+

US20070196286A1 - Aerosol composition comprising formoterol - Google Patents

Aerosol composition comprising formoterol Download PDF

Info

Publication number
US20070196286A1
US20070196286A1 US11/725,903 US72590307A US2007196286A1 US 20070196286 A1 US20070196286 A1 US 20070196286A1 US 72590307 A US72590307 A US 72590307A US 2007196286 A1 US2007196286 A1 US 2007196286A1
Authority
US
United States
Prior art keywords
formoterol
dry powder
carrier
diluent
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/725,903
Inventor
Barbara Haeberlin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10865451&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20070196286(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US11/725,903 priority Critical patent/US20070196286A1/en
Publication of US20070196286A1 publication Critical patent/US20070196286A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • This invention relates to the use of organic compounds in the treatment of chronic obstructive pulmonary disease (COPD), both reversible and irreversible COPD, reversibility being defined by reference to the effect of inhalation of a standard dose of a short-acting beta-2 agonist bronchodilator such as salbutamol on the forced expiratory volume in 1 second (FEV 1 ) measured by spirometry.
  • COPD chronic obstructive pulmonary disease
  • ATS Am J Respir Crit Care Med Vol 152, pp S77-120, 1995
  • ERS Consensus Statement of the European Respiratory society
  • formoterol or a pharmaceutically acceptable salt or solvate thereof or solvate of said salt is particularly effective in the treatment of COPD when administered by inhalation as a dry powder in admixture with a diluent or carrier in an amount of from 400 ⁇ g to 5,000 ⁇ g per ⁇ g of formoterol active ingredient.
  • Administration of such a mixture by inhalation to COPD patients facilitates significant sustained bronchodilation, a very good safety profile, important e.g. for the treatment of COPD without significant concomitant cardiovascular effects, and significant improvement in Quality of Life as assessed by the St George's Respiratory Questionnaire (SGRQ).
  • SGRQ St George's Respiratory Questionnaire
  • the present invention provides, in one aspect, the use of a dry powder comprising (A) formoterol, or a pharmaceutically acceptable salt or solvate thereof, or solvate of said salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of from 400 ⁇ g to 5,000 ⁇ g per ⁇ g of (A) in the preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease.
  • the present invention provides a pharmaceutical composition in the form of a dry powder comprising (A) and (B) as hereinbefore defined for use in the treatment of chronic obstructive pulmonary disease.
  • the present invention provides a method of treating chronic obstructive pulmonary disease which comprises administering by inhalation to a subject in need of such treatment an effective amount of a dry powder comprising (A) formoterol, said formoterol being in free form or in the form of a pharmaceutically acceptable salt or solvate thereof or in the form of a solvate of such a salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of from 400 ⁇ g to 5,000 ⁇ g per ⁇ g of (A).
  • the present invention provides the use of a dry powder comprising (A) formoterol, or a pharmaceutically acceptable salt or solvate thereof, or solvate of said salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of from 400 ⁇ g to 5,000 ⁇ g per ⁇ g of (A), said dry powder being substantially free from fluticasone proprionate, mometasone furoate or tiotropium salts, for the preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease.
  • the formoterol active ingredient (A) may be in any isomeric form or mixture of isomeric forms, for example a pure enantiomer, particularly the R,R-enantiomer, a mixture of enantiomers, a racemate or a mixture thereof.
  • compositions of formoterol include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or organic acids such as acetic, succinic, glutaric, maleic, fumaric, citric, tartaric, lactic, benzoic, salicylic, p-hydroxybenzoic, p-methoxybenzoic, hydroxynapthoic, methanesulfonic, benzesulfonic, or p-toluenesulfonic acid.
  • Suitable solvates of formoterol and pharmaceutically acceptable salts thereof include hydrates.
  • a preferred form of formoterol for use in accordance with the invention is formoterol fumarate, especially formoterol fumarate dihydrate, conveniently in racemic form.
  • Formoterol, salts and hydrates thereof and salt hydrates thereof as hereinbefore described may be prepared by known methods, for example as described in U.S. Pat. No. 3,994,974 or U.S. Pat. No. 5,684,199.
  • the present invention provides the use of a dry powder consisting, or consisting essentially, of (A) formoterol fumarate dihydrate and (B) a pharmaceutically acceptable diluent or carrier in an amount of from 400 ⁇ g to 5,000 ⁇ g per ⁇ g of (A) for the preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease.
  • Suitable diluents or carriers include saccharides and/or sugar alcohols, e.g. monosaccharides, disaccharides and polysaccharides such as glucose, arabinose, dextrose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose or dextran, sugar alcohols such as mannitol and mixtures of two or more thereof.
  • a preferred diluent or carrier is lactose, particularly in the form of the monohydrate.
  • the diluent or carrier is generally present in an amount of 400 to 4000 ⁇ g, for example 800 to 3000 ⁇ g, more preferably 1000 to 2500 ⁇ g, especially 2000 to 2500 ⁇ g, per ⁇ g of formoterol active ingredient (A).
  • the mean particle diameter of the formoterol active ingredient (A) is preferably up to 10 ⁇ m, more preferably up to 5 ⁇ m especially 1 to 5 ⁇ m.
  • the diluent or carrier (B) may be present in the dry powder in the form of particles, having, for example, a maximum diameter of 300 ⁇ m, a preferred maximum being 212 ⁇ m.
  • the diluent or carrier (B) may conveniently have a median particle diameter of 40 to 100 ⁇ m, e.g.
  • the particle size of the formoterol active ingredient (A), and that of the diluent or carrier (B), can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, by sieving, by microprecipitation, by spray-drying, by lyophilisation or by recrystallisation from supercritical media.
  • the dry powder is in a capsule, usually of a pharmaceutically acceptable natural or synthetic polymer such as gelatin or hydroxypropyl methylcellulose, the capsule containing a unit dose of formoterol active ingredient (A).
  • Doses of formoterol active ingredient (A) to be inhaled in accordance with the invention may be, in general, from 1 ⁇ g to 60 ⁇ g.
