WO2020152548A1 - Compositions pour inhalation d'aérosol stables à base de formotérol - Google Patents

Compositions pour inhalation d'aérosol stables à base de formotérol Download PDF

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Publication number
WO2020152548A1
WO2020152548A1 PCT/IB2020/050336 IB2020050336W WO2020152548A1 WO 2020152548 A1 WO2020152548 A1 WO 2020152548A1 IB 2020050336 W IB2020050336 W IB 2020050336W WO 2020152548 A1 WO2020152548 A1 WO 2020152548A1
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WIPO (PCT)
Prior art keywords
aerosol inhalation
acid
inhalation composition
composition according
formoterol
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PCT/IB2020/050336
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English (en)
Inventor
Ulhas Dhuppad
Raveendra Pai
Ashok KATKURWAR
Ramakant CHANAGARE
Kautik SHIROLE
Sushrut Kulkarni
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Glenmark Pharmaceuticals Limited
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Publication of WO2020152548A1 publication Critical patent/WO2020152548A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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

Definitions

  • the present relates to a stable aerosol inhalation compositions to be used with pressurized metered dose inhalers (pMDI) comprising formoterol or its pharmaceutically acceptable salts, optionally in combination with beclomethasone or its pharmaceutically acceptable salt as active ingredients, an alcoholic co-solvent, an organic acid and an environmentally safe hydrofluoroalkane (HFA) as a propellant, its process of preparation and method of administering for the treatment of respiratory disorders in a subject.
  • pMDI pressurized metered dose inhalers
  • pMDI pressurized metered dose inhalers
  • formoterol or its pharmaceutically acceptable salts optionally in combination with beclomethasone or its pharmaceutically acceptable salt as active ingredients
  • an alcoholic co-solvent an organic acid and an environmentally safe hydrofluoroalkane (HFA) as a propellant
  • HFA environmentally safe hydrofluoroalkane
  • Inhalation therapy has been used for thousands of years and is considered to be one of the best options for treating disorders related to respiratory system.
  • the composition for treating respiratory disorders are administered in the form of aerosols dispensed as solutions or suspensions of drugs mixing with liquefied gases known as propellants.
  • propellants comprised a mixture of chlorofluorocarbons (CFCs) to provide the desired solubility, vapor pressure, and stability of the composition.
  • CFCs chlorofluorocarbons
  • HFA hydrofluoroalkane
  • An aerosol composition is forced from the container through the dose metering valve by the high vapor pressure of the propellant to release a fixed, predetermined amount of the drug composition affixed to the container. Concurrently with the activation of the aerosol dose metering valve, the patient inhales the drug composition particles into the lungs.
  • Formoterol N-[2-hydroxy-5-[l-hydroxy-2-[l-(4-methoxyphenyl)propan-2- ylamino] ethyl] phenyl] formamide
  • COPD chronic obstructive pulmonary disease
  • Formoterol is commercially available as metered dose inhaler under the brand name Symbicort® (combination with budesonide), Bevespi Aerosphere (combination with glycopyrrolate) and Dulera® (combination with momentasone).
  • Symbicort® combination with budesonide
  • Bevespi Aerosphere combination with glycopyrrolate
  • Dulera® combination with momentasone
  • formoterol fumarate is available as metered dose inhaler marketed as Atimos Modulite and in combination with beclomethasone dipropionate marketed as Fostair/Foster. Both Atimos Modulite and Fostair comprises hydrochloric acid as a stabilizer.
  • Respiratory disorders related to airway inflammation include a number of lung diseases chronic obstructive pulmonary disease (COPD) and asthma.
  • COPD chronic obstructive pulmonary disease
  • Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli, and manifested by widespread narrowing of the airways that changes in severity either spontaneously or as a result of treatment.
  • the events leading to airway obstruction in asthma include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.
  • COPD is a disease of the respiratory apparatus, characterized by an irreversible obstruction of the airways, of a degree that varies according to the gravity.
  • COPD as a term is used to classify two major airflow obstruction disorders: chronic bronchitis and emphysema.
  • Chronic bronchitis is inflammation of the bronchial airways.
  • Emphysema is inflammation of the alveoli, or air sacs in the lungs.
  • US4174295 discloses the use of propellant systems consisting of combinations of HFAs, which may also contain a saturated hydrocarbon component, suitable for application in the fields of home products such as hair lacquers, anti-perspiration products, perfumes, deodorants, paints, insecticides and the like. It is known in the art that certain HFAs have properties suitable for use as propellants.
  • EP1474118A1 discloses a pMDI compositions of formoterol containing propellant together with polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) as a stabilizer.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • EP2249807A2 teaches compositions comprising a suspension of a pharmaceutically active agents in one or more propellant system and one or more suspension stabilizers such as amino acids and saccharides.
