WO2002072067A2 - Formulation aerosol pharmaceutique - Google Patents

Formulation aerosol pharmaceutique Download PDF

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Publication number
WO2002072067A2
WO2002072067A2 PCT/GB2002/001096 GB0201096W WO02072067A2 WO 2002072067 A2 WO2002072067 A2 WO 2002072067A2 GB 0201096 W GB0201096 W GB 0201096W WO 02072067 A2 WO02072067 A2 WO 02072067A2
Authority
WO
WIPO (PCT)
Prior art keywords
formulation according
purin
tetrazol
ethylamino
furan
Prior art date
Application number
PCT/GB2002/001096
Other languages
English (en)
Other versions
WO2002072067A3 (fr
Inventor
Paul Johnson
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0106018A external-priority patent/GB0106018D0/en
Priority claimed from GB0128335A external-priority patent/GB0128335D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU2002238748A priority Critical patent/AU2002238748A1/en
Publication of WO2002072067A2 publication Critical patent/WO2002072067A2/fr
Publication of WO2002072067A3 publication Critical patent/WO2002072067A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine

Definitions

  • the present invention relates to pharmaceutical formulations for use in the administration of medicaments by inhalation.
  • this invention relates to pharmaceutical formulations for use in pressurised metered dose inhalers (MDI's).
  • MDI's pressurised metered dose inhalers
  • the invention also relates to methods for their preparation and to their use in therapy.
  • Inhalers are well known devices for administering pharmaceutically active materials to the respiratory tract by inhalation.
  • active materials commonly delivered by inhalation include bronchodilators such as ⁇ 2 agonists and anticholinergics, corticosteroids, anti-allergies and other materials that may be efficiently administered by inhalation, thus increasing the therapeuticlndex and reducing side effects of the active material.
  • (2R,3R,4S,5R)-2-[6-Amino-2-(1 S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol (eg as maleate) has recently been disclosed in International Patent Application EP97/07197 (WO 98/28319) as a potent agonist of the adenosine 2a receptor which, as a consequence, results in effective anti- inflammatory properties.
  • MDI Metered dose inhalers
  • MDI formulations are generally characterised as solution formulations or suspension formulations.
  • Hydrofluoroalkanes (HFAs; known also as hydrofluorocarbons or HFCs) contain no chlorine and are considered less destructive to ozone and these are proposed substitutes for CFCs.
  • HFA 134a 1,1,1,2-tetrafluoroethane
  • HFA 227) 1,1,1,2,3,3,3-heptafluoropropane
  • the efficiency of an aerosol device is a function of the dose deposited at the appropriate site in the lungs. Deposition is affected by several factors, of which one of the most important is the aerodynamic particle size. Solid particles and/or droplets in an aerosol formulation can be characterised by their mass median aerodynamic diameter (MMAD, the diameter around which the mass aerodynamic diameters are distributed equally).
  • MMAD mass median aerodynamic diameter
  • the effective aerodynamic diameter is a function of the size, shape and density of the particles and will affect the magnitude of forces acting on them. For example, while inertial and gravitational effects increase with increasing particle size and particle density, the displacements produced by diffusion decrease. In practice, diffusion plays little part in deposition from pharmaceutical aerosols. Impaction and sedimentation can be assessed from a measurement of the MMAD which determines the displacement across streamlines under the influence of inertia and gravity, respectively.
  • Aerosol particles of equivalent MMAD and GSD have similar deposition in the lung irrespective of their composition.
  • the GSD is a measure of the variability of the aerodynamic particle diameters.
  • the particles for inhalation have a diameter of about 0.5 to 5 ⁇ m.
  • Particles which are larger than 5 ⁇ m in diameter are primarily deposited by inertial impaction in the orthopharynx, particles 0.5 to 5 ⁇ m in diameter, influenced mainly by gravity, are ideal for deposition in the conducting airways, and particles 0.5 to 3 ⁇ m in diameter are desirable for aerosol delivery to the lung periphery. Particles smaller than 0.5 ⁇ m may be exhaled.
  • Respirable particles are generally considered to be those with aerodynamic diameters less than 5 ⁇ m. These particles, particularly those with a diameter of about 3 ⁇ m, are efficiently deposited in the lower respiratory tract by sedimentation.
  • particle size in principle is controlled during manufacture by the size to which the solid medicament is reduced, usually by micronisation.
  • the suspended drug has the slightest solubility in propellant, a process known as
  • Ostwald Ripening can lead to particle size growth. Also, particles may have tendency to aggregate, or adhere to parts of the MDI eg. canister or valve. The effect of Ostwald ripening and particularly of drug deposition may be particularly severe for potent drugs which need to be formulated in low doses. Solution formulations do not suffer from these disadvantages, but suffer from different ones in that particle or droplet size is both a function of rate of evaporation of the propellant from the formulation, and of the time between release of formulation from canister and the moment of inhalation. Thus, it may be subject to considerable variability and is generally hard to control.
