[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

NO311635B1 - Vandig legemiddelpreparat med evne til reversibel varmeherdende gel - Google Patents

Vandig legemiddelpreparat med evne til reversibel varmeherdende gel Download PDF

Info

Publication number
NO311635B1
NO311635B1 NO19953189A NO953189A NO311635B1 NO 311635 B1 NO311635 B1 NO 311635B1 NO 19953189 A NO19953189 A NO 19953189A NO 953189 A NO953189 A NO 953189A NO 311635 B1 NO311635 B1 NO 311635B1
Authority
NO
Norway
Prior art keywords
agents
agent
hydrochloride
preparation
preparation according
Prior art date
Application number
NO19953189A
Other languages
English (en)
Norwegian (no)
Other versions
NO953189D0 (no
NO953189L (no
Inventor
Masanobu Takeuchi
Hiroe Suzuki
Toshie Takahashi
Hiroki Maruyama
Miyako Sasaki
Keiko Naitou
Touru Oguma
Masayoshi Goto
Original Assignee
Wakamoto Pharma Co Ltd
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 Wakamoto Pharma Co Ltd filed Critical Wakamoto Pharma Co Ltd
Publication of NO953189D0 publication Critical patent/NO953189D0/no
Publication of NO953189L publication Critical patent/NO953189L/no
Publication of NO311635B1 publication Critical patent/NO311635B1/no

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
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • 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
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Materials For Medical Uses (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Thermotherapy And Cooling Therapy Devices (AREA)
NO19953189A 1993-04-16 1995-08-14 Vandig legemiddelpreparat med evne til reversibel varmeherdende gel NO311635B1 (no)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11234593 1993-04-16
PCT/JP1993/001636 WO1994023750A1 (fr) 1993-04-16 1993-11-10 Composition medicamenteuse se tranformant en gel thermiquement de façon reversible

Publications (3)

Publication Number Publication Date
NO953189D0 NO953189D0 (no) 1995-08-14
NO953189L NO953189L (no) 1995-08-14
NO311635B1 true NO311635B1 (no) 2001-12-27

Family

ID=14584369

Family Applications (1)

Application Number Title Priority Date Filing Date
NO19953189A NO311635B1 (no) 1993-04-16 1995-08-14 Vandig legemiddelpreparat med evne til reversibel varmeherdende gel

Country Status (17)

Country Link
US (1) US5624962A (fr)
EP (1) EP0694310B1 (fr)
KR (1) KR0162025B1 (fr)
CN (1) CN1048393C (fr)
AT (1) ATE189772T1 (fr)
AU (1) AU668447B2 (fr)
CA (1) CA2153234C (fr)
DE (1) DE69327878T2 (fr)
DK (1) DK0694310T3 (fr)
ES (1) ES2141775T3 (fr)
FI (1) FI112778B (fr)
HK (1) HK1017805A1 (fr)
HU (1) HU220864B1 (fr)
IL (1) IL107626A (fr)
NO (1) NO311635B1 (fr)
RU (1) RU2108112C1 (fr)
WO (1) WO1994023750A1 (fr)