  • the dose may be, for example, from 6 ⁇ g to 48 ⁇ g.
  • Preferred doses are from 6 ⁇ g to 36 ⁇ g, for example 6 ⁇ g, 12 ⁇ g, 18 ⁇ g, 24 ⁇ g, 30 ⁇ g, or 36 ⁇ g, the 12 ⁇ g and 24 ⁇ g being especially preferred and the 12 ⁇ g dose the most preferred.
  • These doses may be administered once or twice daily, preferably twice daily, the preferred maximum daily dose being 48 ⁇ g.
  • the 6 ⁇ g or 12 ⁇ g dose is preferred, being inhaled as needed in accordance with a preferred maximum daily dose of 48 ⁇ g.
  • a unit dose of (A) e.g.
  • the amount of diluent/carrier is preferably such as to bring the total weight of dry powder per capsule to between 5 mg and 25 mg, e.g. to 5 mg, 10 mg, 15 mg, 20 mg or, especially, 25 mg.
  • the dry powder is in a capsule, the capsule containing 12 ⁇ g of formoterol active ingredient (A) and 4988 ⁇ g to 49988 ⁇ g, for example 4988 ⁇ g or 9988 ⁇ g or 14988 ⁇ g, more preferably 19988 ⁇ g to 24988 ⁇ g, for example 19988 ⁇ g or, especially, 24988 ⁇ g of diluent or carrier (B).
  • a dry powder contained in a capsule may be inhaled by inserting the capsule in a dry powder inhalation device adapted to pierce a capsule containing the dry powder on actuating the device, thereby releasing the dry powder for inhalation by the user—a dry powder capsule inhaler.
  • a dry powder inhalation device adapted to pierce a capsule containing the dry powder on actuating the device, thereby releasing the dry powder for inhalation by the user—a dry powder capsule inhaler.
  • Such devices are well known in the art and are commercially available.
  • a suitable inhalation device is described in U.S. Pat. No. 3,991,761, which is incorporated herein by reference, particularly as described in the claims of U.S. Pat. No. 3,991,761 and as described with reference to the drawings of U.S. Pat. No.
  • a preferred inhalation device is one adapted to receive a single capsule containing the dry powder, i.e. a single capsule inhaler, for example the commercially available Aerolizer® inhaler.
  • the dry powder may be in a reservoir of a multi-dose dry powder inhaler adapted to deliver a unit dose, for example 5 ⁇ g, 6 ⁇ g, 9 ⁇ g, 10 ⁇ g, 12 ⁇ g, 15 ⁇ g, 18 ⁇ g, 20 ⁇ g, 24 ⁇ g, 25 ⁇ g, 30 ⁇ g or 36 ⁇ g, preferably from 5 to 15 ⁇ g of formoterol active ingredient (A), particularly formoterol fumarate dihydrate, per actuation, for example from a powder having a formoterol fumarate dihydrate:lactose weight ratio of 5:4995, 5:9995, 5:14995, 10:4990, 10:9990, 10:14990, 12:4988, 12:9988 12:14998, 15:9985 or 15:14985.
  • Multi-dose dry powder inhalers are well known in the art and are commercially available. For example, a suitable multi-dose inhaler is that described in WO97/20589
  • Treatment of COPD in accordance with the invention includes treatment of reversible or irreversible, mild, moderate or severe COPD (including chronic bronchitis and emphysema) and conditions associated therewith, e.g. bronchospasm, loss of lung function, loss of exercise capacity, breathlessness, dyspnea or loss of lung elasticity.
  • treatment of COPD in accordance with the invention includes maintenance (prophylactic) treatment or on-demand or rescue treatment of bronchospasm associated with COPD, treatment to slow progressive loss of lung function, treatment to improve exercise capacity, and treatment to improve Quality to Life according to the SGRQ.
  • compositions of the invention in the treatment of COPD can be monitored in a conventional manner, e.g. by determining parameters such as forced expiratory volume in 1 second (FEV 1 ), vital capacity (VC), forced vital capacity (FVC), Quality of Life, peak expiratory flow (PEF), exercise capacity (e.g. Shuttle Walking Test) and lung compliance (CL) at intervals during treatment.
  • FEV 1 forced expiratory volume in 1 second
  • VC vital capacity
  • FVC forced vital capacity
  • FVC forced vital capacity
  • FVC forced vital capacity
  • Quality of Life Quality of Life
  • PEF peak expiratory flow
  • exercise capacity e.g. Shuttle Walking Test
  • lung compliance lung compliance
  • Quality of Life may be measured according to the SGRQ (P. W. Jones et al, Respir Med. 1991; 85 (Suppl B): 25-31).
  • Gelatin capsules suitable for use in a capsule inhaler are prepared, each capsule containing a dry powder consisting of 6 ⁇ g of formoterol fumarate dihydrate which has been ground to a mean particle diameter of 1-5 ⁇ m in an air jet mill and 4994 ⁇ g of lactose monohydrate having a particle diameter of below 212 ⁇ m.
  • These capsules are used in the treatment of COPD patients by inserting a capsule into the capsule chamber of the inhaler described in U.S. Pat. No. 3,991,761 and actuating the piercing devices to perforate the capsule and release the dry powder when air is inhaled through the capsule chamber by a patient.
  • Example 1 is repeated but using the amounts of the formoterol fumarate dihydrate and the lactose monohydrate shown in the table below in place of the amounts used in that Example: Formoterol Fumarate Example Dihydrate ( ⁇ g) Lactose Monohydrate ( ⁇ g) 2 6 9994 3 6 14994 4 6 19994 5 6 24994 6 12 4988 7 12 9988 8 12 14988 9 12 19988 10 12 24988 11 12 29988 12 18 9982 13 18 14982 14 18 19982 15 18 24982 16 18 29982 17 24 9976 18 24 14976 19 24 19976 20 24 24976 21 24 29976 22 30 14970 23 30 19970 24 30 24970 25 30 29970 26 36 14964 27 36 19964 28 36 24964 29 36 29964
  • Two groups of patients suffering from COPD are treated with formoterol.
  • One group has reversible COPD, showing at least 15% increase in FEV 1 30 minutes after inhaling 200 ⁇ g of salbutamol.
  • the other group has irreversible COPD, showing less than 15% increase in FEV 1 30 minutes after inhaling 200 ⁇ g of salbutamol.
  • Both groups are treated by inhalation twice daily for 12 weeks from a capsule containing a dry powder consisting of 12 ⁇ g of formoterol fumarate dihydrate having a mean particle diameter of 1 to 5 ⁇ m and 24988 ⁇ g of lactose monohydrate having a particle diameter below 212 ⁇ m, using an Aerolizer® inhaler.
  • the patients' lung function (FEV 1 ) is measured at intervals for 12 hours after dosing, the measured FEV 1 is plotted against time after dosing and the area under the curve (AUC) of the resulting plot is determined.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Otolaryngology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The use of a dry powder comprising (A) formoterol, or a pharmaceutically. acceptable salt or solvate thereof, or solvate of said salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of from 400 μg to 5000 μg per μg of (A) for the preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease.

