EP1289539A1 - Pharmaceutical anti-inflammatory aerosol formulation - Google Patents

Pharmaceutical anti-inflammatory aerosol formulation

Info

Publication number
EP1289539A1
EP1289539A1 EP01938435A EP01938435A EP1289539A1 EP 1289539 A1 EP1289539 A1 EP 1289539A1 EP 01938435 A EP01938435 A EP 01938435A EP 01938435 A EP01938435 A EP 01938435A EP 1289539 A1 EP1289539 A1 EP 1289539A1
Authority
EP
European Patent Office
Prior art keywords
amino
formulation according
formulation
pharmaceutical aerosol
pentanoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01938435A
Other languages
German (de)
French (fr)
Inventor
Duncan Robert Discovery Chemistry ARMOUR
David Roche Products Limited BROWN
Miles Stuart GlaxoSmithKline CONGREVE
Paul Martin Gore
Darren Victor Steven Green
Stuart Holman
Torquil Iain Maclean Jack
Andrew Mcmurtrie Mason
Karen Morriss
Nigel Grahame Ramsden
Marian Thomas
Peter Ward
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
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
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1289539A1 publication Critical patent/EP1289539A1/en
Withdrawn legal-status Critical Current

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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 present invention relates to a pharmaceutical formulation for use in the administration of medicaments by inhalation.
  • this invention relates to a pharmaceutical formulation 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 therapeutic index and reducing side effects of the active material.
  • (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1-piperidinyl]carbonyl ⁇ oxy)phenyI]-2-[((2S)-4- methyl-2- ⁇ [2-(2-methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid has recently been disclosed in International Patent Application (PCT/EP99/10000) as a novel antagonist of both ⁇ 4 ⁇ 1 and ⁇ 4 ⁇ 7 integrins which, as a consequence, results in effective anti-inflammatory properties.
  • MDIs 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.
  • particle size in principle is controlled during manufacture by the size to which the solid medicament is reduced, usually by micronisation.
  • a process known as Ostwald Ripening can lead to particle size growth.
  • 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 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.
  • a pharmaceutical aerosol formulation comprising a hydrofluoroalkane (HFA) propellant having dissolved therein particulate (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1- piperidinyl]carbonyl ⁇ oxy)phenyl]-2-[((2S)-4-methyl-2- ⁇ [2-(2- methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid or a salt or solvate thereof.
  • HFA hydrofluoroalkane
  • suitable salts include physiologically acceptable salts such as alkali metal salts, for example calcium, sodium and potassium salts and salts with (trishydroxymethyl)aminomethane.
  • the (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1-piperidinyl]carbonyl ⁇ oxy)phenyl]- 2-[((2S)-4-methyl-2- ⁇ [2-(2-methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid will be present as the potassium salt.
  • the free acid is also of 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.
  • Other suitable solubilisation agents include alkanes and ethers (eg dimethyl ether).
  • a further solubilisation agent of interest is dimethoxymethane which has particularly good solvency properties.
  • 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).
  • HFA227 is also of particular interest.
  • a pharmaceutical aerosol formulation comprising: (i) (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1 -piperidinyl]carbonyl ⁇ oxy) phenyl]-2-[((2S)-4-methyl-2- ⁇ [2-(2-methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid or a salt or solvate thereof;
  • the preferred low volatility component is glycerol, propylene glycol or polyethyleneglycol, especially glycerol. Preferably it is present in an amount of 0.5 to 3% (w/w)
  • the preferred solubilisation agent is ethanol.
  • the solubilisation agent will be present within the formulation at a concentration of not greater than 35% (w/w), most preferably between 5 and 30% (w/w).
  • the present invention can be defined as a pharmaceutical aerosol formulation which comprises:
  • solubilisation agent particularly ethanol
  • a further active ingredient suitable for inhalation therapy may be incorporated into the formulation such as a corticosteroid (eg fluticasone propionate) or a bronchodilator (eg salmeterol or albuterol or a salt thereof).
  • a corticosteroid eg fluticasone propionate
  • a bronchodilator eg salmeterol or albuterol or a salt thereof.
  • the formulation according to the invention will be used in association with a suitable metering valve.
  • a suitable metering valve capable of delivering a volume of between 50 ⁇ l and 100 ⁇ l, eg 50 ⁇ l or 63 ⁇ l or 100 ⁇ l.
  • Use of a larger metering chamber eg 100 ⁇ l will generally be preferred.
  • 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 plastics coated glass bottle or preferably a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastics 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 WO92/11190 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 especially the gasket seal, 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.
