WO1999030716A1 - Utilisation de generateurs d'oxyde nitrique pour le traitement de syndromes de l'oeil sec - Google Patents

Utilisation de generateurs d'oxyde nitrique pour le traitement de syndromes de l'oeil sec Download PDF

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Publication number
WO1999030716A1
WO1999030716A1 PCT/US1998/023806 US9823806W WO9930716A1 WO 1999030716 A1 WO1999030716 A1 WO 1999030716A1 US 9823806 W US9823806 W US 9823806W WO 9930716 A1 WO9930716 A1 WO 9930716A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
nitric oxide
gea
dry eye
molsidomine
Prior art date
Application number
PCT/US1998/023806
Other languages
English (en)
Inventor
Daniel A. Gamache
Steven T. Miller
John M. Yanni
Original Assignee
Alcon Laboratories, Inc.
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 Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU13889/99A priority Critical patent/AU1388999A/en
Publication of WO1999030716A1 publication Critical patent/WO1999030716A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione

Definitions

  • the present invention is directed to compositions containing nitric oxide generators
  • Dry eye also known generically as keratoconjunctivitis sicca, is a common
  • a patient may experience burning, a feeling of dryness, and persistent irritation such as
  • tear substitution approach examples include the use of buffered, isotonic saline
  • carrageenans (5,403,841, Lang) which gel upon contact with naturally occurring tear film.
  • Mucins are proteins which are heavily glycosylated with glucosamine-based moieties.
  • Mucins provide protective and lubricating effects to epithelial cells, especially those of
  • Mucins have been shown to be secreted by vesicles and discharged on
  • Mucins are also produced and secreted in other parts of the body including lung airway
  • Nitric oxide has been researched extensively for its effects on vascular dilation, as well
  • Nitric oxide is produced by enzymes generally known as
  • nitric oxide synthases Several different forms are known to exist, and they operate by
  • Nitric oxide has been shown to bind to heme
  • nitric oxide may play a role in mucin secretion in
  • the present invention is directed to compositions and methods for the treatment of dry
  • compositions containing nitric oxide generators discloses compositions containing nitric oxide generators and methods for treating
  • compositions are administered topically to the
  • Nitric oxide (“NO”) is produced in vivo and has been shown to be physiologically
  • NO has been shown to be involved in a number of
  • NO may be enzymatically synthesized by nitric oxide
  • NOS synthase
  • Oxide Generator or “NOG” refer to any compound that is either enzymatically or non-
  • a further requirement of a NOG of the present invention is that it stimulates mucin production
  • the NOGs of the present invention may be selected from a number of
  • the NOGs of the present invention may provide the nitrogen
  • present invention may not provide the nitrogen source, but instead stimulate NOS to form NO.
  • the NOGs of the present invention may also be compounds that stimulate, non-enzymatically,
  • NOGs include, but are not limited to: nitroglycerin, sodium nitroprusside,
  • NOG of the present invention is molsidomine.
  • the NOGs of the present invention may be obtained from natural sources or
  • the NOGs contemplated by the present invention are those already known to be
  • nitric oxide generators or those yet to be elucidated.
  • NOGs may be obtained bio-synthetically or by organic synthesis.
  • the NOGs of the present invention are intended for administration to a human patient
  • the NOGs of the present invention will be administered to a patient suffering from dry eye.
  • the NOGs of the present invention will be administered
  • the NOGs of the present invention may be contained in various types of
  • NOGs will be formulated in solutions for topical ophthalmic
  • compositions of the present invention will include one or more
  • NOG(s) in a pharmaceutically acceptable vehicle Various types of vehicles may be used.
  • Aqueous solutions are generally preferred, based on ease of formulation, biological
  • the NOGs may also be used to instilling one to two drops of the solutions in the affected eyes.
  • the NOGs may also be used to instilling one to two drops of the solutions in the affected eyes.
  • the NOGs may also be used to instilling one to two drops of the solutions in the affected eyes.
  • compositions such as suspensions, viscous or semi-
  • viscous gels or other types of solid or semi-solid compositions. Suspensions may be preferred
  • compositions of the present invention may also include various other ingredients, such as buffers, preservatives, co-
  • An appropriate buffer system e.g., sodium phosphate, sodium acetate or sodium
  • borate may be added to prevent pH drift under storage conditions.
  • Antioxidants may be added to compositions of the present invention to protect the
  • antioxidants examples include vitamin E and
  • Ophthalmic products are typically packaged in multidose form. Preservatives are thus provided.
  • Suitable preservatives include:
  • benzalkonium chloride thimerosal, chlorobutanol, methyl paraben, propyl paraben,
  • Such preservatives are typically employed at a level of from 0.001
  • effective amount refers to an amount which improves the dry eye condition in a human
  • compositions When the compositions are dosed topically, they will generally be in a concentration
  • pharmaceutically acceptable carrier refers to any formulation
  • compositions of the present invention are further illustrated by the following
  • nitric oxide generator denotes a compound of the
  • a topical ophthalmic formulation :
  • a topical ophthalmic formulation :
  • a topical ophthalmic formulation :

