WO2011136753A1 - Combination of carmoterol and fluticasone for use in the treatment respiratory diseases - Google Patents

Combination of carmoterol and fluticasone for use in the treatment respiratory diseases Download PDF

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Publication number
WO2011136753A1
WO2011136753A1 PCT/TR2011/000113 TR2011000113W WO2011136753A1 WO 2011136753 A1 WO2011136753 A1 WO 2011136753A1 TR 2011000113 W TR2011000113 W TR 2011000113W WO 2011136753 A1 WO2011136753 A1 WO 2011136753A1
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composition according
pharmaceutically acceptable
medicament
carmoterol
medicament composition
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PCT/TR2011/000113
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French (fr)
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Mahmut Bilgic
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Mahmut Bilgic
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Priority to EP11720621A priority Critical patent/EP2563364A1/en
Publication of WO2011136753A1 publication Critical patent/WO2011136753A1/en

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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
    • A61K31/33—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
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the active agents carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof so as to be used in the treatment of respiratory diseases, especially in asthma and chronic obstructive pulmonary disease (COPD), and the delivery of this composition.
  • COPD chronic obstructive pulmonary disease
  • bronchia are the channels which function to distribute the inhaled air into the lung tissues.
  • stimulants such as allergen, infection, good and bad smell, smoke cause contractions in the airway muscles (bronchoconstriction) and/or excessive secretion in glands and results in contractions in the airways.
  • bronchoconstriction a chronic obstructive pulmonary disease
  • ⁇ 2- agonists induce an alleviating or eliminating effect on bronchoconstriction in the treatment of respiratory diseases such as asthma and COPD.
  • Carmoterol (Formula 1), which has the chemical name 8 -hydroxy- 5 -[( 1 R)- 1 -hydroxy-2-[[(2R)- 1 -(4-methoxyphenyl)prophane-2- yl] amino] ethyl]- lH-quinolin-2-one, is a ⁇ 2- agonist that was first disclosed in the patent numbered EP0147719.
  • Fluticasone is a corticosteroid named S-(fluoromethyl)-6a,9-difluoro-l i ,17-dihydroxy-16a- methyl-3-oxoandrosta-l,4-dien-17-carbothionate. Fluticasone, which is a potent antiinflammatory drug, was first described in the patent numbered US4335121.
  • ⁇ 2- agonist and a corticosteroid in the treatment of respiratory diseases such as asthma and COPD in is known the prior art.
  • the treatment comprising these drugs may not achieve sufficient reliability in some patients.
  • these drugs should be taken twice or more a day because they do not have long duration of action.
  • the adaptation of patients to the treatment decreases as a result of this frequent dose intake.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the active agents carmoterol or a pharmaceutically acceptable derivative thereof and fluticasone and/or a pharmaceutically acceptable derivative thereof as combined in order to be used in the treatment of respiratory diseases such as asthma, COPD and allergic rhinitis.
  • the inventor has surprisingly found that a significant unexpected therapeutic benefit, particularly a synergistic effect, in the treatment of inflammatory or obstructive airways diseases, is obtained by combination therapy using carmoterol and fluticasone and/or a pharmaceutically acceptable derivative thereof.
  • the pharmaceutical composition comprising carmoterol and fluticasone and/or a pharmaceutically acceptable derivative thereof provides faster onset and has a more long-lasting and efficient therapeutic effect when compared with the pharmaceutical compositions containing only one of these active agents.
  • the present invention provides a treatment method in which the medicament composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is used as a symptomatolytic medicament.
  • Carmoterol has a short onset of action when taken at particular dose amounts. Therefore, this composition can be used as a symptomatolytic medicament.
  • the present invention provides a medicament in which carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof are reciprocally affected in a positive way. Accordingly, carmoterol enhances the anti-inflammatory effect resulting from fluticasone's attaching with glucocorticoid receptors since carmoterol strengthens the translocation of these receptors. Fluticasone, on the other hand, increases the transcription of ⁇ 2 - receptors with which carmoterol attaches.
  • carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof induce therapeutic effect at lower doses when they are used as combined compared with their use alone.
  • side effects that the active agents may cause are minimized with the help of lower dose use.
  • the present invention provides a simplified treatment realized by delivery of the medicament comprising carmoterol which is an ultra long-acting ⁇ 2- agonist and fluticasone which is a corticosteroid inducing anti-inflammatory effect and/or pharmaceutically acceptable derivatives thereof once a day.
  • the active agents of the present invention provide a more long-lasting effect, a more effective, treatment and, as a result, a simpler treatment with less frequent dose delivery is provided and patient compatibility is increased.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is administered by the inhalation route.
  • the medicament taken by the inhalation route is transmitted to the target area faster compared with the oral and the parenteral route. Thus, it provides faster and more efficient relief to the patient.
  • the present invention enables less frequent dose intake of the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof by the inhalation route compared with the oral and the parenteral route and thus, severity of the side effects that the active agent may cause is minimized.
  • the present invention provides the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is provided for simultaneous, sequential or separate administration by the inhalation route in the treatment of inflammatory or obstructive airways diseases.
  • the present invention provides a medicament composition in which carmoterol and fluticasone and or pharmaceutically acceptable derivatives thereof are preferably formulated in the same dosage form. Having the active agents in the same dosage form provides a more effective, simpler and cost-effective treatment. Additionally, it is simpler to track the progress of the patient in the treatments utilizing single dosage forms.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is delivered via single dose or multi dose inhalation devices.
  • the active agents of the present invention can be inhaled from different devices while all of the active agents of the present invention can also be delivered by a single device. However, delivering the active agents as combined by a single device is preferred according to the present invention.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is delivered in aerosol, dry powder, solution or suspension form.
  • the active agents in the medicament of the present invention can be delivered in the same dosage form as well as in different dosage forms. Preferably, all of the active agents of the medicament are delivered in same dosage form.
  • aerosol refers to dispersion or suspension of a liquid, a solution or a solid substance in the air or in a gas.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can be inhaled in aerosol form via a suitable device.
  • the aerosol composition that is contained in the device can be characterized by comprising a propellant gas or not.
  • the active agents of the present invention can be inhaled in the same aerosol composition as well as in different aerosol compositions. According to the present invention, the active agents of the present invention are preferably inhaled in the same aerosol composition.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can contain propellant gas in addition to the active agents.
  • the medicament comprising propellant gas can be delivered by a pressured metered dose inhaler. These propellant gases are targeted to deliver the active agents to the lungs more easily.
