Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/16—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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • 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]
• • 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
  • A61P11/06—Antiasthmatics
• • 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
  • A61P11/08—Bronchodilators
• • 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
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Definitions

• This invention relates to combinations of a beta-2 agonist and a steroid 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.
• Mometasone furoate (11 ⁇ , 16 ⁇ )-9,21-dichloro-17-[(2-furanylcarbonyl)oxy]-l 1-hydroxy-16-methylpregna-1,4-diene-3,20-dione, alternatively designated 9 ⁇ ,21-dichloro-16 ⁇ -methyl-1,4-pregnadiene-11 ⁇ ,17 ⁇ -diol-3,20-dione 17-(2′-furoate), is a topical anti-inflammatory corticosteroid which is described in U.S. Pat. No. 4,472,393.
• 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, in free form or in the form of a salt or solvate thereof, and mometasone furoate.
• formoterol in free form or in the form of a salt or solvate thereof
• mometasone furoate it is possible using this combination therapy to reduce the dosages of mometasone furoate or formoterol required for a given therapeutic effect considerably compared with those required using treatment with mometasone furoate or formoterol alone, thereby minimising possibly undesirable side effects.
• compositions containing formoterol and mometasone furoate induce an anti-inflammatory activity which is significantly greater than that induced by formoterol or mometasone furoate alone and that the amount of mometasone furoate needed for a given anti-inflammatory effect may be significantly reduced when used in admixture with formoterol, thereby reducing the risk of undesirable side effects from the repeated exposure to the steroid involved in the treatment of inflammatory or obstructive airways diseases.
• medicaments which have a rapid onset of action and a long duration of action may be prepared.
• medicaments which result in a significant improvement in lung function may be prepared.
• medicaments which provide improved control of obstructive or inflammatory airways diseases, or a reduction in exacerbations of such diseases may be prepared.
• compositions of the invention medicaments which can be used on demand in rescue treatment of obstructive or inflammatory airways diseases, or which reduce or eliminate the need for treatment with short-acting rescue medicaments such as salbutamol or terbutaline, may be prepared; thus medicaments based on compositions of the invention facilitate the treatment of an obstructive or inflammatory airways disease 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 a solvate of said salt and (B) mometasone furoate, 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 provides a pharmaceutical composition for use in the treatment of an inflammatory or obstructive airways disease comprising (A) and (B) as hereinbefore defined.
• 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.
• 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 aqueouslorganic 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 one or more materials known as pharmaceutically acceptable carriers, preferably 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 one or more materials known as pharmaceutically acceptable carriers, preferably chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabi
• 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 (A) and/or (B) together with the carrier in amounts to bring the total weight of powder per capsule to from 5 mg to 50 mg.
• 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 ⁇ am, for example 0.1 to 5 ⁇ m, preferably 1 to 5 ⁇ m.
• the solid 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, e.g. 50 to 75 ⁇ m.
• the particle size of the active ingredient, and that of a solid 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 a dry powder comprising a dosage unit of (A) and/or (B) or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 3-25 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 a dry powder comprising a dosage unit of (A) and/or (B) or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 3-25 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 mometasone furoate may be, in general, from 2:1 to 1:2000, for example from 1:1 to 1:1000, from 1:2 to 1:100, or from 1:5 to 1:50. More usually, this ratio is from 1:10 to 1:25, for example from 1:15 to 1:25.
• the two drugs may be administered separately in the same ratio. Specific examples of this ratio, to the nearest whole number, include 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24 and 1:25.
• the above weight ratios apply particularly where (A) is formoterol fumarate dihydrate.
• the corresponding molar ratios of (A) to (B) may be, in general, from 1.24:1 to 1:3227, for example from 0.62:1 to 1:1613, from 1:3.2 to 1:161, or from 1:8.1 to 1:80.7; more usually from 1:16.1 to 1:40.3, for example from 1:24.2 to 1:40.3; specific examples of the molar ratio being 1:16.1, 1:17.8, 1:19.4, 1:21, 1:22.6, 1:24.2, 1:25.8, 1:27.4, 1:29, 1:30.7, 1:32.3, 1:33.9, 1:35.5, 1:37.1, 1:38.7 and 1:40.3.
• 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 mometasone furoate for inhalation may be from 50 to 2000 ⁇ g, for example from 100 to 2000 ⁇ g, from 100 to 1600 ⁇ g, from 100 to 1000 ⁇ g, or from 100 to 800 ⁇ g, preferably from 200 to 500 ⁇ g, for instance from 200 to 400 ⁇ g.
• the precise dose used will of course depend on the condition to be treated, the patient and the efficiency of the inhalation device.
• 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 pg.
• a suitable unit dose of mometasone furoate (B) may be from 25 ⁇ g to 2000 ⁇ g. for example from 50 ⁇ g to 1000 ⁇ g, preferably from 500 ⁇ g to 800 ⁇ g, more preferably from 100 ⁇ g to 500 ⁇ g, especially from 100 to 400 ⁇ g. e.g.