  • a pharmaceutically active agents such as amino acids and saccharides.
  • One of the stabilizer is vinyl polymer such as polyvinylpyrrolidone (PVP).
  • EP1787639B1 discloses that the addition of an organic acid does not improve the stability of the aerosol composition. It focuses on aerosol solution compositions comprising formoterol, beclomethasone, a propellant, a co-solvent and an inorganic acid such as hydrochloric acid, nitric and phosphoric acid.
  • Inorganic acids such as hydrochloric, nitric and phosphoric acid are considered to be corrosive which limits their use in pharmaceutical manufacturing process, especially in metered dose inhalers (MDIs). Use of such acids requires complicated safety systems during handling process. Further, inorganic acids cause throat irritation which leads to poor patient compliance.
  • Commercially available formoterol containing products are formulated using strong mineral acids to attain requisite chemical stability. The inventors of the present invention have found that the addition of an organic acid to the HFC propellant/co-solvent system provides the stability to the composition without compromising with the safety aspect.
  • organic acids are non-corrosive as compared to mineral acids even at higher concentrations.
  • the object of this invention is to provide an aerosol inhalation composition comprising formoterol or salt thereof as an active agent, HFA as a propellant, an alcohol as a co-solvent and organic acid.
  • Another object is to provide an aerosol inhalation composition comprising formoterol which remains stable for a sufficiently extended period so that a commercial use is allowed.
  • the present invention provides a stable aerosol inhalation composition of formoterol stabilized using an organic acid.
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) an alcoholic co-solvent (c) an organic acid and (d) an HFA propellant.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) therapeutically effective amount of glucocorticoid selected from beclomethasone, budesonide, dexamethasone, fluticasone, flunisolide, triamcinolone pharmacologically acceptable salts thereof and combinations thereof (c) an alcoholic co-solvent (d) an organic acid and (e) an HFA propellant.
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) therapeutically effective amount of beclomethasone (c) an alcoholic co-solvent (d) an organic acid and (e) an HFA propellant.
  • the stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) therapeutically effective amount of beclomethasone (c) an alcoholic co- solvent (d) an organic acid (e) an HFA propellant (f) optionally an inorganic salt and/or (g) optionally an inorganic acid.
  • a suitable HFA propellant is toxicologically safe and must have a vapor pressure in order to enable the medicament to be administered via a pressurized MDI.
  • An HFA propellant can be selected from HFA- 134(a), HFA-227A, HFA-32 HFC-143(a), HFC-134, HFC-152a and mixture thereof, preferably, HFA- 134(a) and HFA-227. More preferably, the HFA propellant is HFA- 134(a).
  • the alcoholic co-solvent in the present invention comprises one or more of C2- C6 aliphatic alcohols, glycerol, polyoxyethylene alcohols, wherein co-solvent may further comprise water. More preferably, the co-solvent is ethanol.
  • the organic acid is used as a stabilizer and is selected from a group consisting of citric acid, tartaric acid, lactic acid, formic acid, acetic acid, oxalic acid, ascorbic acid, malic acid and succinic acid or mixtures thereof.
  • an organic acid is citric acid, tartaric acid or ascorbic acid. More preferably, an organic acid is citric acid.
  • the stable aerosol inhalation composition is free or substantially free of an inorganic acid.
  • the stable aerosol inhalation composition may contain less than 0.1% of an inorganic acid such as hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids, hypochlorous acid, chlorous acid, chloric acid, perchloric acid.
  • the stable aerosol inhalation composition optionally may have Inorganic salts such as sodium phosphate (both monobasic and dibasic), sodium chloride, calcium phosphate, calcium chloride and other physiologically acceptable salts.
  • Inorganic salts such as sodium phosphate (both monobasic and dibasic), sodium chloride, calcium phosphate, calcium chloride and other physiologically acceptable salts.
  • a stable aerosol inhalation composition is a suspension wherein either or both of formoterol and beclomethasone is present in substantially insoluble form in the composition or a solution wherein both the active ingredients are in solubilized form.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol fumarate dihydrate (b) ethanol as a co-solvent (c) citric acid as a stabilizer and (d) HFA 134a propellant.
  • the present invention relates to a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol fumarate dihydrate (b) therapeutically effective amount of beclomethasone dipropionate (c) ethanol as a co-solvent (d)citric acid as a stabilizer and (e) HFA 134a propellant.
  • the stable aerosol inhalation composition comprises (a) about 0.001% w/w to about 2.5% w/w formoterol fumarate dihydrate, (b) about 5% w/w to about 25% w/w of ethanol as a co-solvent (c) about 0.0001% w/w to about 0.04% w/w of citric acid as a stabilizer and (d) HFA 134a propellant.