  • the propellant gases are preferably hydrocarbons and halohydrocarbons. Only one of these hydrocarbons or a mixture of them can be used.
  • the particularly used propellant gases are HFA134a, HFA227 or mixture thereof; TGI 34a, TG227 or halogenated alkane derivatives selected from mixtures thereof.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can be transmitted to the lungs in a propellant-free aerosol composition by an appropriate inhalation device such as nebulizers.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can also comprise co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusters in addition to the active agents.
  • the medicament delivered in aerosol form and comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can comprise active agent in the range of 0,001% to 8%, preferably in the range of 0,001% to 5% by weight.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can be delivered to the patient as a propellant-free solution or an inhalation composition in suspension form by a nebulizer.
  • All of the active agents of the present invention can be inhaled in a single propellant-free solution or suspension together as well as in separate propellant gas-free solutions or suspensions one by one.
  • Water or water-alcohol mixture can be used as solvent in these inhalation formulations.
  • the rate of ethanol to water is at most 80%, preferably 60% by volume in the case that water- alcohol mixture is used.
  • the pH value of suspensions or solutions comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can be in the range of 2 to 7, preferably in the range of 2 to 5.
  • organic or inorganic acids preferably hydrochloric acid, citric acid, ascorbic acid, formic acid, fumaric acid, tartaric acid, malic acid, sulphuric acid or a mixture of one or several of them can be used as a pH-adjuster.
  • the propellant-free inhalation formulations in solution or suspension form may contain edetic acid (EDTA) or salts thereof, excipients, sodium edetate, stabilizer or complexing agents in addition to said substances.
  • EDTA edetic acid
  • the amount of sodium edetate comprised in said solution or suspension can be in the range of 0 mg/100 ml to 120 mg/100 ml, preferably in the range of 0 mg/100 ml to 50 mg/100 ml, more preferably in the range of 0 mg/100 ml to 10 mg/100 ml.
  • propellant gas-free solutions or suspensions can contain co-solvents and/or other excipients and/or preservative substances in addition to the active agents.
  • the preferred co-solvents are hydroxyl groups, alcohols, especially other polar groups comprising isopropyl alcohols and glycols.
  • the said excipients are substances which do not hold active agent characteristics such as tocopherols, vitamins, provitamins, surfactans.
  • the preservative agents which are used in order to prevent the contamination caused by pathogens are cetyl pyridinium chloride, benzalkonium chloride, benzoic acid or benzoates as known in the prior art.
  • the medicament of the present invention comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is preferably administered in dry powder form and dry powder inhalation devices are used for delivery of the medicament of the present invention.
  • the present invention provides delivery of the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof by dry powder inhalers.
  • tsaid dry powder formulations comprise pharmaceutically acceptable excipients in addition to the active agents.
  • excipients can be selected from monosaccharides (glucose, etc.), disaccharides (lactose, saccharose, maltose, etc.), oligosaccharides and polysaccharides (dextran, etc.), polyalcohols (sorbitol, mannitol, xylitol, etc.), salts (sodium chloride, calcium carbonate, etc.) or a combination thereof.
  • lactose is used as an excipient in the medicament of the present invention.
  • the amount of pharmaceutically acceptable excipient is in the range of 0 to 50 mg, for example in the range of 1 mg to 48 mg, 1 mg to 47 mg, 1 mg to 42 mg, 1 mg to 40 mg, 1 mg to 38 mg, 1 mg to 35 mg, 1 mg to 32 mg, 1 mg to 30 mg, 1 mg to 28 mg, 1 mg to 25 mg , 1 mg to 23 mg, 2 mg to 48 mg, 2 mg to 47 mg, 2 mg to 42 mg, 2 mg to 40 mg, 2 mg to 38 mg, 2 mg to 35 mg, 2 mg to 32 mg, 2 mg to 30 mg, 2 mg to 28 mg, 2 mg to 25 mg , 2 mg to 23 mg, 2 mg to 20 mg, 3 mg to 48 mg, 3 mg to 47 mg, 3 mg to 42 mg, 3 mg to 40 mg, 3 mg to 38 mg, 3 mg to 35 mg, 3 mg to 32 mg, 3 mg to 30 mg, 3 mg to 28 mg, 3 mg to 25 mg.
  • the amount of the pharmaceutically acceptable excipient is most preferably in the range of 3 mg to 20 mg
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is delivered via a dry powder inhaler in which the medicament is stored in a peelable blister pack, reservoir or capsule for the treatment of patients with respiratory diseases.
  • inhalation devices designed to provide delivery of the dry powder medicament
  • a specific dose of the medicament in dry powder form is prepared for inhalation in response to each actuation of the device.
  • the medicament formulation containing more than one dose is stored in the reservoir of the device and one dose of dry powder medicament is inhaled by the patient each time the device is triggered.
  • carmoterol and/or a pharmaceutically acceptable derivative thereof which is one of the active agents in said medicament comprising the combination of active agents, is selected from the pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, the free base, organic salts, inorganic salts, esters, polymorphs, crystalline and amorphous forms of carmoterol and/or a combination thereof.
  • R,R diastereomer of the carmoterol is preferably used in the medicament of the present invention.
  • fluticasone and/or a pharmaceutically acceptable derivative thereof which is one of the active agents contained in said medicament the combination of active agents, is selected from the pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, the free base, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms of fluticasone and/or a combination thereof.
  • Fluticasone propionate is preferably used in the medicament of the present invention.
  • the amount of carmoterol which is one of the active agents comprised in the said medicament containing the combination of carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof, in the range of 0.01 ⁇ g, 0.05 ⁇ g, 0.1 ⁇ g, 0.2 ⁇ g, 0.3 ⁇ g, 0.4 ⁇ & 0.5 ⁇ g, 0.6 ⁇ g, 0.7 ⁇ 3 ⁇ 4 0.8 ⁇ g, 0.9 ⁇ g or 1 ⁇ g to 7 ⁇ & 8 ⁇ g, 9 ⁇ 10 ⁇ g, 12 ⁇ g, 15 ⁇ g, 17 ⁇ g, 20 ⁇ g, 22 ⁇ g, 25 ⁇ g or 30 ⁇ g, for example 0.01 ⁇ g to 30 ⁇ g, 0.01 ⁇ g to 27 ⁇ g, 0.01 ⁇ g to 25 ⁇ g, 0.01 ⁇ g to 23 ⁇ g, 0.01 ⁇ g to 20 ⁇ g, 0.01 ⁇ g to 18 ⁇ g, 0.01 ⁇ g to 15 ⁇
  • the amount of fluticasone or a pharmaceutically acceptable derivative thereof included in the medicament composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is in the range of 1 ⁇ g, 5 ⁇ g, 10 ⁇ & 15 ⁇ g, 25 ⁇ g or 30 ⁇ to 400 ⁇ g, 450 ⁇ g, 500 ⁇ g, 550 ⁇ g, 600 ⁇ ⁇ , 650 ⁇ g, 700 %, 750 ⁇ g, 800 ⁇ g, 850 ⁇ g, 900 ⁇ g, 950 ⁇ g or 1000 ⁇ g for example 1 ⁇ g to 1000 ⁇ g, 1 ⁇ g to 950 ⁇ g, 1 ⁇ g to 900 ⁇ g, 1 ⁇ g to 850 ⁇ g, 1 ⁇ g to 800 ⁇ , 1 ⁇ g to 750 ⁇ & 1 ⁇ g to 700 ⁇ g, 1 g to 650 ⁇ g, 1 ⁇ g to 600 ⁇ g, 1 ⁇ g to 550 ⁇
  • the medicament composition in accordance with the present invention is preferably in the form of micronized dry powder particles.