• unit doses may suitably be administered once or twice daily in accordance with the suitable daily dose mentioned hereinbefore.
• a dosage unit containing 6 ⁇ g or 12 ⁇ g of (A) and 50 ⁇ g or 100 ⁇ g of mometasone furoate (B) is preferred.
• the medicament of the invention is a pharmaceutical composition which is a dry powder in a capsule containing a unit dose of (A) and (B), for example for inhalation from a single capsule inhaler, the capsule suitably containing, where (A) is formoterol fumarate dihydrate, 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 25 ⁇ g to 800 ⁇ g, e.g.
• 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 fiunarate dihydrate, a powder comprising, by weight, 3 to 36 parts, preferably 6 to 24 parts, especially 12 to 24 parts of (A); 25 to 800 parts, e.g. 25 to 500 parts, preferably 50 to 400 parts, especially 100 to 400 parts of (B); and 2164 to 24972 parts, preferably 4164 to 14972 parts, especially 4164 to 9972 parts of a pharmaceutically acceptable carrier as hereinbefore described.
• (A) is formoterol fiunarate dihydrate, a powder comprising, by weight, 3 to 36 parts, preferably 6 to 24 parts, especially 12 to 24 parts of (A); 25 to 800 parts, e.g. 25 to 500 parts, preferably 50 to 400 parts, especially
• 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. (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), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COID), 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 adult respiratory distress syndrome
• COAD chronic obstructive pulmonary, airways or lung disease
• COAD chronic obstructive pulmonary, airways or lung disease
• 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.
• 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, 250 parts of mometasone furoate which has been similarly ground to a mean particle diameter of 1-5 ⁇ m and 4738 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: Formoterol Fumarate Mometasone Lactose Monohydrate Example Dihydrate (Parts) Furoate (Parts) (Parts) 4 12 50 4938 5 12 100 4888 6 12 150 4838 7 12 200 4788 8 6 50 4944 9 6 100 4894 10 6 150 4844 11 6 200 4794 12 6 250 4744 13 18 50 4932 14 18 100 4882 15 18 150 4832 16 18 200 4782 17 18 250 4732 18 24 50 4926 19 24 100 4876 20 24 150 4826 21 24 200 4776 22 24 250 4726 23 30 50 4920 24 30 100 4870 25 30 150 4820 26 30 200 4770 27 30 250 4720 28 36 50 4914 29 36 100 4864 30 36 150 4814 31 36 200 4764 32 36 250 4714 33 6 50 9944 34 6 100 9894 35 6 150 9844 36 6 200 9794 37 6 250 9744 38 12 50 9938 39 12 100 9888 40 12 150
• Gelatin capsules suitable for use in a capsules 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, 250 ⁇ g of mometasone furoate which has been similarly ground to a mean particle diameter of 1 to 5 ⁇ m and 24738 ⁇ 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 Mometasone Lactose Monohydrate Example Dihydrate (Parts) Furoate (Parts) (Parts) 94 12 50 24938 95 12 100 24888 96 12 150 24838 97 12 200 24788 98 6 50 24944 99 6 100 24894 100 6 150 24844 101 6 200 24794 102 6 250 24744 103 18 50 24932 104 18 100 24882 105 18 150 24832 106 18 200 24782 107 18 250 24732 108 24 50 24926 109 24 100 24876 110 24 150 24826 111 24 200 24776 112 24 250 24726 113 30 50 24920 114 30 100 24870 115 30 150 24820 116 30 200 24770 117 30 250 24720 118 36 50 24914 119 36 100 24864 120 36 150 24814 121 36 200 24
• 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 Mometasone Lactose Monohydrate Example Dihydrate (Parts) Furoate (Parts) (Parts) 153 6 25 2969 154 6 50 2944 155 6 100 2894 156 6 150 2844 157 6 200 2794 158 6 250 2744 159 12 25 2963 160 12 50 2938 161 12 100 2888 162 12 150 2838 163 12 200 2788 164 12 250 2738 165 12 300 2638 166 12 350 2588 167 12 400 2538 168 24 25 2951 169 24 50 2926 170 24 100 2876 171 24 150 2826 172 24 200 2776 173 24 250 2726 174 24 300 2676 175 24 350 2626 176 24 400 2576
• 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 Mometasone Lactose Monohydrate Example Dihydrate (Parts) Furoate (Parts) (Parts) 177 6 25 14969 178 6 50 14944 179 6 100 14894 180 6 150 14844 181 6 200 14794 182 6 250 14744 183 6 300 14694 184 6 350 14644 185 6 400 14594 186 12 25 14963 187 12 50 14938 188 12 100 14888 189 12 150 14838 190 12 200 14788 191 12 250 14738 192 12 300 14688 193 12 350 14638 194 12 400 14588 195 12 500 14488 196 24 25 14951 197 24 50 14926 198 24 100 14876 199 24 150 14826 200 24 200 13876 201 24 250 13826 202 24 300 13776 203 6 25 9969 204

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• 1999
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• 2000
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• 2001
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• 2002
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• 2003
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• 2004
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• 2005
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• 2009
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• 2013
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