Description

  • This invention relates to the use of organic compounds in the treatment of chronic obstructive pulmonary disease (COPD), both reversible and irreversible COPD, reversibility being defined by reference to the effect of inhalation of a standard dose of a short-acting beta-2 agonist bronchodilator such as salbutamol on the forced expiratory volume in 1 second (FEV1) measured by spirometry. The characteristics of different stages of COPD are described in the Official Statement of the American Thoracic Society (ATS): Am J Respir Crit Care Med Vol 152, pp S77-120, 1995, and a Consensus Statement of the European Respiratory society (ERS): European Respiratory Journal 1995, 8, 1398-1420.
  • It has now surprisingly been found, in accordance with the invention, that formoterol or a pharmaceutically acceptable salt or solvate thereof or solvate of said salt, each hereinafter alternatively referred to as the formoterol active ingredient, is particularly effective in the treatment of COPD when administered by inhalation as a dry powder in admixture with a diluent or carrier in an amount of from 400 μg to 5,000 μg per μg of formoterol active ingredient. Administration of such a mixture by inhalation to COPD patients facilitates significant sustained bronchodilation, a very good safety profile, important e.g. for the treatment of COPD without significant concomitant cardiovascular effects, and significant improvement in Quality of Life as assessed by the St George's Respiratory Questionnaire (SGRQ).
  • Accordingly, the present invention provides, in one aspect, the use of a dry powder comprising (A) formoterol, or a pharmaceutically acceptable salt or solvate thereof, or solvate of said salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of from 400 μg to 5,000 μg per μg of (A) in the preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease.
  • In a related aspect, the present invention provides a pharmaceutical composition in the form of a dry powder comprising (A) and (B) as hereinbefore defined for use in the treatment of chronic obstructive pulmonary disease.
  • In another aspect, the present invention provides a method of treating chronic obstructive pulmonary disease which comprises administering by inhalation to a subject in need of such treatment an effective amount of a dry powder comprising (A) formoterol, said formoterol being in free form or in the form of a pharmaceutically acceptable salt or solvate thereof or in the form of a solvate of such a salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of from 400 μg to 5,000 μg per μg of (A).
  • In a further aspect, the present invention provides the use of a dry powder comprising (A) formoterol, or a pharmaceutically acceptable salt or solvate thereof, or solvate of said salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of from 400 μg to 5,000 μg per μg of (A), said dry powder being substantially free from fluticasone proprionate, mometasone furoate or tiotropium salts, for the preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease.
  • The formoterol active ingredient (A) may be in any isomeric form or mixture of isomeric forms, for example a pure enantiomer, particularly the R,R-enantiomer, a mixture of enantiomers, a racemate or a mixture thereof. Pharmaceutically acceptable salts of formoterol include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or organic acids such as acetic, succinic, glutaric, maleic, fumaric, citric, tartaric, lactic, benzoic, salicylic, p-hydroxybenzoic, p-methoxybenzoic, hydroxynapthoic, methanesulfonic, benzesulfonic, or p-toluenesulfonic acid. Suitable solvates of formoterol and pharmaceutically acceptable salts thereof include hydrates. A preferred form of formoterol for use in accordance with the invention is formoterol fumarate, especially formoterol fumarate dihydrate, conveniently in racemic form. Formoterol, salts and hydrates thereof and salt hydrates thereof as hereinbefore described may be prepared by known methods, for example as described in U.S. Pat. No. 3,994,974 or U.S. Pat. No. 5,684,199.
  • Accordingly, in a preferred embodiment, the present invention provides the use of a dry powder consisting, or consisting essentially, of (A) formoterol fumarate dihydrate and (B) a pharmaceutically acceptable diluent or carrier in an amount of from 400 μg to 5,000 μg per μg of (A) for the preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease.
  • Suitable diluents or carriers include saccharides and/or sugar alcohols, e.g. monosaccharides, disaccharides and polysaccharides such as glucose, arabinose, dextrose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose or dextran, sugar alcohols such as mannitol and mixtures of two or more thereof. A preferred diluent or carrier is lactose, particularly in the form of the monohydrate. The diluent or carrier is generally present in an amount of 400 to 4000 μg, for example 800 to 3000 μg, more preferably 1000 to 2500 μg, especially 2000 to 2500 μg, per μg of formoterol active ingredient (A). The mean particle diameter of the formoterol active ingredient (A) is preferably up to 10 μm, more preferably up to 5 μm especially 1 to 5 μm. The diluent or carrier (B) may be present in the dry powder in the form of particles, having, for example, a maximum diameter of 300 μm, a preferred maximum being 212 μm. The diluent or carrier (B) may conveniently have a median particle diameter of 40 to 100 μm, e.g. 50 to 75 μm. The particle size of the formoterol active ingredient (A), and that of the diluent or carrier (B), can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, by sieving, by microprecipitation, by spray-drying, by lyophilisation or by recrystallisation from supercritical media.
