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US20060083692A1 - Combination of formoterol and a tiotropium salt - Google Patents

Combination of formoterol and a tiotropium salt Download PDF

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Publication number
US20060083692A1
US20060083692A1 US11/288,548 US28854805A US2006083692A1 US 20060083692 A1 US20060083692 A1 US 20060083692A1 US 28854805 A US28854805 A US 28854805A US 2006083692 A1 US2006083692 A1 US 2006083692A1
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medicament according
formoterol
pharmaceutically acceptable
salt
dry powder
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US11/288,548
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Ian Hassan
Jeremy Clarke
Bernard Cuenoud
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, 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
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays 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-(1-hydroxy-2-((2-(4-methoxyphenyl)-1-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.
  • 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 U.S. Pat. No. 3,994,974 or U.S. Pat. No. 5,684,199, 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, (1 ⁇ ,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 U.S. Pat. No. 5,610,163.
  • 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 surfactant which may be chosen from those lubricants and surfactants known in the art.
  • 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 100 ⁇ 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. 25 to 50 ⁇ l, of the composition, i.e. a device known as a metered dose inhaler.
  • a metered dose such as 10 to 100 ⁇ l, e.g. 25 to 50 ⁇ l
  • 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.
  • 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.
  • MDPI multidose dry powder inhalation
  • Suitable such dry powder inhalation devices are well known.
  • a suitable device for delivery of dry powder in encapsulated form is that described in U.S. Pat. No. 3,991,761, 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.
  • 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 50 mg, for example 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, preferably 20 to 25 mg
  • 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 3 mg to 25 mg 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 inhalation 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. (For convenience this particular asthmatic condition is referred to as “whez-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.
  • inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALI), 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.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • COAD chronic obstructive pulmonary, airways or lung disease
  • COAD chronic obstructive pulmonary, airways or lung disease
  • 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.
  • 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 1-5 ⁇ m in an air-jet mill, 18 parts of tiotropium bromide which has been similarly ground to a mean particle diameter of 1-5 ⁇ m and 4970 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: Formoterol Fumarate Tiotropium Lactose Dihydrate Bromide Monohydrate Example (Parts) (Parts) 4 12 3 4985 5 12 9 4979 6 12 36 4952 7 12 80 4908 8 6 3 4991 9 6 9 4985 10 6 18 4976 11 6 36 4958 12 6 80 4914 13 18 3 4979 14 18 9 4973 15 18 18 4964 16 18 36 4946 17 18 80 4902 18 24 3 4973 19 24 9 4967 20 24 18 4958 21 24 36 4940 22 24 80 4896 23 30 3 4967 24 30 9 4961 25 30 18 4952 26 30 36 4934 27 30 80 4890 28 36 3 4961 29 36 9 4955 30 36 18 4946 31 36 36 4928 32 36 80 4884 33 6 3 9991 34 6 9 9985 35 6 18 9976 36 6 36 9958 37 6 80 9914 38 12 3 9985 39 12 9 9979 40 12 18 9970 41 12 36 9952 42 12 80
  • Gelatin capsules suitable for use in a capsule inhaler such as that described in U.S. Pat. No. 3,991,761 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: Formoterol Fumarate Tiotropium Lactose Dihydrate Bromide Monohydrate Example (Parts) (Parts) (Parts) 94 12 3 24985 95 12 9 24979 96 12 36 24952 97 12 80 24908 98 6 3 24991 99 6 9 24985 100 6 18 24976 101 6 36 24958 102 6 80 24914 103 18 3 24979 104 18 9 24973 105 18 18 24964 106 18 36 24946 107 18 80 24902 108 24 3 24973 109 24 9 24967 110 24 18 24958 111 24 36 24940 112 24 80 24896 113 30 3 24967 114 30 9 24961 115 30 18 24952 116 30 36 24934 117 30 80 24890 118 36 3 24961 119 36 9 24955 120 36 18 24946 121 36 36 24928
  • 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: Formoterol Fumarate Tiotropium Lactose Dihydrate Bromide Monohydrate Example (Parts) (Parts) (Parts) 153 6 3 2991 154 6 9 2985 155 6 18 2976 156 6 25 2969 157 6 36 2958 158 6 80 2914 159 12 3 2985 160 12 9 2979 161 12 18 2970 162 12 25 2963 163 12 36 2952 164 12 45 2943 165 12 60 2928 166 12 72 2916 167 12 80 2908 168 24 3 2973 169 24 9 2967 170 24 18 2958 171 24 25 2951 172 24 36 2940 173 24 45 2931 174 24 60 2916 175 24 72 2904 176 24 80 2896 177 6 25 4969 178 6 45 4949 179 6 60 4934 180 6 72 4922 181 12 25 4963 182 12 45 4943 183 12 60 4928 184 12 72 4916 185
  • 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: Formoterol Fumarate Tiotropium Lactose Dihydrate Bromide Monohydrate Example ( ⁇ g) ( ⁇ g) ( ⁇ g) 217 6 3 14991 218 6 9 14985 219 6 18 14976 220 6 25 14969 221 6 36 14958 222 6 45 14949 223 6 60 14934 224 6 72 14922 225 6 80 14914 226 12 3 14985 227 12 9 14979 228 12 18 14970 229 12 25 14963 230 12 36 14952 231 12 45 14943 232 12 60 14928 233 12 72 14916 234 12 80 14908 235 12 160 14828 236 24 3 14973 237 24 9 14967 238 24 18 14958 239 24 25 14951 240 24 36 14940 241 24 45 14931 242 24 80 14896 243 6 3 9991 244 6

