GB2597755A

GB2597755A - Pharmaceutical composition

Info

Publication number: GB2597755A
Application number: GB2012053.1A
Authority: GB
Inventors: Corr Stuart
Original assignee: Mexichem Fluor SA de CV
Current assignee: Mexichem Fluor SA de CV
Priority date: 2020-08-03
Filing date: 2020-08-03
Publication date: 2022-02-09
Also published as: GB202012053D0

Abstract

A pharmaceutical composition is described. The composition comprises: (i) a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a). The composition has enhanced drug stability, improved aerosolization, reduced global warming potential (GWP) and good compatibility with standard uncoated aluminium cans as well as with standard valves and seals.

Description

PHARMACEUTICAL COMPOSITION

The present invention relates to the delivery of drug formulations from a medical device, such as a metered dose inhaler (MDI), using a propellant comprising 1,1-difluoroethane (HFA-152a). More particularly, the present invention relates to pharmaceutical compositions comprising HFA-152a propellant and a drug formulation which is dissolved or suspended in the propellant and to medical devices containing those compositions. The pharmaceutical compositions of the invention are particularly suited for delivery from a pressurised aerosol container using a metered dose inhaler (MDI).

MDIs are the most significant type of inhalation drug delivery system and are well known to those skilled in the art. They are designed to deliver, on demand, a discrete and accurate amount of a drug to the respiratory tract of a patient using a liquefied propellant in which the drug is dissolved, suspended or dispersed. The design and operation of MDIs is described in many standard textbooks and in the patent literature. They all comprise a pressurised container that holds the drug formulation, a nozzle and a valve assembly that is capable of dispensing a controlled quantity of the drug through the nozzle when it is activated. The nozzle and valve assembly are typically located in a housing that is equipped with a mouth piece. The drug formulation will comprise a propellant, in which the drug is dissolved, suspended or dispersed, and may contain other materials such as polar excipients, surfactants and preservatives.

In order for a propellant to function satisfactorily in MDIs, it needs to have a number of properties. These include an appropriate boiling point and vapour pressure so that it can be liquefied in a closed container at room temperature but develop a high enough pressure when the MDI is activated to deliver the drug as an atomised formulation even at low ambient temperatures. Further, the propellant should be of low acute and chronic toxicity and have a high cardiac sensitisation threshold. It should have a high degree of chemical stability in contact with the drug, the container and the metallic and non-metallic components of the MDI device, and have a low propensity to extract low molecular weight substances from any elastomeric materials in the MDI device. The propellant should also be capable of maintaining the drug in a homogeneous solution, in a stable suspension or in a stable dispersion for a sufficient time to permit reproducible delivery of the drug in use. When the drug is in suspension in the propellant, the density of the liquid propellant is desirably similar to that of the solid drug in order to avoid rapid sinking or floating of the drug particles in the liquid. Finally, the propellant should not present a significant flammability risk to the patient in use. In particular, it should form a non-flammable or low flammability mixture when mixed with air in the respiratory tract.

Dichlorodifluoromethane (R-12) possesses a suitable combination of properties and was 5 for many years the most widely used MDI propellant, often blended with trichlorofluoromethane (R-11). Due to international concern that fully and partially halogenated chlorofluorocarbons (CFCs), such as dichlorodifluoromethane and trichlorofluoromethane, were damaging the earth's protective ozone layer, many countries entered into an agreement, the Montreal Protocol, stipulating that their manufacture and 10 use should be severely restricted and eventually phased out completely. Dichlorodifluoromethane and trichlorofluoromethane were phased out for refrigeration use in the 1990's, but are still used in small quantities in the MDI sector as a result of an essential use exemption in the Montreal Protocol.

1,1,1,2-tetrafluoroethane (HFA-134a) was introduced as a replacement refrigerant and MDI propellant for R-12. 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) was also introduced as a replacement propellant for dichlorotetrafluoroethane (R-114) in the MDI sector and is sometimes used alone or blended with H FA -134a for this application.

Although HFA-134a and HFA-227ea have low ozone depletion potentials (ODPs), they have global warming potentials (GWPs), 1430 and 3220 respectively, which are now considered to be too high by some regulatory bodies, especially for dispersive uses when they are released into the atmosphere.

One industrial area that has received particular attention recently has been the automotive air-conditioning sector where the use of H FA-134a has come under regulatory control as a result of the European Mobile Air Conditioning Directive (2006/40/EC). Industry is developing a number of possible alternatives to HFA-134a in automotive air conditioning and other applications that have a low greenhouse warming potential (GWP) as well as a low ozone depletion potential (ODP). Many of these alternatives include hydrofluoropropenes, especially the tetrafluoropropenes, such as 2,3,3,3-tetrafluoropropene (H FO-1234yf) and 1,3,3,3-tetrafluoropropene (HF0-1234ze).

Although the proposed alternatives to HFA-134a have a low GWP, the toxicological status of many of the components, such as certain of the fluoropropenes, is unclear and they are unlikely to be acceptable for use in the MDI sector for many years, if at all.

Vilanterol and its salt vilanterol trifenatate are long acting beta-2-agonists (LABA) used in the treatment and control of a number of respiratory-related disorders, but particularly asthma and chronic obstructive pulmonary disease (COPD). Whilst vilanterol treatment is very effective, the performance of vilanterol in many of these therapies may be improved by administration in combination with a corticosteroid, such as the glucocorticoid steroid fluficasone.

There is a need for a vilanterol-based pharmaceutical composition which can be delivered using a MDI and that uses a propellant having a reduced GVVP in comparison with HFA- 134a and HFA-227ea. There is also a need for a vilanterol-based pharmaceutical composition which exhibits improved stability.

We have found that a propellant comprising 1,1-difluoroethane (HFA-152a) can be used to successfully deliver vilanterol-based drug formulations using a M DI. These formulations can exhibit improved chemical stability, improved aerosolizafion performance for improved drug delivery, reduced GWP, good compatibility with standard uncoated aluminium cans as well as good compatibility with standard valves and seals.

According to a first aspect of the present invention, there is provided a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising: (i) a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, particularly vilanterol trifenatate; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a).

In one preferred embodiment, the pharmaceutical composition of the first aspect of the present invention contains less than 500 ppm, preferably less than 100 ppm, more preferably less than 50 ppm, still more preferably less than 10 ppm and particularly less than 5 ppm of water based on the total weight of the pharmaceutical composition. In referring to the water content of the pharmaceutical composition, we are referring to the content of free water in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition is water-free.

