WO2000047200A1 - Combinations of formoterol and a tiotropium salt - Google Patents

Combinations of formoterol and a tiotropium salt Download PDF

Info

Publication number
WO2000047200A1
WO2000047200A1 PCT/EP2000/000958 EP0000958W WO0047200A1 WO 2000047200 A1 WO2000047200 A1 WO 2000047200A1 EP 0000958 W EP0000958 W EP 0000958W WO 0047200 A1 WO0047200 A1 WO 0047200A1
Authority
WO
WIPO (PCT)
Prior art keywords
medicament according
medicament
dry powder
pharmaceutically acceptable
dispersion
Prior art date
Application number
PCT/EP2000/000958
Other languages
French (fr)
Inventor
Ian Francis Hassan
Jeremy Guy Clarke
Bernard Cuenoud
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10847254&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2000047200(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to KR1020017009941A priority Critical patent/KR20010101806A/en
Priority to EP00902663A priority patent/EP1158970B1/en
Priority to SK1127-2001A priority patent/SK285884B6/en
Priority to NZ513304A priority patent/NZ513304A/en
Priority to SI200030922T priority patent/SI1158970T1/en
Priority to DE60030844T priority patent/DE60030844T2/en
Priority to BRPI0008039A priority patent/BRPI0008039B1/en
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Novartis Ag
Priority to CA002360248A priority patent/CA2360248C/en
Priority to JP2000598152A priority patent/JP2002536408A/en
Priority to AU24419/00A priority patent/AU770632B2/en
Priority to PL350583A priority patent/PL206965B1/en
Priority to IL14398600A priority patent/IL143986A0/en
Publication of WO2000047200A1 publication Critical patent/WO2000047200A1/en
Priority to IL143986A priority patent/IL143986A/en
Priority to NO20013460A priority patent/NO329911B1/en
Priority to US09/924,246 priority patent/US6537524B1/en
Priority to US10/365,310 priority patent/US20030125350A1/en
Priority to US11/288,548 priority patent/US20060083692A1/en
Priority to CY20061101480T priority patent/CY1105707T1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/535Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/439Heterocyclic 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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4738Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/04Drugs for disorders of the respiratory system for throat disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Definitions

