GB2392915A - Pharmaceutical formulation of fluticasone propionate - Google Patents

Abstract

A pharmaceutical aerosol formulation which comprises <SL> <LI>(i) fluticasone propionate at a concentration of 0.025 to 0.04% w/v; <LI>(ii) 1, 1, 1, 2-tetrafluoroethane (HFA 134a) as propellant; and <LI>(iii) ethanol; characterised in that the fluticasone propionate is completely dissolved in the formulation and characterised in that the formulation contains fluticasone propionate as the only medicament. The formualation may further contain a low volatility component such as glycerol. Also shown is a canister and a metered dose inhaler containing the aerosol formulation. </SL>

Description

GB 2392915 A continuation (72) Inventor(s): Alan Leslie Cripps Paul

Johnson (74) Agent and/or Address for Service: GlaxoSmithKline Corporate Intellectual Property, CN9.25.1, 980 Great West Road, BRENTFORD, Middlesex, TWO 9GS, United Kingdom

Pharmaceutical Formulation of Fluticasone Propionate Background of the invention

Field of the invention

5 The present invention relates to a pharmaceutical formulation for use in the administration of medicaments by inhalation. In particular, this invention relates to a pharmaceutical formulation of fluticasone propionate for use in metered dose inhalers (MDl's). The invention also relates to methods for their preparation and to their use in therapy. Descnction of the bac'.cground 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 bronchodiiators such as,B2 agonists and anticholinergics, 15 corticosteroids, anti-allergies and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material. (6a, 11b, 16a, 17a)-6, 9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropOxy) 20 androsta-1, 4iene-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 (CORD).

Metered dose inhalers (MDl'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 characterized as solution fommulations or suspension forrrulations.

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 celled 'ozone- friendly' propellants.

5 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, 1,1,1,9tetrafluoroethane (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.

1C The efficiency of an aerosol device, sue., as an MDI, is z function of the dose deposited at the approFncte site in the lungs Deposition is affected by several factors, of which one of.he most importar;t.s the aerodynamic particle size. Solid par.icies and/cr droplets in an aerosol formulation can be characterized by their mass median 15 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; 20 2. sedimentation due to gravity; and 3. diffusion resulting from Brownian motion of fine, submicrometer (cram) 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 30 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.

5 For inhalation therapy there is a preference for aerosols in which the particles for inhalation have a diameter of about 0.S to bum Particles which are larger than 5,um in diameter are primarily deposited by inertial impaction in the orthopharynx, particles 0.5 to 5,um in diameter, influenced mainly by gravity, are ideal for deposition in the conducting airways, and particles 0.5 to 3pm in diameter are desirable for aerosol 10 delivery to the lung periphery Particles smeller then 0.5pm may be exhaled.

Respirable par;icies are generally ccns,cered to be these with aerodynaniic diameters less than Am These particles, particularly those with a diameter of about 3pm, are efficiently deposited in the lower respiratory tract by sedimentation.

It has been recently demonstrated in patients with mild and severe airflow obstruction that the particle size of choice for a Q2 agonist or anticholinergic aerosol should be approximately 3pm (Zaanen, P et al, Int. J. Pharm. (1994) 107, 211-217, Int J. Pharm. (1995)114, 111-115, Thorax (1996), 51, 977-980.) 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 MDI eg. canister or valve. The effect of Ostwald ripening and particularly of drug deposition may be particularly 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 she 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.

Besides its impact on the therapeutic profile of a drug, the size of aerosol particles has 5 an important impact on the side effect profile of a chug. 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 10 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 pharmacauticai aerosol 15 formulation for use in a metered dose inhaler, comprising (i) fluticasone propionate and (ii) a hydrofluoroalkane (HFA) propellant; and characterized in that the fluticascne propionate is completely dissolved in the formulation Detailed description of the invention

20 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 (methylai) which has good 25 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) 30 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 5 which omit this component. Solution formulations which omit the higher volatility component generally give rise to a particle she distribution which have a higher content of finer particles; such distributions generally do not match the distribution of the existing commercialized suspension formulations which contain CFC's and may therefore not be big-equivalent. Examples or FiFA propellants include 1,1,1,2-teTrafluorcethane (;FA,34a) and 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA22) and mixtures thereof The preferred propellant is 1,,,12-tetraflucroe+hane (HFA134al. 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% (w/w).