  • ciliary clearance is very rapid and drug delivered by means of suspension formulations may be cleared by the cilia before it has had the opportunity to dissolve and enter the target cells of the target organ.
  • a solution formulation may have advantages since it may speed up absorption thus affording the active ingredient a greater opportunity to exert a therapeutic effect before ciliary clearance takes place. This may also lead to faster onset of action.
  • a pharmaceutical aerosol formulation comprising a hydrofluoroalkane (HFA) propellant having dissolved therein (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol or a salt or solvate thereof.
  • HFA hydrofluoroalkane
  • suitable salts include physiologically acceptable salts such as acid addition salts derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, 1-hydroxy-2-naphthoates, mesylates, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates and maleates.
  • physiologically acceptable salts such as acid addition salts derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, 1-hydroxy-2-naphthoates, mesylates, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates and maleates.
  • suitable salts include tosylates.
  • Suitable solvates include hydrates.
  • the (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl- ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol will be used as the maleate salt.
  • the (2R,3R,4S,5R)-2-[6-Amino-2-(1S- hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro- furan-3,4-diol will be used as the free base. Stability studies using the free base form have been found to give rise to particularly low impurity levels.
  • the (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2- phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol will be used as the 1-hydroxy-2-naphthoate salt. Stability studies using the 1-hydroxy-2- naphthoate salt form have been found to give rise to particularly low impurity levels.
  • HFA propellants examples include 1,1 ,1,2-tetrafluoroethane (HFA134a) and 1,1 ,1,2,3,3,3-heptafluoro-n-propane (HFA227) and mixtures thereof.
  • the preferred propellant is 1,1,1,2-tetrafluoroethane (HFA134a).
  • 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) is also of particular interest.
  • the formulation will generally contain a solubilisation agent to aid solubilisation of the drug in the formulation.
  • Suitable solubilisation agents include propylene glycol, glycerol and ethanol, particularly propylene glycol and ethanol, preferably ethanol. Another example is methylal.
  • a pharmaceutical aerosol formulation comprising:
  • HFA hydrofluoroalkane
  • MMAD mass median aerodynamic diameter
  • the preferred low volatility component is glycerol, propylene glycol or polyethyleneglycol (eg. PEG200 or PEG400).
  • the low volatility component is preferably glycerol.
  • the low volatility component is preferably polyethyleneglycol (eg. PEG200 or PEG400), especially PEG200.
  • polyethylene glycol gives rise to particularly low levels of impurities.
  • it is present in an amount of 0.1 to 3% (w/w), more preferably 0.1 to 1.5% (w/w), particularly 0.1 to 1% (w/w), especially 0.5 to 1% (w/w) eg 0.5 or 1% (w w).
  • the preferred solubilisation agent is ethanol.
  • the concentration of solubilisation agent eg ethanol
  • the amount of ethanol should preferably not exceed around 35%. (w/w).
  • the amount of ethanol will more preferably be in the range 1 to 30% particularly 5 to 30% (w/w), especially 5 to 20% (w/w), particularly 5 to 15% (w/w).
  • the present invention can be defined as a pharmaceutical aerosol formulation which comprises:
  • solubilisation agent particularly ethanol
  • the present invention can be defined as a pharmaceutical aerosol formulation which comprises:
  • a solubilisation agent particularly ethanol
  • the formulation according to the invention will be used in association with a suitable metering valve.
  • a metering valve capable of delivering a volume of between 25 ⁇ l and 10O ⁇ l, eg 25 ⁇ l, 35 ⁇ l, 50 ⁇ l or 63 ⁇ l or 100 ⁇ l.
  • the metering volume will be between 50 ⁇ l and 100 ⁇ l.
  • Use of a larger metering chamber eg 100 ⁇ l will generally be preferred, especially if the use of smaller metering chambers results in a formulation wherein the level of solubilising agent (especially when it is ethanol) exceeds 10% (w/w).
  • the pharmaceutical composition according to the present invention may be filled into canisters suitable for delivering pharmaceutical aerosol formulations.
  • Canisters generally comprise a container capable of withstanding the vapour pressure of the HFA propellant, such as plastic or plastic-coated glass bottle or preferably a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastic-coated, which container is closed with a metering valve. It may be preferred that canisters be coated with a fluorocarbon polymer as described in WO 96/32151 , for example, a co-polymer of polyethersulphone (PES) and polytetrafluoroethylene (PTFE).
  • PES polyethersulphone
  • PTFE polytetrafluoroethylene
  • FEP fluorinated ethylene propylene
  • the metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve.
