US20060257324A1 - Pharmaceutical solution formulations for pressurised metered dose inhalers - Google Patents

Pharmaceutical solution formulations for pressurised metered dose inhalers Download PDF

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Publication number
US20060257324A1
US20060257324A1 US11/408,026 US40802606A US2006257324A1 US 20060257324 A1 US20060257324 A1 US 20060257324A1 US 40802606 A US40802606 A US 40802606A US 2006257324 A1 US2006257324 A1 US 2006257324A1
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United States
Prior art keywords
inhaler
drug substances
hfa
active drug
corticosteroid
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Abandoned
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US11/408,026
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English (en)
Inventor
David Lewis
Brian Meakin
Gaetano Brambilla
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Priority claimed from PCT/EP2000/004635 external-priority patent/WO2001089480A1/fr
Application filed by Chiesi Farmaceutici SpA filed Critical Chiesi Farmaceutici SpA
Priority to US11/408,026 priority Critical patent/US20060257324A1/en
Assigned to CHIESI FARMACEUTICI S.P.A. reassignment CHIESI FARMACEUTICI S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRAMBILLA, GAETANO, LEWIS, DAVID ANDREW, MEAKIN, BRIAN JOHN
Publication of US20060257324A1 publication Critical patent/US20060257324A1/en
Priority to DK07724357.4T priority patent/DK2010190T3/da
Priority to SI200731304T priority patent/SI2010190T1/sl
Priority to PL07724357T priority patent/PL2010190T3/pl
Priority to CA2649556A priority patent/CA2649556C/fr
Priority to RS20130386A priority patent/RS52940B/en
Priority to PCT/EP2007/003420 priority patent/WO2007121913A2/fr
Priority to CN201610483860.4A priority patent/CN106074359A/zh
Priority to PT77243574T priority patent/PT2010190E/pt
Priority to AU2007241336A priority patent/AU2007241336C1/en
Priority to EP07724357.4A priority patent/EP2010190B1/fr
Priority to CN201610428382.7A priority patent/CN105963249A/zh
Priority to MEP-2016-22A priority patent/ME02342B/me
Priority to CNA2007800069518A priority patent/CN101389341A/zh
Priority to ES07724357T priority patent/ES2424753T3/es
Priority to CN2012103537724A priority patent/CN102908308A/zh
Priority to JP2009505773A priority patent/JP5289306B2/ja
Priority to MX2008013460A priority patent/MX2008013460A/es
Priority to KR1020087018846A priority patent/KR101311662B1/ko
Priority to BRPI0709510-4A priority patent/BRPI0709510A2/pt
Priority to EA200802012A priority patent/EA016262B1/ru
Priority to ZA2008/08965A priority patent/ZA200808965B/en
Priority to US12/255,075 priority patent/US20090130026A1/en
Priority to CY20131100703T priority patent/CY1114215T1/el
Priority to HRP20130835TT priority patent/HRP20130835T1/hr
Priority to US15/353,978 priority patent/US10525006B2/en
Priority to US16/689,611 priority patent/US11213485B2/en
Abandoned legal-status Critical Current

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/124—Aerosols; Foams characterised by the propellant
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to pharmaceutical solution to be used with pressurised metered dose inhalers (pMDIs) suitable for aerosol administration.
  • the invention relates to aerosol solution formulations to be used with pressurised metered dose inhalers (pMDIs), suitable for the administration of a medicament to the lungs, said medicament comprising two or more active drug substances.
  • the invention relates to a method for delivering two or more active drug substances to the lungs by inhalation from a single inhaler.
  • one of the drug substances is a long-acting ⁇ 2 -agonist.
  • Treatment of pulmonary disease with inhaled aerosol drugs offers advantages over systemic therapy, including a more rapid onset and reduced adverse effects, because of direct targeting of the lungs.
  • MDIs Pressurised metered dose inhalers
  • MDI uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol.
  • Formulations for aerosol administration via MDIs can be solutions or suspensions.
  • Solution formulations offer the advantage of being homogeneous with the active ingredient and excipients completely dissolved in the propellant vehicle or its mixture with suitable co-solvents such as ethanol. Solution formulations also obviate physical stability problems associated with suspension formulations so assuring more consistent uniform dosage administration.
  • the preferred propellants used in aerosols for pharmaceutical use have been a group of chlorofluorocarbons which are commonly called Freons or CFCs, such as CCl 3 F (Freon 11 or CFC-11), CCl 2 F 2 (Freon 12 or CFC-12), and CClF 2 -CClF 2 (Freon 114 or CFC-114).