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 30 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

i suitable for delivering 2250,ug per actuation, especially 25119, song, 1251lg or 25O'lg 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 5 should desirably remain above around 50psi. Therefore the formulation is most suitable for delivering 25-125pg per actuation, especially 25-509 per actuation.

The formulation according to the invention will be used in association with a suitable metering valve. Yale prefer that the formulation is actuated by a metering valve capable 10 of delivering a volume of between 50,ul and 1001, eg 501 or 6Sul 1001 is also suitable. V\/hen a 501 metering volume is used, the final concentration of fluticasone propionate delivered per actuation would be 0 1% w/v (which equates to 0. 19 of fluticasone propionate per 100mi of ormulaticn) or approx. 0.083% W/'vV (which equates to 0.083g of fluticasone propionate per 100g of formulation) for a 50,ug dose, 0 25% 15 (w/v) or approx. 0.21 % (w/w) for a 125119 dose, 0.5% (w/v) or approx. 0.42% (w/w) for a 25O,l9 dose and 0. 05% (w/v) or approx 0.042% (w/w) for a 251lg dose. Wherein a 63111 metering volume is used, the finli concentration of fluticasone propionate delivered per actuation would be 0.079% (w/v) or approx. 0. 067% (w/w) for a 50g dose, 0.198% (w/v) or approx. 0.167% (w/w) for a 125pg dose, 0.397% (w/v) or approx. 0.333% (w/w) 20 for a 2509 dose and 0. 04% (w/v) or approx. 0.033% (w/w) for a 251lg dose. When a 1001 metering volume is used, the final concentration of fluticasone propionate delivered per actuation would be 0.05% w/v (which equates to 0.059 of fluticasone propionate per 100ml of formulation) or approx. 0.042% w/w (which equates to 0.0429 of fluticasone propionate per 10Og of formulation) for a 5O119 dose, 0.125% (w/v) or 25 approx. 0.11 % (wow) for a 125pg dose, 0.25% (w/v) or approx. 0.21 % (wow) for a 250pg dose and 0.025% (w/v) or approx 0.021 % (w/w) for a 25pg dose. The previously quoted w/w figures are approximate in that they do not compensate in the mismatch in density between HFA134a and ethanol, however the precise figures may be readily determined.

30 The formulation is most suitable for concentrations of fluticasone propionate in the range 0.025 to 0.25 % (wiv), preferably 0.025 to 0.15 % (w/v), more preferably 0.035 to 0.15 % (w/v), particularly 0.04 to 0.1 % (wet). A concentration of 0.025 to 0.04 % (wiv) is also of particular interest. Formulations of the present invention containing

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 5 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 eNect on dosing uniformity through the life of the product.

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

Use of a larger metering Chamber en Afoul Ail generally be prefen-ed.

We prefer the formulation to contain between 0.5 and 2 /o 'N/'N, more preferably between 15 0.8 and 1.6% w/w, particularly between 1.0 and 1.6% w/w glycerol. Ar other range of particular interest is 0.-1% (w/w) glycerol. We especially prefer to use 1.3% (wow) glycerol. We also especially prefer to use 1.0% w/w glycerol.

Depending on the final concentration of fluticasone propionate in the formulation, the 20 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 25 16% w/w is also particularly preferred, more particularly 7 to 1 1% wfw.