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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

  • 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-(1-hydroxy-2-((2-(4-methoxyphenyl)-1-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, (1α,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 U.S. Pat. No. 5,610,163. 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 U.S. Pat. No. 3,994,974 or U.S. Pat. No. 5,684,199, 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, (1α,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 U.S. Pat. No. 5,610,163.
  • 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. Where 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 300 μm, preferably up to 212 μm and conveniently has a mean particle diameter of 40 to 100 μm, 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 U.S. Pat. No. 3,991,761, 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 80 μg, from 1 to 70 μg, 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 6 μg to 12 μg of (A) and 3 μg to 36 μg 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 50 mg, for example 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, 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 3 mg to 25 mg 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 inhalation 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 (ALI), 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 1-5 μm in an air-jet mill, 18 parts of tiotropium bromide which has been similarly ground to a mean particle diameter of 1-5 μm and 4970 of lactose monohydrate having a particle diameter below 212 μm.
    • 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:
    Formoterol
    Fumarate Tiotropium Lactose
    Dihydrate Bromide Monohydrate
    Example (Parts) (Parts) (Parts)
    4 12 3 4985
    5 12 9 4979
    6 12 36 4952
    7 12 80 4908
    8 6 3 4991
    9 6 9 4985
    10 6 18 4976
    11 6 36 4958
    12 6 80 4914
    13 18 3 4979
    14 18 9 4973
    15 18 18 4964
    16 18 36 4946
    17 18 80 4902
    18 24 3 4973
    19 24 9 4967
    20 24 18 4958
    21 24 36 4940
    22 24 80 4896
    23 30 3 4967
    24 30 9 4961
    25 30 18 4952
    26 30 36 4934
    27 30 80 4890
    28 36 3 4961
    29 36 9 4955
    30 36 18 4946
    31 36 36 4928
    32 36 80 4884
    33 6 3 9991
    34 6 9 9985
    35 6 18 9976
    36 6 36 9958
    37 6 80 9914
    38 12 3 9985
    39 12 9 9979
    40 12 18 9970
    41 12 36 9952
    42 12 80 9908
    43 18 3 9979
    44 18 9 9973
    45 18 18 9964
    46 18 36 9946
    47 18 80 9902
    48 24 3 9973
    49 24 9 9967
    50 24 18 9958
    51 24 36 9940
    52 24 80 9896
    53 30 3 9967
    54 30 9 9961
    55 30 18 9952
    56 30 36 9934
    57 30 80 9890
    58 36 3 9961
    59 36 9 9955
    60 36 18 9946
    61 36 36 9928
    62 36 80 9884
    63 6 3 14991
    64 6 9 14985
    65 6 18 14976
    66 6 36 14958
    67 6 80 14914
    68 12 3 14985
    69 12 9 14979
    70 12 18 14970
    71 12 36 14952
    72 12 80 14908
    73 18 3 14979
    74 18 9 14973
    75 18 18 14964
    76 18 36 14946
    77 18 80 14902
    78 24 3 14973
    79 24 9 14967
    80 24 18 14958
    81 24 36 14940
    82 24 80 14896
    83 30 3 14967
    84 30 9 14961
    85 30 18 14952
    86 30 36 14934
    87 30 80 14890
    88 36 3 14961
    89 36 9 14955
    90 36 18 14946
    91 36 36 14928
    92 36 80 14884
    • EXAMPLE 93
  • Gelatin capsules suitable for use in a capsule inhaler such as that described in U.S. Pat. No. 3,991,761 are prepared, each capsule containing a dry powder obtained by mixing 12 μg of formoterol fumarate dihydrate which has been ground to a mean particle diameter of 1 to 5 μm in an air jet mill, 18 μg of tiotropium bromide which has been similarly ground to a mean particle diameter of 1 to 5 μm and 24970 μg of lactose monohydrate having a particle diameter below 212 μm.
    • 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:
    Formoterol
    Fumarate Tiotropium Lactose
    Dihydrate Bromide Monohydrate
    Example (Parts) (Parts) (Parts)
    94 12 3 24985
    95 12 9 24979
    96 12 36 24952
    97 12 80 24908
    98 6 3 24991
    99 6 9 24985
    100 6 18 24976
    101 6 36 24958
    102 6 80 24914
    103 18 3 24979
    104 18 9 24973
    105 18 18 24964
    106 18 36 24946
    107 18 80 24902
    108 24 3 24973
    109 24 9 24967
    110 24 18 24958
    111 24 36 24940
    112 24 80 24896
    113 30 3 24967
    114 30 9 24961
    115 30 18 24952
    116 30 36 24934
    117 30 80 24890
    118 36 3 24961
    119 36 9 24955
    120 36 18 24946
    121 36 36 24928
    122 36 80 24884
    123 6 3 19991
    124 6 9 19985
    125 6 18 19976
    126 6 36 19958
    127 6 80 19914
    128 12 3 19985
    129 12 9 19979
    130 12 18 19970
    131 12 36 19952
    132 12 80 19908
    133 18 3 19979
    134 18 9 19973
    135 18 18 19964
    136 18 36 19946
    137 18 80 19902
    138 24 3 19973
    139 24 9 19967
    140 24 18 19958
    141 24 36 19940
    142 24 80 19896
    143 30 3 19967
    144 30 9 19961
    145 30 18 19952
    146 30 36 19934
    147 30 80 19890
    148 36 3 19961
    149 36 9 19955
    150 36 18 19946
    151 36 36 19928
    152 36 80 19884
    • 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:
    Formoterol
    Fumarate Tiotropium Lactose
    Dihydrate Bromide Monohydrate
    Example (Parts) (Parts) (Parts)
    153 6 3 2991
    154 6 9 2985
    155 6 18 2976
    156 6 25 2969
    157 6 36 2958
    158 6 80 2914
    159 12 3 2985
    160 12 9 2979
    161 12 18 2970
    162 12 25 2963
    163 12 36 2952
    164 12 45 2943
    165 12 60 2928
    166 12 72 2916
    167 12 80 2908
    168 24 3 2973
    169 24 9 2967
    170 24 18 2958
    171 24 25 2951
    172 24 36 2940
    173 24 45 2931
    174 24 60 2916
    175 24 72 2904
    176 24 80 2896
    177 6 25 4969
    178 6 45 4949
    179 6 60 4934
    180 6 72 4922
    181 12 25 4963
    182 12 45 4943
    183 12 60 4928
    184 12 72 4916
    185 24 25 4951
    186 24 45 4931
    187 24 60 4916
    188 24 72 4904
    189 6 25 9969
    190 6 45 9949
    191 6 60 9934
    192 6 72 9922
    193 12 25 9963
    194 12 45 9943
    195 12 60 9928
    196 12 72 9916
    197 24 25 9951
    198 24 45 9931
    199 24 60 9916
    200 24 72 9904
    201 6 25 14969
    202 6 45 14949
    203 6 60 14934
    204 6 72 14922
    205 12 25 14963
    206 12 45 14943
    207 12 60 14928
    208 12 72 14916
    209 24 25 14951
    210 24 45 14931
    211 24 60 14916
    212 24 72 14904
    213 24 90 14886
    214 24 108 14868
    215 24 135 14841
    216 24 160 14816
    • 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:
    Formoterol
    Fumarate Tiotropium Lactose
    Dihydrate Bromide Monohydrate
    Example (μg) (μg) (μg)
    217 6 3 14991
    218 6 9 14985
    219 6 18 14976
    220 6 25 14969
    221 6 36 14958
    222 6 45 14949
    223 6 60 14934
    224 6 72 14922
    225 6 80 14914
    226 12 3 14985
    227 12 9 14979
    228 12 18 14970
    229 12 25 14963
    230 12 36 14952
    231 12 45 14943
    232 12 60 14928
    233 12 72 14916
    234 12 80 14908
    235 12 160 14828
    236 24 3 14973
    237 24 9 14967
    238 24 18 14958
    239 24 25 14951
    240 24 36 14940
    241 24 45 14931
    242 24 80 14896
    243 6 3 9991
    244 6 9 9985
    245 6 18 9976
    246 6 25 9969
    247 6 36 9958
    248 6 45 9949
    249 6 80 9914
    250 12 3 9985
    251 12 9 9979
    252 12 18 9970
    253 12 25 9963
    254 12 36 9952
    255 12 45 9943
    256 12 80 9908