  • the stable aerosol inhalation composition comprises (a) about 0.001% w/w to about 2.5% w/w formoterol fumarate dihydrate, (b) about 0.003% w/w to about 2.5% w/w of beclomethasone dipropionate (c) about 5% w/w to about 25% w/w of ethanol as a co-solvent (d) about 0.0001% w/w to about 0.04% w/w of citric acid as a stabilizer and (e) HFA 134a propellant.
  • the stable aerosol inhalation composition comprises (a) about 0.001% w/w to about 2.5% w/w formoterol fumarate dihydrate, (b) about 0.003% w/w to about 2.5% w/w of beclomethasone dipropionate (c) about 5% w/w to about 25% w/w of ethanol as a co-solvent (d) about 0.0001% w/w to about 0.04% w/w of citric acid as a stabilizer and (e) HFA 134a propellant.
  • the stable aerosol inhalation composition as described herein is substantially free of - (a) a surfactant and; (b) a low volatility component.
  • the stable aerosol inhalation composition as described herein is having a pH about 3.5 to 6.5 and/or is substantially free of an inorganic acid.
  • the stable aerosol inhalation composition as described herein may further comprise water as a solvent.
  • the stable aerosol inhalation composition comprises (a) about 0.01% w/w to 0.02% w/w of formoterol fumarate dihydrate (b) about 10% w/w to 12% w/w of ethanol as a co-solvent (c) about 0.0002% w/w to 0.03% w/w of citric acid as a stabilizer, (d) HFA 134a propellant and; (e) water in an amount in the range of from about 0.01% w/w to 1% w/w based upon total weight of composition, wherein pH of the composition is about 3.5 to about 6.5.
  • the stable aerosol inhalation composition comprises (a) about 0.01% w/w to 0.02% w/w of formoterol fumarate dihydrate (b) about 0.1% w/w to 0.5% w/w of beclomethasone dipropionate (c) about 10% w/w to 12% w/w of ethanol as a co- solvent (d) at least about 0.0002% w/w to 0.01% w/w of citric acid as a stabilizer, (d) HFA 134a propellant and; (e) water in an amount in the range of from about 0.01% w/w to 1% w/w based upon total weight of composition , wherein pH of the composition is about 3.5 to about 6.5.
  • the stable aerosol inhalation composition as described herein is substantially free of an inorganic acid, a surfactant or a low volatility component.
  • the present invention relates to a method of treating a respiratory disorder selected from but not limited to chronic obstructive pulmonary disease and asthma wherein the said method comprises of administering an aerosol inhalation composition of the present invention to the subject in need thereof.
  • the invention relates to the use of the stable aerosol inhalation composition for the treatment of a respiratory disorder selected from chronic obstructive pulmonary disease or asthma in a subject.
  • a method of treating a respiratory disorder in a subject in need thereof comprising administering by inhalation a composition comprising (a) therapeutically effective amount of formoterol fumarate dihydrate (b) ethanol as a co-solvent (c) citric acid as a stabilizer and (d) HFA 134a propellant.
  • the composition further comprises a therapeutically effective amount of beclomethasone dipropionate.
  • the respiratory disorder is selected from chronic obstructive pulmonary disease or asthma.
  • a drug delivery device comprising stable aerosol inhalation composition as described herein.
  • the drug delivery device may be any conventional device designed to administer a pressurized aerosol composition to the lungs.
  • a particularly preferred drug delivery device is a metered-dose inhaler.
  • the compositions of the present invention may be delivered using a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • the aerosol inhalation composition of the present invention is filled in a canister coated with fluorocarbon polymers for inhalation using a pressurized metered dose inhaler.
  • the composition when administered with a drug delivery device provides an efficient drug delivery to the lungs which is defined in terms of fine particle fraction (% FPF), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) when measured using a cascade impactor.
  • % FPF fine particle fraction
  • MMAD mass median aerodynamic diameter
  • GSD geometric standard deviation
  • the aerosol inhalation composition provides a mean median aerodynamic diameter (MMAD) of formoterol and/or beclomethasone particles in the range of about 0.1 to 10 pm, about 0.5 to 8 pm; about 1 to 5 pm; about 1 to 3 pm; or preferably about 1 to 2 pm.
  • the aerosol inhalation composition when administered with a metered dose inhaler exhibits a Mass Median Aerodynamic Diameter (MMAD) of about 1 pm to about 5 pm.
  • MMAD Mass Median Aerodynamic Diameter
  • the aerosol inhalation composition provides a fine particle fraction (FPF) of formoterol and/or beclomethasone particles in the range of about 20% to about 75%, about 25% to about 60%, about 25% to about 50%, about 30% to about 40%.
