WO2002072067A2

WO2002072067A2 - Pharmaceutical aerosol formulation

Info

Publication number: WO2002072067A2
Application number: PCT/GB2002/001096
Authority: WO
Inventors: Paul Johnson
Original assignee: Glaxo Group Limited
Priority date: 2001-03-12
Filing date: 2002-03-11
Publication date: 2002-09-19
Also published as: AU2002238748A1; WO2002072067A3

Abstract

According to the present invention we provide 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.

Description

Pharmaceutical Aerosol Formulation

The present invention relates to pharmaceutical formulations for use in the administration of medicaments by inhalation. In particular, this invention relates to pharmaceutical formulations 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 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.

Metered dose inhalers (MDI's) 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.

Respirable particles are generally considered to be those with aerodynamic diameters less than 5μm. These particles, particularly those with a diameter of about 3μm, are efficiently deposited in the lower respiratory tract by sedimentation.

Many of the factors relevant to the MMAD of particles are relevant to droplets and the additional factors of rate of solvent evaporation, and surface tension are also important.

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 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.

In the case of administration of formulations to the nose, 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. Thus 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. According to the present invention we provide 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.

Examples of 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. Other example salts include tosylates.

We provide the tosylate salt 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 as an aspect of the invention which may be prepared following the general methods of WO98/28319.

Examples of suitable solvates include hydrates.

In a first embodiment, 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.

In a second more preferred embodiment, 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.

In a third preferred embodiment, 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.

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.

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.

As a particular aspect of the present invention we provide a pharmaceutical aerosol formulation comprising:

(i) (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 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 (eg. PEG200 or PEG400). In one embodiment, the low volatility component is preferably glycerol. In a second embodiment, the low volatility component is preferably polyethyleneglycol (eg. PEG200 or PEG400), especially PEG200.

Stability studies have shown that use of polyethylene glycol gives rise to particularly low levels of impurities. Preferably 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. Depending on the final concentration 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 in the formulation, the propellant, and the precise amount of low volatility component, the concentration of solubilisation agent (eg ethanol) required will vary. So as not to suppress the vapour pressure of the propellant to an undesirable extent, 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).

More specifically, according to one aspect the present invention can be defined as a pharmaceutical aerosol formulation which comprises:

(ii) 1,1 ,1 ,2-tetrafluoroethane (HFA 134a);

(iii) 0.1-3% (w/w) glycerol; and

(iv) a solubilisation agent (particularly ethanol) in sufficient quantity to solubilise the drug in the formulation.

More specifically, according to another aspect, the present invention can be defined as a pharmaceutical aerosol formulation which comprises:

(i) (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 or a salt or solvate thereof (especially in the form of the free base);

(ii) 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134a);

(iii) 0.1-3% (w/w) polyethylene glycol (especially PEG200); and

(iv) a solubilisation agent (particularly ethanol) in sufficient quantity to solubilise the drug in the formulation. 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 25μl and 10Oμl, eg 25μl, 35μl, 50μl or 63μl or 100μl. Generally the metering volume will be between 50μl and 100μl. Use of a larger metering chamber eg 100μl 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). 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 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. Spraymiser™). The DF31 valve of Valois, France is also suitable.

Valve seals, especially the gasket seal and also the seals around the metering chamber, 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. As noted above 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.

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 on, and then the propellant is filled into the canister through the valve.

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.

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 0.15- 0.45mm, particularly 0.2-0.45mm are generally suitable eg 0.15, 0.22, 0.25, 0.30, 0.33 or 0.42mm. 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. 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.

Preferably, 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 250μg per day, most preferably between 1 and 50μg 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 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 0.001% to 0.1% w/v. 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. Treatment may be of asthma, chronic obstructive pulmonary disease (COPD) or other respiratory disorder (eg upper respiratory tract disorders such as rhinitis). 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, for example asthma or chronic obstructive pulmonary disease (COPD), which comprises administration by inhalation of an effective amount of a formulation herein before described. In the case of rhinitis, 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.

As mentioned above the advantages of the invention include the fact that 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.