  • 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 onto the canister.
  • each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
  • Each filled canister is conveniently fitted into a suitable channelling device prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient.
  • 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.
  • Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or 'puff, for example in the range of 10 to 5000 ⁇ g medicament per puff.
  • valve stem In a typical arrangement the 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 0.1-0.45mm are generally suitable eg 0.15, 0.22, 0.25, 0.30, 0.33 or 0.42mm. We have found that it is advantageous to use a small diameter eg
  • 0.25mm or less particularly 0.22mm since this tends to result in a higher FPM and lower throat deposition. 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.
  • the dose of (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1- piperidinyl]carbonyl ⁇ oxy)phenylj ⁇ 2-[((2S)-4 ⁇ methyl-2- ⁇ [2-(2- methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid or salt or solvate thereof will be between 0.1 and 10mg per day, most preferably between 0.5 and 3mg per day.
  • Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or 'puff, for example in the. range of 25 to 500 ⁇ g medicament per actuation.
  • the concentration of drug in the formulation will therefore typically be in the range 0.02% to 5% w/w.
  • 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. It will be appreciated that the precise dose administered will depend upon the age and condition of the patient, the quantity and frequency of administration will ultimately be at the discretion of the attendant physician.
  • 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 which comprises administration by inhalation of an effective amount of a formulation herein before described.
  • the respiratory disorder will be asthma.
  • Allergic rhinitis is also of interest.
  • the formulation of the present invention will be delivered via the nasal route.
  • 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 allergic rhinitis.
  • the resin was filtered and washed with dichloromethane (3 x 200ml), methanol (3 x 200ml), 10% water in DMF (2 x 200ml), 10% diisopropylethylamine in DMF (3 x 200ml), DMF (200ml), methanol (3 x 200ml) and dichloromethane (3 x 200ml).
  • the resin was treated with 20% piperidine in DMF (180ml) and stirred for 1h at 20°C.
  • the resin was filtered and washed with DMF (3 x 150ml), dichloromethane (3 x 150ml), DMF (3 x 150ml) and dichloromethane (3 x
  • a slurry of the resin in dichloromethane (60ml) was treated with a solution of tetrakis(triphenylphosphine)palladium(0) (5.21 g) in dichloromethane (140ml) followed by morpholine (13ml). The mixture was stirred for 2h at 20°C then the resin was filtered and washed with dichloromethane (7 x 200ml).
  • a slurry of the resin in dichloromethane (160ml) was treated with diisopropylethylamine (12.4ml) followed by 4-nitrophenyl chloroformate (24.8g) in 3 portions at 5 minute intervals. The mixture was stirred for 1h at 20°C.
  • the resin was filtered and washed with dichloromethane (3 x 200ml).
  • the resin was treated with a solution of isonipecotamide (15.8g) in DMF (180ml) and the mixture was stirred for 1.5h at 20°C.
  • the resin was filtered and washed with
  • the resin was treated with 50% TFA in dichloromethane (200ml). After stirring for 1h at 20°C the resin was filtered and washed with dichloromethane (5 x 200 ml). The combined filtrate and washings were evaporated in vacuo. The residue was azeotroped with toluene (2 x 100ml) then triturated with ether (50ml) and the resulting white solid filtered. To this was added acetonitrile (150ml) and the mixture was heated to reflux. The resulting suspension was allowed to cool to 20°C and stirred for 18h.. The mixture was filtered to give the title compound as a white solid (4.9g).
  • An aluminium canister was filled with a formulation as follows: (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1-piperidinyl]carbonyl ⁇ oxy)phenyl]-2-[((2S)-4- methyl-2- ⁇ [2-(2-methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid (prepared according to Example A) 1 % w/w ethanol 10 %
  • Example 2 An aluminium canister was filled with a formulation as follows: (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1-piperidinyl]carbonyl ⁇ oxy)phenyl]-2-[((2S)-4- methyl-2- ⁇ [2-(2-methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid potassium salt (prepared according to Example B) 1 % w/w ethanol 10 %
  • An aluminium canister was filled with a formulation as follows: (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1-piperidinyl]carbonyl ⁇ oxy)phenyl]-2-[((2S)-4- methyl-2- ⁇ [2-(2-methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid (prepared according to Example A) 3 % w/w ethanol 20 % glycerol 1.3% w/w
  • An aluminium canister was filled with a formulation as follows: (2S)-3-[4-( ⁇ [4-(Aminocarbonyl)-1-piperidinyl]carbonyl ⁇ oxy)phenyl]-2-[((2S)-4- methyl-2- ⁇ [2-(2-methylphenoxy)acetyl]amino ⁇ pentanoyl)amino] propanoic acid potassium salt (prepared according to Example B) 3 % w/w ethanol 20 % glycerol 1.3% w/w 1 ,1 ,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a metering valve.