  • FPF fine particle fraction
  • the aerosol inhalation composition when administered with a metered dose inhaler exhibits a fine particle fraction of about 25% to about 50%.
  • the aerosol inhalation composition exhibits a GSD between 1.5 and 2.5 pm.
  • the aerosol inhalation composition provides a fine particle dose (FPD) of formoterol in the range of about 1 pm to 5 pm.
  • FPD fine particle dose
  • the aerosol inhalation composition provides a fine particle dose (FPD) of beclomethasone in the range of about 30 pm to 50 pm.
  • FPD fine particle dose
  • the aerosol composition of the present invention is prepared and filled using conventional process of mixing and filling in the appropriate canister. It comprises of the following steps:
  • Step 3 Filling the crimped canister (coated or uncoated) with the solution as obtained in Step 2.
  • the solution obtained in step 1 is filled into crimped canister following by charging of propellant containing HFA into the canister through metered valve.
  • stable aerosol inhalation composition means a pharmaceutical composition which exhibits substantial chemical stability over a period of time comprising a medicament suitable for aerosol inhalation administered by pressurized meter dose inhalers used for delivery of the drug to the respiratory tract.
  • terapéuticaally effective amount denotes an amount of an active ingredient delivered upon each actuation and produces a therapeutic benefit in a subject when administered to a subject for treating respiratory disorders.
  • respiratory disorder means a pulmonary disease involving any obstructive or destructive conditions of respiratory tract, vascular diseases and infectious diseases which may or may not be acute or chronic and communicable or non-communicable.
  • the respiratory disorder selected from chronic obstructive pulmonary disease, asthma, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity in a subject.
  • the terms“formoterol” and“beclomethasone” as used herein includes the base form and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, esters, polymorphs, complex, co-crystals thereof.
  • the pharmaceutically acceptable salts of“formoterol” include sulphate, phosphate, maleate, chloride, bromide, tartarate, citrate, benzoate, 4- hydroxybenzoate, 4-chlorobenzoate, acetate, lactate, succinate, benzenesulphonate, gluconate.
  • the formoterol is in form of its fumarate dihydrate salt.
  • the stable aerosol inhalation compositions of the present invention comprise formoterol fumarate dihydrate and beclomethasone dipropionate as active agents.
  • MMAD mass median aerodynamic diameter
  • FPD fine particle dose or fraction
  • GSD geometric standard deviation
  • MMAD mass median aerodynamic diameter
  • Solid particles and/or droplets in an aerosol formulation can be characterized by their MMAD.
  • the present invention provides a stable aerosol inhalation composition comprising formoterol or its salts and an organic acid with a sufficiently small mass median aerodynamic diameter (e.g., less than 5 microns). This helps in ensuring the deposition of the active ingredients below the larynx upon inhalation, and uniformity of delivered dose to provide repeatable and predictable dosing.
  • the MMAD of the composition is maintained from about 1.35 to about 1.65 microns to ensure the delivery of uniform dose upon each actuation of metered dose inhaler.
  • fine particle fraction refers to mass fraction of the dose emitted in this size range by a particular inhaler.
  • the fine particle fraction (FPF) is normally defined as the FPD divided by the ED and expressed as a percentage.
  • a higher fine particle fraction indicates improved delivery efficiency due to a significant decrease in throat deposition. Having a higher fine particle fraction may also allow a lower amount of total drug dose needed to achieve equivalent therapeutic benefits.
  • the compositions of the present invention provide formoterol and beclomethasone with FPF of about 20% to 75%; preferably FPF of about 25% to 65%, more preferably FPF of about 25% to 50%.
  • fine particle dose is the total mass of active agent which is emitted from the device following actuation which is present in an aerodynamic particle size smaller than a defined limit.
  • the compositions of the present invention have a fine particle dose (FPD) for formoterol or its salt of about 0.001 pg to about 20 pg, about 0.01 pg to about 10 pg, about 0.1 pg to about 5 pg, about 1 pg to about 5 pg, or about 1 pg to about 3 pg.
  • compositions of the present invention have a fine particle dose (FPD) for beclomethasone or its salt of about 5 pg to about 80pg, about 10 pg to about 70pg or about 20 pg to about 60 pg or about 30pm to about 50pm.
  • FPD fine particle dose
  • GSD Geometric Standard Deviation
  • d 84 and d 1 ⁇ 2 represent the diameters at which 84% and 16% of the aerosol mass are contained, respectively, in diameters less than these diameters.
  • the aerosol inhalation composition of the present invention exhibits a GSD between 1.5 and 2.5 pm.
  • Anderson Cascade Impactor is an eight-stage impactor that can separate aerosols into nine distinct fractions based on aerodynamic size. The size cutoffs of each stage are dependent upon the flow rate at which the ACI is operated.
