GB2354007A

GB2354007A - A Fluticasone Propionate-Aerosol Composition

Info

Publication number: GB2354007A
Application number: GB0022222A
Authority: GB
Inventors: Alan Leslie Cripps; Paul Johnson
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1999-09-11
Filing date: 2000-09-11
Publication date: 2001-03-14
Anticipated expiration: 2020-09-11
Also published as: WO2001019342A3; FR2798290A1; FR2848453A1; EP1143930A3; US6479035B1; JP2003509359A; GB0022222D0; FR2843882B1; FR2848453B1; GB2354007B; FR2820322A1; ITRM20000491A0; US7220403B2; ES2274803T3; US20040157815A1; AU7026800A; EP1143930B8; WO2001019342A2; DE60031504D1; ATE343374T1

Abstract

The invention relates to a pharmaceutical aerosol formulation which comprises: <SL> <LI>(i) fluticasone propionate and <LI>(ii) a hydrofluoroalkane (HFA) propellant, </SL> characterised in that the fluticasone propionate is completely dissolved in the formulation. The invention also provided canisters containing the formulation and uses thereof.

Description

2354007 Pharmaceutical Formulation of Fluticasone Propiona

Background of the invention

Field of the invention

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 formulatio'n'of fluticasone propionate for use in metered dose inhalers (MDI's). The invention also relates to methods for their preparation and to their use in therapy.

Description of the background art

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 P2 agonists and anticholinergics, corticosteroids, anti-allergics and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.

(6a, 11b, 16a, 17a)-6, 9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(Ioxopropoxy) androsta-1, 4-diene-1 7-carbothioic acid, S-fluoromethyl ester was described as an anti inflammatory steroid by US Patent No. 4,335,121. This compound is also known by the generic name of fluticasone propionate and has since become widely known as a highly effective steroid in the treatment of inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD).

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 (CC13F) in admixture with Freon 12 (CC12F2) and Freon 114 (CF2CI.CF2C1). However, these propellants are now believed to provoke the degradation of stratospheric ozone 2 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 IVIDI, 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 (<lgm) 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.

3 Aerosol particles of equivalent MMAD and GSID (geometric standard deviation) have similar deposition in the lung irrespective of their composition. The GSID 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 5[tm. Particles which are larger than 5[tm in diameter are primarily deposited by inertial impaction in the orthopharynx, particles 0.5 to 5[trn in diameter, influenced mainly by gravity, are ideal for deposition in the conducting airways, and particles 0.5 to 3[tm in diameter are desirable for aerosol 10 delivery to the lung periphery. Particles smaller than 0. 5tm may be exhaled, Respirable particles are generally considered to be those with aerodynamic diameters less than 5Lm. These particles, particularly those with a diameter of about 3Rm, are efficiently deposited in the lower respiratory tract by sedimentation. 15 It has been recently demonstrated in patients with mild and severe airflow obstruction that the particle size of choice for a 02 agonist or anticholinergic aerosol should be approximately 3tim (Zaanen, P. et al, Int. J. Pharm. (1994) 107, 211-217, Int. J. Pharm. (1995) 114, 111-115, Thorax (1996), 51, 977-980.) 20 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 25 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 MIDI eg. canister or valve. The effect of Ostwald ripening and particularly of drug deposition may be particblarly severe for potent drugs 30 (including fluticasone propionate) 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 4 the moment of inhalation. Thus, it may be subject to considerable variability and is generally hard to control.

Besides its impact on the therapeutic profile of a drug, the size of aerosol particles has an important impact on the side effect profile of a drug. For example, it is well known that the orthopharynx deposition of aerosol formulations of steroids can result in side effects such as candidiasis of mouth and throat. Accordingly, throat deposition of such aerosol formulations is generally to be avoided. Furthermore, a higher systemic exposure to the aerosol particles due to deep lung penetration can enhance the undesired systemic effects of certain drugs. For example, the systemic exposure to certain steroids can produce side effects on bone metabolism and growth.

Summary of the invention

Thus, according to the present invention we provide a pharmaceutical aerosol formulation for use in a metered dose inhaler, comprising (i) fluticasone propionate and (ii) a hydrofluoroalkane (HFA) propellant; and characterised in that the fluticasone propionate is completely dissolved in the formulation.

Detailed description of the invention

The formulation according to the invention will generally contain a solubilisation agent to aid solubilisation of the fluticasone propionate in the formulation. Suitable solubilisation agents include propylene glycol and ethanol, preferably ethanol. Other suitable solubilisation agents include ethers (eg dimethyl ether). Alkanes may also be of use.

A further solubilisation agent of interest is dimethoxymethane (methylal) which has good solvency properties. We have also found ethylacetate to be a solubilising agent with good solvency properties.

As a particular aspect of the present invention we provide a pharmaceutical aerosol formulation comprising (i) fluticasone propionate, (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 fluticasone propionate 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; such distributions generally do not match the distribution of the existing commercialised suspension formulations which contain CFC's and may therefore not be bio-equivalent.

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). An alternative propellant of interest is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227).

The preferred low volatility component is glycerol, propylene glycol or polyethyleneglycol (eg PEG 200 or PEG 400), especially glycerol. Polyethylene glycol is also of particular interest, especially PEG400. Preferably it is present in an amount of 0.5 to 3% (w/w), especially around 1% (w1w).

The preferred solubilisation agent is ethanol.

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

(i) fluticasone propionate; (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 fluticasone propionate in the formulation.

We prefer the formulation to be suitable for delivering a therapeutic amount of fluticasone propionate in one or two actuations. Preferably, the formulation will be 6 suitable for delivering 25-250tg per actuation, especially 25Rg, 50tg' 125Rg or 250gg per actuation. However, as mentioned in the foregoing, the amount of ethanol required to dissolve high concentrations of fluticasone propionate may tend to depress the vapour pressure of the propellant to an undesirable degree. The vapour pressure should desirably remain above around 50psi. Therefore the formulation is most suitable for delivering 25-125gg per actuation, especially 25-50gg per actuation.