  • Freons or CFCs such as CCl 3 F (Freon 11 or CFC-11), CCl 2 F 2 (Freon 12 or CFC-12), and CClF 2 -CClF 2 (Freon 114 or CFC-114).
  • CFC chlorofluorocarbon
  • Hydrofluoroalkanes (HFAs) known also as hydro-fluoro-carbons (HFCs)] contain no chlorine and are considered less destructive to ozone and these are proposed as substitutes for CFCs.
  • HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of medicinal aerosol formulations using such HFA propellant systems have been disclosed.
  • Drugs commonly delivered by inhalation include short-acting and long-acting ⁇ 2 -agonists, anticholinergics/antimuscarinic agents, and corticosteroids.
  • ⁇ 2 -Adrenoceptor agonists and antimuscarinic agents are the most effective bronchodilators, whereas corticosteroids are the most effective controllers of the underlying inflammatory process in the airways.
  • Examples of long-acting bronchodilator ⁇ 2 -agonists belonging to the class of the phenylalkylamino derivatives are formoterol, salmeterol and 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone (also referred to as carmoterol).
  • Asthma and chronic obstructive pulmonary disease (COPD) are the most common broncho-pulmonary diseases and represent a major public health problem.
  • Asthma is a disease characterized by airway inflammation and smooth muscle dysfunction. Therefore to achieve optimum asthma control, therapy should be targeted against these underlying components.
  • LAA long-acting inhaled ⁇ 2 -agonist
  • ICS inhaled corticosteroid
  • Bronchodilator therapy is the first step treatment in patients with COPD, but current guidelines recommend the addition of inhaled corticosteroids to bronchodilators.
  • anticholinergics and beta-agonists As far as anticholinergics and beta-agonists are concerned, they reduce bronchoconstriction through different mechanism, and there is a long history of combination therapy in the past with short-acting agents in these classes for chronic obstructive pulmonary disease. More effective drug combinations may allow lower doses and thereby improve safety.
  • a method and formulations in the form of HFA solution to be administered by MDI's aimed at providing pharmaceutical doses of two or more bronchodilating and/or anti-inflammatory compounds to the lung and especially a ⁇ 2 -agonist in combination with at least a further active compound for a more efficacious treatment of broncho-pulmonary diseases, in particular asthma and COPD.
  • FIG. 1 shows the titration curve normalised to the usual fill volume of a pMDI can (12 ml) resulting from Example 1(a);
  • FIG. 2 shows the pH profile for the titration experiment reported in Example 1(b);
  • FIG. 3 shows the cumulative % undersize BDP and FF mass distributions for the sample as determined in Example 6.
  • a pharmaceutical composition comprising two or more active substances and in particular a long acting ⁇ 2 -agonist belonging to the class of phenylalkylamino derivatives in solution in a liquefied HFA propellant and a co-solvent selected from pharmaceutically acceptable alcohols.
  • Active ingredients which may be used in the aerosol compositions of the invention are short- and long-acting ⁇ 2 -adrenergic agonists, preferably long-acting ⁇ 2 -adrenergic agonists such as formoterol, salmeterol, carmoterol and salts thereof and their combinations with other active ingredients, preferably selected from the group of corticosteroids or anticholinergic atropine-like derivatives, antimuscarinic M3 inhibitors or phosphodiesterase 4 (PDE4) inhibitors.
  • ⁇ 2 -adrenergic agonists preferably long-acting ⁇ 2 -adrenergic agonists such as formoterol, salmeterol, carmoterol and salts thereof and their combinations with other active ingredients, preferably selected from the group of corticosteroids or anticholinergic atropine-like derivatives, antimuscarinic M3 inhibitors or phosphodiesterase 4 (PDE4) inhibitors.
  • PDE4 phosphodiesterase 4
  • Preferred corticosteroids are beclomethasone dipropionate, budesonide and its 22R-epimer, rofleponide, ciclesonide, fluticasone propionate, mometasone furoate or triamcinolone and its ester such as triamcinolone acetonide.
  • Preferred anticholinergic atropine-like derivatives are ipratropium bromide, oxitropium bromide, tiotropium bromide or glycopyrronium bromide.
  • Preferred long acting ⁇ 2-agonists are formoterol, carmoterol and salmeterol and salts thereof.