  • the active agents present in said medicament composition have average particle size of 1 ⁇ to 20 ⁇ , preferably from 1 ⁇ to 10 ⁇ , most preferably 1 ⁇ to 6 ⁇ .
  • Lactose particles present in said medicament composition as an excipient has average particle size of not more than 300 ⁇ , preferably not more than 250 ⁇ .
  • the lactose particles in the medicament composition can be found in more than one fraction with different average particle size.
  • the pharmaceutical composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof may additionally comprise one or more substances selected from the group comprising mast cell stabilizer, anticholinergic, adrenergic agonist, glucocorticosteroid, xanthine, anti-leukotriene, PDE IV inhibitor, EGFR inhibitor, anti-allergic, anti-inflammatory, antihistaminic and anti-muscarinic agents.
  • the pharmaceutical composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can additionally comprise one or more substances selected from the group consisting of mast cell stabilizers such as cromoglycate, nedocromil; anticholinergics such as tiotropium, ipratropium, glicopirronium, cromoglycate, oxytropium; ⁇ 2 - agonists such as formoterol, arformoterol, bambuterol, salmeterol, clenbuterol, salbutamol, fenoterol, terbutaline, carbuterol, pirbuterol; corticosteroids such as beclomethasone, budesonide, fluticasone, ciclesonide; xanthines such as doxophylline, theobromine, theophylline, aminophylline; anti-leukotrienes such as montelukast, pranlukast, zafir
  • the pharmaceutical composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can additionally comprise cromoglycate and/or a pharmaceutically acceptable derivative thereof.
  • Cromoglycate derivatives mentioned in the invention comprise the pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, the free base, organic salts, inorganic salts, esters, polymorphs, crystalline and amorphous forms of cromoglycate and/or a combination thereof.
  • Sodium cromoglycate is preferably used in the preparation of the medicament of the present invention.
  • the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof according to the present invention can be used in the treatment of many respiratory diseases, particularly in asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis.
  • these respiratory diseases can be, but not limited to, asthma at any phase, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis, chronic obstructive pulmonary including emphysema and chronic bronchitis, respiratory diseases or lung diseases (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, byssinosis.
  • This treatment can be prophylactic or symptomatic.
  • the composition of the present invention is especially used for symptomatic treatment of asthma and COPD.
  • composition pertaining to the present invention can be explained with, but not limited to, the examples given below.
  • the active agent carmoterol given in the following examples comprises all pharmaceutically acceptable racemates, enantiomers or diastereomers, salts, solvates, esters, hydrates and/or the free base, polymorphs, amorphous and crystalline forms thereof.
  • the active agent fluticasone given in the following examples comprises all pharmaceutically acceptable salts, solvates, esters, hydrates and/or enantiomers, polymorphs, amorphous and crystalline forms thereof.
  • Carmoterol or a pharmaceutically acceptable derivative thereof is preferably in the form of R,R-carmoterol.
  • the pharmaceutically acceptable excipient given in the following examples can optionally be added in a higher or a lower amount.
  • the capsule described in the following examples is made of gelatin; however, it can optionally be made of chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers.
  • the active agent cromoglycate given in the following examples comprises all pharmaceutically acceptable racemates, enantiomers or diastereomers, solvates, esters, hydrates and/or the free base, polymorphs, amorphous and crystalline forms of cromoglycate.
  • a dry powder formulation suitable to be stored in blister packs so as to be used via a multi-dose inhaler comprises 1 part of carmoterol, 400 parts of fluticasone having an average particle size in the range of 1 to 5 ⁇ , and 10000 parts of lactose having a particle size below 300 ⁇ as an excipient all of which are micronized in an air jet mill.
  • the example can be repeated by replacing the amounts given in example 1 with the amounts given in the table below.
  • the dry powder formulation which is suitable to be stored in a gelatin capsule so as to be used via an inhaler comprises 1 part of carmoterol, 200 parts of fluticasone having an average particle size in the range of 1 to 5 ⁇ , and 5500 parts of lactose as an excipient having an average particle size below 300 ⁇ all of which were micronized in an air jet mill.
  • the example can be repeated by replacing the amounts given in the table below with the amounts given in example 20.
  • a dry powder formulation suitable to be stored in blisters so as to be used via a multiple dose inhaler comprises 2 parts of carmoterol, 200 parts of fluticasone and 10000 parts of sodium chromoglycate having an average particle size in the range of 1 to 5 ⁇ , and 10000 parts of lactose as an excipienthaving an average particle size below 300 ⁇ all of which were micronized in an air jet mill.
  • the dry powder formulation which is suitable to be stored in a gelatin capsule so as to be used via an inhaler comprises 2 parts of carmoterol, 200 parts of fluticasone and 10000 parts of sodium chromoglycate sodium having an average particle size in the range of 1 to 5 ⁇ , and 10000 parts of lactose as an excipient having an average particle size below 300 ⁇ all of which were micronized in an air jet mill.
  • An aerosol formulation developed to be used in a metered dose inhalator comprises 2 parts of carmoterol, 200 parts of fluticasone and excipients in a ratio of 97% by weight of the total formulation.

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Abstract

The present invention relates to a pharmaceutical composition comprising carmoterol and fluticasone and/or their pharmaceutically acceptable derivatives as active agents so as to be used in the treatment of respiratory tract diseases, especially in the treatment of asthma and chronic obstructive pulmonary disease (COPD), and the administration of this pharmaceutical composition.