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 50il and 1 00gl, eg 50ld or 63tl. 1 00gl is also suitable. When a 50[d metering volume is used, the final concentration of fluticasone propionate delivered per actuation would be 0. 1 % w/v (which equates to 0. 1 g of fluticasone propionate per 1 00ml of formulation) or approx. 0.083% w/w (which equates to 0.083g of fluticasone propionate per I OOg of formulation) for a 50Lg dose, 0.25% (w/v) or approx. 0.21 % (w/w) for a 125l.Lg dose, 0.5% (w/v) or approx. 0. 42% (w/w) for a 250gg dose and 0.05% (w/v) or approx 0.042% (w/w) for a 25gg dose. Wherein a 63d metering volume is used, the final concentration of fluticasone propionate delivered per actuation would be 0.079% (w/v) or approx. 0.067% (w/w) for a 50tg dose, 0.198% (w/v) or approx. 0.167% (w1w) for a 125gg dose, 0.397% (w/v) or approx. 0. 333% (w/w) for a 250tg dose and 0.04% (w/v) or approx. 0.033% (w/w) for a 25Lg dose. When a loop[ metering volume is used, the final concentration of fluticasone propionate delivered per actuation would be 0.05% w/v (which equates to 0.05g of fluticasone propionate per 100ml of formulation) or approx. 0.042% w/w (which equates to 0.042g of fluticasone propionate per 1 OOg of formulation) for a 50Rg dose, 0. 125% (w/v) or approx. 0.11% (w/w) for a 125Rg dose, 0.25% (w/v) or approx. 0.21% (w/w) for a 250[tg dose and 0.025% (w/v) or approx 0.021% (w/w) for a 25gg dose. The previously quoted w/w figures are approximate in that they do not compensate in the mismatch in density between HFAl 34a and ethanol, however the precise figures may be readily determined.

The formulation is most suitable for concentrations of fluticasone propionate in the range 0.025 to 0.25 % (w/v), preferably 0.025 to 0.15 % (wIv), more preferably 0.035 to 0. 15 % (w/v), particularly 0.04 to 0. 1 % (w/v). A concentration of 0. 025 to 0.04 % (w/v) is also of particular interest. Formulations of the present invention containing 7 such low concentrations of fluticasone propionate may have particular physical stability advantages relative to suspension formulations containing the same wherein particles of fluticasone propionate may be susceptible to Ostwald ripening or to drug deposition on the canister wall or on parts of the valve as discussed above. Drug deposition is especially problematic in low strength fluticasone propionate suspension formulations because the amount of drug lost through deposition on internal surfaces of the metered dose inhaler can represent a significant proportion of the total available drug and therefore have a significant effect on dosing uniformity through the life of the product.

The solution formulations of the present invention overcome or substantially mitigate such disadvantages.

Use of a larger metering chamber eg 100gi will generally be preferred.

We prefer the formulation to contain between 0.5 and 2% w/w, more preferably between 0.8 and 1.6% w1w, particularly between 1.0 and 1.6% w/w glycerol. Another range of particular interest is 0.5-1% (w/W) glycerol. We especially prefer to use 1.3% (w1w) glycerol. We also especially prefer to use 1.0% w/w glycerol.

Depending on the final concentration of fluticasone propionate 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%. The amount of ethanol will more preferably be in the range 5 to 30%, particularly 5 to 20%, more particularly 10 to 20%. A range of -7 to 16% w/w is also particularly preferred, more particularly 7 to 11 % w/w.

When the concentration of fluticasone propionate is around 0. 1 % wIv and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 16-24% w/w eg 16- 18% w/w, especially around 16% w/w is particularly suitable but is more preferably 20-22% w/w especially around 21 % w/w. When the concentration of fluticasone propionate is around 0.05% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 7-11 % w/w eg 7-8% w/w, especially around 7% w/w is particularly suitable but is more preferably 9-11 % w/w especially around 10% w/W. When the concentration of 8 fluticasone propionate is around 0.079% w/v and the propellant is 1,1,1,2 tetrafluoroethane, an amount of ethanol of 15-17% w/w especially around 16% is suitable. When the concentration of fluticasone propionate is around 0. 198% w1v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 34- 36% w/W eg around 35% is suitable. When the concentration of fluticasone propionate is around 0.025% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 7 9% w1w especially around 8%, more preferably around 7% is suitable.

When the concentration of fluticasone propionate is around 0.025% w/v and the propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane, an amount of ethanol of 13-15% w/w especially around 14% is suitable. When the concentration of fluticasone propionate is around 0.05% w/v and the propellant is 1,1,1,2,3,3,3-heptafluoro-n- propane, an amount of ethanol of 17-19% w/w especially around 18% is suitable, When the concentration of fluticasone propionate is around 0.05% w/v and the propellant is 1, 1, 1,2-tetrafluoroethane, an amount of ethylacetate as solubilisation agent of 13-16% w/w especially around 15% is suitable. When the concentration of fluticasone propionate is around 0.05% w/v and the propellant is 1,1,1,2tetrafluoroethane, an amount of dimethoxymethane (methylal) as solubilisation agent of 13-16% w/W especially around 15% is suitable.

The above generally described formulations are particularly preferred in conjunction with 1.0-1.6% w/w glycerol, particularly 1.0% wJw glycerol or 1.3% w/w glycerol.

Formulations according to the invention which are free of surfactants are preferred. Formulations according to the invention which are free of all excipients besides the solubilisation agent (eg ethanol), low volatility component (such as glycerol) and the propellant are particularly preferred. 30 Formulations according to the invention will preferably contain fluticasone propionate as the only medicament. However formulations which contain medicaments in addition to fluticasone propionate such as beta adrenergic agonists, and anti-cholinergic compounds may also be contemplated.

9 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 aluminiurn 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 YVO 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 EPIDM rubber as described in W095/02651 are especially suitable. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (eg.

DF1 0, DF30, DF60), Bespak p1c, UK (eg. BK300, BK356, BK357) and 3MNeotechnic Ltd, UK (eg. SpraymiserTm). 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.

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.

Valves which are entirely or substantially composed of metal components (eg Spraymiser, 3M-Neotechnic) are especially preferred for use according to the invention. 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 10 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 vessei'int o a manufacturing vessel. An aliquot of the formulation is then filled is through the meteri ' ng 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 20 canister under conditions which are sufficiently cold that the formulation does not vaporise, and then a metering valve crimped onto the canister. In an alternative process an aliquot of medicament dissolved in the solubilising agent and any lowvolatility component is dispensed into an empty canister, a metering valve 25 is 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 checkweighed, 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 0.150.45mm 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 10 less, particularly 0.22mm since this tends to result in a higher FPIVI and lower throat deposition. 0.1 5mm 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. is Smaller dimensions are preferred eg 0.65mm or 0. 30mm.

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 250 Lg medicament per puff.