Alternatively, the pharmaceutical composition of the first aspect may contain greater than 0.5 ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as it can in practice be difficult to remove all the water from the composition and then retain it in such a water-free state. Low water contents are preferred because they tend to reduce the degradation of drug compounds resulting in a composition with higher chemical stability.

Accordingly, a preferred embodiment of the first aspect of the present invention provides a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising: (i) a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, particularly vilanterol trifenatate; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a), wherein the composition contains less than 500 ppm, preferably less than 100 ppm, more preferably less than 50 ppm, still more preferably less than 10 ppm and particularly less than 5 ppm of water based on the total weight of the pharmaceutical composition.

In a preferred embodiment, the pharmaceutical composition of the first aspect of the invention contains less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm and particularly less than 50 ppm of dissolved oxygen based on the total weight of the pharmaceutical composition. In an especially preferred embodiment, the pharmaceutical composition is free of dissolved oxygen. Alternatively, the pharmaceutical composition of the first aspect may contain greater than 0.5 ppm of dissolved oxygen, e.g. 1 ppm or greater, but less than the amounts discussed above, as it can in practice be difficult to retain the composition in an oxygen-free state. Low oxygen contents are preferred because they tend to reduce the degradation of drug compounds resulting in a composition with higher chemical stability.

Accordingly, a preferred embodiment of the first aspect of the present invention provides a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising: CO a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, particularly vilanterol trifenatate; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a), wherein the composition contains less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm and especially less than 50 ppm of oxygen based on the total weight of the pharmaceutical composition.

The pharmaceutical composition of the present invention is suitable for delivery to the respiratory tract using a metered dose inhaler (MDI).

The at least one vilanterol compound in the pharmaceutical composition of the invention in all aspects and embodiments disclosed herein is preferably in a micronized form.

Further, the pharmaceutical composition of the invention in all aspects and embodiments disclosed herein is preferably free of perforated microstructures.

Additionally, the pharmaceutical composition of the invention in all aspects and embodiments disclosed herein is preferably free of cannabinoids or the pharmaceutically acceptable derivatives (including salts) thereof.

The at least one vilanterol compound may be dispersed or suspended in the propellant. The drug particles in such suspensions preferably have a diameter of less than 100 microns, more preferably less than 50 microns and particularly less than 10 microns.

However, in an alternative embodiment the pharmaceutical compositions of the invention are solutions with the at least one vilanterol compound dissolved in the propellant, e.g. with the assistance of a polar excipient, such as ethanol. Preferably, the at least one vilanterol compound is suspended in the propellant.

A particularly suitable pharmaceutically acceptable salt/ester of vilanterol is vilanterol trifenatate. Accordingly, in the above described pharmaceutical compositions of the invention, the at least one vilanterol compound is preferably selected from vilanterol and vilanterol trifenatate. In an especially preferred embodiment, the at least one vilanterol compound is vilanterol trifenatate.

The amount of the drug component in the pharmaceutical composition of the first aspect of the present invention will typically be in the range of from 0.01 to 2.5 weight % based on the total weight of the pharmaceutical composition. Preferably, the drug component will comprise from 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0 weight % and especially from 0.05 to 1.5 weight % of the total weight of the pharmaceutical composition.

The drug component may consist essentially of or consist entirely of the at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof By the term "consists essentially of", we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists of the least one vilanterol compound. When the drug component consists entirely of the at least one vilanterol compound, the pharmaceutical composition does not contain any other active pharmaceutical ingredients, such as other long acting beta-2-agonists (LABA), long acting muscarinic antagonists (LAMA), corticosteroids, or short acting beta-2-agonists (SABA).

Alternatively, the drug component may contain other drugs, such as at least one corticosteroid and/or least one long acting muscarinic antagonist (LAMA).

The propellant component in the pharmaceutical composition of the first aspect of the present invention comprises 1,1-difluoroethane (H FA-152a). Thus, we do not exclude the possibility that the propellant component may include other propellant compounds in addition to the HFA-152a. For example, the propellant component may additionally comprise one or more additional hydrofluorocarbon or hydrocarbon propellant compounds, e.g. selected from HFA-227ea, HFA-134a, difluoromethane (HFA-32), propane, butane, isobutane and dimethyl ether. The preferred additional propellants are HFA-227ea and H FA-134a If an additional propellant compound is included, such as HFA-134a or HFA-227ea, at least 60 % by weight, preferably at least 70 % by weight and more preferably at least 80 % by weight of the propellant component should be HFA-152a. Typically, the HFA-152a will constitute at least 90 weight c/o, e.g. from 90 to 99 weight % or from 90 to 100 weight %, of the propellant component. Preferably, the HFA-152a will constitute at least 95 weight %, e.g. from 95 to 99 weight % or from 95 to 100 weight %, and more preferably at least 99 weight c/o of the propellant component.

In a preferred embodiment, the propellant component has a global warming potential (GVVP) of less than 250, more preferably less than 200 and still more preferably less than 150.

In an especially preferred embodiment, the propellant component consists entirely of HFA- 152a so that the pharmaceutical composition of the invention comprises HFA-152a as the sole propellant. By the term "consists entirely of' we do not, of course, exclude the presence of minor amounts, e.g. up to a few hundred parts per million, of impurities that may be present following the process that is used to make the HFA-152a providing that they do not affect the suitability of the propellant in medical applications. Preferably the HFA-152a propellant will contain no more than 10 ppm, e.g. from 0.5 to 10 ppm, more preferably no more than 5 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities, such as vinyl fluoride, vinyl chloride, vinylidene fluoride and chloro-fluoro ethylene compounds.

The amount of propellant component in the pharmaceutical composition of the invention will vary depending on the amounts of the drugs and other components in the pharmaceutical composition. Typically, the propellant component will comprise from 80.0 to 99.99 weight % of the total weight of the pharmaceutical composition. Preferably, the propellant component will comprise from 90.0 to 99.99 weight %, more preferably from 96.5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition of the first aspect of the present invention consists essentially of and more preferably consists entirely of the two components (i) and 00 listed above. By the term "consists essentially of", we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two listed components.

In another embodiment, the pharmaceutical composition of the first aspect of the present invention additionally includes a polar excipient, such as ethanol. Polar excipients have been used previously in pharmaceutical compositions for treating respiratory disorders that are delivered using metered dose inhalers (MDIs). They are also referred to as solvents, co-solvents, carrier solvents and adjuvants. Their inclusion can serve to solubilise a surfactant or the drug in the propellant and/or inhibit deposition of drug particles on the surfaces of the metered dose inhaler that are contacted by the pharmaceutical composition as it passes from the container in which it is stored to the nozzle outlet. They are also used as bulking agents in two-stage filling processes where the drug is mixed with a suitable polar excipient. The most commonly used polar excipient is ethanol. If a polar excipient is used, it will typically be present in an amount of from 0.5 to 10 % by weight, preferably in an amount of from 1 to 5 % by weight based on the total weight of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition of the present invention is free of polar excipients such as ethanol.