Abstract

The present invention relates to a pharmaceutical aerosol formulation comprising a hydrofluoroalkane (HFA) propellant having dissolved therein particulate (2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid or a salt or solvate thereof. Methods and uses of the formulation in the treatment of respiratory disorders are also described, as are canisters and metered dose inhalers containing said formulation.

Description

Pharmaceutical Anti-inflammatory Aerosol Formulation
The present invention relates to a pharmaceutical formulation for use in the administration of medicaments by inhalation. In particular, this invention relates to a pharmaceutical formulation for use in pressurised metered dose inhalers (MDI's). 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. Such active materials commonly delivered by inhalation include bronchodilators such as β2 agonists and anticholinergics, corticosteroids, anti-allergies and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
(2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyI]-2-[((2S)-4- methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid has recently been disclosed in International Patent Application (PCT/EP99/10000) as a novel antagonist of both α4β1 and α4β7 integrins which, as a consequence, results in effective anti-inflammatory properties.
Metered dose inhalers (MDIs) are the most common type of a wide range of inhaler types and utilise a liquefied propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol. MDI formulations are generally characterised as solution formulations or suspension formulations.
The most commonly used aerosol propellants for medicaments have been Freon 11 (CCI3F) in admixture with Freon 12 (CCI2F2) and Freon 114 (CF2CI.CF2CI). However, these propellants are now believed to provoke the degradation of stratospheric ozone and their use is now being phased out to eliminate the use of all CFC containing aerosol propellants. There is thus a need to provide an aerosol formulation for medicaments which employ so called 'ozone-friendly' propellants.
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. 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.
The efficiency of an aerosol device, such as an MDI, 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).
Particle deposition in the lung depends largely upon three physical mechanisms:
1. impaction, a function of particle inertia;
2. sedimentation due to gravity; and 3. diffusion resulting from Brownian motion of fine, submicrometer
(<1μm) particles. The mass of the particles determines which of the three main mechanisms predominates.
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 (geometric standard deviation) have similar deposition in the lung irrespective of their composition. The GSD is a measure of the variability of the aerodynamic particle diameters.
For inhalation therapy there is a preference for aerosols in which the particles for inhalation have a diameter of about 0.5 to 5μm. Particles which are larger than 5μm in diameter are primarily deposited by inertial impaction in the orthopharynx, particles 0.5 to 5μm in diameter, influenced mainly by gravity, are ideal for deposition in the conducting airways, and particles 0.5 to 3μm in diameter are desirable for aerosol delivery to the lung periphery. Particles smaller than 0.5μm may be exhaled.
In suspension formulations, particle size in principle is controlled during manufacture by the size to which the solid medicament is reduced, usually by micronisation. However, if 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 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. According to the present invention we provide a pharmaceutical aerosol formulation, comprising a hydrofluoroalkane (HFA) propellant having dissolved therein particulate (2S)-3-[4-({[4-(Aminocarbonyl)-1- piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2- methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid or a salt or solvate thereof.
Examples of suitable salts include physiologically acceptable salts such as alkali metal salts, for example calcium, sodium and potassium salts and salts with (trishydroxymethyl)aminomethane.