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 (COPID) or other respiratory disorder. 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 25 the discretion of the attendant physician. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1,2,3 or 4 puffs each time. The preferred treatment regime is 1 or 2 puffs of 25, 50, 125 or 250jtg/puff fluticasone propionate, 2 times per day. 30 The filled canisters and metered dose inhalers described herein comprise further aspects of the present invention.

12 A still further aspect of the present invention comprises a method of treating respiratory disorders such as, for example, asthma or chronic obstructive pulmonary disease (COPD), which comprises administration by inhalation of an effective amount of a formulation herein before described.

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 (COPID).

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 is illustrated with reference to the following examples:

Example 1 and 2 Formulations may be prepared with compositions as follows:

Fluticasonepropionate: 0.1%w/v 0.05% W/v Ethanol: 16% w/w 7% Glycerol: 1.3% w/w 1.3% 1,1,1,2-tetrafluoroethane: to 100% to 100% These solution formulations may be filled into an aluminium canister under pressure and fitted with a metering valve having a 50 gI metering chamber.

These formulations are suitable for delivering 50 gg or 25 l-tg fluticasone propionate per actuation respectively.

Example 3

Formulations were prepared with compositions as follows:

Form. 3a Fqrm. 3b Form. 3c Fluticasonepropionate: 0.1%w/v 0.079% w/v 0.05% w/v 13 Ethanol: 21 % w/w 16% w/w 10% Glycerol: 1.0% W/W 1.0% W/W 1.0% 1,1,1,2-tetrafluoroethane: to 100% to 100% to 100% These solution formulations were filled into aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chambers of volume 50 Al, 63 tl and 100 Al respectively. These formulations are suitable for delivering 50 Rg fluticasone propionate per actuation.

Example 4

Formulations were prepared with compositions as follows:

Form. 4a Form. 4b Form. 4c Fluticasonepropionate: 0.1%w/v 0.079% w/v 0.05% wIv Ethanol: 21 % w1w 16% w/w 10% 1,1,1,2-tetrafluoroethane: to 100% to 100% to 100% These solution formulations were filled into aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chambers of volume 50 Ll, 63 Vtl and 100 gi respectively.

These formulations are suitable for delivering 50 gg fluticasone propionate per actuation.

Example 5

A formulation was prepared with compositions as follows:

Fluticasonepropionate: 0.198%wlv Ethanol: 35% w/w Glycerol: 1.0% W/W 1,1,1,2-tetrafluoroethane: to 100% 14 This solution formulation was filled into an aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having mete(ing chamber of volume 63 tl.

This formulation is suitable W delivering 125 tg fluticasone propionate per actuation.

Example 6

A formulation was prepared with compositions as follows:

Fluticasonepropionate: 0.198%w/v Ethanol: 35% w/w 1,1,1,2-tetrafluoroethane: to 100% This solution formulation was filled into an aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chamber of volume 63 gl.

This formulation is suitable for delivering 125 tg fluticasone propionate per actuation.

Example 7

Formulations were prepared with compositions as follows:

Form. 7a Form. 7b Form. 7c Fluticasone propionate: 0.05% w/v 0.05% w/v 0.05% wIv Ethanol: 10% W/W 10% W/W 10% W/W Glycerol: 0.5% w/W 2% w/w 3% w/w 1,1,1,2-tetrafluoroethane: to 100% to 100% to 100% These solution formulations were filled into aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chamber of volume 100 gl. These formulations are suitable for delivering 50 jag fluticasone propionate per actuation. 30 Example 8 Formulations were prepared with compositions as follows:

Fluticasone propionate: 0.025% w/v 0.025% w/v Ethanol: 8% wAN 7% w/WGlycerol: 1.0% W/W 1.0% W/W 1,1,1,2-tetrafluoroethane: to 100% to 100% These solution formulations were filled into an aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chamber of volume 100 gi. These formulations are suitable for delivering 25 [Lg fluticasone propionate per actuation.

Example 9 Formulations were prepared with,compositions as follows: Formulation 9a: Fluticasone propionate: 0.05% w/v Di.methoxymethane: 15% w/w 1,1,1,2-tetrafluoroethane: to 100% Formulation 9b:

Fluticasone propionate: 0.05% w/v Ethylacetate: 15% W/W 1,1,1,2-tetrafluoroethane: to 100% Formulation 9c:

Fluticasone propionate: 0.05% w/v Dimethoxymethane: 15% w/W Glycerol: 1% wtw 1,1,1,2-tetrafluoroethane: to 100% Formulation 9d:

Fluticasone propionate: 0.05% w/v Ethylacetate: 15% w1w Glycerol: 1%W/W 1,1,1,2-tetrafluoroethane: to 100% 16 These solution formulations were filled into aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chamber of volume 100 0.

Example 10

Formulations were prepared with compositions as follows:

Formulation 10a:

Fluticasone propionate: 0.05% w/v Ethanol: 10% W/W Glycerol: I%W/W 1,1,1,2-tetrafluoroethane: to 100% Formulation 10b:

Fluticasone propionate: 0.05% w/v Ethanol: 10% W/W PEG 200: 1% W/W 1,1,1,2-tetrafluoroethane: to 100% Formulation 10c:

Fluticasone propionate: 0.05% w/v Ethanol: 10% W/W PEG 400: 1% W/W 1,1,1,2-tetrafluoroethane: to 100% Formulation 10d:

Fluticasone propionate: 0.05% w/v Ethanol: 10% W/W Propylene glycol: I % wAfv 1,1,1,2-tetrafluoroethane: to 100% Formulation 10e:

Fluticasone propionate: 0.05% w/v Ethanol: 18% w/w 1,1,1,2,3,3,3-heptafluoro-n-propane: to 100% Formulation 10f:.

17 Fluticasone propionate: 0.05% w/v Ethanol: 18% W/W Glycerol: 1%W/W 1,1,1,2,3,3,3-heptafluoro-n-propane: to 100% Formulation 10g:

Fluticasone propionate: 0.025% w/v Ethanol: 14% w/w 1,1,1,2,3,3,3-heptafluoro-n-propane: to 100% Formulation 10h:

Fluticasone propionate: 0.025% w/v Ethanol: 14% w/w Glycerol: 1% W/W 1,1,1,2,3,3,3-heptafluoro-n-propane: to 100% Formulation 10i:

Fluticasone propionate: 0.025% w/v Ethanol: 7% w/w 1,1,1,2-tetrafluoroethane: to 100% Formulation 10j:

Fluticasone propionate: 0.025% w/v Ethanol: 7% w/w Glycerol: 1%w/w 1,1,1,2-tetrafluoroethane: to 100% These. solution formulations were filled into aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chamber of volume 63 il.