When the concentration of fluticasone propionate is around 0.1% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 1624% w/w eg 16-18% w/w, especially around 16% w/w is particularly suitable but is more preferably 20-22% w/w 30 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

fluticasone propionate is around 0.079% w/v and the propellant is 1,1,1,2 tetrafluoroethane, an amount of ethanol of 117% w/w especially around 16% is suitable. When the concentration of fluticasone propionate is around 0. 198% wiv and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 34-36% w/w eg 5 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% w/w especially around 8%, more preferably around 7% is suitable.

VVhen the concentration of fluticasone propionate is around 0.025% wiv and the To propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane, an amount of ethanol of 13-15% wow especially around l A% is suitable. //hen the concentration of fluticasone propionate is around 0.05%'N/V and the propellant is 1,1,1,2,3,3,3-1ep.afluoro-n-propane, an amount of ethanol of 17-, g% w/w especially around 16 JO is suitable.

15 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 soiubilisation 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 1,1,1,2-tetrafluoroethane, an amount of dimethoxymethane (methylal) as solubilisation agent of 13-16% wow 20 especially around 15% is suitable.

The above generally described formulations are particularly preferred in conjunction with 1.1.6% w/w glycerol, particularly 1.0% w/w glycerol or 1. 3% w/w glycerol.

25 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.

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 5 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 96132151, for example, 2 co-polymer of polyethersulphone (PES) and polytetrafluoroethylene (PTFE).

10 Another polymer Or coating that may be contemplated is FEP (fluorinated ethylene propylene) The metennc valves are designed to deliver a metered amount or the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve The gasket may comprise any suitable eiasiomenc material such as for example low density polyethylene, chiorobutyi, black and white butadiene 15 scrylonitnle rubbers, butyl rubber and neoprene. Thermoplastic elastomer valves as described in WO92/11190 and valves containing EPDM rubber as described in WO95/02651 are especially suitable. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (eg.

DF10, DF30, DF60), Bespak pie, UK (eg. BK300, BK356, BK357) and 3MNeotechnic 20 Ltd. UK (eg. Spraymiser_). The DF31 valve of Vaiois, 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 25 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 30 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.

5 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 JO 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 caniste! The medicament is added to a charce vessel and a mixture of ethanol, low volatility component and liquefied prcgellant is pressure filled through the charge vessel Into a manufacturing vessel An aiiquot of the formulation is then filled 15 through the metering valve into the canister Typically, in batches prepared for pharmaceutical use, each filled canister is cneck-weighed, coded with a batch number and pacified 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 low-volatility 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 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.

5 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 10 less, particularly 0.22mm since this tends to result in a higher EPIC and lower throat deposition. 0.15mm is also particularly suitable. The dimensions of the orifice should not be so small that bicc'cage of the jet occurs.

Actuator jet lengths are typically in the range 0.30-1.7mm eg 0.3O, O.55 or 1.5Cmm.

1- 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 fig medicament per puff.

20 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. 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 250pg/puff fluticasone propionate, 2 times per day.

30 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 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 (COPD).

10 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 'Owen throat deposition, be more easily or economically manufactured, or may be otherwise 15 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: 20 Fluticasone propionate: 0.1% wiv 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% 25 These solution formulations may be filled into an aluminium canister under pressure and fitted with a metering valve having a 50 Ill metering chamber.

These formulations are suitable for delivering 50 119 or 25 119 fluticasone propionate per actuation respectively.

30 Example 3

Formulations were prepared with compositions as follows: Form. 3a Form. 3b Form. 3c Fluticasone propionate: 0.1% w/v 0.079% w/v 0.05% w/v

Ethanol: 21% wJw 16% wAu 10% Glycerol: 1.0% w/w 1.0% w/w 1.0% 1,1,1,2tetrafluoroethane: to 100% to 100% to 100% 5 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 HI, 63 pl and 100 Al respectively. These formulations are suitable For delivering 50 119 fluticasone propionate per 1 0 actuation.