Preferably, the (2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]- 2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid will be present as the potassium salt. The free acid is also of 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. Other suitable solubilisation agents include alkanes and ethers (eg dimethyl ether). A further solubilisation agent of interest is dimethoxymethane which has particularly good solvency properties.
Examples of HFA propellants 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.
As a particular aspect of the present invention we provide a pharmaceutical aerosol formulation comprising: (i) (2S)-3-[4-({[4-(Aminocarbonyl)-1 -piperidinyl]carbonyl}oxy) phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino} pentanoyl)amino] propanoic acid or a salt or solvate thereof;
(ii) a hydrofluoroalkane (HFA) propellant;
(iii) a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler; and
(iv) a solubilisation agent in sufficient quantity to solubilise the drug in the formulation.
The presence of the low volatility component in the solution formulation increases the fine particle mass (FPM) as defined by the content of stages 3-5 of an Andersen Cascade Impactor on actuation of the formulation relative to solutions formulations which omit this component. Solution formulations which omit the higher volatility component generally give rise to a particle size distribution which have a higher content of finer particles.
The preferred low volatility component is glycerol, propylene glycol or polyethyleneglycol, especially glycerol. Preferably it is present in an amount of 0.5 to 3% (w/w)
The preferred solubilisation agent is ethanol. Preferably, the solubilisation agent will be present within the formulation at a concentration of not greater than 35% (w/w), most preferably between 5 and 30% (w/w).
More specifically, the present invention can be defined as a pharmaceutical aerosol formulation which comprises:
(i) (2S)-3-[4-({[4-(AminocarbonyI)-1 -piperidinyl]carbonyl}oxy) phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino} pentanoyl)amino] propanoic acid or a salt or solvate thereof; (ii) 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134a);
(iii) 0.5-3% (w/w) glycerol; and
(iv) a solubilisation agent (particularly ethanol) in sufficient quantity to solubilise the drug in the formulation.
Optionally a further active ingredient suitable for inhalation therapy may be incorporated into the formulation such as a corticosteroid (eg fluticasone propionate) or a bronchodilator (eg salmeterol or albuterol or a salt thereof).
The formulation according to the invention will be used in association with a suitable metering valve. We prefer that the formulation is actuated by a metering valve capable of delivering a volume of between 50μl and 100μl, eg 50μl or 63μl or 100μl. Use of a larger metering chamber eg 100μl will generally be preferred.
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 plastics coated glass bottle or preferably a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastics 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). Another polymer for coating that may be contemplated is 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 WO92/11190 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. Spraymiser™). The DF31 valve of Valois, France is also suitable.
Valve seals, especially the gasket seal, 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.
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.
Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aluminium can to form an empty canister. The medicament is added to a charge vessel and a mixture of ethanol, low volatility component and liquefied propellant is pressure filled through the charge vessel into a manufacturing vessel. An aliquot of the formulation is then filled through the metering valve into the canister. Typically, in batches prepared for pharmaceutical use, each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
In an alternative process, 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 onto the canister.
Typically, in batches prepared for pharmaceutical use, each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