  • In a preferred embodiment of the invention, the dry powder is in a capsule, usually of a pharmaceutically acceptable natural or synthetic polymer such as gelatin or hydroxypropyl methylcellulose, the capsule containing a unit dose of formoterol active ingredient (A). Doses of formoterol active ingredient (A) to be inhaled in accordance with the invention may be, in general, from 1 μg to 60 μg. When (A) is formoterol fumarate dihydrate, the dose may be, for example, from 6 μg to 48 μg. Preferred doses are from 6 μg to 36 μg, for example 6 μg, 12 μg, 18 μg, 24 μg, 30 μg, or 36 μg, the 12 μg and 24 μg being especially preferred and the 12 μg dose the most preferred. These doses may be administered once or twice daily, preferably twice daily, the preferred maximum daily dose being 48 μg. For on demand usage, the 6 μg or 12 μg dose is preferred, being inhaled as needed in accordance with a preferred maximum daily dose of 48 μg. When the dry powder is in a capsule containing a unit dose of (A), e.g. 6 μg, 12 μg or 24 μg of (A), the amount of diluent/carrier is preferably such as to bring the total weight of dry powder per capsule to between 5 mg and 25 mg, e.g. to 5 mg, 10 mg, 15 mg, 20 mg or, especially, 25 mg.
  • In especially preferred embodiments the dry powder is in a capsule, the capsule containing 12 μg of formoterol active ingredient (A) and 4988 μg to 49988 μg, for example 4988 μg or 9988 μg or 14988 μg, more preferably 19988 μg to 24988 μg, for example 19988 μg or, especially, 24988 μg of diluent or carrier (B).
  • As will be understood by those skilled in the art, a dry powder contained in a capsule may be inhaled by inserting the capsule in a dry powder inhalation device adapted to pierce a capsule containing the dry powder on actuating the device, thereby releasing the dry powder for inhalation by the user—a dry powder capsule inhaler. Such devices are well known in the art and are commercially available. For example, a suitable inhalation device is described in U.S. Pat. No. 3,991,761, which is incorporated herein by reference, particularly as described in the claims of U.S. Pat. No. 3,991,761 and as described with reference to the drawings of U.S. Pat. No. 3,991,761; this device may be modified by coating the capsule-piercing pins with a polymer, as described in WO99/45987. A preferred inhalation device is one adapted to receive a single capsule containing the dry powder, i.e. a single capsule inhaler, for example the commercially available Aerolizer® inhaler.
  • In another preferred embodiment of the invention, the dry powder may be in a reservoir of a multi-dose dry powder inhaler adapted to deliver a unit dose, for example 5 μg, 6 μg, 9 μg, 10 μg, 12 μg, 15 μg, 18 μg, 20 μg, 24 μg, 25 μg, 30 μg or 36 μg, preferably from 5 to 15 μg of formoterol active ingredient (A), particularly formoterol fumarate dihydrate, per actuation, for example from a powder having a formoterol fumarate dihydrate:lactose weight ratio of 5:4995, 5:9995, 5:14995, 10:4990, 10:9990, 10:14990, 12:4988, 12:9988 12:14998, 15:9985 or 15:14985. Multi-dose dry powder inhalers are well known in the art and are commercially available. For example, a suitable multi-dose inhaler is that described in WO97/20589.
  • Treatment of COPD in accordance with the invention includes treatment of reversible or irreversible, mild, moderate or severe COPD (including chronic bronchitis and emphysema) and conditions associated therewith, e.g. bronchospasm, loss of lung function, loss of exercise capacity, breathlessness, dyspnea or loss of lung elasticity. Thus treatment of COPD in accordance with the invention includes maintenance (prophylactic) treatment or on-demand or rescue treatment of bronchospasm associated with COPD, treatment to slow progressive loss of lung function, treatment to improve exercise capacity, and treatment to improve Quality to Life according to the SGRQ.
  • The effect of compositions of the invention in the treatment of COPD can be monitored in a conventional manner, e.g. by determining parameters such as forced expiratory volume in 1 second (FEV1), vital capacity (VC), forced vital capacity (FVC), Quality of Life, peak expiratory flow (PEF), exercise capacity (e.g. Shuttle Walking Test) and lung compliance (CL) at intervals during treatment. Quality of Life may be measured according to the SGRQ (P. W. Jones et al, Respir Med. 1991; 85 (Suppl B): 25-31).
  • The invention is illustrated by the following Examples.
    • EXAMPLE 1
  • Gelatin capsules suitable for use in a capsule inhaler are prepared, each capsule containing a dry powder consisting of 6 μg of formoterol fumarate dihydrate which has been ground to a mean particle diameter of 1-5 μm in an air jet mill and 4994 μg of lactose monohydrate having a particle diameter of below 212 μm. These capsules are used in the treatment of COPD patients by inserting a capsule into the capsule chamber of the inhaler described in U.S. Pat. No. 3,991,761 and actuating the piercing devices to perforate the capsule and release the dry powder when air is inhaled through the capsule chamber by a patient.
    • EXAMPLE 2-29
  • Example 1 is repeated but using the amounts of the formoterol fumarate dihydrate and the lactose monohydrate shown in the table below in place of the amounts used in that Example:
    Formoterol Fumarate
    Example Dihydrate (μg) Lactose Monohydrate (μg)
    2 6 9994
    3 6 14994
    4 6 19994
    5 6 24994
    6 12 4988
    7 12 9988
    8 12 14988
    9 12 19988
    10 12 24988
    11 12 29988
    12 18 9982
    13 18 14982
    14 18 19982
    15 18 24982
    16 18 29982
    17 24 9976
    18 24 14976
    19 24 19976
    20 24 24976
    21 24 29976
    22 30 14970
    23 30 19970
    24 30 24970
    25 30 29970
    26 36 14964
    27 36 19964
    28 36 24964
    29 36 29964
    • EXAMPLE 30
  • Two groups of patients suffering from COPD are treated with formoterol. One group has reversible COPD, showing at least 15% increase in FEV1 30 minutes after inhaling 200 μg of salbutamol. The other group has irreversible COPD, showing less than 15% increase in FEV1 30 minutes after inhaling 200 μg of salbutamol. Both groups are treated by inhalation twice daily for 12 weeks from a capsule containing a dry powder consisting of 12 μg of formoterol fumarate dihydrate having a mean particle diameter of 1 to 5 μm and 24988 μg of lactose monohydrate having a particle diameter below 212 μm, using an Aerolizer® inhaler. After treatment for 12 weeks, the patients' lung function (FEV1) is measured at intervals for 12 hours after dosing, the measured FEV1 is plotted against time after dosing and the area under the curve (AUC) of the resulting plot is determined.