These formulations are suitable for delivering 31.5 tg (1 Oa-1 Oe) or 15. 75 gg (I Of, I Og) fluticasone propionate per actuation. However the performance of these formulations is a model for formulations that would deliver 50 gg and 25 Lg fluticasone. propionate using a metering valve of 100 pl.

Andersen Cascade Impaction Data 18 Formulations as described in Examples 3, 4, 5 and 6 were profiled using an Andersen Cascade Impactor, using a 0.22mm (orifice) x 0.65mm (jet length) actuator from Bespak (BK621 variant). Testing was performed on canisters at "beginning of use" (BoU) and delivered drug from 10 actuations was collected in the instrument after 4 priming actuations were fired to waste. Results are shown in Tables 1-4 and Figures 1-4 and 11. For comparison, data from a Flixotide Evohaler (trademark) (particulate fluticasone propionate suspensed in HFA1 34a (excipient free) 50 gg per actuation) product is also shown in some figures.

The 0.079% w/v fluticasone propionate products of Examples 3 and 4 (50 Lg per actuation; 63 ptl metering chamber) were profiled using an Andersen Cascade Impactor in a study to see the effect of actuator orifice diameter and length.

Threeactuators were used:

0.50mm diameter orifice x 1.50mm jet length 0.33mm diameter orifice x 1.50mm jet length 0.22mm diameter orifice x 0.65mm jet length Results are shown in Table 5 and Figures 5 to 9. For comparison, data from a Flixotide Evohaler (trademark) (particulate fluticasone propionate suspensed in HFA1 34a (excipient free) 50 ig per actuation) product is also shown in some figures.

The results show the best performance (as indicated by highest FPM) in products containing a relatively low concentration of ethanol (say around 10%) and containing glycerol (say around 11%). A small actuator orifice diameter (say around 0.22mm) is also seen to be preferred.

The solubility of fluticasone propionate in ethanol in the presence of HFA134a is shown in Figure 10.

A study was performed on the 0.05% w/v fluticasone propionate formulations (H FAI 34a/1 0% ethanol) of Examples 3 (Form ulation 3c), 4 (Form ulation 4c) and 7 19 (Formulations 7a, 7b and 7c) with a 0-22mm x 0.65mm actuator using an Andersen Cascade Impactor to consider the effect of glycerol content on the following properties:

(i) MMAD, (ii) throat deposition, and (iii) stage 3-7 deposition. The results are shown in Figures 12-14. For maximum deposition in the desired region without excessive throat deposition the optimal glycerol concentration appears to be around 0.8-1. 6 % w/w, particularly 1.0-1.6 % w/w.

A study was performed using an Andersen Cascade Impactor to compare the properties of formulations containing different solubilising agents. An actuator of dimensions 0.22mm xO.65 mm was used for the study. The results of the analysis of the formulations of Example 9 Formulations 9a, 9b, 9c and 9d and a comparison with the formulations of Example 3 Formulation 3c and Example 4 Formulation 4c are shown in Table 6 and Figure 15. The ethanol with glycerol profile clearly appears the most attractive since it demonstrates the highest FPM content in view of the high dosing in stages 4 and 4 relative to the other profiles. Nevertheless the methylal profiles also looked of significant interest in view of the very low throat deposition. The addition of 1 % glycerol shifted the methylal profile to lower stages only to a small extent, perhaps in view of its greater volatility than ethanol. A higher percentage of glycerol would be expected to increase the magnitude of the shift.

A study was performed using an Andersen Cascade Impactor to compare the properties of formulations containing different low volatility components. An actuator of dimensions 0.22mm xO.65 mm was used for the study. The results of the analysis of the formulations of Example 10 Formulations 10a to 10d are shown in Table 7 and Figure 16. Particularly good profiles are shown by glycerol and PEG400 which demonstrate relatively low throat deposition and high dosing in stages 4 and 5.

A study was performed using an Andersen Cascade Impactor to study the properties of 0.05% fluticasone propionate formulations containing 1,1,1,2,3,3,3- heptafluoro-n propane (HFA227) as propellant. An actuator of dimensions 0.22mm xO.65 mrn was used for the study. The results of the analysis of the formulations of Example 10 Formulations 10e and 1 Of are shown in Table 8 and Figure 17. Comparison with the HFA134a aerosol formulation of Formulation 10a is shown.

A study was performed using an Andersen Cascade Impactor to study the properties of 0.025% fluticasone propionate formulations containing 1,1,1,2- tetrafluoroethane (HFA134a) or 1, 1, 1, 2,3,3,3-heptafluoro-n-pro pane (HFA227) as propellant. An actuator of dimensions 0.22mm xO.65 mm was used for the study. The results of the analysis of the formulations of Example 10 Formulations 10g to 10j are shown in Table 9 and Figures 18 and 19. The HFA1 34a product with ethanol shows a particularly attractive profile eg as shown by a high total delivered dose and a relatively low throat deposition.