Description

COMBINATION OF CARMOTEROL AND FLUTICASONE FOR USE IN THE
TREATMENT RESPIRATORY DISEASES
Field of the invention
The present invention relates to a pharmaceutical composition comprising the active agents carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof so as to be used in the treatment of respiratory diseases, especially in asthma and chronic obstructive pulmonary disease (COPD), and the delivery of this composition.
Background of the invention
Airways, in other words bronchia, are the channels which function to distribute the inhaled air into the lung tissues. In the case of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), stimulants such as allergen, infection, good and bad smell, smoke cause contractions in the airway muscles (bronchoconstriction) and/or excessive secretion in glands and results in contractions in the airways. Hence, one cannot breathe in as the inhaled air cannot be exhaled. β2- agonists induce an alleviating or eliminating effect on bronchoconstriction in the treatment of respiratory diseases such as asthma and COPD. Carmoterol (Formula 1), which has the chemical name 8 -hydroxy- 5 -[( 1 R)- 1 -hydroxy-2-[[(2R)- 1 -(4-methoxyphenyl)prophane-2- yl] amino] ethyl]- lH-quinolin-2-one, is a β2- agonist that was first disclosed in the patent numbered EP0147719.
Figure imgf000002_0001
Formula 1
Fluticasone is a corticosteroid named S-(fluoromethyl)-6a,9-difluoro-l i ,17-dihydroxy-16a- methyl-3-oxoandrosta-l,4-dien-17-carbothionate. Fluticasone, which is a potent antiinflammatory drug, was first described in the patent numbered US4335121.
Combined use of a β2- agonist and a corticosteroid in the treatment of respiratory diseases such as asthma and COPD in is known the prior art. Because of the severe side effect of the beta agonists, the treatment comprising these drugs may not achieve sufficient reliability in some patients. Besides, these drugs should be taken twice or more a day because they do not have long duration of action. The adaptation of patients to the treatment decreases as a result of this frequent dose intake.
Many symptoms such as coughing, difficulty in breathing, chest tightness and wheezing may be observed, when adequate treatment for asthma is not provided. With these symptoms, very serious respiratory diseases may occur. Development of treatment methods to be applied and drugs to be used in order to prevent the occurrence and increase of these symptoms still maintain its significance today.
Consequently, there is still need for a more efficient, simpler treatment with less frequent dose delivery in order to provide the best control of respiratory diseases such as asthma and COPD.
Detailed description of the invention
The present invention provides a pharmaceutical composition comprising the active agents carmoterol or a pharmaceutically acceptable derivative thereof and fluticasone and/or a pharmaceutically acceptable derivative thereof as combined in order to be used in the treatment of respiratory diseases such as asthma, COPD and allergic rhinitis. The inventor has surprisingly found that a significant unexpected therapeutic benefit, particularly a synergistic effect, in the treatment of inflammatory or obstructive airways diseases, is obtained by combination therapy using carmoterol and fluticasone and/or a pharmaceutically acceptable derivative thereof.
It has been found that the pharmaceutical composition comprising carmoterol and fluticasone and/or a pharmaceutically acceptable derivative thereof provides faster onset and has a more long-lasting and efficient therapeutic effect when compared with the pharmaceutical compositions containing only one of these active agents.
According to another aspect, the present invention provides a treatment method in which the medicament composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is used as a symptomatolytic medicament. Carmoterol has a short onset of action when taken at particular dose amounts. Therefore, this composition can be used as a symptomatolytic medicament.
According to another aspect, the present invention provides a medicament in which carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof are reciprocally affected in a positive way. Accordingly, carmoterol enhances the anti-inflammatory effect resulting from fluticasone's attaching with glucocorticoid receptors since carmoterol strengthens the translocation of these receptors. Fluticasone, on the other hand, increases the transcription of β2 - receptors with which carmoterol attaches.
According to the present invention in another aspect, carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof induce therapeutic effect at lower doses when they are used as combined compared with their use alone. Thus, side effects that the active agents may cause are minimized with the help of lower dose use.
According to another aspect, the present invention provides a simplified treatment realized by delivery of the medicament comprising carmoterol which is an ultra long-acting β2- agonist and fluticasone which is a corticosteroid inducing anti-inflammatory effect and/or pharmaceutically acceptable derivatives thereof once a day. With the help of the synergic effects obtained from the combination,, the active agents of the present invention provide a more long-lasting effect, a more effective, treatment and, as a result, a simpler treatment with less frequent dose delivery is provided and patient compatibility is increased.
According to another aspect, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is administered by the inhalation route. The medicament taken by the inhalation route is transmitted to the target area faster compared with the oral and the parenteral route. Thus, it provides faster and more efficient relief to the patient.
According to another aspect, the present invention enables less frequent dose intake of the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof by the inhalation route compared with the oral and the parenteral route and thus, severity of the side effects that the active agent may cause is minimized.
According to another aspect, the present invention provides the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is provided for simultaneous, sequential or separate administration by the inhalation route in the treatment of inflammatory or obstructive airways diseases.
According to another aspect, the present invention provides a medicament composition in which carmoterol and fluticasone and or pharmaceutically acceptable derivatives thereof are preferably formulated in the same dosage form. Having the active agents in the same dosage form provides a more effective, simpler and cost-effective treatment. Additionally, it is simpler to track the progress of the patient in the treatments utilizing single dosage forms.
According to another aspect, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is delivered via single dose or multi dose inhalation devices. The active agents of the present invention can be inhaled from different devices while all of the active agents of the present invention can also be delivered by a single device. However, delivering the active agents as combined by a single device is preferred according to the present invention.
According to another aspect, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is delivered in aerosol, dry powder, solution or suspension form. The active agents in the medicament of the present invention can be delivered in the same dosage form as well as in different dosage forms. Preferably, all of the active agents of the medicament are delivered in same dosage form.
The term "aerosol" refers to dispersion or suspension of a liquid, a solution or a solid substance in the air or in a gas.
According to the present invention, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can be inhaled in aerosol form via a suitable device. The aerosol composition that is contained in the device can be characterized by comprising a propellant gas or not. The active agents of the present invention can be inhaled in the same aerosol composition as well as in different aerosol compositions. According to the present invention, the active agents of the present invention are preferably inhaled in the same aerosol composition.