Families Citing this family (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6436425B1 (en) 1988-11-16 2002-08-20 Mdv Technologies, Inc. Method and non-gelling composition for inhibiting post-surgical adhesions
US5346703A (en) 1990-08-07 1994-09-13 Mediventures, Inc. Body cavity drug delivery with thermo-irreversible polyoxyalkylene and ionic polysaccharide gels
US5318780A (en) * 1991-10-30 1994-06-07 Mediventures Inc. Medical uses of in situ formed gels
ATE281075T1 (de) * 1994-03-28 2004-11-15 Univ Columbia Zusammensetzung zum inaktivieren von reizstoffen in flüssigkeiten
WO1996011672A1 (fr) * 1994-10-13 1996-04-25 Wakamoto Pharmaceutical Co., Ltd. Preparation lyophilisee permettant d'obtenir une composition pharmaceutique a base d'eau se transformant de maniere reversible en gel sous l'effet de la chaleur
DE19511322C2 (de) 1995-03-28 1999-09-02 Mann Gerhard Chem Pharm Fab Sterile Augengele mit einem Gehalt an mittelkettigen Triglyceriden und Verfahren zu deren Herstellung
US5843470A (en) 1995-10-06 1998-12-01 Mdv Technologies, Inc. Method and composition for inhibiting post-surgical adhesions
CA2232855C (fr) * 1997-04-10 2007-10-09 Roche Consumer Health (Worldwide) Sa Preparation pharmaceutique
ES2284202T3 (es) * 1997-05-14 2007-11-01 Senju Pharmaceutical Co., Ltd. Preparaciones acuosas en suspension con excelente redispersabilidad.
JP2001526246A (ja) * 1997-12-23 2001-12-18 アライアンス・ファーマスーティカル・コーポレイション 薬剤送達及び/又は癒着防止のための方法及び組成物
US6197347B1 (en) 1998-06-29 2001-03-06 Andrx Pharmaceuticals, Inc. Oral dosage for the controlled release of analgesic
ES2155027B1 (es) * 1999-05-24 2001-12-01 Univ Pais Vasco Geles para propositos multiples, reversibles y degradables.
WO2000076555A1 (fr) * 1999-06-11 2000-12-21 Pro Duct Health, Inc. Composition de gel pour remplir un canal galactophore d'un sein avant une ablation chirurgicale de ce canal ou d'autres tissus mammaires
US20020061281A1 (en) * 1999-07-06 2002-05-23 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US6576224B1 (en) * 1999-07-06 2003-06-10 Sinuspharma, Inc. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
JP2001158750A (ja) * 1999-12-02 2001-06-12 Lion Corp 眼科用組成物及び抗アレルギー薬の持続性向上方法
JP3450805B2 (ja) * 2000-08-08 2003-09-29 わかもと製薬株式会社 水性医薬組成物
US7420030B2 (en) 2000-09-08 2008-09-02 The Board Of Regents Of The University Of Texas System Aminopeptidase A (APA) targeting peptides for the treatment of cancer
EP1328214A4 (fr) * 2000-09-20 2009-07-29 Shahinian Lee Jr Preparations et medications nasales, inhalables et ophtalmiques locales a conservation spontanee
JP4820024B2 (ja) * 2001-01-10 2011-11-24 昭和薬品化工株式会社 局所麻酔用組成物
WO2003007979A1 (fr) * 2001-07-18 2003-01-30 Board Of Regents, The University Of Texas System Etat anti-angiogene chez les souris et les etres humains souffrant d'une degenerescence cellulaire du photorecepteur retinien
US20040048243A1 (en) * 2001-09-07 2004-03-11 Wadih Arap Methods and compositions for in vitro targeting
US6846846B2 (en) * 2001-10-23 2005-01-25 The Trustees Of Columbia University In The City Of New York Gentle-acting skin disinfectants
US7745425B2 (en) * 2002-02-07 2010-06-29 The Trustees Of Columbia University In The City Of New York Non-irritating compositions containing zinc salts
US7879365B2 (en) * 2002-02-07 2011-02-01 The Trustees Of Columbia University In The City Of New York Zinc salt compositions for the prevention of dermal and mucosal irritation
CA2475224C (fr) 2002-02-07 2011-11-01 The Trustees Of Columbia University In The City Of New York Compositions de sels de zinc contre l'irritation des muqueuses dues a des spermicides et des microbicides
KR20040084931A (ko) * 2002-02-22 2004-10-06 산텐 세이야꾸 가부시키가이샤 미립자 결막하 투여를 위한 약물 수송 시스템
US20030211173A1 (en) * 2002-05-08 2003-11-13 Veach Tom C. Lubrication composition
JPWO2004026953A1 (ja) * 2002-09-18 2006-01-19 わかもと製薬株式会社 透明な可逆性熱ゲル化水性組成物
US7220431B2 (en) * 2002-11-27 2007-05-22 Regents Of The University Of Minnesota Methods and compositions for applying pharmacologic agents to the ear
JP2004196787A (ja) * 2002-12-04 2004-07-15 Santen Pharmaceut Co Ltd 結膜下デポによるドラッグデリバリーシステム
WO2004052399A1 (fr) * 2002-12-10 2004-06-24 Showa Yakuhin Kako Co., Ltd. Composition destinee a une anesthesie topique
US20050085446A1 (en) * 2003-04-14 2005-04-21 Babu M.K. M. Fluoroquinolone formulations and methods of making and using the same
JP4669960B2 (ja) * 2003-06-03 2011-04-13 株式会社 メドレックス 局所麻酔薬を含有する口中用または咽頭部用製剤
CN101217870B (zh) * 2003-07-17 2011-10-12 纽约市哥伦比亚大学托管会 含有季铵化合物及精油和/或精油成分的协同组合的抗微生物组合物
CN1835735B (zh) * 2003-08-20 2010-05-12 参天制药株式会社 微粒眼球筋膜下给药的药物释放系统
FR2860718B1 (fr) * 2003-10-09 2006-02-24 Jean Pascal Conduzorgues Nouvelle formulation et ses applications dans le domaines cosmetiques ou pharmaceutiques