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Compositions contenant un générateur d'oxyde nitrique et leurs procédés d'utilisation pour le traitement de l'oeil sec. Les composés de l'invention favorisent la production de NO, lorsqu'ils sont administrés dans l'oeil. On pense que NO stimule la production de mucine dans l'éphitélium conjonctival humain, et qu'ils sont donc utiles dans le traitement de l'oeil sec. De plus, le NOG de l'invention doit stimuler la production et/ou la sécrétion de mucine dans l'épithélium conjonctival et/ou dans les cellules caliciformes oculaires, à la suite d'une application locale sur l'oeil. Les NOG peuvent être par exemple: nitroglycérine, nitroprussiates, spermine NONOate, (+/-)-(E)-4-éthyl-2-[(E)-hydroxyimino]-5-nitro-3-hexèneamide (FK-409), 1-hydroxy-2-oxo-3-(N-méthyl-3-aminopropyl)-3-méthyl 1-triazène (NOC-7), S-nitrosoglutathione, 4-phényl-3-furoxancarbonitrile, S-nitroso-N-acétyl-pénicillamine (SNAP), dinitrate d'isosorbide, GEA 3264, GEA 5145, GEA 3175, trinitate de glycéryle, molsidomine; 3-morpholinosydnonimine (SIN-1), hydroxylamine, linsidomine, NOC-18, CHF-2363, pirsidomine, N,N'-diméthylhexanediamine (DMHD/NO), 2,2-diéthyl-1-nitroso-oxyhydrazine (DEA/NO), Et 2NN(O)NONa, NO-cétoprofène, NO-dicoflénac, NO-flurbiprofène. Le NOG idéal de l'invention est la molsidomine.
PCT/US1998/023806 1997-12-16 1998-11-10 Utilisation de generateurs d'oxyde nitrique pour le traitement de syndromes de l'oeil sec WO1999030716A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU13889/99A AU1388999A (en) 1997-12-16 1998-11-10 The use of nitric oxide generations for the treatment of dry eye disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6971197P 1997-12-16 1997-12-16
US60/069,711 1997-12-16

Publications (1)

Publication Number Publication Date
WO1999030716A1 true WO1999030716A1 (fr) 1999-06-24

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PCT/US1998/023806 WO1999030716A1 (fr) 1997-12-16 1998-11-10 Utilisation de generateurs d'oxyde nitrique pour le traitement de syndromes de l'oeil sec