  • This invention relates to combinations of formoterol and a tiotropium salt and their use for the treatment of inflammatory or obstructive airways diseases.
  • Formoterol N-[2-hydroxy-5-(l-hydroxy-2-((2-(4-methoxyphenyl)-l-methylethyl)amino)- ethyl)phenyl]formamide, particularly in the form of its fumarate salt, is a bronchodilator used in the treatment of inflammatory or obstructive airways diseases.
  • tiotropium bromide (l ⁇ ,2 ⁇ ,5 ⁇ ,7 ⁇ )-7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-3-oxa-9-azonia- tricyclo(3.3.1.0 2 ' 4 )-nonane bromide, in the treatment of chronic obstructive bronchitis is described in US5610163. It has now surprisingly been found that a significant unexpected therapeutic benefit, particularly a synergistic therapeutic benefit, in the treatment of inflammatory or obstructive airways diseases can be obtained by combination therapy using formoterol, or a salt or solvate thereof, and a tiotropium salt. For instance, it is possible using this combination therapy to reduce the dosages required for a given therapeutic effect considerably compared with those required using treatment with formoterol or a tiotropium salt alone, thereby minimising possibly undesirable side effects.
  • this combination therapy exhibits both a fast onset of action and a long duration of action, so that patients feel a rapid improvement in their condition and, in view of the long duration of action, a reduced need for short-acting rescue medicaments, such as salbutamol or terbutaline.
  • this effect is exhibited even when the two drugs are administered at the same time, i.e. in a composition containing both drugs or sequentially, so that medicaments of the invention facilitate the treatment of inflammatory or obstructive airways diseases with a medicament which need be administered only once a day.
  • medicaments of the invention can be used on demand in rescue treatment of obstructive or inflammatory airways diseases, so that they facilitate treatment of such diseases with a single medicament.
  • the present invention provides a medicament containing, separately or together, (A) formoterol or a pharmaceutically acceptable salt thereof or a solvate of formoterol or said salt and (B) a tiotropium salt of a pharmaceutically acceptable acid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
  • the present invention provides a method of treating an inflammatory or obstructive airways disease which comprises administering to a subject in need of such treatment effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined.
  • the present invention provides a phamaceutical composition
  • a phamaceutical composition comprising a mixture of effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined, optionally together with a pharmaceutically acceptable carrier.
  • the present invention also provides (A) and (B) as hereinbefore defined for use in combination therapy by simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
  • the invention further provides the use of (A) as hereinbefore defined or (B) as hereinbefore defined in the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration of (A) and (B) in the treatment of an inflammatory or obstructive airways disease.
  • the present invention still further provides the use of (A) and (B) as hereinbefore defined for the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
  • salts of formoterol include, for example, salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic acids.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids
  • organic acids such as fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p-me
  • Component (A) may be in any isomeric form or mixture of isomeric forms, for example a pure enantiomer, a mixture of enantiomers, a racemate or a mixture thereof. It may be in the form of a solvate, for example a hydrate, thereof, for example as described in US3994974 or US5684199, and may be present in a particular crystalline form, for example as described in WO95/05805.
  • component (A) is formoterol fumarate, especially in the form of the dihydrate.
  • the tiotropium salt (B) is preferably tiotropium methanesulfonate or , especially, tiotropium bromide,(lcx,2 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ )-7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-3- oxa-9-azoniatricyclo(3.3.1.0 2 ' 4 )-nonane bromide, the preparation of which is described in US5610163.
  • Administration of the medicament or pharmaceutical composition as hereinbefore described, i.e. with (A) and (B) in admixture or separate, is preferably by inhalation, i.e. (A) and (B) or the mixture thereof are in inhalable form.
  • the inhalable form of the medicament i.e. of (A) and/or (B) may be, for example, an atomizable composition such as an aerosol comprising the active ingredient, i.e. (A) and (B) separately or in admixture, in solution or dispersion in a propellant, or a nebulizable composition comprising a dispersion of the active ingredient in an aqueous, organic or aqueous/organic medium.
  • the inhalable form of the medicament may be an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant, or a combination of an aerosol containing (A) in solution or dispersion in a propellant with an aerosol containing (B) in solution or dispersion in a propellant.
  • the inhalable form is a nebulizable composition comprising a dispersion of (A) and (B) in an aqueous, organic or aqueous/organic medium, or a combination of a dispersion of (A) in such a medium with a dispersion of (B) in such a medium.
  • An aerosol composition suitable for use as the inhalable form of the medicament may comprise the active ingredient in solution or dispersion in a propellant, which may be chosen from any of the propellants known in the art.
  • propellants include hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons, and halogen-substituted hydrocarbons, for example fluorine-substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, particularly 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1, 1,2,3,3, 3-heptafluoropropane (HFA227), or mixtures of two or more such halogen-substituted hydrocarbons.
  • hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons
  • the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art.
  • a lubricant and a surfactant which may be chosen from those lubricants and surfactants known in the art.
  • Other suitable aerosol compositions include surfactant-free or substantially surfactant-free aerosol compositions.
  • the aerosol composition may contain up to about 5% by weight, for example 0.002 to 5%, 0.01 to 3%, 0.015 to 2%, 0.1 to 2%, 0.5 to 2% or 0.5 to 1%, by weight of the active ingredient, based on the weight of the propellant.
  • the lubricant and surfactant may be in an amount up to 5% and 0.5% respectively by weight of the aerosol composition.
  • the aerosol composition may also contain a co-solvent such as ethanol in an amount up to 30% by weight of the composition, particularly for administration from a pressurised metered dose inhalation device.
  • the inhalable form is a dry powder, i.e. (A) and/or (B) are present in a dry powder comprising finely divided (A) and/or (B) optionally together with a finely divided pharmaceutically acceptable carrier, which is preferably present and may be chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol.
  • a finely divided pharmaceutically acceptable carrier which is preferably present and may be chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose,
  • the dry powder may be in capsules of gelatin or plastic, or in blisters, for use in a dry powder inhalation device, preferably in dosage units of 1 ⁇ g to 140 ⁇ g of the active ingredient.
  • the dry powder may be contained as a reservoir in a multi- dose dry powder inhalation device.
  • the active ingredient may have an average particle diameter of up to about 10 ⁇ m, for example 0.1 to 5 ⁇ m, preferably 1 to 5 ⁇ m.
  • the finely divided carrier where present, generally has a maximum particle diameter up to 300 ⁇ m, preferably up to 212 ⁇ m and conveniently has a mean particle diameter of 40 to lOO ⁇ m, preferably 50 to 75 ⁇ m.
  • the particle size of the active ingredient, and that of the carrier where present in dry powder compositions can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, microprecipitation, spray-drying, lyophilisation or recrystallisation from supercritical media.
  • the inhalable medicament may be administered using an inhalation device suitable for the inhalable form, such devices being well known in the art.
  • the invention also provides a pharmaceutical product comprising a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described in association with one or more inhalation devices.
  • the invention provides an inhalation device, or a pack of two or more inhalation devices, containing a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described.
  • the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 ⁇ l, e.g.
  • an aerosol composition may be administered from a coated can, for example as described in EP-A-0642992.
  • the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer, for example an electronically controlled device such as an AERx (ex Aradigm, US) or a mechanical device such as a RESPIMAT (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g.
  • a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion
  • a hand-held nebulizer for example an electronically controlled device such as an AERx (ex Aradigm, US) or a mechanical
  • the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing dry powder comprising a dosage unit of (A) and/or (B), or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 5-25 mg of dry powder comprising a dosage unit of (A) and/or (B) per actuation.
  • a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing dry powder comprising a dosage unit of (A) and/or (B), or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 5-25 mg of dry powder comprising a dosage unit of (A) and/or (B) per actuation.
  • MDPI multidose dry powder inhalation
  • the medicament of the invention is preferably a pharmaceutical composition comprising a mixture of (A) as hereinbefore defined and (B) as hereinbefore defined, preferably together with a pharmaceutically acceptable carrier as hereinbefore described.
  • the weight ratio of formoterol, or salt or solvate thereof, to tiotropium salt may be, in general, from 72:1 to 1:160, for example from 72:1 to 1:120, from 72:1 to 1:80, from 60:1 to 1:80, from 60:1 to 1:70, from 50:1 to 1:60, from 60:1 to 1:50, from 50:1 to 1:50, from 60:1 to 1:40, from 50:1 to 1:40, from 50:1 to 1:30, from 50:1 to 1:20, from 50:1 to 1:30, from 50:1 to 1:20, from 50:1 to 1:10, from 40:1 to 1:20, from 40:1 to 1:10, from 30:1 to 1:20, from 30:1 to 1:10, from 20:1 to 1:20, from 20:1 to 1:10, from 20:1 to 1:5, from 16:1 to 1:4, from 10:1 to 1:5, from 6:1 to 1:4, or from 4:1 to 1:3.
  • this ratio is from 3:1 to 1:3, for example from 2.5:1 to 1:2, from 2:1 to 1:2, from 1.5:1 to 1:1.5, or from 1.5:1 to 1:1.2.
  • the two drugs may be administered separately in the same ratio.
  • Specific examples of this ratio include 3:1, 2.9:1, 2.8:1, 2.7:1. 2.6:1. 2.5:1. 2.4:1, 2.3:1, 2.2:1, 2.1:1, 2:1,1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 and 1:2.
  • a suitable daily dose of formoterol, or salt or solvate thereof, particularly as formoterol fumarate dihydrate, for inhalation may be from 1 to 72 ⁇ g, for example from 1 to 60 ⁇ g, generally from 3 to 50 ⁇ g, preferably from 6 to 48 ⁇ g, for instance from 6 to 24 ⁇ g.
  • a suitable daily dose of tiotropium salt, particularly as tiotropium bromide, for inhalation may be from 1 to 160 ⁇ g, for example from 1 to 120 ⁇ g, from 1 to 80 ⁇ g, from 1 to 70 ⁇ g, from 1 to 60 ⁇ g, from 1 to 50 ⁇ g, from 1 to 40 ⁇ g, from 1 to 25 ⁇ g, preferably from 3 to 36 ⁇ g, for instance from 9 to 36 ⁇ g.
  • the precise dose used will of course depend on the condition to be treated, the patient and the efficiency of the inhalation device.
  • the unit doses of (A) and (B) and their frequency of administration may be chosen accordingly.
  • a suitable unit dose of formoterol component (A), particularly as formoterol fumarate dihydrate, may be from 1 to 72 ⁇ g, for example from 1 to 60 ⁇ g, generally from 3 to 48 ⁇ g, preferably from 6 to 36 ⁇ g, especially from 12 to 24 ⁇ g.
  • a suitable unit dose of tiotropium salt (B), particularly as tiotropium bromide, may be from 1 ⁇ g to 80 ⁇ g, for example from 1 ⁇ g to 50 ⁇ g, preferably from 3 ⁇ g to 36 ⁇ g, especially from 9 to 36 ⁇ g.
  • These unit doses may suitably be administered once or twice daily in accordance with the suitable daily dose mentioned hereinbefore. For on demand usage, unit doses of 6 ⁇ g to 12 ⁇ g of (A) and 3 ⁇ g to 36 ⁇ g of (B) are preferred.
  • the capsules may suitably contain, where (A) is formoterol fumarate dihydrate, and (B) is tiotropium bromide, from 3 ⁇ g to 36 ⁇ g of (A), preferably from 6 ⁇ g to 24 ⁇ g of (A), especially from 12 ⁇ g to 24 ⁇ g of (A), and from 3 ⁇ g to 80 ⁇ g of (B), preferably from 5 ⁇ g to 50 ⁇ g of (B), especially from 9 to 36 ⁇ g of (B), together with a pharmaceutically acceptable carrier as hereinbefore described in an amount to bring the total weight of dry powder per capsule to between 5 mg and 50mg, for example 5mg, lOmg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45
  • the medicament of the invention is a pharmaceutical composition which is a dry powder for administration from a reservoir of a multi-dose dry powder inhaler adapted to deliver 3mg to 25mg of powder containing a unit dose of (A) and (B) per actuation, for example, where (A) is formoterol fumarate dihydrate, and (B) is tiotropium bromide, a powder comprising, by weight, 3 to 36 parts, preferably 6 to 24 parts, especially 12 to 24 parts of (A); 3 to 80 parts, preferably 5 to 50 parts, especially 9 to 36 parts of (B); and 2884 to 24994 parts, preferably 4884 to 14994 parts, especially 4884 to 9994 parts of a pharmaceutically acceptable carrier as hereinbefore described.
  • the invention also provides a pharmaceutical kit comprising (A) and (B) as hereinbefore defined in separate unit dosage forms, said forms being suitable for administration of (A) and (B) in effective amounts.
  • a kit suitably further comprises one or more inhalation devices for administration of (A) and (B).
  • the kit may comprise one or more dry powder inhalation devices adapted to deliver dry powder from a capsule, together with capsules containing a dry powder comprising a dosage unit of (A) and capsules containing a dry powder comprising a dosage unit of (B).
  • the kit may comprise a multidose dry powder inhalation device containing in the reservoir thereof a dry powder comprising (A) and a multidose dry powder inhalaiton device containing in the reservoir thereof a dry powder comprising (B).
  • the kit may comprise a metered dose inhaler containing an aerosol comprising comprising (A) in a propellant and a metered dose inhaler containing an aerosol comprising (B) in a propellant.
  • Treatment of inflammatory or obstructive airways diseases in accordance with the invention may be symptomatic or prophylactic treatment.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti- inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping".
  • “Morning dipping” is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
  • inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (All), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis and emphysema, bronchiectasis and exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis and byssinosis.
  • Example 1 Aerosol Composition for Metered Dose Inhaler
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in WO97/20589 is prepared by mixing 12 parts of formoterol fumarate dihydrate which has been ground to a mean particle diameter of l-5 ⁇ m in an air-jet mill, 18 parts of tiotropium bromide which has been similarly ground to a mean particle diameter of l-5 ⁇ m and 4970 parts of lactose monohydrate having a particle diameter below 212 ⁇ m.
  • Example 3 is repeated, but using the amounts of the ingredients shown in the table below in place of the amounts used in that Example :
  • Gelatin capsules suitable for use in a capsule inhaler such as that described in US3991761 are prepared, each capsule containing a dry powder obtained by mixing 12 ⁇ g of formoterol fumarate dihydrate which has been ground to a mean particle diameter of 1 to 5 ⁇ m in an air jet mill, 18 ⁇ g of tiotropium bromide which has been similarly ground to a mean particle diameter of 1 to 5 ⁇ m and 24970 ⁇ g of lactose monohydrate having a particle diameter below 212 ⁇ m.
  • Example 93 is repeated, but using the amounts of the ingredients shown in the table below in place of the amounts used in that Example :
  • Example 3 is repeated, but using the amounts of the ingredients shown in the table below in place of the amounts used in that Example:
  • Example 93 is repeated, but using the amounts of the ingredients shown in the table below in place of the amounts used in that Example:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Otolaryngology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Silicates, Zeolites, And Molecular Sieves (AREA)
  • Inorganic Compounds Of Heavy Metals (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Cephalosporin Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Detergent Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

A medicament containing, separately or together, (A) formoterol or a pharmaceutically acceptable salt thereof or a solvate of formoterol or said salt and (B) a tiotropium salt of a pharmaceutically acceptable acid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.