  • the gasket may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene- acrylonitrile rubbers, butyl rubber and neoprene.
  • Thermoplastic elastomer valves as described in W092/11190 and valves containing EPDM rubber as described in WO95/02651 are especially suitable. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (eg.
  • DF10, DF30, DF60 Bespak pic, UK (eg. BK300, BK356, BK357) and 3M-Neotechnic Ltd, UK (eg. SpraymiserTM).
  • the DF31 valve of Valois, France is also suitable.
  • Valve seals will preferably be manufactured of a material which is inert to and resists extraction into the contents of the formulation, especially when the contents include ethanol.
  • an especially suitable material for manufacture of valve seals is EPDM rubber.
  • Valve materials, especially the material of manufacture of the metering chamber will preferably be manufactured of a material which is inert to and resists distortion by contents of the formulation, especially when the contents include ethanol.
  • Particularly suitable materials for use in manufacture of the metering chamber include polyesters eg polybutyleneterephthalate (PBT) and acetals, especially PBT.
  • Materials of manufacture of the metering chamber and/or the valve stem may desirably be fluorinated, partially fluorinated or impregnated with fluorine containing substances in order to resist drug deposition.
  • an aliquot of the liquified formulation is added to an open canister under conditions which are sufficiently cold that the formulation does not vaporise, and then a metering valve crimped on, and then the propellant is filled into the canister through the valve.
  • each filled canister is check- weighed, coded with a batch number and packed into a tray for storage before release testing.
  • Suitable channelling devices comprise, for example a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient eg. a mouthpiece actuator.
  • valve stem is seated in a nozzle block which has an orifice leading to an expansion chamber.
  • the expansion chamber has an exit orifice which extends into the mouthpiece.
  • Actuator (exit) orifice diameters in the range 0.15- 0.45mm, particularly 0.2-0.45mm are generally suitable eg 0.15, 0.22, 0.25, 0.30, 0.33 or 0.42mm.
  • 0.15mm is also particularly suitable.
  • the dimensions of the orifice should not be so small that blockage of the jet occurs.
  • Actuator jet lengths are typically in the range 0.30-1.7mm eg 0.30, 0.65 or 1.50mm. Smaller dimensions are preferred eg. 0.65mm or 0.30mm.
  • a preferred actuator has dimensions of 0.22mm (diameter) x 0.65mm (length).
  • the precise shape and dimensions of the actuator will be adapted for topical administration to the lung or nose as appropriate.
  • the dose of (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl- ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol or salt or solvate thereof will be between 0.06 and 250 ⁇ g per day, most preferably between 1 and 50 ⁇ g per day. Preferably this amount is based on weight of drug as the free base.
  • Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or 'puff, for example in the range of 1 to 125 ⁇ g medicament per actuation.
  • concentration of drug in the formulation will therefore typically be in the range 0.001% to 0.1% w/v.
  • administration may be one or more inhalations (eg. 1, 2, 3 or 4 inhalations) up to five times per day.
  • Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment.
  • Treatment may be of asthma, chronic obstructive pulmonary disease (COPD) or other respiratory disorder (eg upper respiratory tract disorders such as rhinitis).
  • COPD chronic obstructive pulmonary disease
  • other respiratory disorder eg upper respiratory tract disorders such as rhinitis
  • the filled canisters and metered dose inhalers described herein comprise further aspects of the present invention.
  • a still further aspect of the present invention comprises a method of treating respiratory disorders, for example asthma or chronic obstructive pulmonary disease (COPD), which comprises administration by inhalation of an effective amount of a formulation herein before described.
  • COPD chronic obstructive pulmonary disease
  • the method includes administration by inhalation into the nasal cavity.
  • a further aspect of the present invention comprises the use of a formulation herein before described in the manufacture of a medicament for the treatment of respiratory disorders, eg. asthma or chronic obstructive pulmonary disease (COPD). Rhinitis is also included.
  • respiratory disorders eg. asthma or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • formulations according to the invention may be more environmentally friendly, more stable, less susceptible to Oswald ripening or drug deposition onto internal surfaces of a metered dose inhaler, have better dosing uniformity, deliver a higher FPM, give lower throat deposition, be more easily or economically manufactured, or may be otherwise beneficial relative to known formulations.
  • An aluminium canister was filled with a formulation as follows: (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 10O ⁇ l metering valve.
  • each actuation delivers 12.5 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows: (2R,3R,4S,5R)-2-[6-Amino-2-(1 S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol maleate
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 10O ⁇ l metering valve.