Claims (10)

1-11. (canceled)
12. A method of treating chronic obstructive pulmonary disease consisting essentially of administering by inhalation to a subject in need of such treatment an effective amount of a dry powder comprising (A) formoterol, or a pharmaceutically acceptable salt or solvate thereof, or solvate or said salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of 400 μg to 5,000 μg per μg of (A), and said formoterol is the only active ingredient.
13. A method according to claim 12, in which the formoterol (A) is in the form of formoterol fumarate dihydrate.
14. A method of treating chronic obstructive pulmonary disease which comprises administering by inhalation to a subject in need of such treatment an effective amount of a dry powder consisting, or consisting essentially, of (A) formoterol fumarate dihydrate and (B) a pharmaceutically acceptable diluent or carrier in an amount from 400 μg to 5,000 μg per μg of (A).
15. A method according to claim 14, in which the diluent or carrier (B) is a saccharide, a sugar alcohol or a mixture thereof.
16. A method according to claim 15, in which the diluent or carrier (B) is lactose.
17. A method according to claim 14, in which the diluent or carrier (B) is present in an amount of 800 to 3000 μg per μg of (A).
18. A method according to claim 14, in which the dry powder is in a capsule, the capsule containing a unit dose of (A).
19. A method according to claim 18, in which the capsule contains 12 μg of (A) and 19988-24988 μg of diluent or carrier (B).
20. A method according to claim 14, in which the dry powder is in a reservoir of a multi-dose dry powder inhaler adapted to deliver a unit dose of (A) per actuation.
US11/725,903 1999-11-30 2007-03-20 Aerosol composition comprising formoterol Abandoned US20070196286A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/725,903 US20070196286A1 (en) 1999-11-30 2007-03-20 Aerosol composition comprising formoterol

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GBGB9928311.1A GB9928311D0 (en) 1999-11-30 1999-11-30 Organic compounds
GB9928311.1 1999-11-30
PCT/EP2000/011894 WO2001039745A2 (en) 1999-11-30 2000-11-28 Aerosol composition comprising formoterol
US10/148,043 US6887459B1 (en) 1999-11-30 2000-11-28 Aerosol composition comprising formoterol
US11/059,041 US20050136010A1 (en) 1999-11-30 2005-02-16 Aerosol composition comprising formoterol
US11/725,903 US20070196286A1 (en) 1999-11-30 2007-03-20 Aerosol composition comprising formoterol

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US11/059,041 Continuation US20050136010A1 (en) 1999-11-30 2005-02-16 Aerosol composition comprising formoterol

Publications (1)

Publication Number Publication Date
US20070196286A1 true US20070196286A1 (en) 2007-08-23

Family

ID=10865451

Family Applications (3)

Application Number Title Priority Date Filing Date
US10/148,043 Expired - Lifetime US6887459B1 (en) 1999-11-30 2000-11-28 Aerosol composition comprising formoterol
US11/059,041 Abandoned US20050136010A1 (en) 1999-11-30 2005-02-16 Aerosol composition comprising formoterol
US11/725,903 Abandoned US20070196286A1 (en) 1999-11-30 2007-03-20 Aerosol composition comprising formoterol

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US10/148,043 Expired - Lifetime US6887459B1 (en) 1999-11-30 2000-11-28 Aerosol composition comprising formoterol
US11/059,041 Abandoned US20050136010A1 (en) 1999-11-30 2005-02-16 Aerosol composition comprising formoterol

Country Status (24)

Country Link
US (3) US6887459B1 (en)
EP (3) EP2011484A3 (en)
JP (3) JP2003515551A (en)
KR (1) KR100771281B1 (en)
CN (1) CN1399540A (en)
AU (1) AU769765B2 (en)
BR (1) BR0015908A (en)
CA (1) CA2389349C (en)
CZ (1) CZ20021850A3 (en)
ES (1) ES2178943B1 (en)
FR (1) FR2801506B1 (en)
GB (1) GB9928311D0 (en)
HU (1) HUP0203728A3 (en)
IL (2) IL149362A0 (en)
IT (1) ITMI20002556A1 (en)
MX (1) MXPA02005384A (en)
NO (1) NO20021963D0 (en)
NZ (1) NZ518873A (en)
PL (1) PL354974A1 (en)
RU (1) RU2327452C2 (en)
SK (1) SK7432002A3 (en)
TW (1) TWI278324B (en)
WO (1) WO2001039745A2 (en)
ZA (1) ZA200204147B (en)