Each filled canister is conveniently fitted into a suitable channelling device prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient. 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. Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or 'puff, for example in the range of 10 to 5000 μg medicament per puff.
In a typical arrangement the 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 0.1-0.45mm are generally suitable eg 0.15, 0.22, 0.25, 0.30, 0.33 or 0.42mm. We have found that it is advantageous to use a small diameter eg
0.25mm or less, particularly 0.22mm since this tends to result in a higher FPM and lower throat deposition. 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. Preferably, the dose of (2S)-3-[4-({[4-(Aminocarbonyl)-1- piperidinyl]carbonyl}oxy)phenylj~2-[((2S)-4~methyl-2-{[2-(2- methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid or salt or solvate thereof will be between 0.1 and 10mg per day, most preferably between 0.5 and 3mg per day.
Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or 'puff, for example in the. range of 25 to 500 μg medicament per actuation. We prefer the formulation to be suitable for delivering a therapeutic amount of drug in one or two actuations.
The concentration of drug in the formulation will therefore typically be in the range 0.02% to 5% w/w.
Typically, 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. It will be appreciated that the precise dose administered will depend upon the age and condition of the patient, the quantity and frequency of administration will ultimately be at the discretion of the attendant physician.
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 which comprises administration by inhalation of an effective amount of a formulation herein before described. Preferably, the respiratory disorder will be asthma. Allergic rhinitis is also of interest.
It will be appreciated that when the respiratory disorder is allergic rhinitis the formulation of the present invention will be delivered via the nasal route.
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 allergic rhinitis.
The invention may be illustrated by the following non-limiting examples:
Example A: (2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl]carbonyl} oxy) phenyl]- 2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetylIamino}pentanoyl) amino] propanoic acid
To Wang resin (50g) was added a solution of (2S)-3-[4-(allyloxy)phenyl]-2-[(tert- butoxycarbonyl)amino]propanoic acid (115.8g) and 1-hydroxybenzotriazole (48.6g) in DMF (475ml). After 15 minutes 1 ,3-diisopropylcarbodiimide (56.5ml) was added and the mixture was stirred for 24h at 45°C. The resin was filtered and washed with DMF (3 x 360ml), methanol (3 x 360ml) and dichloromethane (3 x 700ml). To a slurry of the resin in dichloromethane (644ml) was added pyridine (14.7ml). Acetic anhydride (26.9ml) was added and the mixture was stirred for 12h at 20°C. The resin was filtered and washed with dichloromethane (3 x 550ml), methanol (3 x 370ml) and dichloromethane (3 x 550ml). A slurry of 20g of the resin in dichloromethane (100ml) was cooled to 2-5°C and treated with a solution of phenol (20g) in dichloromethane (80ml). Chlorotrimethylsilane (20ml) was added dropwise and the mixture was stirred for 6h at 2-5°C. The resin was filtered and washed with dichloromethane (3 x 200ml), methanol (3 x 200ml), 10% water in DMF (2 x 200ml), 10% diisopropylethylamine in DMF (3 x 200ml), DMF (200ml), methanol (3 x 200ml) and dichloromethane (3 x 200ml).
A slurry of the resin in DMF (55ml) was treated with a solution of Fmoc-leucine (32.7g) and 1-hydroxybenzotriazole (12.5g) in DMF (85ml). After 5 minutes 1 ,3- diisopropylcarbodiimide (19.3ml) was added and the mixture was stirred for 15h at 20°C. The resin was filtered and washed with DMF (3 x 150ml), methanol (3 x 150ml) and dichloromethane (3 x 150ml).
The resin was treated with 20% piperidine in DMF (180ml) and stirred for 1h at 20°C. The resin was filtered and washed with DMF (3 x 150ml), dichloromethane (3 x 150ml), DMF (3 x 150ml) and dichloromethane (3 x