According to the present invention, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can contain propellant gas in addition to the active agents. According to the present invention, the medicament comprising propellant gas can be delivered by a pressured metered dose inhaler. These propellant gases are targeted to deliver the active agents to the lungs more easily. The propellant gases are preferably hydrocarbons and halohydrocarbons. Only one of these hydrocarbons or a mixture of them can be used. The particularly used propellant gases are HFA134a, HFA227 or mixture thereof; TGI 34a, TG227 or halogenated alkane derivatives selected from mixtures thereof. According to the present invention, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can be transmitted to the lungs in a propellant-free aerosol composition by an appropriate inhalation device such as nebulizers.
According to the present invention, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can also comprise co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusters in addition to the active agents.
According to the present invention, the medicament delivered in aerosol form and comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can comprise active agent in the range of 0,001% to 8%, preferably in the range of 0,001% to 5% by weight.
According to the present invention, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can be delivered to the patient as a propellant-free solution or an inhalation composition in suspension form by a nebulizer. All of the active agents of the present invention can be inhaled in a single propellant-free solution or suspension together as well as in separate propellant gas-free solutions or suspensions one by one. Water or water-alcohol mixture can be used as solvent in these inhalation formulations. The rate of ethanol to water is at most 80%, preferably 60% by volume in the case that water- alcohol mixture is used. According to the present invention, the pH value of suspensions or solutions comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can be in the range of 2 to 7, preferably in the range of 2 to 5. In order to provide a value in these ranges, organic or inorganic acids, preferably hydrochloric acid, citric acid, ascorbic acid, formic acid, fumaric acid, tartaric acid, malic acid, sulphuric acid or a mixture of one or several of them can be used as a pH-adjuster.
Additionally, according to the present invention, the propellant-free inhalation formulations in solution or suspension form may contain edetic acid (EDTA) or salts thereof, excipients, sodium edetate, stabilizer or complexing agents in addition to said substances. The amount of sodium edetate comprised in said solution or suspension can be in the range of 0 mg/100 ml to 120 mg/100 ml, preferably in the range of 0 mg/100 ml to 50 mg/100 ml, more preferably in the range of 0 mg/100 ml to 10 mg/100 ml.
Additionally, according to the present invention, propellant gas-free solutions or suspensions can contain co-solvents and/or other excipients and/or preservative substances in addition to the active agents. The preferred co-solvents are hydroxyl groups, alcohols, especially other polar groups comprising isopropyl alcohols and glycols. The said excipients are substances which do not hold active agent characteristics such as tocopherols, vitamins, provitamins, surfactans. The preservative agents which are used in order to prevent the contamination caused by pathogens are cetyl pyridinium chloride, benzalkonium chloride, benzoic acid or benzoates as known in the prior art.
According to the present invention, the medicament of the present invention comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is preferably administered in dry powder form and dry powder inhalation devices are used for delivery of the medicament of the present invention.
According to another aspect, the present invention provides delivery of the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof by dry powder inhalers.
According to the present invention, tsaid dry powder formulations comprise pharmaceutically acceptable excipients in addition to the active agents. These excipients can be selected from monosaccharides (glucose, etc.), disaccharides (lactose, saccharose, maltose, etc.), oligosaccharides and polysaccharides (dextran, etc.), polyalcohols (sorbitol, mannitol, xylitol, etc.), salts (sodium chloride, calcium carbonate, etc.) or a combination thereof. Preferably, lactose is used as an excipient in the medicament of the present invention. According to the present invention, the amount of pharmaceutically acceptable excipient is in the range of 0 to 50 mg, for example in the range of 1 mg to 48 mg, 1 mg to 47 mg, 1 mg to 42 mg, 1 mg to 40 mg, 1 mg to 38 mg, 1 mg to 35 mg, 1 mg to 32 mg, 1 mg to 30 mg, 1 mg to 28 mg, 1 mg to 25 mg , 1 mg to 23 mg, 2 mg to 48 mg, 2 mg to 47 mg, 2 mg to 42 mg, 2 mg to 40 mg, 2 mg to 38 mg, 2 mg to 35 mg, 2 mg to 32 mg, 2 mg to 30 mg, 2 mg to 28 mg, 2 mg to 25 mg , 2 mg to 23 mg, 2 mg to 20 mg, 3 mg to 48 mg, 3 mg to 47 mg, 3 mg to 42 mg, 3 mg to 40 mg, 3 mg to 38 mg, 3 mg to 35 mg, 3 mg to 32 mg, 3 mg to 30 mg, 3 mg to 28 mg, 3 mg to 25 mg. The amount of the pharmaceutically acceptable excipient is most preferably in the range of 3 mg to 20 mg, for example 3 mg to 19 mg, 3.5 mg to 18 mg, 4 mg to 17 mg.
According to another aspect, the medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is delivered via a dry powder inhaler in which the medicament is stored in a peelable blister pack, reservoir or capsule for the treatment of patients with respiratory diseases.
In the inhalation devices designed to provide delivery of the dry powder medicament, a specific dose of the medicament in dry powder form is prepared for inhalation in response to each actuation of the device.
In the case that the dry powder medicament is stored in a reservoir, the medicament formulation containing more than one dose is stored in the reservoir of the device and one dose of dry powder medicament is inhaled by the patient each time the device is triggered.
According to the present invention, carmoterol and/or a pharmaceutically acceptable derivative thereof, which is one of the active agents in said medicament comprising the combination of active agents, is selected from the pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, the free base, organic salts, inorganic salts, esters, polymorphs, crystalline and amorphous forms of carmoterol and/or a combination thereof. R,R diastereomer of the carmoterol is preferably used in the medicament of the present invention.
According to the present invention, fluticasone and/or a pharmaceutically acceptable derivative thereof, which is one of the active agents contained in said medicament the combination of active agents, is selected from the pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, the free base, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms of fluticasone and/or a combination thereof. Fluticasone propionate is preferably used in the medicament of the present invention.