  • the first active ingredient is a long acting ⁇ 2-agonists belonging to the formula sketched below wherein R is 1-formylamino-2-hydroxy-phen-5-yl (formoterol) or 8-hydroxy-2(1H)-quinolinon-5-yl (TA 2005) or one of their salts, solvates, solvates of the salts or stereoisomers.
  • R is 1-formylamino-2-hydroxy-phen-5-yl (formoterol) or 8-hydroxy-2(1H)-quinolinon-5-yl (TA 2005) or one of their salts, solvates, solvates of the salts or stereoisomers.
  • the formulation be suitable for delivering a therapeutic amount of the active ingredient in one or two actuations.
  • the formulation will be suitable for delivering 6 to 12 ⁇ g/dose of formoterol fumarate.
  • the formulation will be advantageously suitable for delivering 0.5 to 8 ⁇ g/dose, preferably 1 to 4 ⁇ g/dose, more preferably from 1 to 2 ⁇ g/dose of carmoterol hydrochloride (TA 2005).
  • dose it is meant the amount of active ingredient delivered by a single actuation of the inhaler.
  • the formulation of the invention may further contain small amounts of a mineral acid to adjust the apparent pH to between 2.5 and 5.0.
  • the formulations of the invention may be contained in a pressurized MDI having part of all of the internal metallic surfaces made of anodised aluminium, stainless steel or lined with an inert organic coating.
  • preferred coatings are epoxy-phenol resins, perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes such as polytetrafluoroethylene, fluorinated-ethylene-propylene, polyether sulfone and a mixture of fluorinated-ethylene-propylene and polyether sulfone.
  • Other suitable coatings could be polyamide, polyimide, polyamideimide, polyphenylene sulfide or their combinations.
  • cans having a rolled-in rim and preferably a part or full rollover rim may be used.
  • the pharmaceutical composition may further contain a low volatility component, further improving the stability of the formulation.
  • a low volatility component with a reduced polarity with respect to the co-solvent such as an ester may allow either to reduce the amount of acid to be added for adjusting the pH and diminish the polarity of the medium so limiting the possible uptake of environmental water.
  • active ingredients such as formoterol, it is well known that the latter (e.g., humidity) could be detrimental to the stability of the active ingredient during storage.
  • a pressurised MDI for administering pharmaceutical doses consisting of a container filled with a pharmaceutical composition comprising a long-acting ⁇ 2 agonist selected from formoterol fumarate in solution in HFA 134a as a propellant in turn containing from 5% to 20%, preferably from 6% to 15% w/w ethanol as a co-solvent, the apparent pH of said solution having been adjusted to between 3.0 and 3.5 by addition of small amounts of hydrochloric acid.
  • % w/w means the weight percentage of the component in respect to the total weight of the composition.
  • a pressurised MDI filled with a pharmaceutical composition consisting of a solution comprising formoterol fumarate in combination with a corticosteroid in HFA 134a as a propellant in turn containing from 6% to 15% w/w, preferably 12% w/w ethanol as a co-solvent, the apparent pH of said solution having been adjusted to between 3.0 and 3.5 by addition of small amounts of hydrochloric acid.
  • the corticosteroid is beclometasone dipropionate.
  • a pressurised MDI consisting of a coated container filled with a pharmaceutical composition consisting of a solution of 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone hydrochloride (TA 2005) in combination with a corticosteroid in HFA 134a as a propellant in turn containing from 6% to 15% w/w, preferably 12% w/w ethanol as a co-solvent, the apparent pH of said solution having been adjusted to between 3.0 and 5.0 by addition of small amounts of a mineral acid.
  • the corticosteroid is budesonide or an epimer thereof.
  • WO 97/47286 disclose HFA formulations in the form of suspensions in which ⁇ 2 -agonists such formoterol and salbutamol are either exemplified and/or claimed.
  • WO 99/65464 refers to HFA formulations containing two or more active ingredients in which at least one is in suspension.
  • the preferred formulations comprise salbutamol sulphate in suspension.
  • WO 98/34596 describes solution compositions for use in an aerosol inhaler, comprising an active material, a propellant containing a hydrofluoroalkane (HFA), a cosolvent and further comprising a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler.
  • HFA hydrofluoroalkane
  • MMAD mass median aerodynamic diameter
  • EP 673240 proposes the use of acids as stabilisers preventing the chemical degradation of the active ingredient in aerosol solution formulations comprising HFAs.