150ml). To a slurry of this in DMF (50ml) was added a solution of (2- methyIphenoxy)acetic acid (17.9g) and 1-hydroxybenzotriazole (14.6g) in DMF (100ml). After 5 minutes 1 ,3-diisopropylcarbodiimide (16.9ml) was added and the mixture was stirred for 65h at 20°C. The resin was filtered and washed with DMF (2 x 150ml), methanol (3 x 150ml) and dichloromethane (3 x 150ml).
A slurry of the resin in dichloromethane (60ml) was treated with a solution of tetrakis(triphenylphosphine)palladium(0) (5.21 g) in dichloromethane (140ml) followed by morpholine (13ml). The mixture was stirred for 2h at 20°C then the resin was filtered and washed with dichloromethane (7 x 200ml). A slurry of the resin in dichloromethane (160ml) was treated with diisopropylethylamine (12.4ml) followed by 4-nitrophenyl chloroformate (24.8g) in 3 portions at 5 minute intervals. The mixture was stirred for 1h at 20°C. The resin was filtered and washed with dichloromethane (3 x 200ml). The resin was treated with a solution of isonipecotamide (15.8g) in DMF (180ml) and the mixture was stirred for 1.5h at 20°C. The resin was filtered and washed with
DMF (4 x 200ml) and dichloromethane (2 x 200ml).
The resin was treated with 50% TFA in dichloromethane (200ml). After stirring for 1h at 20°C the resin was filtered and washed with dichloromethane (5 x 200 ml). The combined filtrate and washings were evaporated in vacuo. The residue was azeotroped with toluene (2 x 100ml) then triturated with ether (50ml) and the resulting white solid filtered. To this was added acetonitrile (150ml) and the mixture was heated to reflux. The resulting suspension was allowed to cool to 20°C and stirred for 18h.. The mixture was filtered to give the title compound as a white solid (4.9g).
Example B: (2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl1carbonyl} oxy) phenyl]-
2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl) a inoj propanoic acid potassium salt
A suspension of (2S)-3-[4-({[4-(Aminocarbonyl)-1.-piperidinyl]carbonyl} oxy) phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy) acetyl]amino}pentanoyl) amino] propanoic acid (10g) in methanol (150ml) was warmed to reflux to obtain a clear solution. To this was added a solution of potassium carbonate (1.16g) in water (7.5ml). After heating under reflux for two minutes the solvents were evaporated in vacuo to give a crisp foam. To this was added acetonitrile (100ml) and the mixture was warmed to reflux, during which time the foam collapsed and started to crystallise. After ten minutes the mixture was allowed to cool to 20°C then filtered under reduced pressure, washed with acetonitrile (25ml) and ether (50ml) to give the title compound as a white solid (10.65g, 100%).
Example 1
An aluminium canister was filled with a formulation as follows: (2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4- methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid (prepared according to Example A) 1 % w/w ethanol 10 %
1 ,1 ,1 ,2-tetrafluoroethane: to 100%
in an amount suitable for 120. actuations and the canister was fitted with a metering valve.
Example 2 An aluminium canister was filled with a formulation as follows: (2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4- methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid potassium salt (prepared according to Example B) 1 % w/w ethanol 10 %
1 ,1 ,1 ,2-tetrafluoroethane: to 100%
in an amount suitable for 120 actuations and the canister was fitted with a metering valve.
Example 3
An aluminium canister was filled with a formulation as follows: (2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4- methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid (prepared according to Example A) 3 % w/w ethanol 20 % glycerol 1.3% w/w
1 ,1 ,1 ,2-tetrafluoroethane: to 100%
in an amount suitable for 120 actuations and the canister was fitted with a metering valve.
Example 4
An aluminium canister was filled with a formulation as follows: (2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4- methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid potassium salt (prepared according to Example B) 3 % w/w ethanol 20 % glycerol 1.3% w/w 1 ,1 ,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a metering valve.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
The contents of the above mentioned patent applications are herein incorporated by reference.