EP1708668A1 (fr) * 2004-01-15 2006-10-11 Oral Bioscience Pty. Limited Gel anesthesique administre par voie orale
US7658947B2 (en) * 2004-06-25 2010-02-09 Kimberly-Clark Worldwide, Inc. Thermo-gelling composition
JP2007277095A (ja) * 2004-07-02 2007-10-25 Wakamoto Pharmaceut Co Ltd アジスロマイシン含有可逆性熱ゲル化水性組成物
US7459416B2 (en) * 2004-07-12 2008-12-02 Panasonic Corporation Fluid bearing unit and spindle motor using the same
KR20070113284A (ko) 2005-03-10 2007-11-28 쓰리엠 이노베이티브 프로퍼티즈 캄파니 미생물 오염의 감소방법
JP4979258B2 (ja) * 2005-04-08 2012-07-18 ロート製薬株式会社 アシタザノラスト含有水性組成物
CN100463668C (zh) * 2005-05-09 2009-02-25 凌沛学 可逆性热凝胶化水性药物组合物
CN100430069C (zh) * 2005-07-28 2008-11-05 凌沛学 一种中药及其复方的可逆性热凝胶化水性药物组合物
JP5011118B2 (ja) * 2005-10-17 2012-08-29 興和株式会社 インドメタシンを含有する外用液剤
EA008737B1 (ru) * 2005-12-07 2007-08-31 Леонид Андреевич Кожемякин Средство для профилактики и лечения конъюнктивитов и кератитов различной этиологии (варианты), способ его применения
US7759327B2 (en) 2006-01-06 2010-07-20 The Trustees Of Columbia University In The City Of New York Compositions containing zinc salts for coating medical articles
US20070249546A1 (en) * 2006-04-22 2007-10-25 Sawaya Assad S Ophthalmic and related aqueous solutions containing antifungal agents, uses therefor and methods for preparing them
US20070253909A1 (en) * 2006-05-01 2007-11-01 Medi-Flex, Inc. Aqueous Antiseptic Solution and Compatible Cationic Dye for Staining Skin
US20080108674A1 (en) * 2006-05-01 2008-05-08 Enturia, Inc. Cationic antiseptic and dye formulation
US20070254854A1 (en) * 2006-05-01 2007-11-01 Medi-Flex, Inc. Aqueous Antiseptic Solution and Compatible Anionic Dye for Staining Skin
TW200808375A (en) * 2006-05-12 2008-02-16 Otsuka Pharma Co Ltd Hydrogel suspension and manufacturing process thereof
EA014780B1 (ru) * 2007-01-05 2011-02-28 Промед Экспортс Пвт. Лтд. Офтальмическая композиция
DE102007002073A1 (de) * 2007-01-09 2008-07-10 Matthias Habenicht Mittel zur Pflege und antimikrobiellen Behandlung der Haut
CN101784287B (zh) * 2007-06-26 2013-04-24 若素制药株式会社 水性组合物
PT2193795E (pt) * 2007-08-29 2014-10-22 Wakamoto Pharma Co Ltd Composição farmacêutica aquosa contendo latanoprost
WO2009074853A2 (fr) * 2007-12-10 2009-06-18 Promed Research Centre Composition ophtalmique comprenant de la phényléphrine
US8030297B2 (en) * 2008-05-14 2011-10-04 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of OTIC disorders
US10517839B2 (en) * 2008-06-09 2019-12-31 Cornell University Mast cell inhibition in diseases of the retina and vitreous
TW201023912A (en) * 2008-12-05 2010-07-01 Alcon Res Ltd Pharmaceutical suspension
KR20110123789A (ko) * 2009-03-03 2011-11-15 알콘 리서치, 리미티드 리셉터 티로신 키나제 저해(RTKi) 화합물을 눈에 전달하기 위한 약학 조성물
WO2010101989A1 (fr) * 2009-03-03 2010-09-10 Alcon Research, Ltd. Composition pharmaceutique pour l'administration à l'oeil de composés inhibant les récepteurs tyrosine kinase (rtki)
AU2010221369B2 (en) * 2009-03-03 2014-03-13 Alcon Research, Ltd. Pharmaceutical composition for delivery of receptor tyrosine kinase inhibiting (RTKi) compounds to the eye
US8299079B2 (en) 2009-05-22 2012-10-30 Kaufman Herbert E Preparations and methods for ameliorating or reducing presbyopia
US20100298335A1 (en) * 2009-05-22 2010-11-25 Kaufman Herbert E Preparations and Methods for Ameliorating or Reducing Presbyopia
CN103079595B (zh) 2010-08-27 2015-11-25 若素制药株式会社 滴眼用水性组合物
TWI544922B (zh) 2011-05-19 2016-08-11 愛爾康研究有限公司 高濃度歐羅派特錠(olopatadine)眼用組成物
WO2013169458A1 (fr) * 2012-05-11 2013-11-14 Bausch & Lomb Incorporated Compositions pharmaceutiques et méthodes de traitement, de contrôle, d'amélioration, ou d'inversion des troubles de la kératoconjonctivite sèche
RU2485939C1 (ru) * 2012-06-19 2013-06-27 Станислав Анатольевич Кедик Офтальмологический препарат в виде глазных капель, содержащий дисульфирам и таурин
US10507245B2 (en) * 2012-07-19 2019-12-17 Luis Felipe Vejarano Restrepo Ophthalmic formulation and method for ameliorating presbyopia
RU2517033C1 (ru) * 2013-03-05 2014-05-27 федеральное государственное бюджетное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации Композиция для комплексного лечения больных с первичной открытоугольной глаукомой и заболеваниями глазной поверхности
CN103239390B (zh) * 2013-05-15 2014-08-06 中国人民解放军第三军医大学第二附属医院 托吡卡胺眼用温度敏感原位凝胶及其制备方法
WO2015095634A1 (fr) * 2013-12-20 2015-06-25 The Procter & Gamble Company Médicament liquide stable contenant de la diphénehydramine
JP6714247B2 (ja) * 2017-10-06 2020-06-24 有限会社ジーエヌコーポレーション 尿道狭窄治療剤および尿道狭窄治療方法
WO2019230750A1 (fr) * 2018-05-29 2019-12-05 学校法人 神野学園 Composition topique
US20220008336A1 (en) * 2018-11-26 2022-01-13 Aiviva Biopharma, Inc. Pharmaceutical biodissolvable gels for drug delivery