  • Most examples relate to ipratropium bromide, an anticholinergic drug and only an example is presented for a ⁇ 2 -agonist, i.e. fenoterol.
  • salbutamol is claimed, no exemplary formulations are provided.
  • the stability data are reported only for ipratropium and the patentee does not distinguish between the use of organic and inorganic acids.
  • no guidance is given with respect to the amount of acid which has to be added in order to stabilise the medicaments without compromising the stability of the whole composition in the can. The only hint can be found on page 5, lines 15 to 16 which says that an amount of inorganic acid should be added to obtain a pH value from 1 to 7, so a very broad and generic range.
  • WO 98/34596 refers to solution formulations containing a propellant and a physiologically acceptable polymer which could help the solubilisation and the stability as well of the active ingredients.
  • WO 00/06121 refers to propellant mixtures for aerosol dinitrogen monoxide and a hydrofluoroalkane in the preparation of suspension and solution aerosols.
  • the use of dinitrogen monoxide may improve the stability at storage of oxidation-sensitive active ingredients.
  • ⁇ 2 -agonist such as levosalbutamol sulphate, formoterol fumarate and salmeterol xinafoate, only examples referred to suspensions are reported.
  • Examples refer to solutions of formoterol fumarate containing an HFA propellant and ethanol as co-solvent, filled in conventional aluminium or plastic coated glass cans.
  • loss of 10% of active ingredient does not meet the criteria of acceptance.
  • following the teaching of WO 99/65460 stable formoterol solution formulations cannot be provided.
  • WO 03/074025 refers to a pharmaceutical aerosol formulation to be administered by pressurized metered dose inhalers which comprises as active ingredient a long acting ⁇ 2-agonist selected from a 2(1H)-quinolinone derivative, a stereoisomer, physiologically acceptable salt and solvate thereof, in a solution consisting of a liquefied HFA propellant, a co-solvent and optionally an amount of water up to 5% on the total weight of the formulation.
  • a long acting ⁇ 2-agonist selected from a 2(1H)-quinolinone derivative, a stereoisomer, physiologically acceptable salt and solvate thereof, in a solution consisting of a liquefied HFA propellant, a co-solvent and optionally an amount of water up to 5% on the total weight of the formulation.
  • the formulation is able to deliver, on actuation of the inhaler, a fraction of superfine particles equal to or less than 1.1 micron up to 50% or more so allowing the drug to reach the small peripheral airways region where it exercises its pharmacological effects.
  • WO 2004/075896 refers to a combined preparation comprising:
  • One of the preferred combination products comprises the hydrochloride salt CHF 4226 and a corticosteroid: it has indeed been found that, in such a combination, both the bronchodilator and the anti-inflammatory effects increase.
  • a filled device such as an aerosol inhaler
  • a composition of the invention comprising:
  • the formulation is actuated by a metering valve capable of delivering a volume of between 50 ⁇ l and 100 ⁇ l.
  • Metering valves fitted with gaskets made of chloroprene-based rubbers can preferably be used to reduce the ingress of moisture which, as previously mentioned, can adversely affect the stability of the drug during storage.
  • further protection can be achieved by packaging the product in a sealed aluminium pouch.
  • the hydrofluorocarbon propellant is preferably selected from the group of HFA 134a, HFA 227 and mixtures thereof.
  • the co-solvent is usually an alcohol, preferably ethanol.
  • the low volatility component when present, has a vapour pressure at 25° C. lower than 0.1 kPa, preferably lower than 0.05 kPa.
  • it could be selected from the group of glycols, particularly propylene glycol, polyethylene glycol and glycerol or esters, for example ascorbyl palmitate, isopropyl myristate and tocopherol esters.
  • compositions of the present invention may contain from 0.1 to 10% w/w of said low volatility component, preferably between 0.3 to 5% w/w, more preferably between 0.4 and 2.0% w/w.
  • Propylene glycol, polyethylene glycol, glycerol with residual water less than 0.1% w/w and esters of long-chain fatty acids are the preferred low-volatility components. More preferred are those with a dipole moment less than 2.0 or with a dielectric static constant less than 20, preferably less than 10. Particularly preferred is isopropyl myristate.
  • the function of the low volatility component is to modulate the MMAD of the aerosol particles and optionally to further improve the stability of the formulation.
  • particularly preferred is the use of isopropyl myristate.