  • the ACI is made up of multiple stages consisting of a series of nozzles (i.e., a jet plate) and an impaction surface (i.e., an impaction disc). At each stage an aerosol stream passes through the nozzles and impinges upon the surface. Respirable dry particles in the aerosol stream with a large enough inertia will impact upon the plate.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) an alcoholic co-solvent (c) an organic acid and (d) an HFA propellant.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) therapeutically effective amount of glucocorticoid selected from beclomethasone, budesonide, dexamethasone, flunisolide, triamcinolone, pharmacologically acceptable salts thereof and combinations thereof (c) an alcoholic co-solvent (d) an organic acid and (e) an HFA propellant.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) therapeutically effective amount of beclomethasone (c) an alcoholic co-solvent (d) an organic acid and (e) an HFA propellant.
  • HFA propellant Hydrofluoroalkane; also known as hydrofluorocarbon or HFC propellant
  • a pharmaceutically suitable HFA propellant is toxicologic ally safe and must have a vapor pressure in order to enable the medicament to be administered via a pressurized MDI.
  • An HFA propellant can be selected from 1,1,1,2-tetrafluoroethane (HFC-134(a)), 1,1,1,2,3,3,3,-heptafluoropropane (HFC-227), HFA-32 (difluoromethane), HFC-143(a) (1,1,1-trifluoroethane), HFC-134 (1,1,2,2-tetrafluoroethane), and HFC-152a (1,1-difluoroethane), preferably from 1,1,1,2- tetrafluoroethane (HFC-134(a)) and 1,1,1,2,3,3,3,-heptafluoropropane (HFC-227). More preferably, the HFA propellant is HFA- 134(a).
  • a co-solvent is any solvent which forms a homogenous composition in which the drug(s) can be dissolved.
  • the function of the co-solvent is to increase the solubility of the drug(s) and the excipients.
  • the alcoholic co- solvent in the present invention comprises one or more of C2- C6 aliphatic alcohols, glycerol, polyoxyethylene alcohols, wherein co-solvent may further comprise water. More preferably, the co-solvent is ethanol.
  • An organic acid is used as a stabiliser in the composition of the present invention to maintain the desired apparent pH, preferably in the range of 3.5 -6.5, more preferably in the range of 4.0 to 6.0 to impart stability and most preferably in the range of 4.5-5.5.
  • the organic acid is selected from a group consisting of citric acid, tartaric acid, lactic acid, formic acid, acetic acid, oxalic acid, ascorbic acid, malic acid and succinic acid or mixtures thereof.
  • an organic acid is citric acid, tartaric acid or ascorbic acid. More preferably, an organic acid is citric acid.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol fumarate dihydrate (b) ethanol as a co-solvent (c) citric acid as a stabilizer and (d) HFA 134a propellant.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol fumarate dihydrate (b) therapeutically effective amount of beclomethasone dipropionate (c) ethanol as a co-solvent (d) citric acid as a stabilizer and (e) HFA 134a propellant.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) therapeutically effective amount of beclomethasone (c) an alcoholic co- solvent (d) an organic acid (e) an HFA propellant (f) optionally an inorganic salt and/or (g) optionally an inorganic acid.
  • the stable aerosol inhalation composition may be a solution or a suspension.
  • a stable aerosol inhalation composition is a solution wherein both the active ingredients are in solubilized form.
  • the stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) therapeutically effective amount of beclomethasone (c) an alcoholic co-solvent (d) an organic acid and (e) an HFA propellant wherein either or both of formoterol and beclomethasone is present in substantially insoluble form in the composition.
  • the present invention relates to a stable aerosol inhalation composition
  • a stable aerosol inhalation composition comprising (a) therapeutically effective amount of formoterol (b) therapeutically effective amount of beclomethasone (c) an alcoholic co-solvent (d) an organic acid and (e) an HFA propellant wherein either or both of formoterol and beclomethasone is present in soluble form in the composition.
  • the stable aerosol inhalation composition of the present invention comprises of formoterol or its pharmaceutically acceptable salt is in an amount from about 0.0005 % w/w to about 5 % w/w or from about 0.001 % w/w to about 2.5 % w/w or from about 0.005% w/w to about 1.5% w/w or from about 0.01% w/w to about 0.5% w/w or from about 0.01% w/w to about 0.05% w/w or from about 0.01% w/w to about 0.02% w/w based upon the total weight of the aerosol composition.
  • the stable aerosol inhalation composition of the present invention comprises of beclomethasone or its salt in an amount from about 0.001% w/w to about 5% w/w or from about 0.003 % w/w to about 2.5 % w/w or from about 0.01% w/w to about 1.5% w/w or from about 0.05% w/w to about 1% w/w or from about 0.1% w/w to 0.5% w/w based upon the total weight of the aerosol composition.