The pharmaceutical composition of the first aspect of the present invention may also include a surfactant component comprising at least one surfactant compound. Surfactant compounds of the type that have been in use hitherto in pharmaceutical formulations for MDIs may be used in the pharmaceutical compositions of the present invention. Preferred surfactants are selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid, ethyl oleate, sorbitan monooleate, sorbitan trioleate, isopropyl myristate and lecithin. By the term oleic acid, we are not necessarily referring to pure (9Z)-octadec-9-enoic acid.

When sold for surfactant use in medical applications, oleic acid is typically a mixture of several fatty acids, with (9Z)-octadec-9-enoic acid being the predominant fatty acid, e.g. present in an amount of at least 65 weight % based on the total weight of the surfactant.

In a preferred embodiment, the surfactant component, if included, consists essentially of and still more preferably consists entirely of at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid, ethyl oleate, sorbitan monooleate, sorbitan trioleate, isopropyl myristate and lecithin. By the term "consists essentially of', we mean that at least 95 weight °AD, more preferably at least 98 weight % and especially at least 99 weight % of the surfactant component is composed of the listed surfactants.

If a surfactant component is used, preferably it is free from fluorinated surfactant compounds If a surfactant component is used, it will typically be present in an amount of from 0.1 to 2.5 °/iii by weight, preferably in an amount of from 0.2 to 1.5 % by weight based on the total weight of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition of the first aspect of the present invention is surfactant free.

In another embodiment, the pharmaceutical composition of the first aspect of the present invention is also free of one or more of (i) acid stabilisers, such as organic and inorganic acids, (ii) polymers having amide and/or carboxylic acid ester repeating structural units, and (iii) pharmaceutically acceptable salts of both cromoglycic acid and nedocromil.

The pharmaceutical composition of the invention may also include at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof, such as fluticasone furoate and fluticasone propionate. Preferred compounds include fluticasone and fluticasone furoate, especially fluticasone furoate.

Accordingly, a second aspect of the present invention provides a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising: (i) a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, especially vilanterol trifenatate, and at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof, especially fluticasone furoate; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a).

The at least one fluticasone compound in the pharmaceutical composition of the second aspect of the present invention in all aspects and embodiments disclosed herein is preferably in a micronized form.

In one preferred embodiment, the pharmaceutical composition of the second aspect of the present invention may contain less than 500 ppm, preferably less than 100 ppm, more preferably less than 50 ppm, still more preferably less than 10 ppm and particularly less than 5 ppm of water based on the total weight of the pharmaceutical composition. In referring to the water content of the pharmaceutical composition, we are referring to the content of free water in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition of the second aspect of the present invention is water-free. Alternatively, the pharmaceutical composition of the second aspect may contain greater than 0.5 ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as it can in practice be difficult to remove all the water from the composition and then retain it in such a water-free state. Low water contents are preferred because they tend to reduce the degradation of drug compounds resulting in a composition with higher chemical stability.

In a preferred embodiment, the pharmaceutical composition of the second aspect of the invention contains less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm and particularly less than 50 ppm of dissolved oxygen based on the total weight of the pharmaceutical composition. In an especially preferred embodiment, the pharmaceutical composition is free of dissolved oxygen. Alternatively, the pharmaceutical composition of the second aspect may contain greater than 0.5 ppm of dissolved oxygen, e.g. 1 ppm or greater, but less than the amounts discussed above, as it can in practice be difficult to retain the composition in an oxygen-free state. Low oxygen contents are preferred because they tend to reduce the degradation of drug compounds resulting in a composition with higher chemical stability.

Suitable and preferred vilanterol compounds in the pharmaceutical composition of the second aspect of the present invention are as discussed above for the pharmaceutical composition of the first aspect of the present invention.

Typical and preferred amounts of the drug component and the propellant component in the pharmaceutical composition of the second aspect of the present invention and suitable, typical and preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the invention. The drug component may consist essentially of or consist entirely of the at least one vilanterol compound and the at least one fluticasone compound. By the term "consists essentially of', we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists of the at least one vilanterol compound and the at least one fluticasone compound. "Mien the drug component consists entirely of the at least one vilanterol compound and the at least one fluticasone compound, the pharmaceutical composition does not contain any other active pharmaceutical ingredients.

In one embodiment, the pharmaceutical composition of the second aspect of the present invention consists essentially of and more preferably consists entirely of the two components (i) and (ii) listed above. By the term "consists essentially of", we mean that at least 98 weight °/0, more preferably at least 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two listed components.

In another embodiment, the pharmaceutical composition of the second aspect of the invention may contain one or both of a polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect of the invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect of the invention. Typical and preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first aspect of the invention.

In another embodiment, the pharmaceutical composition of the second aspect of the present invention is free of one or both of polar excipients and surfactant compounds.

In an especially preferred embodiment of the second aspect of the invention, the drug component comprises vilanterol trifenatate and fluficasone furcate. Preferably, the vilanterol trifenatate and fluticasone furoate are the only pharmaceutical actives in the pharmaceutical composition of the second aspect of the invention.

In one embodiment, the pharmaceutical composition of the second aspect of the present invention is free of one or more of (i) acid stabilisers, such as organic and inorganic acids, (ii) polymers having amide and/or carboxylic acid ester repeating structural units, and (iii) pharmaceutically acceptable salts of both cromoglycic acid and nedocromil.

The pharmaceutical compositions of the first and second aspects of the present invention may also include a long acting muscarinic antagonist (LAMA) in addition to the specified drug compounds. Any of the long acting muscarinic antagonists that have been in use hitherto for treating asthma and chronic obstructive pulmonary diseases and that can be delivered using a MDI can be used in the pharmaceutical compositions of the present invention. Suitable long acting muscarinic antagonists include umeclidinium, ipratropium, tiotropium, aclidinium and the pharmaceutically acceptable salts thereof. Other suitable long acting muscarinic antagonists include the pharmaceutically acceptable salts of glycopyrrolate (also known as glycopyrronium), such as glycopyrronium bromide.

The pharmaceutical compositions of the first and second aspects of the present invention may also comprise one or more other additives of the type that are used conventionally in drug formulations for pressurised MDIs, such as valve lubricants. Where other additives are included in the pharmaceutical compositions, they are normally used in amounts that are conventional in the art.