Brief description of the drawings

Table 1: Effect of valve on FPM in fluticasone propionate HFA134a solution aerosols (50tg/actuation) Table 2: Effect of different levels of ethanol on FPM in fluticasone propionate/HFAl 34a solution aerosols Table 3: Effect of different levels of ethanol on FPM in fluticasone propionate/HFA134a solution aerosols (valve size effect ignored) Table 4: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (125gg/actuation) containing 35% ethanol or 35% ethanol and 1% glycerol Table 5: Cascade impaction analysis of fluticasone propionatelHFA134a solution aerosols (50gg/actuation) containing 16% ethanol or 16% ethanol and 1 % glycerol Table 6: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (50Lg/actuation) containing various solubiling agents with and without 1 % glycerol Table 7: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (50gg/actuation) containing various low volatility components Table 8: Cascade impaction analysis of fluticasone propionate solution aerosols (50gg/actuation) containing various propellants Table 9: Cascade impaction analysis of fluticasone propionate solution aerosols (25gg/actuation) containing various propellants Figure 1: Effect of valve size and glycerol on FPM in fluticasone propionate, solution aerosols in HFA134a (50gg/actuation) 21 Figure 2: Effect of level of ethanol on FPM in various fluticasone propionate/HFA134a solution aerosols with no addition of glycerol Figure 3: Effect of level of ethanol on FPM in various fluticasone propionate/HFAl 34a solution aerosols with addition of 1% glycerol Figure 4: Effect of glycerol on FPM in fluticasone propionate 125Ag /HFA134a solution aerosols containing 35% ethanol or 35% ethanol and 1% glycerol Figure 5: Effect of actuator dimensions on FPM and throat in fluticasone propionate/HFA134a solution aerosols (50gg/actuation) containing 16% ethanol Figure 6: Effect of actuator dimensions on FPM and throat in fluticasone propionate/HFA134a solution aerosols (50gg/actuation) containing 16% ethanol and 1% ethanol Figure 7: The effect of addition of glycerol on FPM in fluticasone propionate 50gg/HFAl 34a solution aerosols containing 16% ethanol or 16% ethanol and 1 % glycerol (0.22mm diameter actuator orifice) Figure 8: The effect of addition of glycerol on FPM in fluticasone propionate 50gg/HFAl 34a solution aerosols containing 16% ethanol or 16% ethanol and 1 % glycerol (0.33mm diameter actuator orifice) Figure 9: Effects of addition of glycerol and actuator dimensions on FPM in fluticasone propionate 50Ag/HFA134a solution aerosols containing 16% ethanol or 16% ethanol and 1 % glycerol (all actuator variants) Figure 10: Solubility of fluticasone propionate in ethanol/HFA134a.

Figure 11: Effects of addition of glycerol and actuator dimensions on FPM in fluticasone propionate 50gg/HFA134a solution aerosols containing 10% ethanol or 10% ethanol and 1% glycerol Figure 12: Effects of addition of glycerol on MMAD in fluticasone propionate 50Lg/HFA134a solution aerosols containing 10% ethanol Figure. 13: Effects of addition of glycerol on throat deposition in fluticasone propionate 50[Lg/HFA134a solution aerosols containing 10% ethanol Figure 14: Effects of addition of glycerol on stage 3-7 deposition in fluticasone propionate 50[tg/HFAI34a solution aerosols containing 10% ethanol Figure 15: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (50ig/actuation) containing ethanol, methylal or ethylacetate as solubilising agent, with and without 1 % glycerol 22 Figure 16: Cascade impaction analysis of fluticasone propionate/HFAI34a solution aerosols (50gg/actuation) containing various low volatility components and 10% ethanol Figure 17: Cascade impaction analysis of fluticasone propionate/HFA227 solution aerosols (5ORg actuation) containing 18% ethanol with and without 1 % glycerol and comparison with HFA134a aerosol Figure 18: Cascade impaction analysis of fluticasone propionate in HFA227 or HFA134a solution aerosols (25Rg actuation) containing ethanol Figure 19: Cascade impaction analysis of fluticasone propionate in HFA227 or HFAI 34a solution aerosols (25gg actuation) containing ethanol and 1 % glycerol 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.

Above mentioned patents and patent applications are hereinbefore incorporated by reference.

Abbreviations FPM fine particle mass FP fluticasone propionate M/c metering chamber Bou beginning of use PEG polyethyleneglycol Form. Formulation MMAD mass median aerodynamic diameter Table 1

The effect of valve on FPM in FP50pg solution aerosols All data generated with 0.22mm actuator, except HFA134a suspension product tested with 0. 50mm actuator pg Results Cascade Impaction Formulation Ethanol only Ethanol and 1% glycerol HFA134a Ethanol cone. i 00/ow/w 16%w/w 2 1 %w/w 1 O%w/w 16%w/w 21 %w/w Valve size 1 OOPI 63VI 50PI 100PI 63VI 50pl 50VI Product FP FP FP FP FP FP FP Product strength 50pg 50pg 50pg 50pg 50pg 50pg 50pg Device 5.7 4.3 5.3 5.2 4.1 5.2 6.6 Throat 12.7 15.2 21.2 16.0 17.1 23.1 13.5 Stage 0 4.5 2.2 2.8 3.4 3.1 2.9 1.6 Stage 1 0.3 0.3 0.3 0.7 0.5 0.6 0.8 Stage 2 0.2 0.2 0.2 1.1 0.9 0.8 1.1 Stage 3 0.3 0.2 0.3 5.4 3.9 3.8 3.2 Stage 4 0.9 0.6 1.0 7.6 5.9 5.2 9.8 Stage 5 9.8 6.5 7.0 8.5 7.3 5.3. 11.2 Stage 6 8.6 6.8 5.6 2.4 1.6 1.6 1.4 Stage 7 5.5 3.4 2.8 1.4 1.0 0.8 0.3 Filter 4.7 2.7 -2.1 0.9 0.7 0.5 0.2 Total 53.2 42.4 48.6 52.6 46.1 49.8 48.0 Total ex-device 47.5 38.1 43.3 47.4 42.0 44.6 43.3 FPM, St3+St4+St5 11.0 7.3 8.3 21.5 17.1 14.3 15.7 FPM, St5+St6+St7 23.9 16.7 15.4 12.3 9.9 7.7 8.8 t") W Flixotide Evohaler suspension formulation Table 2

Effect of different levels of Ethanol on FPM in FP/HFA1 34a solution aerosols All fitted with 63VI m/c and tested with 0.22mm actuator O/oResults Cascade Impaction Formulation Ethanol only Ethanol and 1% glycerol Ethanol cone. 160/ow/w 35%w/w 160/ow/w 350/ow/w Valve size 63VI 63VI 63VI 63pI Product FP FP FP FP Product strength 50pg 125pg 50pg 125pg Device 10.1 12.1 8.6 12.6 Throat 35.8 62.6 38.8 63.1 Stage 0 5.2 6.5 6.3 5.8 Stage 1 0.7 0.0 1.0 1.0 Stage 2 0.5 0.0 1.7 1.0 Stage 3 0.5 0.9 8.2 2.9 Stage 4 1.4 1.9 12.6 4.9 Stage 5 15.3 6.5 15.9 4.9 Stage 6 16.0 4.7 3.3 1.9 Stage 7 8.0 1.9 2.1 1.0 Filter 6.4 2.8 1.4 1.0 Total 100.0 100.0 100.0 100.0 Total ex-device 89.9 87.9 91.4 87.4 FPM, St3+St4+St5 17.2 9.3 36.7 12.6 FPM, St5+St6+St7 39.3 13.1 21.3 7.8 N) 4.- Table 3