  • the stable aerosol inhalation composition of present invention may further comprises water in an amount in the range of from about 0.01% w/w to 1% w/w or from 0.02% w/w to 0.5% w/w.
  • the stable aerosol inhalation composition comprises (a) about 0.001% w/w to about 2.5% w/w or from about 0.005% w/w to about 1% w/w formoterol fumarate dihydrate, (b) about 5% w/w to about 25% w/w of ethanol as a co-solvent (c) about 0.0001% w/w to about 0.04% w/w of citric acid as a stabilizer and (d) HFA 134a propellant; wherein composition further comprises water in an amount in the range of from about 0.01% w/w to 1% w/w.
  • the stable aerosol inhalation composition comprises (a) about 0.001% w/w to about 2.5% w/w formoterol fumarate dihydrate, (b) about 0.003% w/w to about 2.5% w/w of beclomethasone dipropionate (c) about 5% w/w to about 25% w/w of ethanol as a co- solvent (d) about 0.0001% w/w to about 0.04% w/w of citric acid as a stabilizer and (e) HFA 134a propellant; wherein composition further comprises water in an amount in the range of from about 0.01% w/w to 1% w/w.
  • the stable aerosol inhalation composition comprises (a) about 0.001% w/w to about 2.5% w/w formoterol fumarate dihydrate, (b) about 0.003% w/w to about 2.5% w/w of beclomethasone dipropionate (c) about 5% w/w to about 25% w/w of ethanol as a co-solvent (d) about 0.0001% w/w to about 0.04% w/w of citric acid as a stabilizer (e) HFA 134a propellant (f) optionally less than about 2% of an inorganic salt and optionally about less than 0.1% of an inorganic acid; wherein composition further comprises water in an amount in the range of from about 0.01% w/w to 1% w/w.
  • the stable aerosol inhalation composition as described herein is having a pH about 3.5 to 6.5 or preferably 4.5 to 5.5 and/or is substantially free of an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid.
  • the stable aerosol inhalation composition comprises (a) about 0.01% w/w to about 0.02% w/w of formoterol fumarate dihydrate (b) about 10% w/w to about 12% w/w of ethanol as a co-solvent (c) about 0.0002% w/w to 0.01% w/w of citric acid as a stabilizer, (d) HFA 134a propellant and (e) water in an amount in the range of from about 0.01% w/w to 1% w/w based upon total weight of composition , wherein pH of the composition is about 3.5 to about 6.5.
  • the stable aerosol inhalation composition comprises (a) about 0.01% w/w to about 0.02% w/w of formoterol fumarate dihydrate (b) about 0.1% w/w to 0.5% w/w of beclomethasone dipropionate (c) about 10% w/w to about 12% w/w of ethanol as a co solvent (d) about 0.0002% w/w to 0.01% w/w of citric acid as a stabilizer, (d) HFA 134a propellant and; (e) water in an amount in the range of from about 0.01% w/w to 1% w/w based upon total weight of composition , wherein pH of the composition is about 3.5 to about 6.5.
  • the stable aerosol inhalation composition as described herein is substantially free of- (a) a surfactant and; (b) a low volatility component.
  • the Low volatility component includes polyvinylpyrrolidone (PVP), propylene glycol, polyethylene glycol or glycerol, isopropyl myristate, ascorbyl palmitate and tocopherol.
  • PVP polyvinylpyrrolidone
  • propylene glycol polyethylene glycol or glycerol
  • isopropyl myristate isopropyl myristate
  • ascorbyl palmitate tocopherol.
  • the surfactants include sorbitan trioleate, cetyl pyridinium chloride, soya lecithin, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (10) stearyl ether, polyoxyethylene (2) oleyl ether, polyoxyethylene-polyoxypropylene-ethylenediamine block copolymers, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene-polyoxypropylene block copolymers, oleic acid, castor oil ethoxylate, and mixtures.
  • the stable aerosol inhalation composition comprises (a) about 0.01% w/w to about 0.02% w/w of formoterol fumarate dihydrate (b) about 10% w/w to about 12% w/w of ethanol as a co-solvent (c) about 0.0002% w/w to 0.01% w/w of citric acid as a stabilizer, (d) HFA 134a propellant and; (e) water in an amount in the range of from about 0.01% w/w to 1% w/w based upon total weight of composition, wherein the composition is substantially free of an inorganic acid, a surfactant or a low volatility component.
  • the stable aerosol inhalation composition comprises (a) about 0.01% w/w to about 0.02% w/w of formoterol fumarate dihydrate (b) about 0.1% w/w to 0.5% w/w of beclomethasone dipropionate (c) about 10% w/w to about 12% w/w of ethanol as a co solvent (d) about 0.0002% w/w to 0.01% w/w of citric acid as a stabilizer, (e) HFA 134a propellant and; (e) water in an amount in the range of from about 0.01% w/w to 1% w/w based upon total weight of composition, wherein the composition is substantially free of an inorganic acid, a surfactant or a low volatility component.