It has been found that the use of propellants comprising 1,1-difluoroethane (HFA-152a) in pharmaceutical compositions comprising a vilanterol compound, such as vilanterol trifenatate, and the propellant can unexpectedly improve the chemical stability of the vilanterol compound compared to the stability it exhibits in pharmaceutical compositions comprising either HFA-134a or HFA-227ea as the propellant but which are otherwise identical.

Accordingly, in a third aspect of the present invention there is provided a method of improving the stability of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA-152a).

The pharmaceutical composition in the stabilisation method of the third aspect of the present invention may be a suspension or a solution, preferably a suspension.

In a preferred embodiment of the stabilisation method, the components and conditions for the preparation of the pharmaceutical composition are selected to maintain the water content of the pharmaceutical composition below 500 ppm, preferably below 100 ppm, more preferably below 50 ppm, still more preferably below 10 ppm and particularly below ppm of water based on the total weight of the pharmaceutical composition. In referring to the water content of the pharmaceutical composition, we are referring to the content of free water in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition is water-free. Alternatively, the resulting pharmaceutical composition may contain greater than 0.5 ppm of water, e.g. greater than 1 ppm, based on the total weight thereof, but less than the amounts discussed above, as it can in practice be difficult to remove all the water from the composition and then retain it in such a water-free state. Low water contents are preferred because they tend to reduce the degradation of drug compounds resulting in a composition with higher chemical stability.

Accordingly, in a preferred embodiment of the third aspect of the present invention there is provided a method of improving the stability of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA-152a) and selecting the components and conditions for the preparation of the pharmaceutical composition to maintain the water content of the pharmaceutical composition below 500 ppm, preferably below 100 ppm, more preferably below 50 ppm, even more preferably below 10 ppm and particularly below 5 ppm based on the total weight of the pharmaceutical composition.

In practice, preparing a pharmaceutical composition with the low water levels recited above involves using a propellant component with a suitably low water content, as it is the propellant component that can tend to contain adventitious amounts of water, and then preparing the pharmaceutical composition under suitably dry conditions, e.g. in a dry nitrogen atmosphere. Preparing pharmaceutical compositions under dry conditions is well known and the techniques involved are well understood by those skilled in the art. However, if the pharmaceutical composition contains significant amounts of other components, e.g. a pharmaceutical excipient such as ethanol, then it may also be important to control the water content of those components as well as the propellant, e.g. by drying to reduce the water content to suitably low levels. Suitable drying techniques are well known to those skilled in the art and include the use of a molecular sieve or other inorganic desiccant and membrane drying processes. Other steps to obtain a low water content in the finished pharmaceutical composition may include drying and storing the can and valve components with which the composition will come into contact in a moisture-controlled atmosphere, e.g. dry nitrogen or air, prior to and during device assembly.

In a preferred embodiment, the pharmaceutical composition used in the method of the third aspect of the invention contains less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm and particularly less than 50 ppm of dissolved oxygen based on the total weight of the pharmaceutical composition. In an especially preferred embodiment, the pharmaceutical composition is free of dissolved oxygen. Alternatively, the pharmaceutical composition of the third aspect may contain greater than 0.5 ppm of dissolved oxygen, e.g. 1 ppm or greater, but less than the amounts discussed above, as it can in practice be difficult to retain the composition in an oxygen-free state. Low oxygen contents are preferred because they tend to reduce the degradation of drug compounds resulting in a composition with higher chemical stability.

In the stabilisation method of the third aspect of the present invention suitable and preferred vilanterol compounds are as described above for the pharmaceutical composition of the first aspect of the present invention. In addition, typical and preferred amounts of the drug component and the propellant component in the stabilisation method of the third aspect of the present invention and suitable, typical and preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the invention The drug component in the stabilisation method of the third aspect of the present invention may consist essentially of or consist entirely of the at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof. By the term "consists essentially or, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists of the least one vilanterol compound. Alternatively, the drug component may also comprise at least one additional drug compound such as at least one corticosteroid and/or at least one long acting muscarinic antagonist. In one preferred embodiment, the drug component in the stabilisation method of the third aspect of the present invention additionally comprises at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof, such as fluticasone propionate and especially fluticasone furoate.

In one embodiment, the pharmaceutical composition in the third aspect of the present invention consists essentially of and more preferably consists entirely of the drug component and the propellant component as defined above. By the term "consists essentially or, we mean that at least 98 weight °/0, more preferably at least 99 weight % and especially at least 99.9 weight cro of the pharmaceutical composition consists of the two components.

In an alternative embodiment, the pharmaceutical composition in the third aspect of the invention may contain one or both of a polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect of the invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect of the invention. Typical and preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first aspect of the invention.

In a preferred embodiment, the pharmaceutical composition that is provided in the stabilisation method of the third aspect of the present invention is free of one or more of (i) acid stabilisers, such as organic and inorganic acids, (U) polymers having amide and/or carboxylic acid ester repeating structural units, and (iii) pharmaceutically acceptable salts of both cromoglycic acid and nedocromil.

In one preferred stabilisation method, the resulting pharmaceutical composition after storage at 40°C and 75 % relative humidity for 3 months will produce less than 4 % by weight, preferably less than 3 % by weight and more preferably less than 2 % by weight of impurities from the degradation of the at least one vilanterol compound based on the total weight of the at least one vilanterol compound and the impurities.

In another preferred stabilisation method in which the pharmaceutical composition also comprises at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof, the resulting pharmaceutical composition after storage at 40°C and 75 % relative humidity for 3 months will produce less than 4 % by weight, preferably less than 3 % by weight and more preferably less than 2 % by weight of impurities from the degradation of the at least one vilanterol compound based on the total weight of the at least one vilanterol compound and the impurities.

In yet another preferred stabilisation method, at least 90 % by weight, preferably at least 92 % by weight and more preferably at least 941% by weight of the at least one vilanterol compound that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage at 40°C and 75 % relative humidity for 3 months.

In still another preferred stabilisation method in which the pharmaceutical composition also comprises at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof, at least 90 % by weight, preferably at least 92 % by weight and more preferably at least 94 % by weight of the at least one vilanterol compound that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage at 40°C and 75 % relative humidity for 3 months.

One preferred pharmaceutical composition of the first and second aspects of the present invention will produce less than 4 % by weight, preferably less than 3 % by weight, and even more preferably less than 2 % by weight of total impurities from the degradation of the at least one vilanterol compound after storage at 40°C and 75 % relative humidity for 3 months.

The weight % of impurities indicated above are based on the total weight of the at least one vilanterol compound and the impurities.