Effect of different levels of Ethanol on FPM in FP/HFA134a solution aerosols (valve size effect ignored) All tested with 0.22mm actuator, except HFA134a suspension product tested with 0.50mm actuator %Results Cascade Impaction Formulation Ethanol only Ethanol and 1% glycerol HFA134a Ethanol cone. 10%w/w 16%w/w 210/ow/w 35%w/w 1 001OW/W 16%w/w 21%w/w, 35%w/w Valve size 1 OOPI 63VI 50pl 63pl 1 OOPI 63pl 50pl 63pl 50pl Product FP FP FP FP FP FP FP FP FP Product strength 50pg 50pg 50pg 125pg 50pg 50pg 50pg 125pg 50pg Device 10.7 10.1 10.9 12.1 9.9 8.6 10.4 12.6 13.3 Throat 23.9 35.8 43.6 62.6 30.4 38.8 46.4 63.1 27.2 Stage 0 8.5 5.2 5.8 6.5 6.5 6.3 5.8 5.8 3.2 Stage 1 0.6 0.7 0.6 0.0 1.3 1.0 1.2 1.0 1.6 Stage 2 0.4 0.5 0.4 0.0 2.1 1.7 1.6 1.0 2.2 Stage 3 0.6 0.5 0.6 0.9 10.3 8.2 7.6 2.9 6.4 Stage 4 1.7 1.4 2.1 1.9 14.4 12.6 10.4 4.9 19.7 Stage 5 18.4 15.3 14.4 6.5 16.2 15.9 10.6 4.9 22.5 Stage 6 16.2 16.0 11.5 4.7 4.6 3.3 3.2 1.9 2.8 Stage 7 10.3 8.0 5.8 1.9 2.7 2.1 1.6 1.0 0.6 Filter 8.8 6.4 4.3 2.8 1.7 1.4 1 1.0 0.4 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100 Total ex-device 89.3 89.8 89.1 87.8 90.1 91.3 89.6 87.4 86.7 FPM, St3+St4+St5 20.7 17.2 17.1 9.3 40.9 36.7 28.6 12.7 48.7 FPM, St5+St6+St7 44.9 39.3 31.7 13.1 23.5 21.3 15.4 7.8 25.9 N) Ln Flixotide Evohaler Suspension Formulation Table 4

Cascade Impaction analysis of FP/HFA134a 125pq solution aerosols containing 35% ethanol or 35% ethanol and 1% glycerol (0.22mm actuator 63[d rn/c Valois valve) Formulation Ethanol only Ethanol and glycerol Stage of Use BoU (act.1-10) BoU (act.1-10) Sample ID FP125/A3/1 FP1251A3/1 Mean FP125IA3/1 FP125JA312 Mean Device 13.6 10.7 12.2 14.4 10.9 12.7 Throat 59.2 73.9 66.6 64.7 64.4 64.6 Stage 0 6.8 6.9 6.9 5.6 5.9 5.8 Stage 1 0.5 0.3 0.4 0.5 0.5 0.5 Stage 2 0.3 0.1 0.2 0.6 0.8 0.7 Stage 3 0.5 0.4 0.5 2.4 2.6 2.5 Stage 4 2.2 1.7 2.0 4.8 5.0 4.9 Stage 5 8.5 6.1 7.3 5.5 5.0 5.3 Stage 6 5.2 4.1 4.7 2.0 1.7 1.9 Stage 7 2.4 1.8 2.1 1.1 0.8 1.0 Filter 2.1 2.7 2.4 0.7 0.5 0.6 Total 101.3 108.7 105.0 102.3 98.1 100.2 Total ex-device 87.7 98.0 92.9 87.9 87.2 87.6 FPM, St3+St4+St5 11.2 8.2 9.7 12.7 12.6 12.7 FPM, St5+St6+St7 16.1,__ 12.0 14.1 8.6 7.5 8.1 All means, Totals and FPMs were calculated by Excel on rounded individual data A3 = Actuator 0.22mm x 0.65mm Table 5

Cascade Impaction analysis of FP/HFA134a 50pg solution aerosols containing 16% ethanol or 1 61D/o ethanol and 1 O/o glycerol (63 pl m/c Valois valve DF60 M K3 7) Formulation Ethanol only Ethanol and glyr-crol FP/134a 50pg Stage of Use BoU (act.1-10) BoU (act.1-10) Initial, BoU Product FP50 IFP50 Mean FP50 FP50 Mean FP50 FP50 Mean FP50 FP50 Mean FP50 FP50Mean Mean Actuator 0.50mm 0.50mm 0.33mm 0.33mm 0.22mm 0.22mm 0.33mm 0.33mm 0.22mm 0. 22mm 0.50mm DeVice 4.2 4.2 4.2 5.3 4.2 4.8 5.2 3.3 4.3 4.7 4.4 4.6 4.4 3.7 4.1 6.6 Throat 32.4 32.3 32.4 25.1 25.9 25.5 13.9 16.4 15.2 26.2 28.5 27.4 16.3 17.8 17.1 13.5 Stagt 0 1.4 1.4 1.4 1.0 1.7 1.4 2.3 2.1 2.2 1.0 1.3 1.2 3 6 2.6 3.1 1.6 Stage 1 0.1 0.1 0.1 0.1 0.1 0.1 0.3 03 0.3 0.2 0.4 0.3 0.6 0.4 0.5 0.8 Stage 2 0.0 0.1 0.1 0.1 0.1 0.1 0.2 0.2 0.2 0.3 0.4 0.4 1.0 0.7 0.9 1.1 Stage 3 0.1 0.1 0.1 0.1 0.3 0.2 0.2 0.2 0.2 1.4 1.5 1.5 4.3 3.5 3.9 3.2 Stage 4 0.3 0.3 0.3 0.3 0.5 0.4 0.7 0.5 0.6 2.6 2.5 2.6 6.2 5.5 5.9 9.8 Stage 5 1.8 2.0 1.9 3.6 3.9 3.8 6.4 6.5 6.5 4.0 3.5 3.8 7.5 7.0 7.3 11.2 Stage 6 1.5 1.6 1.6 3.5 3.5 3.5 6.8 6.8 6.8 1.0 0.9 1.0 1.8 1.4 1.6 1.4 Stage 7 0.9 1.0 1.0 2.1 2.0 2.1 3.4 3.4 3.4 0.6 0.5 0.6 1.0 0.9 1.0 0.3 Filter 1.3 1.4 1.4 2.1 2.6 2.4 2.7 2.7 2.7 0.5 0.4 0.5 0.7 0.6 0.7 0.2 Total 44.0 44.5 44.3 43.3 44.8 44.1 42.1 42.4 42.3 42.5 44.3 43.4 47.4 44, 1 45.8 44.9 Total ex-device 90 39.0 7.0 40.0 38.5 36.0 38.0 37.0 38.0 39.0 38.5 44.0 43.0 43.5 43.3 01 3 FPM, St3+St4+StS 2.0 2. 4.0 4.0 4 - 0 7 - 0 7.0 7 - 0 0 8.0 8.0 18 - 0 17. 0 17.5 17.3 FPM. StS+St6+St7 4.6 4.4 9.21 9.41 9.31 16.61 16.17_ 16.71 5.61 4.91 5.31 10.31 9.3 9.8 9.61 All means, Totals and FPMs were calculated by Excel on rounded individual data Flixotide Evohafer suspension formulation Table 6

