) * 2006-11-17 2010-04-02 ベシンズ・ヘルスケアー ビスホスホネート化合物を含む液体薬剤組成物
EP1925621A1 (en) 2006-11-27 2008-05-28 Novartis AG Crystalline forms of zoledronic acid
US20080139514A1 (en) * 2006-11-29 2008-06-12 Subhash Pandurang Gore Diphosphonic acid pharmaceutical compositions
KR100775440B1 (ko) * 2006-12-20 2007-11-12 동우신테크 주식회사 리세드로네이트 나트륨 헤미펜타히드레이트의 제조방법
US8974801B2 (en) * 2006-12-21 2015-03-10 Amphastar Pharmaceuticals Inc. Long term sustained release pharmaceutical composition containing aqueous suspension of bisphosphonate
TW200843802A (en) 2007-02-09 2008-11-16 Drugtech Corp Compositions for improving gastrointestinal nutrient and drug absorption
AU2008229604B2 (en) 2007-03-20 2013-05-30 Scf Pharma Inc. Compositions comprising polyunsaturated fatty acid monoglycerides or derivatives thereof and uses thereof
US20090023683A1 (en) * 2007-07-16 2009-01-22 Chandrasekhar Kocherlakota Complexes comprising zoledronic acid and cyclodextrins
WO2009018834A1 (en) 2007-08-06 2009-02-12 Pharmathen S.A. Pharmaceutical composition containing bisphosphonate and method for the preparation thereof
KR101165455B1 (ko) 2007-09-10 2012-07-12 한스바이오메드 주식회사 인산칼슘 마이크로스피어 약물전달체 및 이의 제조방법
WO2009042179A1 (en) 2007-09-24 2009-04-02 Teva Pharmaceutical Industries Ltd. Crystalline forms of ibandronic acid and processeses for the preparation thereof
SI2200588T1 (sl) 2007-09-25 2019-08-30 Solubest Ltd. Sestavki, ki obsegajo lipofilne aktivne spojine, in postopek za njihovo pripravo
US20090082312A1 (en) * 2007-09-25 2009-03-26 Protia, Llc Deuterium-enriched zoledronic acid
ITPA20070034A1 (it) 2007-10-30 2009-04-30 Tetrapharm S R L Bifosfonati geminali, loro preparazione e loro impiego in campo oncologico.
US8737985B2 (en) * 2007-11-26 2014-05-27 Wavemarket, Inc. Methods and systems for zone creation and adaption
EP2225252B1 (en) 2007-11-30 2012-06-27 Novartis AG C2-c5-alkyl-imidazole-bisphosphonates
WO2009072119A2 (en) 2007-12-04 2009-06-11 Ben-Gurion University Of The Negev Research And Development Authority Amphiphilic peptide matrices for treatment of osteoporosis
EP2255199A1 (en) * 2008-02-19 2010-12-01 Jovesis Inc. Microparticle compositions to modify cancer promoting cells
GEP20125664B (en) 2008-02-26 2012-10-10 Takeda Pharmaceuticals Co Condensed heterocyclic derivatives and application thereof
FR2928270B1 (fr) 2008-03-10 2011-01-21 Erytech Pharma Formulation methode pour la prevention ou le traitement des metastases osseuses et autres maladies de l'os
WO2009121935A2 (en) 2008-04-04 2009-10-08 Novartis Ag Pharmaceutical composition with bisphosphonate
JP2009302891A (ja) 2008-06-13 2009-12-24 Sony Corp 情報処理装置
WO2010014766A1 (en) 2008-07-31 2010-02-04 Warner Chilcott Company, Llc Low dosage forms of risedronate or its salts
US8008329B2 (en) * 2008-08-01 2011-08-30 Dong Wha Pharmaceutical Co., Ltd. Method of treating or preventing osteoporosis comprising administering to a patient in need thereof an effective amount of pharmacuetical composition comprising benzamidine derivative or it's salt, and bisphosphonate
WO2010060619A1 (en) 2008-11-26 2010-06-03 Synthon B.V. Process for making zoledronic acid
WO2010071866A2 (en) 2008-12-19 2010-06-24 Nuon Therapeutics, Inc. Combination therapy for arthritis with tranilast
JP2012518686A (ja) * 2009-02-25 2012-08-16 メリオン・リサーチ・Iii・リミテッド ビスホスホネート類の組成物および薬物送達
ES2650665T3 (es) 2009-07-31 2018-01-19 Grünenthal GmbH Método de cristalización y biodisponibilidad
WO2011014781A1 (en) * 2009-07-31 2011-02-03 Thar Pharmaceuticals, Inc. Novel oral forms of a phosphonic acid derivative
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US20160016982A1 (en) 2009-07-31 2016-01-21 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US20110182985A1 (en) * 2010-01-28 2011-07-28 Coughlan David C Solid Pharmaceutical Composition with Enhancers and Methods of Preparing thereof
HRP20171201T1 (hr) 2010-02-06 2017-10-06 Grünenthal GmbH Postupak kristalizacije i biodostupnost
WO2011132826A1 (en) 2010-04-19 2011-10-27 Snu R&Db Foundation Transdermal drug delivery system and pharmaceutical composition for preventing or treating bone diseases
US8946199B2 (en) * 2010-04-26 2015-02-03 Ketan Desai Co-administration of steroids and Zoledronic acid to prevent and treat side effects from Zoledronic acid infusion
WO2012071517A2 (en) 2010-11-24 2012-05-31 Thar Pharmaceuticals, Inc. Novel crystalline forms
CN102070668B (zh) 2010-12-23 2013-07-24 蚌埠丰原医药科技发展有限公司 一种利用相转移催化剂制备唑来膦酸及其钠盐的方法
US8993057B2 (en) 2011-10-22 2015-03-31 Masoud Salavati-Niasari Method for preparing silica-dysprosium oxide core-shell nanoparticles
DK2849758T3 (en) 2012-05-14 2018-05-14 Antecip Bioventures Ii Llc COMPOSITIONS INCLUDING ZOLEDRONIC ACID OR RELATED COMPOUNDS TO RELIEVE INFLAMMATORY Pain and RELATED CONDITIONS
US20140349974A1 (en) 2014-08-12 2014-11-27 Antecip Bioventures Ii Llc Zoledronic acid dosage forms for the treatment of pain
CN103070668A (zh) 2013-01-02 2013-05-01 北京工业大学 心脏年龄检测仪及其检测方法
EP3052104B1 (en) 2013-10-04 2020-12-02 The Regents of The University of California Treating inflammation using llp2a-bisphosphonate conjugates and mesenchymal stem cells
EP3362071A4 (en) 2015-09-18 2019-07-17 Grünenthal GmbH CRYSTALLIZATION PROCESS AND BIOVERABILITY
WO2017208070A1 (en) 2016-05-31 2017-12-07 Grünenthal GmbH Bisphosphonic acid and coformers with lysin, glycin, nicotinamide for treating psoriatic arthritis