  • formoterol and/or beclomethasone are present in an amount such that upon actuation of inhaler therapeutically effective dose is delivered.
  • the stable aerosol inhalation composition comprises formoterol in the range of from about 0.1pg/pl to about 0.3pg/pl or from about 0.12 pg/pl to about 0.25pg/pl and beclomethasone in the range of from about 1.5 pg/pl to about 4.5pg/pl or from about 2pg/pl to about 4.3 pg/pl.
  • the therapeutically effective dose of formoterol fumarate dihydrate is 5-14pg and the dose of beclomethasone dipropionate is 90-220pg delivered upon each actuation.
  • a person skilled in that art may chose appropriate metering valve to deliver requisite amount of drug upon actuation.
  • each actuation delivers 50pl volume of the aerosol composition containing 6pg formoterol fumarate dihydrate and lOOpg or 200pg beclomethasone dipropionate.
  • the invention relates to the use of the stable aerosol inhalation composition for the treatment of a respiratory disorder selected from but not limited to chronic obstructive pulmonary disease or asthma in a subject.
  • a drug delivery device comprising a stable aerosol inhalation compositions as described herein.
  • the drug delivery device may be any conventional device designed to administer a pressurized aerosol composition to the lungs.
  • a particularly preferred drug delivery device is a metered-dose inhaler.
  • the compositions of the present invention may be delivered using a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • the drug delivery device comprises a suitable aerosol canister with a metering valve containing a stable aerosol inhalation composition of the present invention and an actuator housing adapted to hold the canister and allow for drug delivery.
  • the canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister.
  • the stable aerosol inhalation composition of the present invention can be used in conventional metered-dose inhalers. Furthermore, the compositions do not clog any part of the drug delivery device, e.g., valve.
  • the canister may be made of any suitable material such as aluminium, aluminium alloys, stainless steel, tin, plastic or glass which may be coated or uncoated. Some drugs tend to adhere to the inner surfaces, i.e., walls of the canister and may clog metering valves of the device components. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each activation of the MDI. Coating the inner surface of the container with a suitable polymer can reduce this adhesion problem. Suitable coatings include fluorocarbon copolymers such as FEP-PES (fluorinated ethylene propylene and polyethersulphone) and PFA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene.
  • FEP-PES fluorinated ethylene propylene and polyethersulphone
  • PFA-PES perfluoroalkoxyalkane and polyethersulphone
  • the inner surfaces of the canister may be anodized, plasma treated or plasma coated.
  • the aerosol inhalation composition of the present invention is filled into aluminum canister whose inner surface are coated with fluorocarbon polymer.
  • the canister is fitted with a valve, preferably a metering valve.
  • Metering valves suitable to deliver a specific amount of the composition each time the device is actuated. Once a valve is crimped into place, the canisters must be able to adequately seal the propellant without leaking.
  • the metering valve delivers about 50pl of composition of present invention.
  • a gasket is also used between the valve and the canister to prevent leakage of the composition.
  • the gasket used in rubber or polymer gasket more preferably, the gasket used is ethylene propylene diene monomer rubber.
  • the aerosol composition of the present invention may be placed in the canister using conventional methods such as cold filling or back filling leaving a sufficient“head space”.
  • the filled canisters are then placed in a suitable housing to complete the drug delivery device.
  • a fixed amount of composition is released initially through the metering valve and then though the cylindrical passage of the housing.
  • the propellant vaporizes, the drug is suspended in air. Patients then inhale the suspended drug, thereby effecting pulmonary drug administration.
  • the stable aerosol inhalation composition as described herein is filled in a canister with the capacity of 15-22ml wherein the filled volume of the composition is about 8ml to about 20ml.
  • the actuator used for dispensing the drug delivers the volume of about 50m1 per actuation.
  • Patient may use one or two puffs once or twice daily as per the requirement or severity of disease-.
  • the aerosol composition of the present invention is prepared and filled using conventional process of mixing and filling in the appropriate canister. It comprises of the following steps:
  • Step 3 Filling the crimped canister (coated or uncoated) with the solution as obtained in Step 2.
  • the solution obtained in step 1 is filled into crimped canister following by charging of propellant containing HFA into the canister through metered valve.
  • the aerosol composition of the present invention is prepared and filled using conventional process of mixing and filling in the appropriate canister. It comprises of the following steps:
  • Step 3 Filling the crimped canister (coated or uncoated) with the solution as obtained in Step 2.
  • the solution obtained in step 1 is filled into crimped canister following by charging of propellant containing HFA into the canister through metered valve.