Cascade Impaction analysis of FP/HFA134a 60pg solution aerosols containing various solubilising agents (100pl Valois valve, Bespak 0.22mm x 0.65mm actuator) Formulation FP 50pg FP 50pg FP 50pg Stage of Use BoU (act.1-10) BoU (act.1-10) BoU (act. 1-10) Valve 100PI 1 OOPI 1 OOPI 1 OOPI 1 OOPI 1 OOPI LVC 1%glycerol - 1 %glycerol 1 %glycerol Solvent 15%methylal 15%methylal 15%ethyl acetate 15%ethyl acetate 1 O%ethanol 1 O%ethanol Device 5.9 6.2 9.0 6.4 4.3 4.4 Throat 5.8 6.3 5.3 13.8 15.2 14.0 Stage 0 1.4 3.9 1.2 1.6 2.2 3.3 Stage 1 0.5 0.8 0.5 0.6 0.3 0.7 Stage 2 0.6 0.7 0.5 0.8 0.2 1.0 Stage 3 0.9 1.4 1.1 1.7 0.2 5.3 Stage 4 1.6 2.3 0.8 1.8 0.6 8.1 CO Stage 5 6.9 10.3 1.9 9.2 6.5 8.8 Stage 6 8.8 7.6 5.0 6.2 6.8 2.4 Stage 7 6.0 3.8 4.4 3.2 3.4 1.3 Filter 4.8 2.0 3.0 2.0 2.7 0.7 Total 43.2 45.1 32.4 47.1 42.3 49.8 Total ex-device 37.3 39.0 23.4 40.7 37.0 45.5 FPM, St3+St4+St5 9.4 13.9 3.7 12.7 7.0 22.2 Result based on one can only (can 2 data rejected as an atypical result) LVG = low volatility component Table 7

Cascade Impaction analysis of FP/HFA134a 50pg solution aerosols containing various low volatility components (63pi m/c Valois valve DF60 or 100pi Valois valve, Bespak 0.22mm x 0.66mm actuator) Formulation FP50pg HFA134a FP50pg HFA1 34a FP50pg HFA134a a Stage of Use BoU (act. 1-10) BOU (act. 1-10) BOU (act.1-10) BoU (act.1- 10) Valve 63pl NormallsedforlOOpI _63pi Normalised for 100pi 63pl Normalised for 100pl 63pl Normalised for I 00pl LVC I %propylene glycol 1%propylene glycol 1 %PEG200 I%PEG200 1 %PEG400 1 %PEG400 I %glycerol _ I %glycerol Solvent 10%ethanol Methanol Methanol Methanol Methanol 10%ethanol 1 O%ethanol 10%ethanol Device 2.2 3.5 2.3 3.7 2.0 3.1 1.7 2.7 Throat 7.3 11.6 6.1 9.7 5.5 8.7 5.5 8.7 Stage 0 0.7 1.1 0.8 1.3 0.9 1.4 1.2 1.9 Stage 1 0.3 0.5 0.3 0.5 0.2 0.4 0.3 0.5 Stage 2 0.6 1.0 0.6 1.0 0.6 1.0 0.7 1.1 Stage 3 3.1 4.9 3.5 5.6 2.9 4.6 3.0 4.8 Stage 4 3.6 5.7 4.7 7.5 5.2 8.3 5.5 8.7 Stage 5 3.7 5.9 5.7 9.0 6.4 10.2 5.2 8.3 Stage 6 1.0 1.6 1.7 2.7 1.7 2.7 1.5 2.4 Stage 7 1.4 2.2 0.9 1.4 1.0 1.5 0.7 1.1 Filter 0.6 1.0 0.1 0.2 0.6 0.9 0.4 0.6 Total 24.3 38.6 26.5 42.1 27.0 42.8 25.4 40.3 Total ex-device 22.1 35.1 24.21 38.4 25'0 39.7 23.8 37.8 FPM, St3+St4+St5 10.3 16.3 13.8 21.9 14.5 23.0 13.61 21.6 LVC = low volatility 6mponent I Table 8

Cascade Impaction analysis of FP 50pg solution aerosols containing various propellants (63pl m/c Valois valve DF60 or 100pl Valois valve, Bespak 0.22mm x 0.65mm actuator) Formulation FP50pg HFA227ea FP50pg HFA227ea FP50p HFA134a Stage of Use BoU (act.1-10) BoU (act. 1-10) BoU (act. 1-10) Valve 63pi Normalised for 100pl 63pl Normalised for I 00pl 63pl Normalised for 100pl LVC 1 %glycerol 1 %glycerol 1 %glycerol 1 %glycerol Solvent Methanol 180/oethanol Methanol Methanol 1 Methanol 1 Methanol Device 2V 3.8 2.4 3.8 1.7 2.7 Throat 14.4 22.9 13.8 21.8 5.5 8.7 Stage 0 2.0 3.2 2.3 3.7 1.2 1.9 Stage 1 0.3 0.5 0.4 0.6 0.3 0.5 Stage 2 0.2 0.3 0.7 1.1 0.7 1.1 Stage 3 0.2 0.3 2.4 3.7 3.0 4.8 Stage 4 0.4 0.6 2.9 4.6 5.5 8.7 CD Stage 5 3.0 4.8 2.4 3.8 5.2 8.3 Stage 6 2.7 4.3 0.6 1.0 1.5 2.4 Stage 7 1.4 2.2 0.3 0.5 0.7 1.1 Filter 1.2 1.9 0.1 0.2 0.4 0.6 Total 28.1 44.6 28.2 44.8 25.4 40.3 Total ex-device 25.7 40.8 25.8 41.0 23.8 37.8 FPM, St3+St4+St5 3.6 5.7 7.7 12.1 13.6 21.6 LVG = low volatility component Table 9