Claims (20)

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 of (A) and (B) in the treatment of an inflammatory or obstructive airways disease.
2. A medicament according to claim 1 which is a pharmaceutical 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, in which (A) is formoterol fumarate dihydrate and (B) is tiotropium bromide.
4. A medicament according to claim 2, in which (A) is formoterol fumarate dihydrate and (B) is tiotropium bromide.
5. A medicament according to claim 1, which is in inhalable form.
6. A medicament according to claim 2, which is in inhalable form.
7. A medicament according to claim 1 which is in inhalable form, said form being 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.
8. A medicament according to claim 7, in which the aerosol comprises 0.002 to 5% by weight of active ingredient, based on the weight of the propellant.
9. A medicament according to claim 1 which is inhalable form, said form being 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 1 which is in inhalable form, said form being 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 claim 10, in which (A) and/or (B) has an average particle diameter up to 10 μm.
14. A medicament according to claim 2, 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 5 mg 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. 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) 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.
20. A pharmaceutical kit comprising (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 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).
US11/288,548 1999-02-08 2005-11-29 Combination of formoterol and a tiotropium salt Abandoned US20060083692A1 (en)

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US10/365,310 US20030125350A1 (en) 1999-02-08 2003-02-12 Combination of formoterol and a tiotropium salt
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