  • Example 1 Formoterol aerosol inhalation composition
  • Formoterol was dissolved in HFA 134a containing ethanol, organic acid (citric acid, oxalic acid & lactic acid) & water in order to maintain the pH in the range of 4.5 to 5.5. 2.
  • the solution prepared in step 1 was transferred into appropriate crimped canister coated with fluorocarbon polymers.
  • Example 2 Formoterol and Beclomethasone containing aerosol inhalation composition:
  • Formoterol and Beclomethasone were dissolved in HFA134a containing ethanol, organic acid and water in order to maintain the pH in the range of 4.5 to 5.5.
  • step 2 The solution prepared in step 1 was transferred into appropriate crimped canister coated with fluorocarbon polymers.
  • Example 3 Formoterol and Beclomethasone containing aerosol inhalation composition:
  • Formoterol and Beclomethasone were dissolved in HFA134a containing ethanol, organic acid (citric acid, ascorbic acid & tartaric acid) and water in order to maintain the pH in the range of 4.5 to 5.5.
  • step 2 The solution prepared in step 1 was transferred into appropriate crimped canister coated with fluorocarbon polymers.
  • Example 4 Formoterol and Beclomethasone containing aerosol inhalation composition:
  • Formoterol and Beclomethasone were dissolved in HFA134a containing ethanol, organic acid, inorganic acid, inorganic salt and water in order to maintain the pH in the range of
  • Example 5 Formoterol and Beclomethasone containing aerosol inhalation composition:
  • step 3 The concentrate prepared in step 2 was filled in a canister and crimped with 50 mcl
  • Example 5 was evaluated using an Anderson cascade Impactor (ACI) device. Evaluation measures include, but are not limited to, Fine particle fraction (FPF), Fine particle dose (FPD), Mass Median Aerodynamic Diameter (MMAD), Geometric Standard Deviation (GSD) etc.
  • FPF Fine particle fraction
  • FPD Fine particle dose
  • MMAD Mass Median Aerodynamic Diameter
  • GSD Geometric Standard Deviation

Abstract

La présente invention concerne des compositions pour inhalation d'aérosol stables destinées à être utilisées avec des aérosols-doseurs sous pression (pMDI) comprenant du formotérol ou ses sels pharmaceutiquement acceptables, éventuellement en combinaison avec du béclométhasone ou son sel pharmaceutiquement acceptable en tant que principes actifs, un cosolvant alcoolique, un acide organique et un hydrofluoroalcane (HFA) sans danger pour l'environnement en tant que propulseur, leur procédé de préparation et un procédé d'administration pour le traitement de troubles respiratoires chez un sujet.
PCT/IB2020/050336 2019-01-24 2020-01-16 Compositions pour inhalation d'aérosol stables à base de formotérol WO2020152548A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994013262A1 (fr) * 1992-12-09 1994-06-23 Boehringer Ingelheim Pharmaceuticals, Inc. Formulations de solutions medicinales aerosol stabilisees
WO1999065464A1 (fr) * 1998-06-18 1999-12-23 Boehringer Ingelheim Pharmaceuticals, Inc. Preparations pharmaceutiques pour aerosols a deux principes actifs ou plus
EP1787639A2 (fr) * 2000-05-22 2007-05-23 CHIESI FARMACEUTICI S.p.A. Formulations de solutions pharmaceutiques stables pour inhalateurs à dosage mesuré pressurisés
WO2007121913A2 (fr) * 2006-04-21 2007-11-01 Chiesi Farmaceutici S.P.A. Formulations en solution pharmaceutiques pour aérosols-doseurs pressurisés
WO2018051131A1 (fr) * 2016-09-19 2018-03-22 Mexichem Fluor S.A. De C.V. Composition pharmaceutique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994013262A1 (fr) * 1992-12-09 1994-06-23 Boehringer Ingelheim Pharmaceuticals, Inc. Formulations de solutions medicinales aerosol stabilisees
WO1999065464A1 (fr) * 1998-06-18 1999-12-23 Boehringer Ingelheim Pharmaceuticals, Inc. Preparations pharmaceutiques pour aerosols a deux principes actifs ou plus
EP1787639A2 (fr) * 2000-05-22 2007-05-23 CHIESI FARMACEUTICI S.p.A. Formulations de solutions pharmaceutiques stables pour inhalateurs à dosage mesuré pressurisés
WO2007121913A2 (fr) * 2006-04-21 2007-11-01 Chiesi Farmaceutici S.P.A. Formulations en solution pharmaceutiques pour aérosols-doseurs pressurisés
WO2018051131A1 (fr) * 2016-09-19 2018-03-22 Mexichem Fluor S.A. De C.V. Composition pharmaceutique

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