Families Citing this family (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
ES2165768B1 (en) 1999-07-14 2003-04-01 Almirall Prodesfarma Sa NEW DERIVATIVES OF QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.
GB9928311D0 (en) * 1999-11-30 2000-01-26 Novartis Ag Organic compounds
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
SI3384931T1 (en) * 2002-03-01 2019-11-29 Chiesi Farm Spa Formoterol superfine formulation
EP1494732B1 (en) 2002-03-20 2008-01-30 MannKind Corporation Inhalation apparatus
GB0219511D0 (en) 2002-08-21 2002-10-02 Norton Healthcare Ltd Method of preparing dry powder inhalation compositions
JP2006516531A (en) * 2002-08-21 2006-07-06 ノートン　ヘルスケアー　リミテッド Inhalation composition
US8273331B2 (en) 2002-08-21 2012-09-25 Norton Healthcare Ltd. Inhalation compositions
GB0312148D0 (en) 2003-05-28 2003-07-02 Aventis Pharma Ltd Stabilized pharmaceutical products
GB0315889D0 (en) 2003-07-08 2003-08-13 Aventis Pharma Ltd Stable pharmaceutical products
TWI359675B (en) 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
US20050026948A1 (en) * 2003-07-29 2005-02-03 Boehringer Ingelheim International Gmbh Medicaments for inhalation comprising an anticholinergic and a betamimetic
US20050026884A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a beta-agonist bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
ES2257152B1 (en) * 2004-05-31 2007-07-01 Laboratorios Almirall S.A. COMBINATIONS THAT INCLUDE ANTIMUSCARINIC AGENTS AND BETA-ADRENERGIC AGONISTS.
ES2245612B1 (en) * 2004-06-29 2007-08-16 Universidad De Barcelona NEW THERAPEUTIC USE OF FORMOTEROL.
WO2006023849A2 (en) 2004-08-20 2006-03-02 Mannkind Corporation Catalysis of diketopiperazine synthesis
DK1791542T3 (en) 2004-08-23 2015-06-15 Mannkind Corp Diketopiperazinsalte for pharmaceutical delivery
JP5465878B2 (en) 2005-09-14 2014-04-09 マンカインド コーポレイション Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents
MX360812B (en) 2006-02-22 2018-11-16 Mannkind Corp A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent.
GB0616299D0 (en) * 2006-08-16 2006-09-27 Cambridge Consultants Drug Capsules for dry power inhalers
GB0617171D0 (en) * 2006-08-31 2006-10-11 Generics Uk Ltd Novel compositions and methods
JP2010519195A (en) 2007-02-19 2010-06-03 シプラ・リミテッド Pharmaceutical composition
CN101342155B (en) * 2007-07-11 2012-01-04 天津帝士力投资控股集团有限公司 (R,R)-formoterol inhalation dust cloud agent and preparation method thereof
NZ587561A (en) * 2008-02-26 2012-10-26 Elevation Pharmaceuticals Inc Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations (an muscarinic antagnoist)
US20100055045A1 (en) * 2008-02-26 2010-03-04 William Gerhart Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
EP2100599A1 (en) 2008-03-13 2009-09-16 Laboratorios Almirall, S.A. Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease
EP2100598A1 (en) 2008-03-13 2009-09-16 Laboratorios Almirall, S.A. Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
SG10201507038VA (en) 2008-06-13 2015-10-29 Mannkind Corp A dry powder inhaler and system for drug delivery
ES2421385T3 (en) 2008-06-20 2013-09-02 Mannkind Corp Interactive device and procedure to establish the profile, in real time, of inhalation efforts
TWI532497B (en) 2008-08-11 2016-05-11 曼凱公司 Ultra-fast use of insulin
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
PL2405963T3 (en) 2009-03-11 2014-04-30 Mannkind Corp Apparatus, system and method for measuring resistance of an inhaler
CN102647979B (en) 2009-06-12 2015-03-04 曼金德公司 Diketopiperazine particles with defined specific surface areas