Description

Combinations of Formoterol and a Tiotropium Salt
This invention relates to combinations of formoterol and a tiotropium salt and their use for the treatment of inflammatory or obstructive airways diseases.
Formoterol,N-[2-hydroxy-5-(l-hydroxy-2-((2-(4-methoxyphenyl)-l-methylethyl)amino)- ethyl)phenyl]formamide, particularly in the form of its fumarate salt, is a bronchodilator used in the treatment of inflammatory or obstructive airways diseases. Use of tiotropium bromide, (lα,2β,5α,7β)-7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-3-oxa-9-azonia- tricyclo(3.3.1.02'4)-nonane bromide, in the treatment of chronic obstructive bronchitis is described in US5610163. It has now surprisingly been found that a significant unexpected therapeutic benefit, particularly a synergistic therapeutic benefit, in the treatment of inflammatory or obstructive airways diseases can be obtained by combination therapy using formoterol, or a salt or solvate thereof, and a tiotropium salt. For instance, it is possible using this combination therapy to reduce the dosages required for a given therapeutic effect considerably compared with those required using treatment with formoterol or a tiotropium salt alone, thereby minimising possibly undesirable side effects.
In a further aspect, this combination therapy exhibits both a fast onset of action and a long duration of action, so that patients feel a rapid improvement in their condition and, in view of the long duration of action, a reduced need for short-acting rescue medicaments, such as salbutamol or terbutaline. Surprisingly this effect is exhibited even when the two drugs are administered at the same time, i.e. in a composition containing both drugs or sequentially, so that medicaments of the invention facilitate the treatment of inflammatory or obstructive airways diseases with a medicament which need be administered only once a day. Where necessary, medicaments of the invention can be used on demand in rescue treatment of obstructive or inflammatory airways diseases, so that they facilitate treatment of such diseases with a single medicament.
In one aspect, the present invention provides a medicament containing, separately or together, (A) formoterol or a pharmaceutically acceptable salt thereof or a solvate of formoterol or said salt and (B) a tiotropium salt of a pharmaceutically acceptable acid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease. In another aspect, the present invention provides a method of treating an inflammatory or obstructive airways disease which comprises administering to a subject in need of such treatment effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined.
In a further aspect, the present invention provides a phamaceutical composition comprising a mixture of effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined, optionally together with a pharmaceutically acceptable carrier.
The present invention also provides (A) and (B) as hereinbefore defined for use in combination therapy by simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
The invention further provides the use of (A) as hereinbefore defined or (B) as hereinbefore defined in the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration of (A) and (B) in the treatment of an inflammatory or obstructive airways disease.
The present invention still further provides the use of (A) and (B) as hereinbefore defined for the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
Pharmaceutically acceptable salts of formoterol include, for example, salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic acids.
Component (A) may be in any isomeric form or mixture of isomeric forms, for example a pure enantiomer, a mixture of enantiomers, a racemate or a mixture thereof. It may be in the form of a solvate, for example a hydrate, thereof, for example as described in US3994974 or US5684199, and may be present in a particular crystalline form, for example as described in WO95/05805. Preferably, component (A) is formoterol fumarate, especially in the form of the dihydrate. The tiotropium salt (B) is preferably tiotropium methanesulfonate or , especially, tiotropium bromide,(lcx,2β,4β,5α,7β)-7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-3- oxa-9-azoniatricyclo(3.3.1.02'4)-nonane bromide, the preparation of which is described in US5610163.
Administration of the medicament or pharmaceutical composition as hereinbefore described, i.e. with (A) and (B) in admixture or separate, is preferably by inhalation, i.e. (A) and (B) or the mixture thereof are in inhalable form. The inhalable form of the medicament i.e. of (A) and/or (B) may be, for example, an atomizable composition such as an aerosol comprising the active ingredient, i.e. (A) and (B) separately or in admixture, in solution or dispersion in a propellant, or a nebulizable composition comprising a dispersion of the active ingredient in an aqueous, organic or aqueous/organic medium. For example, the inhalable form of the medicament may be an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant, or a combination of an aerosol containing (A) in solution or dispersion in a propellant with an aerosol containing (B) in solution or dispersion in a propellant. In another example, the inhalable form is a nebulizable composition comprising a dispersion of (A) and (B) in an aqueous, organic or aqueous/organic medium, or a combination of a dispersion of (A) in such a medium with a dispersion of (B) in such a medium.
An aerosol composition suitable for use as the inhalable form of the medicament may comprise the active ingredient in solution or dispersion in a propellant, which may be chosen from any of the propellants known in the art. Suitable such propellants include hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons, and halogen-substituted hydrocarbons, for example fluorine-substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, particularly 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1, 1,2,3,3, 3-heptafluoropropane (HFA227), or mixtures of two or more such halogen-substituted hydrocarbons. here the active ingredient is present in suspension in the propellant, i.e. where it is present in particulate form dispersed in the propellant, the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art. Other suitable aerosol compositions include surfactant-free or substantially surfactant-free aerosol compositions. The aerosol composition may contain up to about 5% by weight, for example 0.002 to 5%, 0.01 to 3%, 0.015 to 2%, 0.1 to 2%, 0.5 to 2% or 0.5 to 1%, by weight of the active ingredient, based on the weight of the propellant. Where present, the lubricant and surfactant may be in an amount up to 5% and 0.5% respectively by weight of the aerosol composition. The aerosol composition may also contain a co-solvent such as ethanol in an amount up to 30% by weight of the composition, particularly for administration from a pressurised metered dose inhalation device.
In another embodiment of the invention, the inhalable form is a dry powder, i.e. (A) and/or (B) are present in a dry powder comprising finely divided (A) and/or (B) optionally together with a finely divided pharmaceutically acceptable carrier, which is preferably present and may be chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol. An especially preferred carrier is lactose. The dry powder may be in capsules of gelatin or plastic, or in blisters, for use in a dry powder inhalation device, preferably in dosage units of 1 μg to 140 μg of the active ingredient. Alternatively, the dry powder may be contained as a reservoir in a multi- dose dry powder inhalation device.
In the finely divided particulate form of the medicament, and in the aerosol composition where the active ingredient is present in particulate form, the active ingredient may have an average particle diameter of up to about 10 μm, for example 0.1 to 5 μm, preferably 1 to 5 μm. The finely divided carrier, where present, generally has a maximum particle diameter up to 300μm, preferably up to 212 μm and conveniently has a mean particle diameter of 40 to lOOμm, preferably 50 to 75 μm. The particle size of the active ingredient, and that of the carrier where present in dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, microprecipitation, spray-drying, lyophilisation or recrystallisation from supercritical media.