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3311577A (en) * 1965-03-29 1967-03-28 Burton Parsons Chemicals Inc Underwater contact lens solution
US4100271A (en) * 1976-02-26 1978-07-11 Cooper Laboratories, Inc. Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes
US4188373A (en) * 1976-02-26 1980-02-12 Cooper Laboratories, Inc. Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes
DE2714065A1 (de) * 1977-03-30 1978-10-12 Boehringer Mannheim Gmbh Instillationszubereitung
US4474752A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
US4474753A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Topical drug delivery system utilizing thermosetting gels
US4474751A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Ophthalmic drug delivery system utilizing thermosetting gels
US4478822A (en) * 1983-05-16 1984-10-23 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
FR2588189B1 (fr) * 1985-10-03 1988-12-02 Merck Sharp & Dohme Composition pharmaceutique de type a transition de phase liquide-gel
GB2203039B (en) * 1987-03-02 1990-10-24 American Cyanamid Co Stable ophthalmic preparations containing acetazolamide
US5252318A (en) * 1990-06-15 1993-10-12 Allergan, Inc. Reversible gelation compositions and methods of use
US5077033A (en) * 1990-08-07 1991-12-31 Mediventures Inc. Ophthalmic drug delivery with thermo-irreversible gels of polxoxyalkylene polymer and ionic polysaccharide
MX9200339A (es) * 1991-01-28 1992-08-01 Hoechst Ag Preparado para la liberacion controlada de sustancias activas, que son apropiadas como terapeuticos o para mejorar el crecimiento y el aprovechamiento de los piensos en rumiantes
AU679937B2 (en) * 1992-11-18 1997-07-17 Johnson & Johnson Consumer Products, Inc. Extrudable compositions for topical or transdermal drug delivery