  • each actuation delivers 12.5 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows: (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol
  • Example 4 (prepared according to method of WO 98/28319, Example 11 ) 0.0125% w/v ethanol 10 % w/w glycerol 0.5% w/w 1,1,1,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve. Thus, each actuation delivers 12.5 ⁇ g medicament.
  • Example 4 (prepared according to method of WO 98/28319, Example 11 ) 0.0125% w/v ethanol 10 % w/w glycerol 0.5% w/w 1,1,1,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve. Thus, each actuation delivers 12.5 ⁇ g medicament.
  • Example 4 Example 4
  • An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 12.5 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • An aluminium canister was filled with a formulation as follows: (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol maleate (prepared according to method of WO 98/28319, Example 11e) 0.0125% w/v ethanol 15 % w/w glycerol 0.5% w/w 1,1,1 ,2,3,3,3-heptafluoro-n-propane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve. Thus, each actuation delivers 12.5 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • An aluminium canister was filled with a formulation as follows:
  • 1,1 ,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 6.25 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 6.25 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows: (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol maleate (prepared according to method of WO 98/28319, Example 11e) 0.00625% w/v ethanol 7.5% w/w glycerol 0.5% w/w
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 6.25 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2,3,3,3-heptafluoro-n-propane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 12.5 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • each actuation delivers 12.5 ⁇ g medicament (weight based on that of free base)
  • An aluminium canister was filled with a formulation as follows: (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 6.25 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 6.25 ⁇ g medicament (weight based on that of free base).
  • An aluminium canister was filled with a formulation as follows: (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol 1-hydroxy-2-naphthoate
  • An aluminium canister was filled with a formulation as follows: (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol 1 -hydroxy-2-naphthoate
  • each actuation delivers 12.5 ⁇ g medicament (weight based on that of free base).
  • An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 5 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 5 ⁇ g medicament.
  • Example 19 An aluminium canister was filled with a formulation as follows:
  • each actuation delivers 2.5 ⁇ g medicament.
  • Examples 20A and 20B An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 2.5 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 12.5 ⁇ g medicament.
  • Example 22A and 22B An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 25 ⁇ g or 3 ⁇ g medicament.
  • An aluminium canister was filled with a formulation as follows:
  • 1,1,1 ,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 25 ⁇ g or 3 ⁇ g medicament (weight based on that of free base).
  • Example 24 An aluminium canister was filled with a formulation as follows:
  • PEG200 1% w/w 1,1 ,1,2-tetrafluoroethane to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100 ⁇ l metering valve.
  • each actuation delivers 25 ⁇ g medicament (weight based on that of free base).
  • An aluminium canister was filled with a formulation as follows:
  • An aluminium canister was filled with a formulation as follows:
  • An aluminium canister was filled with a formulation as follows:
  • An aluminium canister was filled with a formulation as follows:
  • each actuation delivers 12.5 ⁇ g medicament (based on weight of base).
  • Examples 29A and 29B An aluminium canister was filled with a formulation as follows:
  • each actuation delivers 12.5 ⁇ g medicament (based on weight of base).
  • Formulations of the examples were studied for chemical stability by exposing them to stressed conditions (40°C, 75% relative humidity) for a 6 week period. Results are shown in Table 1. Impurities are assumed to have a response factor (a correlation between peak area and concentration) of 1 relative to that of the parent molecule. The impurity at 0.35 was found, however, to have a response of 10. The corrected concentration is given in brackets, however the figure in brackets is not included in the total.
  • the columns headed "input material” relates to solid drug substance (micronised) which has been exposed to ambient conditions (room temperature and humidity) for the corresponding period of time. The drug as free base, together with polyethylene glycol (PEG200) as low volatility component (Example 25) appeared optimal since it demonstrated no impurities not shown by the input drug sample.
  • Performance data Formulations of the examples were studied using an Andersen Cascade Impactor to determine the deposition profile and in particular the fine particle mass (FPM) content (defined as the contents of stages 3-5 of the Cascade Impactor). Results are shown in Table 2 and Figure 1. The formulations of Examples 27A, 27B, 27C and 29A showed particularly high FPM.