Cascade Impaction analysis of FP 25pg solution aerosols containing various propellants (63pl m/c Valois valve DF60 or 100pi Valois valve, Bespak 0.22mm x 0.65mm actuator) Formulation_ FP25pg HFA1 34a FP25pg HFA134a FP25p HFA227ea FP25p HFA227ea Stage of Use Bou (act. 1-10) Bou (act.1-10) BOU (act. 1-10) BoU (act.1- 10) valve 63pl Normalised for 100pl 63pi Normalised for 1 00pl 63pl Normalised for 1 05pl 63pl Normalised for 100pl LVC I%g cerol I %glycerol 1%glycerol 1 %glycerol Solvent Methanol Methanol Methanol Methanol 14%ethanol 14%ethanol 14%ethanol 14%ethanol Device 1.3 2.1 1.1 1.7 1.1 1.7 1.0 1.6 Throat 1.3 2.1 1.6 2.5 4.2 6.7 4.5 7.1 Stage 0 0.1 0.2 0.3 0.5 1.1 1.7 1.5 2.4 Stage 1 0.0 0.0 0.1 0.2 0.1 0.2 0.3 0.5 Stage 2 0.0 0.0 0.2 0.3 0.1 0.2 0.4 0.6 Stage 3 0.0 0.0 1.1 1.7 0.1 0.2 1.6 2.5 Stage 4 0.1 0.2 2.7 4.3 0.1 0.2 1.9 3.0 Stage 5 1.0 1.6 4.1 6.5 1.9 3.0 1.5 2.4 Stage 6 2.8 4.4 1.3 2.1 2.4 3.8 0.4 0.6 Stage 7 2.4 3.8 0.6 1.0 1.4 2.2 0.2 0.3 Filter 1.9 3.0 0.3 0.5 1.0 1.6 0.2 0.3 Total 10.8 17.1 13.3 21.1 13.3 21.1 13.3 21.1 Total ex-device 9.5 15.1 12.2 19.4 12.31 19.5 12.3 19.5 FPM, St3+St4+St5 1.1 1.7 7.81 12.41 2.1 3.3 4.9 7-8 LVC = low volatility component 32

Claims

What is claimed is:

1 A pharmaceutical aerosol formulation which comprises:

(i) fluticasone propionate and (ii) a hydrofluoroalkane (HFA) propellant, characterised in that the fluticasone propionate is completely dissolved in the formulation.

2. A pharmaceutical formulation according to claim 1 which comprises:

(i) fluticasone propionate; (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 fluticasone propionate in the formulation.

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

4. A pharmaceutical formulation according to any one of claims 1 to 3 containing a low volatility component which is glycerol, propylene glycol or polyethylene glycol.

5. A pharmaceutical formulation according to claim 4 containing a low volatility component which is polyethylene glycol.

6. A pharmaceutical formulation according to claim 4 containing a low volatility component which is glycerol.

7. A pharmaceutical formulation according to any one of claims 4 to 6 wherein the low volatility component is present at a concentration of 0.5 to 3% w/w.

33

8. A pharmaceutical formulation according to any one of claims I to 7 which comprises:

W fluticasone propionate; (ii) 1,1,1,2-tetrafluoroethane (HFA 134a); (iii) 0.5-3% (w/W) glycerol; and (iv) a solubilisation agent in sufficient quantity to solubilise the fluticasone propionate in the formulation.

9. A pharmaceutical formulation according to any one of claims 1 to 8 which contains between 0.8 and 1.6% (w/w) glycerol.

10. A pharmaceutical formulation according to claim 9 which contains between 1.0 and 1.6% (w/w) glycerol.

11. A pharmaceutical formulation according to claim 10 which contains 1. 3% (w/w) glycerol.

12. A pharmaceutical formulation according to claim 10 which contains 1. 0% (w/w) glycerol.

13. A formulation according to any one of claims I to 12 wherein the concentration of fluticasone propionate is 0.025 to 0. 15% w/v.

14. A formulation according to claim 13 wherein the concentration of fluticasone propionate is 0.035 to 0.15% w/v.

15. A formulation according to claim 14 wherein the concentration of fluticasone propionate is 0. 04 to 0. 1 % w/v.

16. A formulation according to claim 13 wherein the concentration of fluticasone propionate is 0.025 to 0.04% w/v.

34

17. A formulation according to any one of claims 1 to 16 wherein a solubilisation agent is present which is ethanol or propylene glycol.

18. A formulation according to any one of claims 1 to 16 wherein a solubilisation agent is present which is an alkane or ether.

19. A formulation according to any one of claims I to 16 wherein a solubilisation agent is present which is dimethoxymethane.

20. A formulation according to any one of claims 1 to 16 wherein a solubilisation agent is present which is ethylacetate.

21. A formulation according to claim 17 wherein a solubilisation agent is present which is ethanol.

is

22. A formulation according to claim 21 wherein the concentration of ethanol is 5 to 30% W/W.

23. A formulation according to claim 22 wherein the concentration of ethanol is 10 to 20% w1w.

24. A formulation according to claim 22 wherein the concentration of ethanol is 7 to 16% W/W.

25. A formulation according to claim 22 wherein the concentration of ethanol is 7 to 11 % W/W.

26. A formulation according to claim 22 wherein the concentration of ethanol is 7 to 8% W/W.

27. A formulation according to claim 19 or 20 wherein the concentration of solubilisation agent is 14 to 16% w/w.

28. A canister comprising a metering valve and containing a composition according to any one of claims 1 to 27.

29. A canister according to claim 28 comprising an aluminium can which is anodised, lacquer-coated and/or plastic coated.

30. A canister according to claim 29 which is coated with a fluorocarbon polymer.

31. A canister according to any one of claims 28 to 30 fitted with a metering valve of metering volume 100

32. A metered dose inhaler which comprises a canister as claimed in any one of claims 28 to 31 fitted into a suitable channelling device.

33. A metered dose inhaler according to claim 32 wherein the channelling device comprises a mouthpiece actuator having an actuator orifice of diameter 0. 25mm or less.

34. 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 27.

35. Use of a formulation according to any one of claims 1 to 27 in the manufacture of a medicament for the treatment of respiratory disorders, eg. asthma or chronic obstructive pulmonary disease (COPID).