Example 4

Formulations were prepared with compositions as follows: Form 4a Form. 4b Form. Jc 15 Fluticasone propionate: O.1% W;V 0.079% YV/V 0.05% w/v Ethanol: 21% w/w 16% wow 10% 1,1,1,2-tetrafluoroethane: to 100% to 100% to 100% These solution formulations were filled into aluminium canisters (120 20 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chambers of volume 50 Ill, 63 Al and 100 pi respectively. These formulations are suitable for delivering 50 119 fluticasone propionate per actuation. Example 5

A formulation was prepared with compositions as follows: Fluticasone propionate: 0.198% w/v Ethanol: 35% w/w 30 Glycerol: 1.0% w/w 1,1, 1,2tetrafluoroethane: to 100%

This solution formulation was filled into an aluminium canisters (120 actuationslcanister; overage of 40 actuations) under pressure and fitted with a metering valve (Valois DF60) having metering chamber of volume 63 1.

This formulation is suitable for delivering 125 p9 fluticasone propionate per actuation.

Example 6

A formulation was prepared with compositions as follows: Fluticasone propionate: 0. 198% w/v Ethanol: 35% w/w lO 1,1,1,2-tetrafluoroethane: to 100% This sclutior formulation was filled into an alumir.ium canisters (120 actuations,'canister; overage of 40 actuaticrsj under pressure and fitted with a rnetenns valve (Valois DF60) having metering chamber of volume 63 pi.

15 This Formulation is suitable for delivering 125 fig fluticasone propicnate per actuation.

Example 7

Formulations were prepared with compositions as follows: Form. 7a Form 7b Form. 7c 20 Fiuticasone propionate: 0.05% w/v 0.05% w/v 0.05% w/v Ethanol: 10% w/w 10% w/w 10% w/w Glycerol: 0.5% w/w 2% wfw 3% wfw 1,1,1,2tetrafluoroethane: to 100% to 100% to 100% 25 These solution formulations were filled into aluminium canisters (120 actuations/canister; overage of40 actuations) under pressure and fitted with a metering valve (\/alois DF60) having metering chamber of volume 100 Ill.

These formulations are suitable for delivering 50 119 fluticasone propionate per actuation. Example 8

Formulations were prepared with compositions as follows: Fluticasone propionate: 0.025% w/v 0.025% w/v

Ethanol: 8% w/w 7% w/w Glycerol: 1.0% w/w 1.0% w/w 1,1,1,2tetrafluoroethane: to 100% to 100% 5 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 Ill.

These formulations are suitable for delivering 25 119 Fluticasone propionate per actuation. Example 9

Formulations were prepared with compositions as follows: Formulation Ca: Fluticasone propionate: 0.05% w/v 15 Dimethoxymethane: 15% w/w 1,1,1,2tetrafluoroethane: to 100% Formulation 9b: Fluticasone propionate: 0.05% who Ethylacetate: 15% wow 20 1,1,1,2-tetrafluoroethane: to 100% Formulation 9c: Fluticasone propionate: 0.05% w/v Dimethoxymethane: 15% w/w Glycerol: 1% w/w 25 1,1,1,2-tetrafluoroethane: to 100% Formulation 9d: Fluticasone propionate: 0.05% who Ethylacetate: 15% w/w Glycerol: 1% w/w 30 1,1,1,2-tetrafluoroethane: to 100%

À 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 pI.

These formulations are suitable for delivering 50 p9 fluticasone propionate per 5 actuation. Example 10

Formuiations were prepared with compositions as follows: Formulation 10a: lO Flutcasone propionate: 0.05% w/v Ethanoi: 1 0 7o 'N/ll G,ycerol: 1 to vJv 1, 1,1,9-tetr2fluoroethane: tc 100 ,io Formoiation 10b: 15 Fluticasone propionate: 0.05% w/v Ethanoi: 10% wlw PEC 200: 1% w/w 1,1, 1,2-tetrafluoroethane: to 100% Forrnulabon 10c: 20 Fluticasone propionate: 0.05% w/v Ethanol: 10% wAv PEG 400: 1% w/w 1,1,1,2- tetrafluoroethane: to 100% Formulation 10d: 25 Fluticasone propionate: 0. 05% w/v Ethanol: 10% w/w Propylene glycol: 1% wlw 1, 1,1,2- tetrafluoroethane: to 100% Formulation 10e: 30 Fluticasone propionate: 0. 05% w/v Ethanol: 18% wlw 1,1,1,2,3,3,3eptafluoro-n-propane: to 100% Formulation 10f:

Fluticasone propionate: 0.05% w/v Ethanol: 18% w/w Glycerol: 1% wow 1,1,1, 2,3,3,3-heptafluoro-n-propane: to 100% 5 Formulation 1 Og: Fluticasone propionate: 0.025% w/v Ethanol: 14% wow 1,1,1,2,3,3,3-heptafluoro-npropane: to 100% Formulation 10h: 10 Fluticasone propionate: 0.025% wiv Ethanol: 14% w/w Giyceroi: 1 % w/w 1,1,1,2,3,3,3-heptcflucro-n-procane: to 100 .o Formulation 10i: 15 Fluticasone propionate: 0.025% wiv Ethanol: 7% wow 1,1,1,2-tetrafluoroethane: to 100% Formulation 10j: Fluticasone propionate: 0.025% w/v 20 Ethanol: 7% wow Glycerol: 1% w/w 1,1,1,2tetrafluoroethane: to 100% 25 These.soiution formulations were hiled into aluminium canisters (120 actuations/canister; overage of 40 actuations) under pressure and fitted with a metering valve (/alois DF60) having metering chamber of volume 63 Ill.

These formulations are suitable for delivering 31.5 9 (10a-1 Oe) or 15.75 p9 (10f,10g) fluticasone propionate per actuation. However the performance of these formulations is 30 a model for formulations that would deliver 50 p9 and 25 p9 Fluticasone propionate using a metering valve of 100 pi.

Andersen Cascade Impaction Data

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 user (BoU) and 5 delivered drug from 10 actuations was collected in the instrument after 4 priming actuations were fired to waste. Results are shown in Tables 14 and Figures 14 and 11. For comparison, data from a Flixotide Evohaler (trademark) (particulate fluticasone propionate suspensed in HFA134a (excipient free) 50 119 per actuation) product is also shown in some figures.

The 0.079%'N/V fluticasone prcpicnete prctuc+s Of Examples 3 and <50 tic per actuation; 63 Al metering chamber) were prowled using an Andersen rascace 'mpactcr in a study to see the effect Of actuator orifice diameter and length.

15 Three actuators were used: 0.50mm diameter orifice x 1.50mm jet length G.33mm diameter orifice x 1.50mm jet length 0.22mm diameter orifice x 0. 65mm jet length 20 Results are shown in Table 5 and Figures 5 to 9. For comparison, data from a Flixotide Evohaler (trademark) (particulate fluticasone propionate suspensed in HFA134a (excipient free) 50 log per actuation) product is also shown in some figures.

The results show the best performance (as indicated by highest FPM) in products 25 containing a relatively low concentration of ethanol (say around 10%) and containing glycerol (say around 1 %). 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 30 in Figure 10.

A study was performed on the 0.05% w/v fluticasone propionate formulations (HFA134a/10% ethanol) of Examples 3 (Formulation 3c), 4 (Formulation 4c) and 7

(Formulations 7a, 7b and 7c) wffl 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 5 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 or formulations containing different solubilising agents. An actuator of dimensions 10 0.22mm x0.65 mm was used for the study. The results of the analysis of the formulations of Example Formulations 9a, 9b, 9c and 9d and a comparison with the formulations of Example 3 Formulation 3c and Example 4 Formniation 4c are shown in Table 6 and Figure 1. The ethanol with glycerol profile clearly appe^-rs the most attractive since it demonstrates the highest FPM content in view of the high dosing in 15 stages 4 and 4 relative to the other,crofiies. Nevertheless the methylal profiles also looked of significant interest in view of the very low throat deposition. The addition of 1% glycerol shifted the methylai 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 x0.65 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 25 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 30 propane (HFA227) as propellant. An actuator of dimensions 0.22mm x0.65 mm was used for the study. The results of the analysis of the formulations of Example 10 Formulations 1 Oe and 10f are shown in Table 8 and Figure 17. Comparison with the HFA134a aerosol formulation of Formulation 10a is shown.