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AR (1) AR017215A1 (fr)
AU (1) AU1388999A (fr)
WO (1) WO1999030716A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056864A2 (fr) * 2001-01-18 2002-07-25 Scimed Life Systems, Inc. Administration differentielle d'oxyde nitrique
EP1491181A2 (fr) * 2003-06-27 2004-12-29 L'oreal Composition cosmétique à base de précurseur(s) de radical thiyl pour la déformation permanente des fibres kératiniques
WO2008153762A2 (fr) * 2007-05-25 2008-12-18 N30 Pharmaceuticals, Llc Formulations s-nitrosothiol et systèmes d'entreposage
JP2010254589A (ja) * 2009-04-22 2010-11-11 Morinaga & Co Ltd ドライシンドロームの改善用組成物
US9297928B2 (en) 2004-11-22 2016-03-29 Johnson & Johnson Vision Care, Inc. Ophthalmic compositions comprising polyether substituted polymers

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5192535A (en) * 1988-02-08 1993-03-09 Insite Vision Incorporated Ophthalmic suspensions
WO1994013275A1 (fr) * 1992-12-04 1994-06-23 Massachusetts Eye And Ear Infirmary Traitement du glaucome

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5192535A (en) * 1988-02-08 1993-03-09 Insite Vision Incorporated Ophthalmic suspensions
WO1994013275A1 (fr) * 1992-12-04 1994-06-23 Massachusetts Eye And Ear Infirmary Traitement du glaucome

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ENDO, R.M. AND GOMES, J.A.P.: "Effect of Natrium Nitrate Eye Drops on Tear Production", INVESTIGATIVE OPHTHALMOLOGY AND VISUAL SCIENCE, vol. 37, no. 3, 1996, pages S852, XP002094237 *
NATHANSON J A: "NITROVASODILATORS AS A NEW CLASS OF OCULAR HYPOTENSIVE AGENTS", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 260, no. 3, 1 March 1992 (1992-03-01), pages 956 - 965, XP000568204 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7799335B2 (en) 2001-01-18 2010-09-21 Boston Scientific Scimed, Inc. Differential delivery of nitric oxide
WO2002056864A3 (fr) * 2001-01-18 2004-01-08 Scimed Life Systems Inc Administration differentielle d'oxyde nitrique
US6706274B2 (en) 2001-01-18 2004-03-16 Scimed Life Systems, Inc. Differential delivery of nitric oxide
WO2002056864A2 (fr) * 2001-01-18 2002-07-25 Scimed Life Systems, Inc. Administration differentielle d'oxyde nitrique
EP1491181A2 (fr) * 2003-06-27 2004-12-29 L'oreal Composition cosmétique à base de précurseur(s) de radical thiyl pour la déformation permanente des fibres kératiniques
EP1491181A3 (fr) * 2003-06-27 2006-03-22 L'oreal Composition cosmétique à base de précurseur(s) de radical thiyl pour la déformation permanente des fibres kératiniques
US9297928B2 (en) 2004-11-22 2016-03-29 Johnson & Johnson Vision Care, Inc. Ophthalmic compositions comprising polyether substituted polymers
US9511089B2 (en) 2004-11-22 2016-12-06 Johnson & Johnson Vision Care, Inc. Ophthalmic compositions comprising polyether substituted polymers
US9606263B2 (en) 2004-11-22 2017-03-28 Johnson & Johnson Vision Care, Inc. Ophthalmic compositions comprising polyether substituted polymers
US9849081B2 (en) 2004-11-22 2017-12-26 Johnson & Johnson Vision Care, Inc. Ophthalmic compositions comprising polyether substituted polymers
US10441533B2 (en) 2004-11-22 2019-10-15 Johnson & Johnson Vision Care, Inc. Ophthalmic compositions comprising polyether substituted polymers
WO2008153762A3 (fr) * 2007-05-25 2009-07-23 N30 Pharmaceuticals Llc Formulations s-nitrosothiol et systèmes d'entreposage
WO2008153762A2 (fr) * 2007-05-25 2008-12-18 N30 Pharmaceuticals, Llc Formulations s-nitrosothiol et systèmes d'entreposage
JP2010254589A (ja) * 2009-04-22 2010-11-11 Morinaga & Co Ltd ドライシンドロームの改善用組成物

Also Published As

Publication number Publication date
AU1388999A (en) 1999-07-05
AR017215A1 (es) 2001-08-22

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