Abstract

L'invention concerne une formulation aérosol pharmaceutique comportant un propulseur hydrofluoroalcane (HFA) dans lequel est dissous (2R,3R,4S,5R)-2-[6-amino-2-(1S-hydroxyméthyl-2-phényléthylamino)-purine-9-yl]-5-(2-éthyl-2H-tétrazol-5-yl)-tétrahydrofurane-3,4-diol ou un sel ou solvate de ce dernier.
PCT/GB2002/001096 2001-03-12 2002-03-11 Formulation aerosol pharmaceutique WO2002072067A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002238748A AU2002238748A1 (en) 2001-03-12 2002-03-11 Pharmaceutical aerosol formulation

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0106018A GB0106018D0 (en) 2001-03-12 2001-03-12 Pharmaceutical aerosol formulation
GB0106018.5 2001-03-12
GB0128335A GB0128335D0 (en) 2001-11-27 2001-11-27 Pharmaceutical aerosol formulation
GB0128335.7 2001-11-27

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Publication Number Publication Date
WO2002072067A2 true WO2002072067A2 (fr) 2002-09-19
WO2002072067A3 WO2002072067A3 (fr) 2004-02-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor

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WO1998024420A1 (fr) * 1996-12-04 1998-06-11 Bioglan Ireland (R & D) Limited Compositions pharmaceutiques et leurs dispositifs d'administration
WO1998028319A1 (fr) * 1996-12-24 1998-07-02 Glaxo Group Limited Derives de 2-(purine-9-yl)-tetrahydrofuran-3,4-diol
GB2326334A (en) * 1997-06-13 1998-12-23 Chiesi Farma Spa Pharmaceutical aerosol compositions
WO2000023457A1 (fr) * 1998-10-16 2000-04-27 Pfizer Limited Derives d'adenine
WO2000077018A2 (fr) * 1999-06-15 2000-12-21 Pfizer Limited Derives de purine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024420A1 (fr) * 1996-12-04 1998-06-11 Bioglan Ireland (R & D) Limited Compositions pharmaceutiques et leurs dispositifs d'administration
WO1998028319A1 (fr) * 1996-12-24 1998-07-02 Glaxo Group Limited Derives de 2-(purine-9-yl)-tetrahydrofuran-3,4-diol
GB2326334A (en) * 1997-06-13 1998-12-23 Chiesi Farma Spa Pharmaceutical aerosol compositions
WO2000023457A1 (fr) * 1998-10-16 2000-04-27 Pfizer Limited Derives d'adenine
WO2000077018A2 (fr) * 1999-06-15 2000-12-21 Pfizer Limited Derives de purine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor

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WO2002072067A3 (fr) 2004-02-19

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