In a further preferred pharmaceutical composition of the first and second aspects of the present invention at least 90 % by weight, preferably at least 92 % by weight and more preferably at least 94 % by weight of the at least one vilanterol compound that is contained originally in the pharmaceutical composition of the invention immediately following preparation will be present in the composition after storage at 40°C and 75 % relative humidity for 3 months.

In referring to the storage of the pharmaceutical compositions in the above described stabilisation methods, we are referring, in particular, to the storage of those compositions in uncoated aluminium containers. Similarly, in referring to the storage of the above described pharmaceutical compositions, we are referring, in particular, to their storage in uncoated aluminium containers.

The pharmaceutical compositions of the invention are normally stored in a pressurised container or canister which is to be used in association with a medication delivery device. When so stored, the propellant component is normally a liquid. In a particularly preferred embodiment, the pressurised container is a coated aluminium can or an uncoated aluminium can, especially the latter.

The pharmaceutical compositions of the invention find particular utility in the delivery of the vilanterol compounds, and where included the fluticasone compounds and long acting muscarinic antagonist compounds, from a pressurised aerosol container using a metered dose inhaler (MD1). For this application, the pharmaceutical compositions are contained in the pressurised aerosol container and the HFA-152a propellant functions to deliver the drug as a fine aerosol spray.

Accordingly, a fourth aspect of the present invention provides a pressurised container holding the pharmaceutical composition of the first or second aspect of the present invention. In a fifth aspect, the present invention provides a medication delivery device, especially a metered dose inhaler, having a pressurised container holding the pharmaceutical composition of the first or second aspect of the present invention.

In preferred embodiments, the medication delivery device is a metered dose inhaler which comprises a nozzle and valve assembly attached to the pressurized aerosol container and a gasket made from an elastomeric material selected from EPDM, chlorobutyl, bromobutyl and cycloolefin copolymer rubbers to provide a seal between the container and the nozzle/valve assembly.

The pharmaceutical compositions of the present invention are for use in medicine for treating a patient suffering or likely to suffer from a respiratory disorder and especially asthma or a chronic obstructive pulmonary disease.

Accordingly, the present invention also provides a method for treating a patient suffering or likely to suffer from a respiratory disorder, especially asthma or a chronic obstructive pulmonary disease, which comprises administering to the patient a therapeutically or prophylactically effective amount of a pharmaceutical composition as discussed above.

The pharmaceutical composition is preferably delivered to the patient using a MDI.

The present invention also provides a pharmaceutical composition as discussed above for use in the treatment of a respiratory disorder, especially asthma or chronic obstructive pulmonary disease. The pharmaceutical composition is preferably delivered to the patient using a MDI.

The pharmaceutical compositions of the invention can be prepared and the MDI devices filled using techniques that are standard in the art, such as pressure filling and cold filling.

For example, the pharmaceutical compositions can be prepared by a simple blending operation in which the at least one vilanterol compound and any optional compounds that are to be included, such as an additional drug compound(s), a surfactant and a polar excipient, are mixed together with the HFA-152a-containing propellant in the required proportions in a suitable mixing vessel. Mixing can be promoted by stirring as is common in the art. Conveniently, the HFA-152a-containing propellant is liquefied to aid mixing. If the pharmaceutical composition is made in a separate mixing vessel, it can then be transferred to pressurised containers for storage, such as pressurised containers that are used as part of medication delivery devices and especially M Dls.

The pharmaceutical compositions of the invention can also be prepared within the confines of a pressurised container, such as an aerosol canister or vial, from which the compositions are ultimately released as an aerosol spray using a medication delivery device, such as a MDI. In this method, a weighed amount of the at least one vilanterol compound and weighed amounts of any optional drug compounds that are to be included are introduced into the open container. A valve is then crimped onto the container and the HFA-152acontaining propellant component, in liquid form, introduced through the valve into the container under pressure, optionally after first evacuating the container through the valve. Other components, such as a surfactant and a polar excipient, if included, can be mixed with the drug component or, alternatively, introduced into the container after the valve has been fitted, either alone or as a premix with the propellant component. The whole mixture can then be treated to disperse the drug component in the propellant component, e.g. by vigorous shaking or using an ultrasonic bath. Suitable containers may be made of plastics, metal, e.g. aluminium, or glass. Preferred containers are made of metal, especially aluminium which may be coated or uncoated. Uncoated aluminium containers are especially preferred.

The container may be filled with enough of the pharmaceutical composition to provide for a plurality of dosages. The pressurized aerosol canisters that are used in MDIs typically contain 50 to 150 individual dosages.

The present invention also provides a method of reducing the global warming potential (GVVP) of a pharmaceutical composition comprising a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable derivatives thereof and a propellant component, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA-152a). This method is applicable to the preparation of all the pharmaceutical compositions disclosed herein in all their aspects and embodiments.

Preferably, at least 90 weight %, more preferably at least 95 weight % and still more preferably at least 99 weight % of the propellant component used is HFA-152a. In an especially preferred embodiment, the propellant component used is entirely HFA-152a.

The propellant component that is used will preferably have a global warming potential (GVVP) of less than 250, more preferably less than 200 and still more preferably less than 150 Further aspects and embodiments of the invention are set out in the following numbered paragraphs: 1. A pharmaceutical composition comprising: a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof; and a propellant component comprising 1,1-difluoroethane (HFA-152a).

2. The pharmaceutical composition of numbered paragraph 1, wherein the composition contains less than 500 ppm, preferably less than 100 ppm, more preferably less than 50 ppm, still more preferably less than 10 ppm and especially less than 5 ppm of water based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition of numbered paragraph 2, wherein the composition contains greater than 0.5 ppm, e.g. greater than 1 ppm, of water based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the composition contains less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm and particularly less than 50 ppm of dissolved oxygen based on the total weight of the pharmaceutical composition.

5. The pharmaceutical composition of numbered paragraph 4, wherein the composition contains greater than 0.5 ppm, e.g. greater than 1 ppm, of dissolved oxygen based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the at least one vilanterol compound is selected from vilanterol and vilanterol trifenatate.

7. The pharmaceutical composition of numbered paragraph 6, wherein the at least one vilanterol compound is vilanterol trifenatate.

8. The pharmaceutical composition of any one the preceding numbered paragraphs, wherein the at least one vilanterol compound is in a micronized form.

9. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the drug component additionally comprises at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof.

10. The pharmaceutical composition of numbered paragraph 9, wherein the at least one fluticasone compound is selected from fluticasone and fluticasone furoate.

11. The pharmaceutical composition of numbered paragraph 10, wherein the at least one fluticasone compound is fluticasone furoate.

12. The pharmaceutical composition of any one of numbered paragraphs 9 to 11, wherein the at least one fluticasone compound is in a micronized form.