  • the apparent pH range is advantageously comprised between 2.5 and 5.0, preferably between 3.0 and 5.0.
  • Strong mineral acids such as hydrochloric, nitric, sulphuric or phosphoric are preferably used to adjust the apparent pH.
  • the amount of acid to be added to reach the desired apparent pH will be pre-determined in the model vehicle reported before.
  • an amount comprised between 3 and 3.5 ⁇ l of 1.0 M hydrochloric acid should be added to obtain an apparent pH between 3.0 and 3.5.
  • a recommended combination is the combination of an inhaled corticosteroid (ICS) and a long-acting ⁇ 2-agonist (LABA) bronchodilator in the treatment of persistent asthma, to provide both anti-inflammatory and bronchodilating effects.
  • ICS inhaled corticosteroid
  • LAA long-acting ⁇ 2-agonist
  • the size of the solid particles can be easily pre-determined by the micronization process.
  • Co-deposition in the same lung region could maximize the synergistic effects, but the two active ingredients have to show exactly the same distribution profile.
  • each liquid particle generated during the MDIs atomisation process contains drug concentrations consistent with the liquid properties of the product's solution formulation and that this consistency is maintained for the residual particles following excipient evaporation.
  • substantially all of the liquid particles emitted on actuation of the inhaler contain the two or more drug substances in a ratio which is substantially the same as the ratio of the two or more drug substances in the solution formulation contained in the inhaler.
  • the liquid droplets emitted on actuation of the inhaler contain the two or more drug substances in a ratio (when expressed as a ratio obtained by dividing the mass of the major component by the mass of the minor component) which preferably differs by less than 15%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2%, even more preferably less than 1%, from the ratio of the two or more drug substances in the solution formulation contained in the inhaler.
  • the ratio of the two or more drug substances in the solution formulation will in part depend on the identity of the drug substances and the condition and subject being treated. However, in view of the teachings of the present specification, determination of such ratios is within the abilities of those skilled in the art.
  • the mass ratio of beclometasone to formoterol fumarate may preferably be 100:0.1 to 100:50, more preferably 100:1 to 100:20, even more preferably 100:2 to 100:10.
  • the mass ratio of budesonide to carmoterol hydrochloride may preferably be 100:0.01 to 100:15, more preferably 100:0.05 to 100:10, even more preferably 100:0.1 to 100:7, even more preferably 100:0.5 to 100:5, even more preferably 100:0.5 to 100:4, even more preferably 100:0.5 to 100:3.
  • each droplet of the aerosol cloud emitted on actuation of the inhaler containing a solution of different active drug substances dries to give particles of the active materials with identical size distributions in the correct ratio.
  • the liquid droplets dry to give particles of the two or more drug substances, and the particles of the two or more drug substances have substantially the same particle size distribution.
  • the fine particle fractions (at ⁇ 5 ⁇ m) of the two or more drug substances preferably differ by less than 15%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2%, even more preferably less than 1%.
  • the fine particle fractions (at ⁇ 1 ⁇ m) of the two or more drug substances preferably differ by less than 15%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2%, even more preferably less than 1%.
  • the spray cloud of finely divided liquid particles dispersed in a gas stream emitted from the MDI is a dynamic system quickly evaporating and moving through the air way from the actuator.
  • the invention is particularly directed to a method for delivering two or more active drug substances to the lung by inhalation from a single pressurized metered dose inhaler product, said inhaler containing a HFA/cosolvent based solution formulation wherein all the active drug substances are fully dissolved in the formulation.
  • PSD particle size distribution
  • FIG. 1 shows the resultant titration curve normalised to the usual fill volume of a pMDI can (12 ml).
  • Formoterol formulations (12 ⁇ g/100 ⁇ l) were prepared by dissolving 1.44 mg of formoterol fumarate in HFA 134a containing 12% w/w ethanol with and without 1.0% w/w isopropyl myristate. The latter was included as a non-volatile excipient with the potential for increasing MMAD if so desired. It also improves the solubility of formoterol in the vehicle and reduces polarity of the vehicle compared to the addition of glycerol.
  • pMDI cans containing 3.1 to 3.4 ⁇ l 1.0 M hydrochloric acid were set down on storage, upright and inverted, at 4° C. to 50° C. and samples taken for analysis of formoterol content at appropriate intervals.