The inhalable medicament may be administered using an inhalation device suitable for the inhalable form, such devices being well known in the art. Accordingly, the invention also provides a pharmaceutical product comprising a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described in association with one or more inhalation devices. In a further aspect, the invention provides an inhalation device, or a pack of two or more inhalation devices, containing a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described. Where the inhalable form of the active ingredient is an aerosol composition, the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 μl, e.g. 25 to 50 μl, of the composition, i.e. a device known as a metered dose inhaler. Suitable such aerosol vials and procedures for containing within them aerosol compositions under pressure are well known to those skilled in the art of inhalation therapy. For example, an aerosol composition may be administered from a coated can, for example as described in EP-A-0642992. Where the inhalable form of the active ingredient is a nebulizable aqueous, organic or aqueous/organic dispersion, the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer, for example an electronically controlled device such as an AERx (ex Aradigm, US) or a mechanical device such as a RESPIMAT (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g. 10 to 100 μl, than conventional nebulizers. Where the inhalable form of the active ingredient is the finely divided particulate form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing dry powder comprising a dosage unit of (A) and/or (B), or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 5-25 mg of dry powder comprising a dosage unit of (A) and/or (B) per actuation. Suitable such dry powder inhalation devices are well known. For example, a suitable device for delivery of dry powder in encapsulated form is that described in US3991761, while a suitable MDPI device is that described in WO97/20589.
The medicament of the invention is preferably a pharmaceutical composition comprising a mixture of (A) as hereinbefore defined and (B) as hereinbefore defined, preferably together with a pharmaceutically acceptable carrier as hereinbefore described.
The weight ratio of formoterol, or salt or solvate thereof, to tiotropium salt may be, in general, from 72:1 to 1:160, for example from 72:1 to 1:120, from 72:1 to 1:80, from 60:1 to 1:80, from 60:1 to 1:70, from 50:1 to 1:60, from 60:1 to 1:50, from 50:1 to 1:50, from 60:1 to 1:40, from 50:1 to 1:40, from 50:1 to 1:30, from 50:1 to 1:20, from 50:1 to 1:30, from 50:1 to 1:20, from 50:1 to 1:10, from 40:1 to 1:20, from 40:1 to 1:10, from 30:1 to 1:20, from 30:1 to 1:10, from 20:1 to 1:20, from 20:1 to 1:10, from 20:1 to 1:5, from 16:1 to 1:4, from 10:1 to 1:5, from 6:1 to 1:4, or from 4:1 to 1:3. More usually, this ratio is from 3:1 to 1:3, for example from 2.5:1 to 1:2, from 2:1 to 1:2, from 1.5:1 to 1:1.5, or from 1.5:1 to 1:1.2. The two drugs may be administered separately in the same ratio. Specific examples of this ratio include 3:1, 2.9:1, 2.8:1, 2.7:1. 2.6:1. 2.5:1. 2.4:1, 2.3:1, 2.2:1, 2.1:1, 2:1,1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 and 1:2. The above weight ratios apply particularly where (A) is formoterol fumarate dihydrate and (B) is tiotropium bromide. Thus, since the molecular weights of formoterol fumarate dihydrate and tiotropium bromide are 840.9 and 472.4 respectively, the corresponding molar ratios, which apply to any forms of (A) and (B), can be readily calculated. For instance, the above weight ratios of 60:1 and 1:80 correspond to molar ratios of 33.7:1 and 1:142.3 respectively.
A suitable daily dose of formoterol, or salt or solvate thereof, particularly as formoterol fumarate dihydrate, for inhalation may be from 1 to 72 μg, for example from 1 to 60 μg, generally from 3 to 50 μg, preferably from 6 to 48 μg, for instance from 6 to 24 μg. A suitable daily dose of tiotropium salt, particularly as tiotropium bromide, for inhalation may be from 1 to 160 μg, for example from 1 to 120 μg, from 1 to 80μg, from 1 to 70μg, from 1 to 60 μg, from 1 to 50 μg, from 1 to 40 μg, from 1 to 25 μg, preferably from 3 to 36 μg, for instance from 9 to 36 μg. The precise dose used will of course depend on the condition to be treated, the patient and the efficiency of the inhalation device. The unit doses of (A) and (B) and their frequency of administration may be chosen accordingly. A suitable unit dose of formoterol component (A), particularly as formoterol fumarate dihydrate, may be from 1 to 72 μg, for example from 1 to 60 μg, generally from 3 to 48 μg, preferably from 6 to 36 μg, especially from 12 to 24 μg. A suitable unit dose of tiotropium salt (B), particularly as tiotropium bromide, may be from 1 μg to 80 μg, for example from 1 μg to 50 μg, preferably from 3 μg to 36 μg, especially from 9 to 36 μg. These unit doses may suitably be administered once or twice daily in accordance with the suitable daily dose mentioned hereinbefore. For on demand usage, unit doses of 6μg to 12 μg of (A) and 3μg to 36μg of (B) are preferred.
In one preferred embodiment of the invention, when the medicament of the invention is a pharmaceutical composition which is a dry powder in capsules containing a unit dose of (A) and (B), for example for inhalation from a single capsule inhaler, the capsules may suitably contain, where (A) is formoterol fumarate dihydrate, and (B) is tiotropium bromide, from 3 μg to 36 μg of (A), preferably from 6 μg to 24 μg of (A), especially from 12 μg to 24 μg of (A), and from 3 μg to 80 μg of (B), preferably from 5 μg to 50 μg of (B), especially from 9 to 36 μg of (B), together with a pharmaceutically acceptable carrier as hereinbefore described in an amount to bring the total weight of dry powder per capsule to between 5 mg and 50mg, for example 5mg, lOmg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg or 50mg, preferably 20 to 25 mg, especially 25 mg.
In another preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is a dry powder for administration from a reservoir of a multi-dose dry powder inhaler adapted to deliver 3mg to 25mg of powder containing a unit dose of (A) and (B) per actuation, for example, where (A) is formoterol fumarate dihydrate, and (B) is tiotropium bromide, a powder comprising, by weight, 3 to 36 parts, preferably 6 to 24 parts, especially 12 to 24 parts of (A); 3 to 80 parts, preferably 5 to 50 parts, especially 9 to 36 parts of (B); and 2884 to 24994 parts, preferably 4884 to 14994 parts, especially 4884 to 9994 parts of a pharmaceutically acceptable carrier as hereinbefore described.
In accordance with the above, the invention also provides a pharmaceutical kit comprising (A) and (B) as hereinbefore defined in separate unit dosage forms, said forms being suitable for administration of (A) and (B) in effective amounts. Such a kit suitably further comprises one or more inhalation devices for administration of (A) and (B). For example, the kit may comprise one or more dry powder inhalation devices adapted to deliver dry powder from a capsule, together with capsules containing a dry powder comprising a dosage unit of (A) and capsules containing a dry powder comprising a dosage unit of (B). In another example, the kit may comprise a multidose dry powder inhalation device containing in the reservoir thereof a dry powder comprising (A) and a multidose dry powder inhalaiton device containing in the reservoir thereof a dry powder comprising (B). In a further example, the kit may comprise a metered dose inhaler containing an aerosol comprising comprising (A) in a propellant and a metered dose inhaler containing an aerosol comprising (B) in a propellant.
Treatment of inflammatory or obstructive airways diseases in accordance with the invention may be symptomatic or prophylactic treatment. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".) Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti- inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (All), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis and emphysema, bronchiectasis and exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
The invention is illustrated by the following Examples, in which parts are by weight unless stated otherwise.
Example 1 - Aerosol Composition for Metered Dose Inhaler
Ingredient % by weight
Formoterol fumarate dihydrate 0.01
Tiotropium bromide 0.01
Ethanol (absolute) 2.50
HFA 227 60.92
HFA134a 36.56 Example 2 - Dry Powder
Ingredient % by weight
Formoterol fumarate dihydrate 0.05 Tiotropium bromide 0.05 Lactose monohydrate 99.90
Example 3
A dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in WO97/20589 is prepared by mixing 12 parts of formoterol fumarate dihydrate which has been ground to a mean particle diameter of l-5μm in an air-jet mill, 18 parts of tiotropium bromide which has been similarly ground to a mean particle diameter of l-5μm and 4970 parts of lactose monohydrate having a particle diameter below 212μm.
Examples 4 - 92
Example 3 is repeated, but using the amounts of the ingredients shown in the table below in place of the amounts used in that Example :
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Example 93
Gelatin capsules suitable for use in a capsule inhaler such as that described in US3991761 are prepared, each capsule containing a dry powder obtained by mixing 12μg of formoterol fumarate dihydrate which has been ground to a mean particle diameter of 1 to 5μm in an air jet mill, 18μg of tiotropium bromide which has been similarly ground to a mean particle diameter of 1 to 5μm and 24970μg of lactose monohydrate having a particle diameter below 212μm.
Examples 94 - 152
Example 93 is repeated, but using the amounts of the ingredients shown in the table below in place of the amounts used in that Example :
Figure imgf000014_0002
Figure imgf000015_0001
Examples 153 - 216
Example 3 is repeated, but using the amounts of the ingredients shown in the table below in place of the amounts used in that Example:
Figure imgf000016_0002
Figure imgf000017_0001
Figure imgf000018_0001
Examples 217 - 256
Example 93 is repeated, but using the amounts of the ingredients shown in the table below in place of the amounts used in that Example:
Figure imgf000018_0002
Figure imgf000019_0001