13. The pharmaceutical composition of any one of numbered paragraphs 9 to 12, wherein the at least one fluticasone compound is the only corticosteroid in the composition.

14. The pharmaceutical composition of any of the preceding numbered paragraphs, wherein the drug component additionally comprises at least one long acting muscarinic antagonist (LAMA).

15. The pharmaceutical composition of numbered paragraph 14, wherein the at least one long acting muscarinic antagonist is selected from the group consisting of umeclidinium, ipratropium, tiotropium, aclidinium and the pharmaceutically acceptable salts thereof; preferably from umeclidinium, ipratropium, aclidinium and the pharmaceutically acceptable salts thereof.

16. The pharmaceutical composition of numbered paragraph 14, wherein the at least one long acting muscarinic antagonist is a pharmaceutically acceptable salt of glycopyrrolate, especially glycopyrronium bromide.

17. The pharmaceutical composition of any one of numbered paragraphs 14 to 16, wherein the at least one long acting muscarinic antagonist is in a micronized form.

18. The pharmaceutical composition of any one of numbered paragraphs 1 to 14, which is free from tiotropium or pharmaceutically acceptable derivatives (including salts) thereof 19. The pharmaceutical composition of any one of numbered paragraphs 1 to 15, which is free from pharmaceutically acceptable salts of glycopyrrolate, such as glycopyrronium zo bromide.

20. The pharmaceutical composition of any one of numbered paragraphs 1 to 13, which is free from long acting muscarinic antagonists (LAMA).

21. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the drug component comprises from 0.01 to 2.5 weight %, preferably from 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0 weight % and especially from 0.05 to 1.5 weight % of the total weight of the pharmaceutical composition.

22. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the propellant component comprises from 80.0 to 99.99 weight %, preferably from 90.0 to 99.99 weight cro, more preferably from 96.5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the pharmaceutical composition.

23. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein at least 90 weight c/o, preferably at least 95 weight % and more preferably at least 99 weight % of the propellant component is 1,1-difluoroethane (HFA152a).

24. The pharmaceutical composition of any one of the numbered paragraphs 1 to 22, wherein the propellant component is entirely 1,1-difluoroethane (HFA-152a).

25. The pharmaceutical composition of numbered paragraph 23 or 24, wherein the propellant component contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities.

26. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein at least 95 weight °/0, preferably at least 98 weight % and more preferably at least 99 weight % of the composition consists of the two components (i) and 00.

27. The pharmaceutical composition of any one of the preceding numbered paragraphs further comprising a surfactant component comprising at least one surfactant 15 compound.

28. The pharmaceutical composition of numbered paragraph 27, wherein the surfactant component comprises at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid, ethyl oleate, sorbitan monooleate, sorbitan trioleate, isopropyl myristate and lecithin.

29. The pharmaceutical composition of numbered paragraph 27 or 28, wherein the surfactant component is free of fluorinated surfactant compounds.

30. The pharmaceutical composition of numbered paragraph 29, wherein the surfactant component is free of fluorinated surfactant compounds and free of surfactant compounds selected from C8.16 fatty acids or salts, bile salts, phospholipids and alkyl saccharides 31. The pharmaceutical composition of any one of the preceding numbered paragraphs further comprising a polar excipient.

32. The pharmaceutical composition of numbered paragraph 31, wherein the polar excipient is ethanol.

33. The pharmaceutical composition of any one of numbered paragraphs 1 to 30 which is free of polar excipients.

34. The pharmaceutical composition of any one of numbered paragraphs 1 to 30 which is free of ethanol.

35. The pharmaceutical composition of any one of numbered paragraphs 1 to 26 which consists entirely of the two components (i) and 00.

36. The pharmaceutical composition of any one of the preceding numbered paragraphs which after storage in uncoated aluminium containers at 40°C and 75 % relative humidity for 3 months will produce less than 4 % by weight, preferably less than 3 % by weight, even more preferably less than 2 % by weight of impurities from the degradation of the at least one vilanterol compound based on the total weight of the at least one vilanterol compound and the impurities.

37. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein at least 90 % by weight, preferably at least 92 % by weight and more preferably at least 94 % by weight of the at least one vilanterol compound that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage in uncoated aluminium containers at 40°C and 75 % relative humidity for 3 months.

38. The pharmaceutical composition of any one of numbered paragraphs 1 to 36, wherein at least 90 To, preferably at least 92 To and more preferably at least 94 % of the original pharmaceutical activity of the composition is retained after storage in uncoated aluminium containers at 40°C and 75 % relative humidity for 3 months.

39. The pharmaceutical composition of any one of the preceding numbered paragraphs in the form of a suspension.

40. The pharmaceutical composition of any one of numbered paragraphs 27 to 30 and any one of numbered paragraphs 31 to 34 and 36 to 38 when dependent on any one of numbered paragraphs 27 to 30, wherein the composition comprises a suspension of drug particles and wherein the surfactant component is not present as a surface coating on the suspended drug particles.

41. The pharmaceutical composition of any one of numbered paragraphs 'I to 38 in the form of a solution.

42. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the pharmaceutical composition is free of perforated microstructures.

43. The pharmaceutical composition of any one of the preceding numbered paragraphs which is free of polymers having amide and/or carboxylic acid ester repeating structural units.

44. The pharmaceutical composition of any one of the preceding numbered paragraphs which is free of acid stabilisers.

45. The pharmaceutical composition of any one of the preceding numbered paragraphs which is free of pharmaceutically acceptable salts of both cromoglycic acid and nedocromil.

46. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the propellant component has a global warming potential (GWP) of less than 250, preferably less than 200 and more preferably less than 150.

47. A pharmaceutical composition comprising: a) a drug component comprising vilanterol trifenatate; and b) a propellant component comprising 1,1-difluoroethane (HFA-152a).

48. A pharmaceutical composition comprising: a) a drug component comprising vilanterol trifenatate and fluticasone furoate; and b) a propellant component comprising 1,1-difluoroethane (HFA-152a).

49. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the stated compounds of the drug component are the only pharmaceutically active ingredients in the pharmaceutical composition.

50. A sealed container that contains a pharmaceutical composition as defined in any one of numbered paragraphs 1 to 49.

51. The sealed container of numbered paragraph 50 which is an uncoated aluminium can 52. The sealed container of numbered paragraph 50 or 51 which is a pressurized aerosol container for use with a metered dose inhaler (MD1).