i 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-propane (HFA227) as propellant. An actuator 5 of dimensions 0.22mm x0.65 mm was used for the study. The results of the analysis of the formulations of Example 10 Formulations 1Og to 10j are shown in Table 9 and Figures 18 and 19. The HFA134a 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 propicnate HFA134a solution aerosols (50,ug/actuation) Table 2: Effect of different levels of ethanol On FP\I in fluticasone propionate.HFA134a 15 solution aerosols Table 3: Effect of different levels of ethanol on FPM in fluticasone propionatelHFA134a solution aerosols (valve size effect ignored) Table 4: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (125pglactuation) containing 35% ethanol or 35% ethanol and 1% glycerol 20 Table 5: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (50pg/actuation) containing 16% ethanol or 16% ethanol and 1% glycerol Table 6: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (501lg/actuation) containing various solubiling agents with and without 1 % glycerol 25 Table 7: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (5OIlg/actuation) containing various low volatility components Table 8: Cascade impaction analysis of fluticasone propionate solution aerosols (5O'lg/actuation) containing various propellants Table 9: Cascade impaction analysis of fluticasone propionate solution aerosols 30 (251lg/actuation) containing various propellants Figure 1: Effect of valve size and glycerol on FPM in fluticasone propionate solution aerosols in HFA134a (50pg/actuation)

i Figure 2: Effect of level of ethanol on FPM in various fluticasone propionatelHFA134a solution aerosols with no addition of glycerol Figure 3: Effect of level of ethanol on FPM in various fluticasone propionate/HFA1 34a solution aerosols with addition of 1% glycerol 5 Figure 4: Effect of glycerol on FPM in fluticasone propionate 125119 /HFA134a solution aerosols containing 35% ethanol or 35% ethanol and 1% glycerol Figure 5: Effect of actuator dimensions on FPM and throat in fluticasone propionatelHFA134a solution aerosols (50ug/actuation) containing 16% ethanol Figure 6: Effect of actuator dimensions on FPM and throat in fluticasone 10 propionate/HFA134a solution aerosols (5OIlg/actuation) containing 16% ethanol and 1% ethanol Figure 7: T he effect of addition Of glyc_rci on rPAr1 in fluticasone propionate 50ugit3FA134a solution aerosols containing,60/0 ethanol or 16% ethanol and, .'0 glycerol (0.22mm diameter actuator orifice) 15 Figure 8: The effect of addition of glycerol on FPM in fluticasone propionate 509/HFA134a 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 5OIlg/HFA134a solution aerosols containing 16% ethanol or 16% ethanol 20 and 1% glycerol (all actuator variants) Figure 10: Solubility of fluticasone propionate in ethanollHFA134a.

Figure 11: Effects of addition of glycerol and actuator dimensions on FPM in fluticasone propionate 50,ug/HFA134a solution aerosols containing 10% ethanol or 10% ethanol and 1% glycerol 25 Figure 12: Effects of addition of glycerol on MMAD in fluticasone propionate 509/HFA1 34a solution aerosols containing 10% ethanol Figure 13: Effects of addition of glycerol on throat deposition in fluticasone propionate 5OIlg/HFA134a solution aerosols containing 10% ethanol Figure 14: Effects of addition of glycerol on stage 3-7 deposition in fluticasone 30 propionate 50pg/HFA134a solution aerosols containing 10% ethanol Figure 15: Cascade impaction analysis of fluticasone propionate/HFA134a solution aerosols (50g/actuation) containing ethanol, methylal or ethylacetate as solubilising agent, with and without 1% glycerol