  • a matrix of formulations containing 1.44 mg (12 ⁇ g/100 ⁇ l) formoterol fumarate were prepared in HFA 134a containing 12.0% w/w ethanol with or without 1.0% w/w isopropyl myristate as non-volatile excipient. Aliquots of drug concentrate were transferred to anodised cans and 3.15 to 3.35 ⁇ l of 1.0M hydrochloric acid added prior to crimping with 50 ⁇ l valves and gassing; between 22 and 28 replicates at each acid strength were prepared.
  • pMDI coated cans containing 3.25 ⁇ l 1.0 M hydrochloric acid were set down on storage inverted, at 4° C. and samples taken for analysis of formoterol and BDP contents at appropriate intervals.
  • TA 2005 (3.5 ⁇ g/50 ⁇ l) were prepared by dissolving 0.84 mg of the active ingredient in HFA 134a containing 12% w/w ethanol and 1.0% w/w of ispropyl myristate.
  • pMDI coated cans containing 1.0, 1.4, and 1.8 ⁇ l 0.08 M hydrochloric acid (corresponding respectively to an apparent pH of about 4.8, 3.2, and 2.9) were set down on storage, upright at 50° C., and samples taken for analysis of TA 2005 contents at appropriate intervals.
  • the solution formulation contained BDP (100 ⁇ g) and FF (6 ⁇ g) per 50 ⁇ l dose in HFA 134a propellant vehicle with 12% w/w ethanol as cosolvent and 0.024% w/w hydrochloric acid (1M) as stabiliser.
  • the formulation was packed in cans fitted with 50 ⁇ l valves and fired using a 0.30 mm actuator. Aerodynamic particle size assessments were conducted using an Andersen Cascade Impactor fitted with a USP induction port at the beginning and end of can-use life from each of two batches. Each determination was obtained by sampling 15 consecutive doses at a sampling flow rate of 28.31/min.
  • the delivered dose was determined using DUSA methodology (Dose Unit Spray Apparatus) at the beginning, middle and end of can-use life. Quantification of BDP and FF within test samples was performed using a HPLC method. Metered dose, delivered dose, fine particle dose, fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD) for each impactor measurement were calculated.
  • DUSA methodology Dose Unit Spray Apparatus
  • MMAD mass median aerodynamic diameter
  • GSD geometric standard deviation
  • the mean ratio of BDP to FF presented in Table 7 is 17.6 ⁇ 0.6, which is consistent with the ratio of metered BDP and FF (17.6 ⁇ 0.6).
  • the consistent ratio of the drug masses over the size fractions implies that each particle generated during the atomisation process contains drug concentrations consistent with the liquid properties of the product's solution formulation, and that this consistency is maintained for the residual particles following excipient evaporation, such that the measured particle size distributions for both resident drugs are identical.
  • the LABA is present in the combination at a strength 1 ⁇ g/actuation while the ICS is present at 100 ⁇ g/actuation within an acidified ethanol solution pressurized with HFA 134a.
  • Aerodynamic assessment of fine particles was performed by sampling 10 consecutive doses from each pMDI into an ACI.
  • the impactor was fitted with a USP induction port and operated at a sampling flow rate of 28.3 l/min.
  • Three pMDIs were tested (from the beginning, middle, and end of batch) and were tested at the beginning and end of life.
  • Drug deposition within the impactor was quantified using an HPLC assay.
  • the fine particle dose (FPD) was determined by summation of the drug collected on the ACI stages between S3 and filter.
  • Table 8 summarizes the deposition of the LABA and the ICS on the individual stages of the ACI.
  • the nominal dose of the combination pMDI was 1 ⁇ g LABA: 100 ⁇ g ICS.
  • FIG. 4 summarizes these results expressed as the % metered dose.

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US11/408,026 US20060257324A1 (en) 2000-05-22 2006-04-21 Pharmaceutical solution formulations for pressurised metered dose inhalers
MX2008013460A MX2008013460A (es) 2006-04-21 2007-04-19 Formulaciones farmaceuticas en solucion para inhaladores presurizados de dosis calibradas.