According to the present invention, the amount of carmoterol, which is one of the active agents comprised in the said medicament containing the combination of carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof, in the range of 0.01 μg, 0.05 μg, 0.1 μg, 0.2 μg, 0.3 μg, 0.4 μ& 0.5 μg, 0.6 μg, 0.7 μ¾ 0.8 μg, 0.9 μg or 1 μg to 7 μ& 8 μg, 9 μ 10 μg, 12 μg, 15 μg, 17 μg, 20 μg, 22 μg, 25 μg or 30 μg, for example 0.01 μg to 30 μg, 0.01 μg to 27 μg, 0.01 μg to 25 μg, 0.01 μg to 23 μg, 0.01 μg to 20 μg, 0.01 μg to 18 μg, 0.01 μg to 15 μ¾ 0.01 μg to 12 μg, 0.01 μg to 10 μg, 0.01 μg to 8 μg, 0.01 μg to 7 μg, 0.05 μβ to 30 μg, 0.05 μg to 27 μg, 0.05 μg to 25 μg, 0.05 μg to 23 μg, 0.05 μg to 20 μg, 0.05 μg to 18 μg, 0.05 μg to 15 μ 0.05 μg to 12 μg, 0.05 μg to 10 μg, 0.05 μg to 8 μg, 0.05 μg to 7 μg, 0.1 μg to 30 μg, 0.1 μg to 27 μg, 0.1 μg to 25 μg, 0.1 μg to 23 μg, 0.1 μg to 20 μg, 0.1 μg to 18 μg, 0.1 μg to 15 μg, 0.1 μg to 12 μg, 0.1 μg to 10 μg, 0.1 μg to 8 μg, 0.1 μg to 7 μg, 0.2 μg to 30 μg, 0.2 μg to 27 μg, 0.2 μg to 25 μg, 0.2 μg to 23 μ& 0.2 μg to 20 μg, 0.2 μg to 18 μg, 0.2 μg to 15 μg, 0.2 μg to 12 μg, 0.2 μg to 10 μg, 0.2 μg to 8 μ 0.2 μg to 7 μ^ 0.3 μg to 30 μ , 0.3 μg to 27 μg, 0.3 μg to 25 μg, 0.3 μ§ to 23 μ¾ 0.3 μ to 20 μg, 0.3 μg to 18 μ 0.3 μg to 15 μg, 0.3 μg to 12 μg, 0.3 μδ to 10 μ¾ 0.3 μg to 8 μ¾ 0.3 μg to 7 μδ, 0.4 μ to 30 μβ, 0.4 μβ to 27 μg, 0.4 μ& to 25 μ^ 0.4 μg to 23 μ¾ 0.2 μg to 20 μ¾ 0.4 μg to 18 μg, 0.4 μg to 15 μ¾ 0.4 μβ to 12 μ^ 0.4 μg to 10 μg, 0.4 μ to 8 μg, 0.4 μg to 7 μ 0.5 μ to 30 μ 0.5 μ to 27 μ , 0.5 μg to 25 μg, 0.5 μg to 23 μg, 0.5 μg to 20 μg, 0.5 μg to 18 μ , 0.5 μg to 15 μg, 0.5 μg to 12 μg, 0.5 μg to 10 μg, 0.5 μg to 8 μg, 0.5 μg to 7 μg, 0.6 μg to 30 μg, 0.6 μξ to 27 μg, 0.6 g to 25 μg, 0.6 μg to 23 μg, 0.6 μg to 20 μg, 0.6 μg to 18 μg, 0.6 μg to 15 μg, 0.6 μg to 12 μg, 0.6 μg to 10 μg, 0.6 μg to 8 μg, 0.6 μg to 7 μg, 0.7 μg to 30 μg, 0.7 μg to 27 μg, 0.7 μg to 25 μ^ 0.7 μg to 23 μ , 0.7 μg to 20 μg, 0.7 μg to 18 μg, 0.7 μδ to 15 μ& 0.7 μg to 12 μg, 0.7 μg to 10 μg, 0.7 μg to 8 μg, 0.7 μg to 7 μg, 0.8 μg to 30 μg, 0.8 μg to 27 μg, 0.8 μg to 25 μg, 0.8 μg to 23 μg, 0.8 μg to 20 μg, 0.8 μg to 18 μg, 0.8 μg to 15 μg, 0.8 μg to 12 μg, 0.8 μg to 10 μg, 0.8 μg to 8 μ^ 0.8 μg to 7 μg, 0.9 μg to 30 μ^ 0.9 μg to 27 μg, 0.9 μg to 25 μg, 0.9 μg to 23 μ^ 0.9 μg to 20 μg, 0.9 μg to 18 μg, 0.9 μg to 15 μg, 0.9 μg to 12 μg, 0.9 μg to 10 μg, 0.9 μg to 8 μβ, 0.9 μg to 7 μg, 1 μg to 30 μg, 1 μg to 27 μg, 1 μg to 25 μg, 1 μg to 23 μg, 1 μg to 20 μg, 1 μg to 18 μg, 1 μg to 15 μg, 1 μg to 12 μg, 1 μg to 10 μg, 1 μg to 8 μg, 1 μg to 7 μg, preferably 0.01 μg to 10 μg, 0.05 μg to 10 μg, 0.1 μg to 10 μg, 0.2 μg to 10 μg , 0.3 μg to 10 μg , 0.4 μg to 10 μg, 0.5 μg to 10 μg, 0.6 μg to 10 μg, 0.7 μg to 10 μg, 0.8 μg to 10 , 0.9 μg to 10 μg, 1 μg to 10 μg, most preferably 0.2 μg to 6 μg, 0.5 μg to 5.5 μg, 0.5 μg to 5 μg, 0.5 μg to 4 μg, 1 μg to 4 μg. .
According to the present invention, the amount of fluticasone or a pharmaceutically acceptable derivative thereof included in the medicament composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof is in the range of 1 μg, 5 μg, 10 μ& 15 μg, 25 μg or 30 μ to 400 μg, 450 μg, 500 μg, 550 μg, 600 μβ, 650 μg, 700 %, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg or 1000 μg for example 1 μg to 1000 μg, 1 μg to 950 μg, 1 μg to 900 μg, 1 μg to 850 μg, 1 μg to 800 μ , 1 μg to 750 μ& 1 μg to 700 μg, 1 g to 650 μg, 1 μg to 600 μg, 1 μg to 550 μg, 1 μg to 500 μg, 1 μg to 450 μg, 1 μg to 400 μg, 5 μg to 1000 μg, 5 μδ to 950 μg, 5 μg to 900 μg, 5 μg to 850 μg, 5 μg to 800 μg, 5 μg to 750 μg, 5 μg to 700 μg, 5 μg to 650 μg, 5 μg to 600 μg, 5 μg to 550 μ& 5 μg to 500 μg, 5 μg to 450 μg, 5 μg to 400 μg, 10 μg to 1000 μ , 10 μg to 950 μ , 10 μg to 900 μ^ 10 μg to 850 μg, 10 μg to 800 μ , 10 μg to 750 μ& 10 μg to 700 μg, 10 μg to 650 μ& 10 μg to 600 μ& 10 μg to 550 μg, 10 μg to 500 μ , 10 μg to 450 μ& 10 μg to 400 μg, 15 μg to 1000 μg, 15 μg to 950 μg, 15 μg to 900 μ& 15 μg to 850 μg, 15 μg to 800 μg, 15 μg to 750 μg, 15 μg to 700 μg, 15 μ to 650 μg, 15 μg to 600 μg, 15 μg to 550 μg, 15 μ to 500 μg, 15 μg to 450 μg, 15 μg to 400 μg, 25 μg to 1000 μg, 25 μg to 950 μg, 25 μg to 900 μg, 25 μg to 850 μg, 25 μg to 800 μg, 25 μg to 750 μg, 25 μg to 700 μ 25 μg to 650 μ^ 25 μg to 600 μ& 25 μg to 550 μ^ 25 μg to 500 μ^ 25 μg to 450 μ^ 25 μg to 400 μ& 30 μg to 1000 μg, 30 μg to 950 μ& 30 μg to 900 μg, 30 μg to 850 μ 30 μg to 800 μ¾ 30 μg to 750 μ^ 30 μg to 700 μ¾ 30 μg to 650 μ^ 30 μg to 600 μ^ 30 μg to 550 μ¾ 30 μg to 500 μ¾ 30 μg to 450 μ^ 30 μg to 400 μ^ preferably 30 μg to 800 μ^ 40 μg to 750 μg, 45 μg to 600 μg, 45 μg to 550 μg, most preferably 45 μg to 500μg.