The invention may be illustrated by the following non-limiting examples: Examples Example 1

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

(prepared according to method of WO 98/28319, Example 11 ) 0.0125% w/v ethanol 10 % w/w

1,1,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 10Oμl metering valve. Thus, each actuation delivers 12.5μg medicament.

Example 2

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

(prepared according to method of WO 98/28319, Example 11 e) 0.0125 % w/v ethanol 15 % w/w

Example 3

(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 100μl metering valve. Thus, each actuation delivers 12.5μg medicament. Example 4

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 11 e) 0.0125% w/v ethanol 15 % 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 100μl metering valve. Thus, each actuation delivers 12.5μg medicament.

Example 5

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

(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 ,2,3,3,3-heptafluoro-n-propane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 12.5μg medicament.

Example 6

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 100μl metering valve. Thus, each actuation delivers 12.5μg medicament. Example 7

An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11 ) 0.00625% w/v ethanol 5 % w/w

1 ,1 ,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 6.25μg medicament.

Example 8

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 11 e) 0.00625% w/v ethanol 7.5 % w/w

1,1 ,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 6.25μg medicament.

Example 9

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 (prepared according to method of WO 98/28319, Example 11 ) 0.00625% w/v ethanol 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 100μl metering valve. Thus, each actuation delivers 6.25μg medicament.

Example 10

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

Example 11

An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11 ) 0.0125% w/v ethanol 8 % 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 100μl metering valve. Thus, each actuation delivers 12.5μg medicament.

Example 12

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 (weight based on that of free base) ethanol 14 % 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 100μl metering valve. Thus, each actuation delivers 12.5μg medicament (weight based on that of free base)

Examples 13A and 13B

(prepared according to method of WO 98/28319, Example 11 ) 0.00625% w/v ethanol 5 % w/w polyethyleneglycol (PEG200 or PEG400) 0.5%w/w

Examples 14A and 14B

An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11e) 0.00625% w/v (weight based on that of free base) ethanol 7.5% w/w polyethyleneglycol (PEG200 or PEG400) 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 100μl metering valve. Thus, each actuation delivers 6.25μg medicament (weight based on that of free base).

Example 15

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

(prepared according to method of WO 98/28319, Example 11b) 0.0125% w/v

(weight based on that of free base) ethanol 15% 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 100μl metering valve. Thus, each actuation delivers 12.5μg medicament (weight based on that of free base). Example 16

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

(prepared according to method of WO 98/28319, Example 11b) 0.0125% w/v (weight based on that of free base) ethanol 15% w/w glycerol 0.5% 1,1,1,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 12.5μg medicament (weight based on that of free base).

Example 17

An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11) 0.005% w/v ethanol 5% w/w

1,1,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 5μg medicament.

Examples 18A and 18B

An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11) 0.005% w/v ethanol 5% w/w polyethyleneglycol (PEG200 or PEG400) 0.5% (w/w)

Example 19 An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11) 0.0025% w/v ethanol 3% w/w 1,1,1,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 2.5μg medicament.

Examples 20A and 20B An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11 ) 0.0025% w/v ethanol 5% w/w polyethyleneglycol (PEG200 or PEG400) 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 100μl metering valve. Thus, each actuation delivers 2.5μg medicament.

Example 21

An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11) 0.0125% w/v ethanol 15% w/w glycerol 1% (w/w)

Example 22A and 22B An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11) 0.025% w/v or 0.003% w/v ethanol 14% w/w glycerol 1 % (w/w)

1,1,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 25μg or 3μg medicament.

Example 23A and 23B

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 (prepared according to method of WO 98/28319, Example 11 b) 0.025% w/v or 0.003% w/v (weight based on that of free base) ethanol 24% w/w glycerol 1% w/w

1,1,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 25μg or 3μg medicament (weight based on that of free base).

Example 24 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 (prepared according to method of WO 98/28319, Example 11b) 0.025% w/v (weight based on that of free base) ethanol 24% w/w

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 100μl metering valve. Thus, each actuation delivers 25μg medicament (weight based on that of free base).