53. A metered dose inhaler (M DI) fitted with a sealed container as defined in numbered paragraph 52.

54. The metered dose inhaler of numbered paragraph 53 which comprises a nozzle and valve assembly attached to the pressurized aerosol container and a gasket made from an elastomeric material selected from EPDM, chlorobutyl, bromobutyl and cycloolefin copolymer rubbers to provide a seal between the container and the nozzle/valve assembly.

55. A method of improving the stability of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA-152a).

56. The method of numbered paragraph 55, further comprising selecting the components and conditions for the preparation of the pharmaceutical composition to maintain the water content of the pharmaceutical composition below 500 ppm, preferably below 100 ppm, more preferably below 50 ppm, still more preferably below 10 ppm and particularly below 5 ppm based on the total weight of the pharmaceutical composition.

57. The method of numbered paragraph 56, wherein the water content of the pharmaceutical composition is above 0.5 ppm, e.g. above 1 ppm, based on the total weight of the pharmaceutical composition.

58. The method of any one of numbered paragraphs 55 to 57, wherein the dissolved oxygen content of the resulting pharmaceutical composition is below 1000 ppm, preferably below 500 ppm, more preferably below 100 ppm and particularly below 50 ppm based on the total weight of the pharmaceutical composition.

59. The method of numbered paragraph 58, wherein the dissolved oxygen content of the pharmaceutical composition is greater than 0.5 ppm, e.g. greater than 1 ppm, based on the total weight of the pharmaceutical composition.

60. The method of any one of numbered paragraphs 55 to 59, wherein the at least one vilanterol compound is vilanterol or vilanterol trifenatate, especially vilanterol trifenatate.

61. The method of any one of numbered paragraphs 55 to 60, wherein the at least one vilanterol compound is in a micronized form.

62. The method of any one of numbered paragraphs 55 to 61, wherein the drug component additionally comprises at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof.

63. The method of numbered paragraph 62, wherein the at least one fluticasone compound is selected from fluticasone and fluticasone furoate.

64. The method of numbered paragraph 63, wherein the at least one fluticasone compound is fluticasone furoate.

65. The method of any one of numbered paragraphs 62 to 64, wherein the at least one fluticasone compound is in a micronized form.

66. The method of any one of numbered paragraphs 55 to 65, wherein the drug component additionally comprises at least one long acting muscarinic antagonist (LAMA).

67. The method of numbered paragraph 66, wherein the at least one long acting muscarinic antagonist is selected from the group consisting of umeclidinium, ipratropium, tiotropium, aclidinium and the pharmaceutically acceptable derivatives thereof; preferably from umeclidinium, ipratropium, aclidinium and the pharmaceutically acceptable derivatives thereof.

68. The method of numbered paragraph 66, wherein the at least one long acting muscarinic antagonist is a pharmaceutically acceptable salt of glycopyrrolate, especially glycopyrronium bromide.

69. The method of any one of numbered paragraphs 66 to 68, wherein the at least one long acting muscarinic antagonist is in a micronized form.

70. The method of any one of numbered paragraphs 55 to 65, wherein the pharmaceutical composition is free from long acting muscarinic antagonists (LAMA).

71. The method of any one of numbered paragraphs 55 to 66, wherein the pharmaceutical composition is free from tiotropium or pharmaceutically acceptable derivatives (including salts) thereof 72. The method of any one of numbered paragraphs 55 to 67, wherein the pharmaceutical composition is free from pharmaceutically acceptable salts of glycopyrrolate, such as glycopyrronium bromide.

73. The method of any one of numbered paragraph 55 to 72, wherein the pharmaceutical composition is free from cannabinoids or pharmaceutically acceptable derivatives (including salts) thereof 74. The method of any one of numbered paragraphs 55 to 73, wherein the drug component comprises from 0.01 to 2.5 weight %, preferably from 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0 weight % and especially from 0.05 to 1.5 weight c/o of the total weight of the pharmaceutical composition.

75. The method of any one of numbered paragraphs 55 to 74, wherein the propellant component comprises from 80.0 to 99.99 weight c/o, preferably from 90.0 to 99.99 weight %, more preferably from 96.5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the pharmaceutical composition.

76. The method of any one of numbered paragraphs 55 to 75, wherein at least 90 weight c/o, preferably at least 95 weight % and more preferably at least 99 weight % of the propellant component is 1,1-difluoroethane (HFA-152a).

77. The method of any one of numbered paragraphs 55 to 75, wherein the propellant component is entirely 1,1-difluoroethane (HFA-152a).

78. The method of numbered paragraph 76 or 77, wherein the propellant component zo contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities.

79. The method of any one of numbered paragraphs 55 to 78, wherein at least 95 weight %, preferably at least 98 weight % and more preferably at least 99 weight % of the pharmaceutical composition consists of the drug component and the propellant 25 component.

80. The method of any one of numbered paragraphs 55 to 79, wherein the pharmaceutical composition further comprises a surfactant component comprising at least one surfactant compound.

81. The method of numbered paragraph 80, wherein the surfactant component comprises at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid, ethyl oleate, sorbitan monooleate, sorbitan trioleate, isopropyl myristate and lecithin.

82. The method of numbered paragraph 80 or 81, wherein the surfactant component is free of fluorinated surfactant compounds.

83. The method of numbered paragraph 82, wherein the surfactant component is free of fluorinated surfactant compounds and free of surfactant compounds selected from C8_16 fatty acids or salts, bile salts, phospholipids and alkyl saccharides.

84. The method of any one of numbered paragraphs 55 to 83, wherein the pharmaceutical composition further comprises a polar excipient.

85. The method of numbered paragraph 84, wherein the polar excipient is ethanol.

86. The method of any one of numbered paragraphs 55 to 83, wherein the pharmaceutical composition is free of polar excipients.

87. The method of any one of numbered paragraphs 55 to 83, wherein the pharmaceutical composition is free of ethanol.

88. The method of any one of numbered paragraphs 55 to 79, wherein the pharmaceutical composition consists entirely of the drug component and the propellant component.

89. The method of any one of numbered paragraphs 55 to 88, wherein the pharmaceutical composition after storage in uncoated aluminium containers at 40°C and 75 % relative humidity for 3 months will produce less than 4 % by weight, preferably less than 3 % by weight, even more preferably less than 2 % by weight of impurities from the degradation of the at least one vilanterol compound based on the total weight of the at least one vilanterol compound and the impurities.

90. The method of any one of numbered paragraphs 55 to 89, wherein at least 90 % by weight, preferably at least 92 % by weight and more preferably at least 94 % by weight of the at least one vilanterol compound that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage in uncoated aluminium containers at 40°C and 75% relative humidity for 3 months.