Figure 16: Cascade impaction analysis of fluticasone propionateJHFA134a solution aerosols (5O,lg/actuation) containing various low volatility components and 10% ethanol Figure 17: Cascade impaction analysis of fluticasone propionate/HFA227 solution aerosols (509 actuation) containing 18% ethanol with and without 1% glycerol and 5 comparison with HFA134a aerosol Figure 18: Cascade impaction analysis of fluticasone propionate in HFA227 or HFA134a solution aerosols (251lg actuation) containing ethanol Figure 19: Cascade impaction analysis of fluticasone propionate in HFA227 or HFA134a solution aeroscis (25pg actuation) containing ethanol and 1% glycerol hrcughcut 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 20 FPM fine particle mass FP fluticasone propionate m/c metering chamber BoU beginning of use PEG polyethyleneglycol 25 Form. Formulation MMAD mass median aerodynamic diameter

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Claims (21)

PG3711/GB Div4 32 Claims

1. A pharmaceutical aerosol formulation which comprises (i) fluticasone propionate at a concentration of 0.025 to 0.04% 5 w/v; (ii) 1, 1, 1, 2tetrafluoroethane (HFA 134a) as propellant; and (iii) ethanol; characterized in that the fluticasone propionate is completely dissolved in the formulation and characterized in that the formulation contains fluticasone propionate as the to only medicament.

2. A pharmaceutical aerosol formulation according to claim 1 which is free of surfactant. 15

3. A pharmaceutical aerosol formulation according to claim 1 or claim 2, wherein the concentration of ethanol is 5 to 20% w/w.

4. A pharmaceutical aerosol formulation according to claim 3 wherein the concentration of ethanol is 7 to 9% w/w.

5. A pharmaceutical aerosol formulation according to any one of claims 1 to 4 which comprises a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler.

6. A pharmaceutical aerosol formulation according to claim 5 which comprises a low volatility component which is glycerol, propylene glycol or polyethyleneglycol. 30

7. A pharmaceutical aerosol formulation according to claim 6 wherein the low volatility component is glycerol.

8. A pharmaceutical aerosol formulation according to any one of claims 6 to 7 wherein the low volatility component is present in an amount of 0.5 to 35 - 3% wow.

9. A pharmaceutical aerosol formulation according to any one of claims 6 to 7 wherein the low volatility component is present in an amount of around 1 % w/w.

10. A pharmaceutical aerosol formulation according to claim 1 or claim 2 which contains:

PG371 1/GB Div 4 33 0.025% w/v fluticasone propionate; 7% w/w ethanol; 1, 1,1,2-tetrafluoroethane as propellant.

S

11. A pharmaceutical aerosol formulation according to claim 10 which further contains 1% w/w glycerol.

12. A canister comprising a container sealed with a metering valve and containing a pharmaceutical aerosol formulation according to any one of 10 claims 1 to 11.

13. A canister according to claim 12 wherein the container! is an aiuminium can. 15

14. A canister according to claim 12 or claim 13 wherein the metering valve is capable of delivering a volume of 63ul.

15. A canister according to claim 12 or claim 13 wherein the metering valve is capable of delivering a volume of 1001.

16. A metered dose inhaler which comprises a canister according to any one of claim 12 to 15 fitted into suitable channelling device.

17. A metered dose inhaler according to claim 16 wherein the channelling 25 device comprises a valve actuator having an actuator exit orifice of diameter 0.25mm or less.

18. A metered dose inhaler according to claim 17 wherein the actuator exit orifice diameter is 0.22mm.

19. Use of a pharmaceutical aerosol formulation according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of respiratory disorders.

35

20. Use of a pharmaceutical aerosol formulation according to claim 19 wherein the respiratory disorder is asthma.

21. Use of a pharmaceutical aerosol formulation according to claim 19 wherein the respiratory disorder is chronic obstructive pulmonary disease 40 (CORD).