KR1020087018846A KR101311662B1 (ko) 2006-04-21 2007-04-19 압축계량된 도스흡입기용 약제용액제제
BRPI0709510-4A BRPI0709510A2 (pt) 2006-04-21 2007-04-19 formulações de soluções farmacêuticas para inaladores dosimetrados pressurizados
EA200802012A EA016262B1 (ru) 2006-04-21 2007-04-19 Фармацевтические препараты в форме раствора для дозирующих ингаляторов под давлением
CN201610428382.7A CN105963249A (zh) 2006-04-21 2007-04-19 用于加压计量吸入器的药物溶液制剂
ES07724357T ES2424753T3 (es) 2006-04-21 2007-04-19 Formulaciones en disolución farmacéuticas para inhaladores de dosis medidas presurizados
PL07724357T PL2010190T3 (pl) 2006-04-21 2007-04-19 Formulacje roztworu farmaceutycznego do inhalatorów ciśnieniowych z dozownikiem
CA2649556A CA2649556C (fr) 2006-04-21 2007-04-19 Formulations en solution pharmaceutiques pour aerosols-doseurs pressurises
RS20130386A RS52940B (en) 2006-04-21 2007-04-19 PHARMACEUTICAL FORMULATIONS OF SOLUTION FOR MEASURED DOSES OF PRESSURE INHALATORS
PCT/EP2007/003420 WO2007121913A2 (fr) 2006-04-21 2007-04-19 Formulations en solution pharmaceutiques pour aérosols-doseurs pressurisés
CN201610483860.4A CN106074359A (zh) 2006-04-21 2007-04-19 用于加压计量吸入器的药物溶液制剂
PT77243574T PT2010190E (pt) 2006-04-21 2007-04-19 Formulações em soluções farmacêuticas para inaladores pressurizados doseáveis
AU2007241336A AU2007241336C1 (en) 2006-04-21 2007-04-19 Pharmaceutical solution formulations for pressurised metered dose inhalers
EP07724357.4A EP2010190B1 (fr) 2006-04-21 2007-04-19 Formulations en solution pharmaceutiques pour aérosols-doseurs pressurisés
DK07724357.4T DK2010190T3 (da) 2006-04-21 2007-04-19 Farmaceutisk opløsningsformulering til tryksatte, dosisregulerede inhalatorer
MEP-2016-22A ME02342B (me) 2006-04-21 2007-04-19 Farmaceutske formulacije rastvora za izmjerene doze inhalatora pod pritiskom
CNA2007800069518A CN101389341A (zh) 2006-04-21 2007-04-19 用于加压计量吸入器的药物溶液制剂
SI200731304T SI2010190T1 (sl) 2006-04-21 2007-04-19 Formulacije farmacevtske raztopine za odmerno-dozirne inhalatorje pod tlakom
CN2012103537724A CN102908308A (zh) 2006-04-21 2007-04-19 用于加压计量吸入器的药物溶液制剂
JP2009505773A JP5289306B2 (ja) 2006-04-21 2007-04-19 加圧式定量噴霧吸入器用の薬学的溶液製剤
ZA2008/08965A ZA200808965B (en) 2006-04-21 2008-10-20 Pharmaceutical solution formulations for pressurised metered dose inhalers
US12/255,075 US20090130026A1 (en) 2006-04-21 2008-10-21 Pharmaceutical solution formulations for pressurised metered dose inhalers
CY20131100703T CY1114215T1 (el) 2006-04-21 2013-08-14 Φαρμακευτικες συνθεσεις διαλυματος για υπο πιεση εισπνευστηρες μετρουμενης δοσης
HRP20130835TT HRP20130835T1 (hr) 2006-04-21 2013-09-09 Farmaceutske formulacije otopine za davanje kao stlaäśeni inhalat u inhalatoru
US15/353,978 US10525006B2 (en) 2006-04-21 2016-11-17 Pharmaceutical solution formulations for pressurised metered dose inhalers
US16/689,611 US11213485B2 (en) 2006-04-21 2019-11-20 Pharmaceutical solution formulations for pressurized metered dose inhalers

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PCT/EP2000/004635 WO2001089480A1 (fr) 2000-05-22 2000-05-22 Preparation en solution pharmaceutique stable pour aerosols-doseurs sous pression
US09/860,689 US6716414B2 (en) 2000-05-22 2001-05-21 Stable pharmaceutical solution formulations for pressurized metered dose inhalers
US10/640,005 US7018618B2 (en) 2000-05-22 2003-08-14 Stable pharmaceutical solution formulations for pressurized metered dose inhalers
US11/289,479 US20060083693A1 (en) 2000-05-22 2005-11-30 Stable pharmaceutical solution formulations for pressurised metered dose inhalers
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US15/353,978 Active US10525006B2 (en) 2006-04-21 2016-11-17 Pharmaceutical solution formulations for pressurised metered dose inhalers
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