Example 25

An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11) 0.025% w/v ethanol 14% w/w

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 100μl metering valve. Thus, each actuation delivers 25μg medicament.

Examples 26

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 11 e) 0.025% w/v

(weight based on that of free base) ethanol 18% w/w glycerol 1% w/w

1 ,1 ,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 25μg medicament (weight based on that of free base). Examples 27A. 27B and 27C

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 11 e) 0.0125% w/v ethanol 15 % w/w glycerol 0.5% or 1 % or 2% w/w

1 ,1 ,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 12.5μg medicament.

Example 28

An aluminium canister was filled with a formulation as follows:

(prepared according to method of WO 98/28319, Example 11 e) 0.0125 % w/v

(based on weight of base) ethanol 15 % w/w

1 ,1 ,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 12.5μg medicament (based on weight of base).

Examples 29A and 29B 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 PEG200 0.5% or 2% w/w

1 ,1,1 ,2-tetrafluoroethane: to 100% in an amount suitable for 120 actuations and the canister was fitted with a 100μl metering valve. Thus, each actuation delivers 12.5μg medicament (based on weight of base).

Stability data

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.

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. C

^*spurious peak not seen in a previous analysis of this batch nd = not detected (<0.1 %)

H σ

CD

t

C

Claims

1. 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.

2. A pharmaceutical aerosol formulation according to claim 1 wherein 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 is used as 1- hydroxy-2-naphthoate salt.

3. A pharmaceutical aerosol formulation according to claim 1 wherein the (2R,3R,4S_I5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin- 9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol is used as the free base.

4. A pharmaceutical aerosol formulation according to claim 1 wherein 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 is used as the maleate salt.

5. A pharmaceutical aerosol formulation according to any one of claims 1 to 4 which comprises a solubilisation agent.

6. A formulation according to claim 5 wherein the solubilisation agent is selected from: propylene glycol, glycerol and ethanol.

7. A formulation according to claim 6 wherein the solubilisation agent is ethanol.

8. A formulation according to any one of claims 5 to 7 wherein the solubilisation agent is present within the formulation at a concentration of 1-30 % (w/w).

9. A formulation according to any one of claims 1 to 8 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.

10. A formulation according to claim 9 wherein the hydrofluoroalkane (HFA) propellant is 1,1,1,2-tetrafluoroethane (HFA134a).

11. A pharmaceutical aerosol formulation comprising:

(i) (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 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

12. A formulation according to claim 11 wherein the low volatility component is glycerol, propylene glycol or polyethyleneglycol.

13. A formulation according to claim 12 wherein the low volatility component is glycerol.

14. A formulation according to claim 12 wherein the low volatility component is polyethylene glycol.

15. A formulation according to claim 14 wherein the low volatility component is PEG200.

16. A formulation according to any one of claims 11 to 15 wherein the low volatility component is present within the formulation at an amount of 0.1% to 3% (w/w).

17. A pharmaceutical aerosol formulation according to claim 1 which comprises: (i) (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 or a salt or solvate thereof;

(ii) 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134a); (iii) 0.1-3% (w/w) glycerol; and

18. A pharmaceutical aerosol formulation according to claim 1 which comprises: (i) (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 or a salt or solvate thereof;

(ii) 1,1 ,1 ,2-tetrafluoroethane (HFA 134a); (iii) 0.1-3% (w/w) polyethylene glycol; and

19. A pharmaceutical aerosol formulation according to claim 17 wherein 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 is used as the free base.

20. A pharmaceutical aerosol formulation according to claim 18 or claim 19 wherein the polyethylene glycol is PEG200.

21. A formulation according to any one of claims 1 to 20 wherein 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 or a salt thereof is present within the formulation in an amount between 0.001 and 0.1 % (w/v).

22. A canister comprising a metering valve and containing a pharmaceutical aerosol formulation according to any one of claims 1 to 21.

23. A metered dose inhaler which comprises a canister as claimed in claim 22 fitted into a suitable channelling device.

24. 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 21.

25. Use of a pharmaceutical aerosol formulation according to any one of claims 1 to 21 in the manufacture of a medicament for the treatment of respiratory disorders.