Claims

Claims
1. A pharmaceutical aerosol formulation comprising a hydrofluoroalkane (HFA) propellant having dissolved therein particulate (2S)-3-[4-({[4- (Aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2- methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid or a salt or solvate thereof.
2. A pharmaceutical aerosol formulation according to claim 1 wherein the (2S)-3-[4-({[4-(Aminocarbonyl)-1 -piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4- methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid is present as the potassium salt.
3. A pharmaceutical aerosol formulation according to claim 1 wherein the (2S)-3-[4-({[4-(Aminocarbonyl)-1 -piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4- methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid is present as the free acid.
4. A pharmaceutical aerosol formulation according to claim 1 which comprises a solubilisation agent.
5. A formulation according to claim 4 wherein the solubilisation agent is selected from: propylene glycol, glycerol, ethanol, alkanes, ethers (eg dimethyl ether) and dimethoxymethane.
6. A formulation according to claim 4 wherein the solubilisation agent is ethanol.
7. A formulation according to any one of claims 4 to 6 wherein the solubilisation agent is present within the formulation at a concentration of 5-30 % (w/w).
8. A formulation according to any one of claims 1 to 7 wherein the hydrofluoroalkane (HFA) propellant is 1 ,1 ,1 ,2-tetrafluoroethane (HFA134a) or 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane (HFA227) or a mixture thereof.
9. A formulation according to claim 8 wherein the hydrofluoroalkane (HFA) propellant is 1 ,1 ,1 ,2-tetrafluoroethane (HFA134a).
10. A pharmaceutical aerosol formulation comprising: (i) (2S)-3-[4-({[4-(Aminocarbonyl)-1-piperidinyl]carbonyl} oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino} pentanoyl)amino] propanoic acid or a salt or solvate thereof;
(ii) a hydrofluoroalkane (HFA) propellant;
(iii) a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler; and
(iv) a solubilisation agent in sufficient quantity to solubilise the drug in the formulation.
11. A formulation according to claim 10 wherein the low volatility component is glycerol, propylene glycol or polyethyleneglycol.
12. A formulation according to claim 11 wherein the low volatility component is glycerol.
13. A formulation according to any one of claims 10 to 12 wherein the low volatility component is present within the formulation at an amount of 0.5% to 3% (w/w).
14. A pharmaceutical aerosol formulation which comprises: (i) (2S)-3-[4-({[4-(Aminocarbonyl)-1 -piperidinyl]carbonyl}oxy) phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino} pentanoyl)amino] propanoic acid or a salt or solvate thereof; (ii) 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134a); (iii) 0.5-3% (w/w) glycerol; and
(iv) a solubilisation agent (particularly ethanol) in sufficient quantity to solubilise the drug in the formulation.
15. A formulation according to any one of claims.1 to 14 wherein the (2S)- 3-[4-({[4-(Aminocarbonyl)-1 -piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2- {[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino] propanoic acid or a salt thereof is present within the formulation in an amount between 0.02 and 5 % (w/w).
16. A canister comprising a metering valve and containing a pharmaceutical aerosol formulation according to any one of claims 1 to 15.
17. A metered dose inhaler which comprises a canister as claimed in claim 16 fitted into a suitable channelling device.
18. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation according to any one of claims 1 to 15.
19. A method of treating asthma which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation according to any one of claims 1 to 15.
20. A method of treating allergic rhinitis which comprises administration via the nasal route of an effective amount of a pharmaceutical aerosol formulation according to any one of claims 1 to 15.
21. Use of a pharmaceutical aerosol formulation according to any one of claims 1 to 15 in the manufacture of a medicament for the treatment of respiratory disorders, eg. asthma or allergic rhinitis.
EP01938435A 2000-06-16 2001-06-15 Pharmaceutical anti-inflammatory aerosol formulation Withdrawn EP1289539A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0014881 2000-06-16
GBGB0014881.7A GB0014881D0 (en) 2000-06-16 2000-06-16 Pharmaceutical aerosol formulation
PCT/GB2001/002613 WO2001095925A1 (en) 2000-06-16 2001-06-15 Pharmaceutical anti-inflammatory aerosol formulation

Publications (1)

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EP1289539A1 true EP1289539A1 (en) 2003-03-12

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EP (1) EP1289539A1 (en)
JP (1) JP2004503505A (en)
AU (1) AU2001264113A1 (en)
GB (1) GB0014881D0 (en)
WO (1) WO2001095925A1 (en)

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Publication number Priority date Publication date Assignee Title
GB9828074D0 (en) * 1998-12-18 1999-02-17 Glaxo Group Ltd Therapeutically useful compounds

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Title
See references of WO0195925A1 *

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