Claims

Claims
1. A medicament containing, separately or together, (A) formoterol or a pharmaceutically acceptable salt thereof or a solvate of formoterol or said salt and (B) a tiotropium salt of a pharmaceutically acceptable acid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
2. A medicament according to claim 1 which is a phamaceutical composition comprising a mixture of effective amounts of (A) and (B), optionally together with a pharmaceutically acceptable carrier.
3. A medicament according to claim 1 or 2, in which (A) is formoterol fumarate.
4. A medicament according to claim 3, in which formoterol fumarate is in the form of the dihydrate thereof.
5. A medicament according to any one of claims 1 to 4, in which (B) is tiotropium bromide.
6. A medicament according any one of claims 1 to 5, which is in inhalable form.
7. A medicament according to claim 6, in which (A) and/or (B) are present in an atomizable composition.
8. A medicament according to claim 7, in which the inhalable form is an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant, or a combination of an aerosol containing (A) in solution or dispersion in a propellant with an aerosol containing (B) in solution or dispersion in a propellant.
9. A medicament according to claim 7, in which the inhalable form is a nebulizable composition comprising a dispersion of (A) and (B) in an aqueous, organic or aqueous/organic medium or a combination of a dispersion of (A) in said medium with a dispersion of (B) in said medium.
10. A medicament according to claim 6, in which (A) and/or (B) are present in a dry powder comprising finely divided (A) and/or (B) optionally together with a pharmaceutically acceptable carrier in finely divided form.
11. A medicament according to claim 10, in which the carrier is present and is a saccharide.
12. A medicament according to claim 11, in which the carrier is lactose.
13. A medicament according to any one of claims 10 to 12, in which (A) and/or (B) has an average particle diameter up to 10 μm.
14. A medicament according to any one of the preceding claims, in which the weight ratio of (A) to (B) is from 72:1 to 1:160.
15. A medicament according to claim 14, in which said ratio is from 60:1 to 1:80.
16. A medicament according to claim 15, in which said ratio is from 3:1 to 1:3.
17. A medicament according to claim 2, which is a dry powder in a capsule, the capsule containing from 3 to 36 μg of (A) as formoterol fumarate dihydrate, from 3 to 80 μg of (B) as tiotropium bromide and a pharmaceutically acceptable carrier in an amount to bring the total weight of dry powder per capsule to betwen 5mg and 50 mg.
18. A medicament according to claim 2, which is a dry powder comprising, by weight, 3 to 36 parts of (A) as formoterol fumarate dihydrate, 3 to 80 parts of (B) as tiotropium bromide and 2884 to 24994 parts of a pharmaceutically acceptable carrier.
19. The use of (A) as defined in any one of claims 1, 3 and 4 or (B) as defined in claim 1 or 5 in the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration of (A) and (B) in the treatment of an inflammatory or obstructive airways disease.
20. The use of (A) as defined in claim 1, 3 or 4 and (B) as defined in claim 1 or 5 for the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
21. A pharmaceutical kit comprising (A) as defined in claim 1, 3 or 4 and (B) as defined in claim 1 or 5 in separate unit dosage forms, said forms being suitable for administration of (A) and (B) in effective amounts, together with one or more inhalation devices for administration of (A) and (B).
22. A method of treating an inflammatory or obstructive airways disease which comprises administering to a subject in need of such treatment effective amounts of (A) as defined in claim 1, 3 or 4 and (B) as defined in claim 1 or 5.
PCT/EP2000/000958 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt WO2000047200A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
CA002360248A CA2360248C (en) 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt
IL14398600A IL143986A0 (en) 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt
SK1127-2001A SK285884B6 (en) 1999-02-08 2000-02-07 Combined preparation of formoterol and tiotropium salt, its use and pharmaceutical kit comprising the same
NZ513304A NZ513304A (en) 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt
SI200030922T SI1158970T1 (en) 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt
DE60030844T DE60030844T2 (en) 1999-02-08 2000-02-07 COMBINATIONS OF FORMOTEROL AND TIOTROPIUM SALT
BRPI0008039A BRPI0008039B1 (en) 1999-02-08 2000-02-07 medicament, use of formoterol combinations and a tiotropium salt for preparation thereof, as well as a pharmaceutical kit.
AU24419/00A AU770632B2 (en) 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt
JP2000598152A JP2002536408A (en) 1999-02-08 2000-02-07 Combination of formoterol and tiotropium salt
KR1020017009941A KR20010101806A (en) 1999-02-08 2000-02-07 Combinations of Formoterol and a Tiotropium Salt
EP00902663A EP1158970B1 (en) 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt
PL350583A PL206965B1 (en) 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt
IL143986A IL143986A (en) 1999-02-08 2001-06-25 Combinations of formoterol and a tiotropium salt
NO20013460A NO329911B1 (en) 1999-02-08 2001-07-12 Medicament containing formoterol and a tiotropium salt, use thereof and a pharmaceutical device containing said drug
US09/924,246 US6537524B1 (en) 1999-02-08 2001-08-08 Combinations of formoterol and a tiotropium salt
US10/365,310 US20030125350A1 (en) 1999-02-08 2003-02-12 Combination of formoterol and a tiotropium salt
US11/288,548 US20060083692A1 (en) 1999-02-08 2005-11-29 Combination of formoterol and a tiotropium salt
CY20061101480T CY1105707T1 (en) 1999-02-08 2006-10-16 COMBINATIONS OF FORMOTEROL AND A TRIOTROP SALT

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9902689.0A GB9902689D0 (en) 1999-02-08 1999-02-08 Organic compounds
GB9902689.0 1999-02-08

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/924,246 Continuation US6537524B1 (en) 1999-02-08 2001-08-08 Combinations of formoterol and a tiotropium salt

Publications (1)

Publication Number Publication Date
WO2000047200A1 true WO2000047200A1 (en) 2000-08-17

Family

ID=10847254

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/000958 WO2000047200A1 (en) 1999-02-08 2000-02-07 Combinations of formoterol and a tiotropium salt

Country Status (27)