Also Published As

Publication number Publication date
PT2459176T (pt) 2017-12-11
EP2459176B1 (en) 2017-09-27
EP3295935B1 (en) 2020-07-22
HRP20171755T1 (hr) 2017-12-29
NO2459176T3 (enExample) 2018-02-24
LT2459176T (lt) 2017-12-11
AU2010278860A1 (en) 2012-02-16
US9334296B2 (en) 2016-05-10
EP3295935A2 (en) 2018-03-21
US20180333425A1 (en) 2018-11-22
KR20120047275A (ko) 2012-05-11
US20140107076A1 (en) 2014-04-17
KR101813728B1 (ko) 2017-12-29
CN102573809A (zh) 2012-07-11
CA2769633A1 (en) 2011-02-03
CA2769633C (en) 2017-06-06
US8933057B2 (en) 2015-01-13
IL217828A0 (en) 2012-03-29
JP5852569B2 (ja) 2016-02-03
EP3295935A3 (en) 2018-04-18
SI2459176T1 (en) 2018-01-31
WO2011014766A2 (en) 2011-02-03
IL217828B (en) 2019-09-26
US10323052B2 (en) 2019-06-18
US8399023B2 (en) 2013-03-19
EP2459176A4 (en) 2013-01-30
ES2650665T3 (es) 2018-01-19
US20170022226A1 (en) 2017-01-26
JP2013500995A (ja) 2013-01-10
IN2012DN01216A (enExample) 2015-04-10
WO2011014766A3 (en) 2011-04-07
AU2016219654A1 (en) 2016-09-15
HUE034784T2 (en) 2018-02-28
DK2459176T3 (en) 2017-12-04
AU2016219654B2 (en) 2018-05-31
AU2010278860B2 (en) 2016-05-26
US20110028435A1 (en) 2011-02-03
EP2459176A2 (en) 2012-06-06
US20140057875A1 (en) 2014-02-27
CY1121952T1 (el) 2020-07-31
CN102573809B (zh) 2017-07-21

Similar Documents

Publication Publication Date Title
LT2459176T (lt) Kristalizacijos būdas ir bioprieinamumas
IL221306A0 (en) Crystallization method and bioavailability
AU2012216632A1 (en) Crystallization Method and Bioavailability
GB0905140D0 (en) Method
GB0902476D0 (en) Method
GB0910707D0 (en) Method
GB0913525D0 (en) Method
GB0918940D0 (en) Method
GB0913433D0 (en) Method
GB0901444D0 (en) Method
GB0921375D0 (en) Method
GB0903316D0 (en) Method
GB0917457D0 (en) Method
GB0916570D0 (en) Method
GB0905367D0 (en) Method
GB0916013D0 (en) Method
GB0908770D0 (en) Method
GB0902034D0 (en) Method
GB0919901D0 (en) Method
GB0917988D0 (en) Method
GB0911362D0 (en) Method
GB0904946D0 (en) Method
GB0900560D0 (en) Method
GB0920089D0 (en) Method
GB0914702D0 (en) Method