The medicament composition in accordance with the present invention is preferably in the form of micronized dry powder particles. The active agents present in said medicament composition have average particle size of 1 μηι to 20 μηι, preferably from 1 μηι to 10 μιη, most preferably 1 μιη to 6 μπι. Lactose particles present in said medicament composition as an excipient has average particle size of not more than 300 μηι, preferably not more than 250 μπι. The lactose particles in the medicament composition can be found in more than one fraction with different average particle size.
According to the present invention, the pharmaceutical composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof may additionally comprise one or more substances selected from the group comprising mast cell stabilizer, anticholinergic, adrenergic agonist, glucocorticosteroid, xanthine, anti-leukotriene, PDE IV inhibitor, EGFR inhibitor, anti-allergic, anti-inflammatory, antihistaminic and anti-muscarinic agents.
According to the present invention, the pharmaceutical composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can additionally comprise one or more substances selected from the group consisting of mast cell stabilizers such as cromoglycate, nedocromil; anticholinergics such as tiotropium, ipratropium, glicopirronium, cromoglycate, oxytropium; β2 - agonists such as formoterol, arformoterol, bambuterol, salmeterol, clenbuterol, salbutamol, fenoterol, terbutaline, carbuterol, pirbuterol; corticosteroids such as beclomethasone, budesonide, fluticasone, ciclesonide; xanthines such as doxophylline, theobromine, theophylline, aminophylline; anti-leukotrienes such as montelukast, pranlukast, zafirlukast, ritolukast, sulukast, tomelukast, verlukast, iralukast, ablukast ve cinalukast; antihistamines such as cetirizine, levocetirizine, loratadine, desloratadine, clemastine, chlorphenamine, diphenhydramine and pheniramine; PDE IV inhibitors such as roflumilast, piclamilast, cilomilast; preferably cromoglycate, tiotropium, montelukast, levocetirizine, desloratadine, roflumilast. According to the present invention, the pharmaceutical composition comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof can additionally comprise cromoglycate and/or a pharmaceutically acceptable derivative thereof. Cromoglycate derivatives mentioned in the invention comprise the pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, the free base, organic salts, inorganic salts, esters, polymorphs, crystalline and amorphous forms of cromoglycate and/or a combination thereof. Sodium cromoglycate is preferably used in the preparation of the medicament of the present invention.
The medicament comprising carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof according to the present invention can be used in the treatment of many respiratory diseases, particularly in asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis. Accordingly, these respiratory diseases can be, but not limited to, asthma at any phase, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis, chronic obstructive pulmonary including emphysema and chronic bronchitis, respiratory diseases or lung diseases (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, byssinosis. This treatment can be prophylactic or symptomatic. In addition, the composition of the present invention is especially used for symptomatic treatment of asthma and COPD.
The pharmaceutical composition pertaining to the present invention can be explained with, but not limited to, the examples given below.
The active agent carmoterol given in the following examples comprises all pharmaceutically acceptable racemates, enantiomers or diastereomers, salts, solvates, esters, hydrates and/or the free base, polymorphs, amorphous and crystalline forms thereof. The active agent fluticasone given in the following examples comprises all pharmaceutically acceptable salts, solvates, esters, hydrates and/or enantiomers, polymorphs, amorphous and crystalline forms thereof. Carmoterol or a pharmaceutically acceptable derivative thereof is preferably in the form of R,R-carmoterol. The pharmaceutically acceptable excipient given in the following examples can optionally be added in a higher or a lower amount. The capsule described in the following examples is made of gelatin; however, it can optionally be made of chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers.
The active agent cromoglycate given in the following examples comprises all pharmaceutically acceptable racemates, enantiomers or diastereomers, solvates, esters, hydrates and/or the free base, polymorphs, amorphous and crystalline forms of cromoglycate.
Example 1
A dry powder formulation suitable to be stored in blister packs so as to be used via a multi-dose inhaler comprises 1 part of carmoterol, 400 parts of fluticasone having an average particle size in the range of 1 to 5 μιη, and 10000 parts of lactose having a particle size below 300 μηι as an excipient all of which are micronized in an air jet mill.
The example can be repeated by replacing the amounts given in example 1 with the amounts given in the table below.
Figure imgf000012_0001
14 1 400 17000
15 1 400 16900
16 1 400 14690
17 2 200 14780
18 2 200 15960
19 2 200 16360
Example 20
The dry powder formulation which is suitable to be stored in a gelatin capsule so as to be used via an inhaler comprises 1 part of carmoterol, 200 parts of fluticasone having an average particle size in the range of 1 to 5 μηι, and 5500 parts of lactose as an excipient having an average particle size below 300 μιη all of which were micronized in an air jet mill.
The example can be repeated by replacing the amounts given in the table below with the amounts given in example 20.
Figure imgf000013_0001
30 2 400 12350
31 2 200 11920
32 2 300 10980
33 1 400 13000
34 1 400 9660
35 2 200 8600
36 2 200 4900
37 1 400 6230
38 1 400 5360
Example 39
A dry powder formulation suitable to be stored in blisters so as to be used via a multiple dose inhaler comprises 2 parts of carmoterol, 200 parts of fluticasone and 10000 parts of sodium chromoglycate having an average particle size in the range of 1 to 5 μηι, and 10000 parts of lactose as an excipienthaving an average particle size below 300 μιη all of which were micronized in an air jet mill.