Country Link
US (3) US6537524B1 (en)
EP (1) EP1158970B1 (en)
JP (1) JP2002536408A (en)
KR (1) KR20010101806A (en)
CN (1) CN1338928A (en)
AT (1) ATE339954T1 (en)
AU (1) AU770632B2 (en)
BR (1) BRPI0008039B1 (en)
CA (1) CA2360248C (en)
CY (1) CY1105707T1 (en)
CZ (1) CZ302198B6 (en)
DE (1) DE60030844T2 (en)
DK (1) DK1158970T3 (en)
ES (1) ES2270806T3 (en)
GB (1) GB9902689D0 (en)
HU (1) HUP0200083A3 (en)
ID (1) ID29181A (en)
IL (2) IL143986A0 (en)
NO (1) NO329911B1 (en)
NZ (1) NZ513304A (en)
PL (1) PL206965B1 (en)
PT (1) PT1158970E (en)
RU (1) RU2238085C2 (en)
SK (1) SK285884B6 (en)
TR (1) TR200102226T2 (en)
WO (1) WO2000047200A1 (en)
ZA (1) ZA200105648B (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2801506A1 (en) * 1999-11-30 2001-06-01 Novartis Ag New use of dry powder containing formoterol for preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease
WO2002030389A1 (en) * 2000-10-12 2002-04-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel tiotropium-containing inhalation powder
US6433027B1 (en) 1999-05-12 2002-08-13 Boehringer Ingelheim Pharma Kg Medicament compositions based on tiotropium bromide and formoterol fumarate
WO2002072095A2 (en) * 2001-03-13 2002-09-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium salts for treating inflammatory diseases
WO2002100319A2 (en) * 2001-06-13 2002-12-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Method for cleaning hard gelatine capsules
US6585959B2 (en) 2000-10-12 2003-07-01 Boehringer Ingelheim Pharma Kg Process for preparing powder formulations
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
WO2004024156A1 (en) * 2002-09-13 2004-03-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium salts for reducing respiratory mortality rate
WO2004047796A2 (en) * 2002-11-28 2004-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pulverulent formulation for inhalation containing tiotropium
US6890517B2 (en) 2000-10-31 2005-05-10 Boehringer Ingelheim Pharma Kg Inhalable formulation of a solution containing a tiotropium salt
US7078412B2 (en) 1999-07-14 2006-07-18 Almirall Prodesfarma Ag Quinuclidine derivatives and medicinal compositions containing the same
US7214687B2 (en) 1999-07-14 2007-05-08 Almirall Ag Quinuclidine derivatives and medicinal compositions containing the same
EP2080523A1 (en) * 2008-01-15 2009-07-22 CHIESI FARMACEUTICI S.p.A. Compositions comprising an antimuscarinic and a long-acting beta-agonist
US7763280B2 (en) 2002-11-28 2010-07-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium containing powder formulation for inhalation
EP2319582A1 (en) 2002-08-29 2011-05-11 Cipla Ltd. Pharmaceutical products and compositions comprising formoterol, budesonide and tiotropium or oxitropium
WO2011037551A3 (en) * 2009-09-23 2011-06-09 Mahmut Bilgic Carrying of a combination containing tiotropium in a blister strip
WO2011037549A3 (en) * 2009-09-23 2011-06-09 Bilgic Mahmut Dry powder formulation of tiotropium carried in blister strip
WO2011078816A1 (en) 2009-12-25 2011-06-30 Bilgic Mahmut Dry powder combination of tiotropium, formoterol and a cromoglicic acid derivative
US8022082B2 (en) 2002-04-09 2011-09-20 Boehringer Ingelheim Pharma Gmbh & Co., Kg Method for the administration of an anticholinergic by inhalation
US8044205B2 (en) 2006-07-21 2011-10-25 Laboratorios Almirall, S.A. Process for manufacturing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide
WO2011049538A3 (en) * 2009-10-20 2011-11-03 Bilgic Mahmut Pharmaceutical composition in dry powder form
US8834931B2 (en) 2009-12-25 2014-09-16 Mahmut Bilgic Dry powder formulation containing tiotropium for inhalation
US9254262B2 (en) 2008-03-13 2016-02-09 Almirall, S.A. Dosage and formulation
EP3053921A1 (en) * 2002-03-20 2016-08-10 Boehringer Ingelheim Pharma GmbH & Co. KG Crystalline micronisate of tiotropium bromide
US9597396B2 (en) 2001-04-17 2017-03-21 Mylan Specialty Lp Formoterol/steroid bronchodilating compositions and methods of use thereof
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
NO342935B1 (en) * 2000-05-22 2018-09-03 Chiesi Farm Spa Stable pharmaceutical solution formulations for use in metered dose inhalers
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
EP2228064B1 (en) 2004-05-18 2019-12-11 Novartis AG Pharmaceutical composition containing glycopyrrolate and a beta2 adrenoceptor agonist

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9902689D0 (en) * 1999-02-08 1999-03-31 Novartis Ag Organic compounds
US20100197719A1 (en) * 1999-05-12 2010-08-05 Boehringer Ingelheim Pharma Kg Medicament compositions containing anticholinergically-effective compounds and betamimetics
US20040002548A1 (en) * 1999-05-12 2004-01-01 Boehringer Ingelheim Pharma Kg Medicament compositions containing anticholinergically-effective compounds and betamimetics
US20030026766A1 (en) * 2000-04-13 2003-02-06 Mark Sanders Medicaments for treating respiratory disorders comprising formoterol and fluticasone
IT1318514B1 (en) * 2000-05-12 2003-08-27 Chiesi Farma Spa FORMULATIONS CONTAINING A GLUCOCORTICOSTEROID DRUG FOR THE TREATMENT OF BRONCOPOLMONARY DISEASES.
US20060257324A1 (en) * 2000-05-22 2006-11-16 Chiesi Farmaceutici S.P.A. Pharmaceutical solution formulations for pressurised metered dose inhalers
GB0029562D0 (en) * 2000-12-04 2001-01-17 Novartis Ag Organic compounds
US20030070679A1 (en) * 2001-06-01 2003-04-17 Boehringer Ingelheim Pharma Kg Capsules containing inhalable tiotropium
US20030008001A1 (en) * 2001-06-13 2003-01-09 Boehringer Ingelheim Pharma Kg Process for cleaning hard gelatine capsules
US20030018019A1 (en) * 2001-06-23 2003-01-23 Boehringer Ingelheim Pharma Kg Pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics
US7931022B2 (en) * 2001-10-19 2011-04-26 Respirks, Inc. Method and apparatus for dispensing inhalator medicament
US7311894B2 (en) * 2002-03-28 2007-12-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations containing an anticholinergic
US7244415B2 (en) * 2002-03-28 2007-07-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations of an anhydrate
UA80123C2 (en) 2002-04-09 2007-08-27 Boehringer Ingelheim Pharma Inhalation kit comprising inhalable powder of tiotropium
SE527200C2 (en) * 2003-06-19 2006-01-17 Microdrug Ag Administration of metered dry powder combined doses of finely divided dry medication powders involves selecting first and second medicaments for forming of pharmaceutical, combined doses
US20050026948A1 (en) * 2003-07-29 2005-02-03 Boehringer Ingelheim International Gmbh Medicaments for inhalation comprising an anticholinergic and a betamimetic
DE102004016179A1 (en) * 2004-03-30 2005-10-20 Boehringer Ingelheim Pharma Compounds for the treatment of proliferative processes
ES2257152B1 (en) * 2004-05-31 2007-07-01 Laboratorios Almirall S.A. COMBINATIONS THAT INCLUDE ANTIMUSCARINIC AGENTS AND BETA-ADRENERGIC AGONISTS.
AU2005263577C1 (en) 2004-07-16 2010-08-26 Proteosys Ag Muscarinic antagonists with PARP and SiR modulating activity as cytoprotective agents
JP2008538758A (en) * 2005-04-23 2008-11-06 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Pharmaceutical composition for inhalation containing beta-receptor stimulant and steroid in addition to anticholinergic
US20060239935A1 (en) * 2005-04-23 2006-10-26 Boehringer Ingelheim International Gmbh Compositions for inhalation
JP2009504604A (en) * 2005-08-06 2009-02-05 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Use of tiotropium salt in the treatment of severe persistent asthma
AU2006334367B2 (en) * 2006-01-04 2012-11-08 Boehringer Ingelheim International Gmbh Use of tiotropium salts in the treatment of moderate persistent asthma
CA2608561A1 (en) * 2007-10-29 2009-04-29 Carl Paluszkiewicz Motorcycle wind deflector accessory support
GB2468073B (en) * 2008-02-26 2012-09-05 Elevation Pharmaceuticals Inc Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
US20100055045A1 (en) 2008-02-26 2010-03-04 William Gerhart Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
WO2010081825A2 (en) 2009-01-13 2010-07-22 Proteosys Ag Pirenzepine as an agent in cancer treatment
LT2435025T (en) 2009-05-29 2016-09-26 Pearl Therapeutics, Inc. Respiratory delivery of active agents
US8815258B2 (en) 2009-05-29 2014-08-26 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
CN103110584A (en) * 2013-01-29 2013-05-22 青岛大学 Tiotropium bromide powder inhalation and preparation method thereof
KR102391332B1 (en) 2013-03-15 2022-04-26 펄 테라퓨틱스 인코포레이티드 Methods and systems for conditioning of particulate crystalline materials
CN105125542A (en) * 2015-08-23 2015-12-09 杭州紫金医药科技有限公司 Medicine composition with tiotropium bromide and formoterol, application of medicine composition and preparation
EP3525773A1 (en) 2016-10-14 2019-08-21 Glenmark Specialty S.A. Nebulizable compositions of tiotropium and formoterol

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005805A1 (en) * 1993-08-27 1995-03-02 Astra Aktiebolag Process for conditioning substances
WO2000007567A1 (en) * 1998-08-04 2000-02-17 Jago Research Ag Medicinal aerosol formulations
WO2000016814A1 (en) * 1998-09-22 2000-03-30 Aeropharm Technology Incorporated Medicinal aerosol formulation
DE19847970A1 (en) * 1998-10-17 2000-04-20 Boehringer Ingelheim Pharma Stable concentrated liquid formulation of inhalable drug, e.g. formoterol or salbutamol, in solution or suspension medium, used after dilution for treatment of respiratory disorders by inhalation