CA2778698A1 (en) 2009-11-03 2011-05-12 Mannkind Corporation An apparatus and method for simulating inhalation efforts
RU2571331C1 (en) 2010-06-21 2015-12-20 Маннкайнд Корпорейшн Systems and methods for dry powder drug delivery
JOP20120023B1 (en) * 2011-02-04 2022-03-14 Novartis Ag Dry powder formulations of particles that contain two or more active ingredients for treating obstructive or inflammatory airways diseases
KR101940832B1 (en) 2011-04-01 2019-01-21 맨카인드 코포레이션 Blister package for pharmaceutical cartridges
EP2510928A1 (en) 2011-04-15 2012-10-17 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
US9233159B2 (en) 2011-10-24 2016-01-12 Mannkind Corporation Methods and compositions for treating pain
CN104619369B (en) 2012-07-12 2018-01-30 曼金德公司 Dry-powder medicament induction system and method
WO2014066856A1 (en) 2012-10-26 2014-05-01 Mannkind Corporation Inhalable influenza vaccine compositions and methods
ES2754388T3 (en) 2013-03-15 2020-04-17 Mannkind Corp Compositions and methods of microcrystalline dicetopiperazine
CN114848614A (en) 2013-07-18 2022-08-05 曼金德公司 Thermally stable dry powder pharmaceutical compositions and methods
CA2920488C (en) 2013-08-05 2022-04-26 Mannkind Corporation Insufflation apparatus and methods
WO2015065220A1 (en) * 2013-10-28 2015-05-07 Шолекс Девелопмент Гмбх Inhaled drug for the treatment of bronchial asthma and chronic obstructive pulmonary disease and method for producing same
WO2015065221A1 (en) * 2013-10-28 2015-05-07 Шолекс Девелопмент Гмбх Inhaled drug for the treatment of bronchial asthma and chronic obstructive pulmonary disease and method for producing same
WO2015148905A1 (en) 2014-03-28 2015-10-01 Mannkind Corporation Use of ultrarapid acting insulin
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3994974A (en) 1972-02-05 1976-11-30 Yamanouchi Pharmaceutical Co., Ltd. α-Aminomethylbenzyl alcohol derivatives
IT1016489B (en) 1974-03-18 1977-05-30 Isf Spa INHALER
GB8911259D0 (en) * 1989-05-17 1989-07-05 Fisons Plc Inhalation medicament
US5795564A (en) * 1991-04-05 1998-08-18 Sepracor, Inc. Methods and compositions for treating pulmonary disorders using optically pure (R,R)-formoterol
ATE213946T1 (en) * 1991-12-18 2002-03-15 COMPOSITION CONTAINING FORMOTEROL AND BUDESONIDE
ES2099428T3 (en) * 1992-03-10 1997-05-16 Fisons Plc PHARMACEUTICAL COMPOSITIONS FOR INHALATION.
SE9404080L (en) 1993-12-28 1995-06-29 Ciba Geigy Ag Process for preparing an optically pure enantiomer of formoterol
SE9700134D0 (en) * 1997-01-20 1997-01-20 Astra Ab New formulation
AR002009A1 (en) * 1994-12-22 1998-01-07 Astra Ab PHARMACEUTICAL COMPOSITION, PROCEDURE FOR THE MANUFACTURE OF A PROLIPOSOMA POWDER AS USED IN SUCH COMPOSITION, PROCEDURE FOR LAMANUFACTURE OF SUCH COMPOSITION, USE OF SUCH PHARMACEUTICAL COMPOSITION IN THE MANUFACTURE OF A DISPOSAL MEDICINAL PRODUCT.
ATE261324T1 (en) 1995-12-07 2004-03-15 Jago Res Ag MOUTHPIECE FOR AN INHALER FOR THE MULTIPLE DOSE DELIVERY OF A PHARMACOLOGICAL DRY POWDER
AU738192B2 (en) 1997-09-19 2001-09-13 Neuren Pharmaceuticals Limited Neuronal rescue agent
SE9703407D0 (en) * 1997-09-19 1997-09-19 Astra Ab New use
GB9805102D0 (en) 1998-03-10 1998-05-06 Ciba Geigy Ag Device
GB9806462D0 (en) * 1998-03-26 1998-05-27 Glaxo Group Ltd Improved compositions for inhalation
GB9807232D0 (en) * 1998-04-03 1998-06-03 Univ Cardiff Aerosol composition
GB9902689D0 (en) * 1999-02-08 1999-03-31 Novartis Ag Organic compounds
GB9904919D0 (en) * 1999-03-03 1999-04-28 Novartis Ag Organic compounds
GB9928311D0 (en) * 1999-11-30 2000-01-26 Novartis Ag Organic compounds