Also Published As

Publication number Publication date
US5624962A (en) 1997-04-29
DK0694310T3 (da) 2000-06-05
IL107626A0 (en) 1994-02-27
FI953575A0 (fi) 1995-07-26
DE69327878T2 (de) 2000-06-15
CN1048393C (zh) 2000-01-19
EP0694310B1 (fr) 2000-02-16
AU668447B2 (en) 1996-05-02
IL107626A (en) 1997-09-30
EP0694310A4 (fr) 1996-04-24
CN1097593A (zh) 1995-01-25
WO1994023750A1 (fr) 1994-10-27
CA2153234A1 (fr) 1994-10-27
ES2141775T3 (es) 2000-04-01
HU9502086D0 (en) 1995-09-28
DE69327878D1 (de) 2000-03-23
RU2108112C1 (ru) 1998-04-10
HK1017805A1 (en) 1999-11-26
FI112778B (fi) 2004-01-15
KR0162025B1 (ko) 1998-12-01
AU5433394A (en) 1994-11-08
NO953189D0 (no) 1995-08-14
ATE189772T1 (de) 2000-03-15
HUT71676A (en) 1996-01-29
KR960700075A (ko) 1996-01-19
EP0694310A1 (fr) 1996-01-31
FI953575A (fi) 1995-07-26
CA2153234C (fr) 1999-02-16
HU220864B1 (en) 2002-06-29
NO953189L (no) 1995-08-14

Similar Documents

Publication Publication Date Title
NO311635B1 (no) Vandig legemiddelpreparat med evne til reversibel varmeherdende gel
US7612115B2 (en) Aqueous pharmaceutical compositions
RU95122560A (ru) Водная лекарственная композиция, обладающая свойством обратимого терморегулируемого гелеобразования
US20200197336A1 (en) Ketorolac tromethamine compositions for treating or preventing ocular pain
US20060188576A1 (en) Pirenzepine ophthalmic gel
NO314434B1 (no) Lav-viskositets oftalmisk blanding
NO314435B1 (no) Lav-viskositets oftalmisk blanding
WO2005042026A1 (fr) Composition a base d'eau soumise a une thermoregulation reversible
WO2011018800A2 (fr) Nouvelle solution formant un gel in situ pour l’administration de médicaments par voie oculaire
CN100463668C (zh) 可逆性热凝胶化水性药物组合物
EA030535B1 (ru) Не содержащий консерванта офтальмологический фармацевтический состав
CN101977630A (zh) 眼药组合物
CN103977011B (zh) 含有曲伏前列素和噻吗洛尔的眼用凝胶剂及其制备方法
JP2729859B2 (ja) 可逆性熱ゲル化水性医薬組成物
JP6672512B2 (ja) 一酸化窒素放出プロスタミドを含有する眼科用組成物
US20070059274A1 (en) Ophthalmic compositions containing a PVA/borate gelling system
JP2023038930A (ja) 眼表面薬物滞留化剤およびこれを含む点眼剤、並びに、これらの剤を用いた眼表面薬物滞留方法および眼科疾患治療方法
WO1997033562A1 (fr) Composition ophtalmologique subissant une transition de phase liquide/gel
JP3504656B2 (ja) 水性医薬組成物
CN110200904A (zh) 一种降眼压缓释滴眼组合物及其制备方法
US20120028947A1 (en) Ophthalmic Compositions
WO2004026953A1 (fr) Compositions aqueuses transparentes et a thermogelification reversible
Singh 2³-Factorial Design Studies to Optimize the Ophthalmic Drug Delivery

Legal Events

Date Code Title Description
MM1K Lapsed by not paying the annual fees