Example 40
The dry powder formulation which is suitable to be stored in a gelatin capsule so as to be used via an inhaler comprises 2 parts of carmoterol, 200 parts of fluticasone and 10000 parts of sodium chromoglycate sodium having an average particle size in the range of 1 to 5 μηι, and 10000 parts of lactose as an excipient having an average particle size below 300 μη all of which were micronized in an air jet mill.
Example 41
An aerosol formulation developed to be used in a metered dose inhalator comprises 2 parts of carmoterol, 200 parts of fluticasone and excipients in a ratio of 97% by weight of the total formulation.

Claims

Claims
1. A medicament comprising a combination of carmoterol and/or a pharmaceutically acceptable derivative thereof and fluticasone and/or a pharmaceutically acceptable derivative thereof for simultaneous, sequential or seperate administration in the treatment of respiratory diseases.
2. The medicament composition according to claim 1 characterized in that said composition is delivered once a day.
3. The medicament composition according to claim 1 characterized in that said composition comprises carmoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof in combination.
4. The medicament composition according to claims 1 to 3, wherein the amount of carmoterol and/or the pharmaceutically acceptable derivative thereof is in the range of 0.01 to 30 μg.
5. The medicament composition according to claim 4, wherein the amount of carmoterol and/or the pharmaceutically acceptable derivative thereof is in the range of 0.01 to 10 μg.
6. The medicament composition according to claim 5, wherein the amount of carmoterol and/or the pharmaceutically acceptable derivative thereof is in the range of 0.02 to 6 μg.
7. The medicament composition according to claims 1 to 3, wherein the amount of fluticasone and/or the pharmaceutically acceptable derivative thereof is in the range of 1 to 1000 μg.
8. The medicament composition according to claim 7, wherein the amount of fluticasone and/or the pharmaceutically acceptable derivative thereof is in the range of 30 to 800 μg.
9. The medicament composition according to claims 1 to 3 characterized in that carmoterol and/or a pharmaceutically acceptable derivative thereof comprises pharmaceutically acceptable solvates, the free base, hydrates, diastereomers, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms thereof and/or a combination of these.
10. The medicament composition according to claim 9 characterized in that the pharmaceutically acceptable derivative of carmoterol is in the form of R,R-carmoterol.
11. The medicament composition according to claims 1 to 3 characterized in fluticasone and/or a pharmaceutically acceptable derivative thereof comprises its pharmaceutically acceptable solvates, the free base, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms and/or a combination thereof.
12. According to claim 11, the pharmaceutically acceptable derivative of fluticasone is preferably fluticasone furoate.
13. The medicament composition according to claim 1 characterized in that said composition is delivered by the inhalation route.
14. The medicament composition according to claim 13 characterized in that said composition is delivered to the lungs via an inhalation device.
15. The medicament composition according to claim 14 characterized in that said composition is via single-dose or multiple dose inhalation devices.
16. The medicament composition according to claims 13 to 15 characterized in that said composition is in aerosol, dry powder, solution or suspension forms.
17. The medicament composition according to claim 16 characterized in that said composition is in aerosol form.
18. The medicament composition according to claim 17 characterized in that said composition is in propellant-free aerosol form.
19. The medicament composition according to claim 17 characterized in that said composition is in aerosol form containing propellant.
20. The medicament composition according to claim 19 characterized in that the propellants contained in said composition are selected from the group comprising hydrocarbons and halohydrocarbons .
21. The medicament composition according to claim 20 characterized in that said composition is in dry powder form.
22. The medicament composition according to claim 21 characterized in that said composition comprises a pharmaceutically acceptable excipient.
23. The medicament composition according to claim 22 characterized in that said pharmaceutically acceptable excipient is selected from a group comprising monosaccarides, disaccarides, polysaccarides and oligosaccarides.
24. The medicament composition according to claim 23 characterized in that said pharmaceutically acceptable excipient is lactose.
25. The medicament composition according to claim 16 characterized in that said composition is in solution or suspension form.
26. The medicament composition according to any preceding claims characterized in that said composition additionally comprises one or more substances selected from the group comprising anticholinergic, adrenergic agonist, glucocorticosteroid, xanthine, antileukotriene, PDEIV inhibitor, EGFR inhibitors, anti-allergic, anti-inflammatory, antihistamine and antimuscarinic substances.
27. The medicament composition according to claim 26 characterized in that said composition additionally comprises one or more substances selected from the group comprising mast cell stabilizers such as chromoglycate and nedocromile; anticholinergics such as tiotropium, ipratropium, glycopyrronium, chromoglycate and oxytropium; p2-agonists such as formoterol, arformoterol, bambuterol, salmeterol, clenbuterol, salbutamol, fenoterol, terbutaline, carbuterol and pirbuterol; corticosteroids such as beclomethasone, budesonide, mometasone and ciclesonide; xanthines such as doxyphylline, theobromine, theophylline and aminophylline; antileukotrienes such as montelukast, pranlukast, zafirlukast, ritolukast, sulukast, tomelukast, verlukast, iralukast, ablukast and cinalukast; antihistamines such as cetirizine, levocetirizine, loratadin, desloratadin, clemastine, chlorphenamine, diphenhydramine and pheniramine; PDEIV inhibitors such as roflumilast, piclamilast and cilomilast.
28. The medicament composition according to claim 27 characterized in that said composition additionally comprises one or more substances selected from the group comprising chromoglycate, tiotropium, montelukast, levocetirizine, desloratadine and roflumilast.
29. The medicament composition according to claim 28 characterized in that said composition additionally comprises a chromoglycate.
30. The medicament composition according to claim 29 characterized in that chromoglycate comprised in said composition is in the form of sodium salt.
31. The medicament according to any preceding claims characterized in that said composition is used in the treatment of many respiratory tract diseases, especially in asthma, chronic obstructive pulmonary disorder (COPD) and allergic rhinitis.
PCT/TR2011/000113 2010-04-26 2011-04-25 Combination of carmoterol and fluticasone for use in the treatment respiratory diseases WO2011136753A1 (en)

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WO2013109218A1 (en) * 2012-01-16 2013-07-25 Mahmut Bilgic Dry powder formulations comprising carmoterol and ciclesonide
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WO2012166070A1 (en) * 2011-06-02 2012-12-06 Mahmut Bilgic Dry powder formulation with improved flow characteristics
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US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
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