Also Published As

Publication number Publication date
US20050136010A1 (en) 2005-06-23
BR0015908A (en) 2002-08-06
KR100771281B1 (en) 2007-10-29
CA2389349C (en) 2009-10-20
EP2011484A2 (en) 2009-01-07
NO20021963L (en) 2002-04-25
IL149362A0 (en) 2002-11-10
EP2011484A3 (en) 2009-01-14
WO2001039745A3 (en) 2001-12-20
IL149362A (en) 2015-06-30
MXPA02005384A (en) 2002-11-29
HUP0203728A2 (en) 2003-03-28
CZ20021850A3 (en) 2002-08-14
WO2001039745A2 (en) 2001-06-07
ZA200204147B (en) 2003-01-29
JP2003515551A (en) 2003-05-07
HUP0203728A3 (en) 2003-12-29
EP1233757A2 (en) 2002-08-28
FR2801506A1 (en) 2001-06-01
RU2327452C2 (en) 2008-06-27
NZ518873A (en) 2004-02-27
SK7432002A3 (en) 2002-10-08
ES2178943A1 (en) 2003-01-01
RU2002116251A (en) 2004-01-20
US6887459B1 (en) 2005-05-03
GB9928311D0 (en) 2000-01-26
KR20020058050A (en) 2002-07-12
NO20021963D0 (en) 2002-04-25
JP2015108020A (en) 2015-06-11
JP2013075909A (en) 2013-04-25
ES2178943B1 (en) 2004-03-16
PL354974A1 (en) 2004-03-22
AU769765B2 (en) 2004-02-05
CA2389349A1 (en) 2001-06-07
AU2837401A (en) 2001-06-12
EP3050558A1 (en) 2016-08-03
ITMI20002556A1 (en) 2002-05-28
TWI278324B (en) 2007-04-11
CN1399540A (en) 2003-02-26
FR2801506B1 (en) 2002-12-27

Similar Documents

Publication Publication Date Title
US6887459B1 (en) Aerosol composition comprising formoterol
CA2405705C (en) The treatment of respiratory diseases
RU2249454C2 (en) Compositions including formoterol and flucticason propionate indicated for treating asthma
RU2238085C2 (en) Compositions comprising formoterol and thiotropium salt
RU2270670C2 (en) Medicinal agent and pharmaceutical set designated for asthma treatment
JP2003515551A5 (en)
JP2001516715A (en) Methods and compositions for treating pulmonary disorders using optically pure (S) -salmeterol
WO2006030221A1 (en) Pharmaceutical composition comprising a betaminetic agent and a mucolytic agent
AU776913C (en) The treatment of respiratory diseases

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载