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US115681A (en) * 1871-06-06 Improvement in water-wheels
US5610163A (en) * 1989-09-16 1997-03-11 Boehringer Ingelheim Gmbh Esters of thienyl carboxylic acids and amino alcohols and their quaternization products
US5874063A (en) * 1991-04-11 1999-02-23 Astra Aktiebolag Pharmaceutical formulation
DE69232462T2 (en) * 1991-12-18 2002-10-10 Astrazeneca Ab, Soedertaelje COMPOSITION CONTAINING FORMOTEROL AND BUDESONIDE
EP0673240B1 (en) * 1992-12-09 1999-03-24 Boehringer Ingelheim Pharmaceuticals Inc. Stabilized medicinal aerosol solution formulations
US5603918A (en) 1995-06-09 1997-02-18 Boehringer Ingelheim Pharmaceuticals, Inc. Aerosol composition of a salt of ipratropium and a salt of albuterol
WO1998034595A1 (en) * 1997-02-05 1998-08-13 Jago Research Ag Medical aerosol formulations
DE19835335C1 (en) * 1998-08-05 1999-11-25 Draeger Sicherheitstech Gmbh Infra optical gas sensor for measuring carbon dioxide
DE19835346A1 (en) * 1998-08-05 2000-02-10 Boehringer Ingelheim Pharma Two-part capsule for pharmaceutical preparations for powder inhalers
DE19847968A1 (en) * 1998-10-17 2000-04-20 Boehringer Ingelheim Pharma Separate storage of an active material and a solvent comprises a closure cap and a container, with a chamber attached to the unit.
DE19847969A1 (en) 1998-10-17 2000-04-20 Boehringer Ingelheim Pharma Stable liquid formulation of formoterol in solution or suspension medium, used after dilution for treatment of asthma by inhalation
US6235725B1 (en) * 1998-10-30 2001-05-22 Baker Norton Pharmaceuticals, Inc. Methods and compositions for the prevention of tolerance to medications
GB9902689D0 (en) * 1999-02-08 1999-03-31 Novartis Ag Organic compounds
DE19921693A1 (en) * 1999-05-12 2000-11-16 Boehringer Ingelheim Pharma Pharmaceutical composition for treating respiratory disorders, e.g. asthma, comprises combination of anticholinergic and beta-mimetic agents having synergistic bronchospasmolytic activity and reduced side-effects
US6471435B1 (en) * 1999-11-05 2002-10-29 Multibeam Systems, Inc. Flexural joint

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005805A1 (en) * 1993-08-27 1995-03-02 Astra Aktiebolag Process for conditioning substances
WO2000007567A1 (en) * 1998-08-04 2000-02-17 Jago Research Ag Medicinal aerosol formulations
WO2000016814A1 (en) * 1998-09-22 2000-03-30 Aeropharm Technology Incorporated Medicinal aerosol formulation
DE19847970A1 (en) * 1998-10-17 2000-04-20 Boehringer Ingelheim Pharma Stable concentrated liquid formulation of inhalable drug, e.g. formoterol or salbutamol, in solution or suspension medium, used after dilution for treatment of respiratory disorders by inhalation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BARNES P J: "Chronic obstructive pulmonary disease: new opportunities for drug development", TRENDS IN PHARMACOLOGICAL SCIENCES,GB,ELSEVIER TRENDS JOURNAL, CAMBRIDGE, vol. 19, no. 10, October 1998 (1998-10-01), pages 415 - 423, XP004156947, ISSN: 0165-6147 *
LECKIE M.J. ET AL: "Novel therapy for COPD.", EXPERT OPINION ON INVESTIGATIONAL DRUGS, (2000) 9/1 (3-23)., XP000911149 *

Cited By (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6455524B1 (en) 1999-03-12 2002-09-24 Boehringer Ingelheim Pharma Kg Medicament compositions based on anticholinergically-effective compounds and beta-mimetics
EP1570861A2 (en) * 1999-05-12 2005-09-07 Boehringer Ingelheim Pharma GmbH & Co.KG Pharmaceutical compositions based on anticholinergically effective compounds and beta-mimetics
EP2266621A3 (en) * 1999-05-12 2013-01-23 Boehringer Ingelheim Pharma GmbH & Co. KG Pharmaceutical compositions based on anticholinergically effective compounds and beta-mimetics
EP2269647A3 (en) * 1999-05-12 2012-04-18 Boehringer Ingelheim Pharma GmbH & Co. KG Pharmaceutical compositions based on anticholinergically effective compounds and beta-mimetics
EP2269648A3 (en) * 1999-05-12 2012-04-18 Boehringer Ingelheim Pharma GmbH & Co. KG Pharmaceutical compositions based on anticholinergically effective compounds and beta-mimetics
US6433027B1 (en) 1999-05-12 2002-08-13 Boehringer Ingelheim Pharma Kg Medicament compositions based on tiotropium bromide and formoterol fumarate
EP1570861A3 (en) * 1999-05-12 2010-12-29 Boehringer Ingelheim Pharma GmbH & Co.KG Pharmaceutical compositions based on anticholinergically effective compounds and beta-mimetics
US7750023B2 (en) 1999-07-14 2010-07-06 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US7078412B2 (en) 1999-07-14 2006-07-18 Almirall Prodesfarma Ag Quinuclidine derivatives and medicinal compositions containing the same
US10588895B2 (en) 1999-07-14 2020-03-17 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US7897617B2 (en) 1999-07-14 2011-03-01 Almirall Prodesfarma S.A. Quinuclidine derivatives and medicinal compositions containing the same
US7214687B2 (en) 1999-07-14 2007-05-08 Almirall Ag Quinuclidine derivatives and medicinal compositions containing the same
US7196098B2 (en) 1999-07-14 2007-03-27 Almirall Prodesfarma Ag Quinuclidine derivatives and medicinal compositions containing the same
US10034867B2 (en) 1999-07-14 2018-07-31 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9687478B2 (en) 1999-07-14 2017-06-27 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9333195B2 (en) 1999-07-14 2016-05-10 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US8129405B2 (en) 1999-07-14 2012-03-06 Almirall Prodesfarma S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9056100B2 (en) 1999-07-14 2015-06-16 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US6887459B1 (en) 1999-11-30 2005-05-03 Novartis, Ag Aerosol composition comprising formoterol
WO2001039745A3 (en) * 1999-11-30 2001-12-20 Novartis Ag Aerosol composition comprising formoterol
FR2801506A1 (en) * 1999-11-30 2001-06-01 Novartis Ag New use of dry powder containing formoterol for preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease
WO2001039745A2 (en) * 1999-11-30 2001-06-07 Novartis Ag Aerosol composition comprising formoterol
JP2003515551A (en) * 1999-11-30 2003-05-07 ノバルティス アクチエンゲゼルシャフト Aerosol containing formoterol
EP2011484A2 (en) 1999-11-30 2009-01-07 Novartis Ag Use of a dry powder composition of formoterol in the treatment of chronic obstructive pulmonary disease
ES2178943A1 (en) * 1999-11-30 2003-01-01 Novartis Ag Aerosol composition comprising formoterol
NO342935B1 (en) * 2000-05-22 2018-09-03 Chiesi Farm Spa Stable pharmaceutical solution formulations for use in metered dose inhalers
USRE38912E1 (en) * 2000-10-12 2005-12-06 Boehringer Ingelheim Pharma Kg Process for preparing powder formulations
AP1712A (en) * 2000-10-12 2007-01-24 Boehringer Ingelheim Pharma Novel tiotropium-containing inhalation powder
CZ301465B6 (en) * 2000-10-12 2010-03-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg. Inhalation powder containing tiotropium
US6585959B2 (en) 2000-10-12 2003-07-01 Boehringer Ingelheim Pharma Kg Process for preparing powder formulations
EP1430887A1 (en) * 2000-10-12 2004-06-23 Boehringer Ingelheim Pharma GmbH & Co.KG Powder for inhalation containing Tiotropium
US7070800B2 (en) 2000-10-12 2006-07-04 Boehringer Ingelheim Pharma Kg Inhalable powder containing tiotropium
WO2002030389A1 (en) * 2000-10-12 2002-04-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel tiotropium-containing inhalation powder
US6890517B2 (en) 2000-10-31 2005-05-10 Boehringer Ingelheim Pharma Kg Inhalable formulation of a solution containing a tiotropium salt
EP1690539A2 (en) * 2001-03-13 2006-08-16 Boehringer Ingelheim Pharma GmbH & Co. KG Salts of tiotropium for treating inflammatory disorders
US7994188B2 (en) 2001-03-13 2011-08-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg Compounds for treating inflammatory diseases
WO2002072095A2 (en) * 2001-03-13 2002-09-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium salts for treating inflammatory diseases
WO2002072095A3 (en) * 2001-03-13 2003-11-27 Boehringer Ingelheim Pharma Tiotropium salts for treating inflammatory diseases
EP1690539A3 (en) * 2001-03-13 2006-08-30 Boehringer Ingelheim Pharma GmbH & Co. KG Salts of tiotropium for treating inflammatory disorders
JP2004528305A (en) * 2001-03-13 2004-09-16 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト Compounds for treating inflammatory diseases
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
US9597396B2 (en) 2001-04-17 2017-03-21 Mylan Specialty Lp Formoterol/steroid bronchodilating compositions and methods of use thereof
WO2002100319A3 (en) * 2001-06-13 2003-03-20 Boehringer Ingelheim Pharma Method for cleaning hard gelatine capsules
WO2002100319A2 (en) * 2001-06-13 2002-12-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Method for cleaning hard gelatine capsules
EP1785422B1 (en) * 2002-03-20 2016-11-16 Boehringer Ingelheim Pharma GmbH & Co. KG Micronised crystalline tiotropium bromide
NO346754B1 (en) * 2002-03-20 2022-12-12 Boehringer Ingelheim Pharma Crystalline micronisate of tiotropium bromide
NO344427B1 (en) * 2002-03-20 2019-12-02 Boehringer Ingelheim Pharma Process for the preparation of crystalline tiotropium bromide micronisate
EP3053921A1 (en) * 2002-03-20 2016-08-10 Boehringer Ingelheim Pharma GmbH & Co. KG Crystalline micronisate of tiotropium bromide
US8022082B2 (en) 2002-04-09 2011-09-20 Boehringer Ingelheim Pharma Gmbh & Co., Kg Method for the administration of an anticholinergic by inhalation
EP2319585A1 (en) 2002-08-29 2011-05-11 Cipla Ltd. Pharmaceutical products and compositions comprising salmeterol, fluticasone and ipratropium or tiotropium
EP2329861A1 (en) 2002-08-29 2011-06-08 Cipla Ltd. Pharmaceutical products and compositions comprising formoterol, budesonide and ipratropium
EP2319582A1 (en) 2002-08-29 2011-05-11 Cipla Ltd. Pharmaceutical products and compositions comprising formoterol, budesonide and tiotropium or oxitropium
EP2319583A1 (en) 2002-08-29 2011-05-11 Cipla Ltd. Pharmaceutical products and compositions comprising salmeterol, budesonide and ipratropium
EP2322243A1 (en) 2002-08-29 2011-05-18 Cipla Ltd. Pharmaceutical products and compositions comprising formoterol, ciclesonide and tiotropium
EP2319584A1 (en) 2002-08-29 2011-05-11 Cipla Ltd. Pharmaceutical products and compositions comprising salmeterol, ciclesonide and tiotropium
WO2004024156A1 (en) * 2002-09-13 2004-03-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium salts for reducing respiratory mortality rate
EA011549B1 (en) * 2002-11-28 2009-04-28 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Novel pulverulent formulation for inhalation containing tiotropium
US7763280B2 (en) 2002-11-28 2010-07-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium containing powder formulation for inhalation
US8197845B2 (en) 2002-11-28 2012-06-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Encapsulated tiotropium containing powder formulation for inhalation
WO2004047796A2 (en) * 2002-11-28 2004-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pulverulent formulation for inhalation containing tiotropium
WO2004047796A3 (en) * 2002-11-28 2004-09-30 Boehringer Ingelheim Pharma Pulverulent formulation for inhalation containing tiotropium
EP2228064B1 (en) 2004-05-18 2019-12-11 Novartis AG Pharmaceutical composition containing glycopyrrolate and a beta2 adrenoceptor agonist
US8044205B2 (en) 2006-07-21 2011-10-25 Laboratorios Almirall, S.A. Process for manufacturing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide
WO2009090010A1 (en) * 2008-01-15 2009-07-23 Chiesi Farmaceutici S.P.A. Compositions comprising an antimuscarinic and a long-acting beta-agonist
EP2080523A1 (en) * 2008-01-15 2009-07-22 CHIESI FARMACEUTICI S.p.A. Compositions comprising an antimuscarinic and a long-acting beta-agonist
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
US9254262B2 (en) 2008-03-13 2016-02-09 Almirall, S.A. Dosage and formulation
US11000517B2 (en) 2008-03-13 2021-05-11 Almirall, S.A. Dosage and formulation
WO2011037551A3 (en) * 2009-09-23 2011-06-09 Mahmut Bilgic Carrying of a combination containing tiotropium in a blister strip
WO2011037549A3 (en) * 2009-09-23 2011-06-09 Bilgic Mahmut Dry powder formulation of tiotropium carried in blister strip
WO2011049538A3 (en) * 2009-10-20 2011-11-03 Bilgic Mahmut Pharmaceutical composition in dry powder form
WO2011078816A1 (en) 2009-12-25 2011-06-30 Bilgic Mahmut Dry powder combination of tiotropium, formoterol and a cromoglicic acid derivative
US8834931B2 (en) 2009-12-25 2014-09-16 Mahmut Bilgic Dry powder formulation containing tiotropium for inhalation
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients

Also Published As

Publication number Publication date
ZA200105648B (en) 2002-08-12
KR20010101806A (en) 2001-11-14
PL206965B1 (en) 2010-10-29
NZ513304A (en) 2003-01-31
EP1158970B1 (en) 2006-09-20
GB9902689D0 (en) 1999-03-31
RU2238085C2 (en) 2004-10-20
CN1338928A (en) 2002-03-06
HUP0200083A2 (en) 2002-06-29
IL143986A0 (en) 2002-04-21
CZ20012856A3 (en) 2001-11-14
US20060083692A1 (en) 2006-04-20
US20030125350A1 (en) 2003-07-03
ES2270806T3 (en) 2007-04-16
PL350583A1 (en) 2003-01-13
HUP0200083A3 (en) 2003-04-28
CY1105707T1 (en) 2010-12-22
CA2360248C (en) 2009-01-27
CA2360248A1 (en) 2000-08-17
PT1158970E (en) 2006-12-29
BRPI0008039B1 (en) 2015-10-20
US6537524B1 (en) 2003-03-25
DK1158970T3 (en) 2006-12-27
JP2002536408A (en) 2002-10-29
BR0008039A (en) 2001-11-06
ID29181A (en) 2001-08-09
NO329911B1 (en) 2011-01-24
DE60030844D1 (en) 2006-11-02
TR200102226T2 (en) 2002-01-21
CZ302198B6 (en) 2010-12-15
ATE339954T1 (en) 2006-10-15
AU2441900A (en) 2000-08-29
NO20013460D0 (en) 2001-07-12
EP1158970A1 (en) 2001-12-05
SK11272001A3 (en) 2001-12-03
SK285884B6 (en) 2007-10-04
AU770632B2 (en) 2004-02-26
DE60030844T2 (en) 2007-02-08
IL143986A (en) 2007-03-08
NO20013460L (en) 2001-09-13

Similar Documents

Publication Publication Date Title
CA2360248C (en) Combinations of formoterol and a tiotropium salt
CA2362499C (en) Combinations of formoterol and mometasone furoate for asthma
EP1152753B1 (en) Combinations of formoterol and fluticasone propionate for asthma
MXPA01008001A (en) Combinations of formoterol and a tiotropium salt
MXPA01008879A (en) Combinations of formoterol and mometasone furoate for asthma
MXPA01008360A (en) Combinations of formoterol and fluticasone propionate for asthma

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 1200100643

Country of ref document: VN

Ref document number: 00803395.1

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2000902663

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 143986

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 24419/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2001/05648

Country of ref document: ZA

Ref document number: 200105648

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: IN/PCT/2001/1052/CHE

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 513304

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2001/02226

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 11272001

Country of ref document: SK

Ref document number: PV2001-2856

Country of ref document: CZ

ENP Entry into the national phase

Ref document number: 2360248

Country of ref document: CA

Ref document number: 2360248

Country of ref document: CA

Kind code of ref document: A

Ref document number: 2000 598152

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020017009941

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 09924246

Country of ref document: US

Ref document number: PA/a/2001/008001

Country of ref document: MX

WWP Wipo information: published in national office

Ref document number: 1020017009941

Country of ref document: KR

Ref document number: PV2001-2856

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 2000902663

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWG Wipo information: grant in national office

Ref document number: 24419/00

Country of ref document: AU

WWR Wipo information: refused in national office

Ref document number: 1020017009941

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 2000902663

Country of ref document: EP