91. The method of any one of numbered paragraphs 55 to 89, wherein at least 90 %, preferably at least 92 % and more preferably at least 94 % of the original pharmaceutical activity of the composition is retained after storage in uncoated aluminium containers at 40°C and 75 % relative humidity for 3 months.

92. The method of any one of numbered paragraphs 55 to 91, wherein the pharmaceutical composition is in the form of a suspension.

93. The method of any one of numbered paragraphs 80 to 83 and any one of numbered paragraphs 84 to 87 and 89 to 91 when dependent on any one of numbered paragraphs 80 to 83, wherein the pharmaceutical composition comprises a suspension of drug particles and wherein the surfactant component is not present as a surface coating on the suspended drug particles.

94. The method of any one of numbered paragraphs 55 to 91, wherein the pharmaceutical composition is in the form of a solution.

95. The method of any one of numbered paragraphs 55 to 94, wherein the pharmaceutical composition is free of perforated microstructures.

96. The method of any one of numbered paragraphs 55 to 95, wherein the pharmaceutical composition is free of polymers having amide and/or carboxylic acid ester repeating structural units.

97. The method of any one of numbered paragraphs 55 to 96, wherein the pharmaceutical composition is free of acid stabilisers.

98. The method of any one of numbered paragraphs 55 to 97, wherein the pharmaceutical composition is free of pharmaceutically acceptable salts of both cromoglycic acid and nedocromil.

99. The method of any one of numbered paragraphs 55 to 98, wherein the propellant component has a global warming potential (GWP) of less than 250, preferably less than and more preferably less than 150.

100. The method of any one of numbered paragraphs 55 to 99, wherein the stated compounds of the drug component are the only pharmaceutically active ingredients in the pharmaceutical composition.

101. A method for treating a patient suffering or likely to suffer from a respiratory disorder which comprises administering to the patient a therapeutically or prophylactically effective amount of a pharmaceutical composition as defined in any one of numbered paragraphs 1 to 49.

102. The method of numbered paragraph 101, wherein the respiratory disorder is asthma or a chronic obstructive pulmonary disease.

103. The method of numbered paragraph 101 or 102, wherein the pharmaceutical composition is delivered to the patient using a metered dose inhaler (MDI).

104. The pharmaceutical composition of any one of numbered paragraphs 1 to 49 for use in the treatment of a respiratory disorder.

105. The pharmaceutical composition for use of numbered paragraph 104, wherein the respiratory disorder is asthma or a chronic obstructive pulmonary disease.

106. The pharmaceutical composition for use of numbered paragraph 104 or 105, wherein the pharmaceutical composition is delivered to the patient using a metered dose inhaler (MDI).

107. A method of reducing the global warming potential (GWP) of a pharmaceutical composition comprising a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable derivatives thereof and a propellant component, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA-152a).

108. The method of numbered paragraph 107, wherein at least 90 weight %, preferably at least 95 weight % and more preferably at least 99 weight % of the propellant component used is 1,1-difluoroethane (HFA-152a).

109. The method of numbered paragraph 107, wherein the propellant component used is entirely 1,1-difluoroethane (HFA-152a).

110. The method of numbered paragraph 107, wherein the pharmaceutical composition is as described in any one of numbered paragraphs 1 to 49.

111. The method of any one of numbered paragraphs 107 to 110, wherein the propellant component used has a global warming potential (GWP) of less than 250, preferably less than 200 and more preferably less than 150.

The present invention is now illustrated but not limited by the following examples.

Example 1

A number of experiments were conducted to investigate the stability of combination drug formulations of vilanterol trifenatate and fluticasone furoate in either HFA-134a or HFA-152a.

Pharmaceutical formulations of vilanterol trifenatate and fluticasone furoate were prepared in either HFA-134a or HFA-152a (Mexichem, UK). Micronized vilanterol trifenatate and fluticasone furoate were weighed directly into standard uncoated 14 ml aluminium canisters. The canisters were then crimped with a 50 tL valve following which the propellant was filled into the canisters through the valve using a manual Pamasol crimper/filler (Pamasol, Switzerland). Finally, the canisters were sonicated for 20 minutes to aid dispersion of the drugs in the suspension. The nominal dose of vilanterol trifenatate was 22 pg and the nominal dose of fluticasone furoate was 185 pg.

The stability of the two drugs in the propellants was investigated immediately after preparation, i.e. at time zero (t=0), and after storage, valve down and valve up, for 5 days (t = 5 days), 10 days (t = 10 days), 15 days (t = 15 days) and 30 days (t = 30 days) at 50°C and 75% relative humidity (RH), and for 1 month (t = 1 month) and 3 months (t = 3 months) at 40 °C and 75% relative humidity (RH).

Reverse-phase high performance liquid chromatography (H PLC) was used to determined drug content following the stability studies (see below). The HPLC system was equipped with a binary pump, an autosampler, a column block heater, a multi-wavelength UV detector and a 100 mm x 3 mm Accucore Phenyl-X column with a 2.6 pm particle size.

The multi-wavelength UV detector was used to detect vilanterol trifenatate at a wavelength of 215 nm and fluticasone furoate at a wavelength of 230 nm.

The column was operated at 40°C and the autosampler was operated at ambient temperature with 100 pl samples being injected into the column for the analyses. The mobile phase comprised a mixture of 10 mM sodium phosphate solution at pH3 (mobile phase A) and acetonitrile (mobile phase B). The composition of the mobile phase was varied during the analyses as shown in Table 1 below.

Table 1

Time (minutes) % Mobile phase A % Mobile phase B 0 52.5 47.5 2 42.5 57.5 2.5 52.5 47.5 4.0 52.5 47.5 The flow rate through the column was 1000 ml/min and the total run time was 4 minutes.

The results of investigating the chemical stability of the vilanterol trifenatate and fluticasone furoate binary drug formulations in HFA-134a and HFA-152a in uncoated aluminium canisters are shown in Tables 2 to 5 below.

Table 2. Chemical stability of vilanterol trifenatate in HFA-134a in uncoated aluminium canisters based on percentage assay at time t = 0 and after storage for 5, 10, 15 and 30 days g 50°C/75 % RH; and after storage for 1 month and 3 months @ 40°C/75 % RH Time % Assay (LC) Initial time, t = 0 97.5 t = 5 days @ 50/75 96.5 t = 10 days @50/75 95.5 t = 15 days @50/75 96.7 t = 30 days @ 50/75 92.1 t = 1 month @ 40/75 89.5 t = 3 months @ 40/75 80.4 Table 3. Chemical stability of vilanterol trifenatate in HFA-152a in uncoated aluminium canisters based on percentage assay at time t = 0 and after storage for 5, 10, 15 and 30 days @ 50°C/75 % RH; and after storage for 1 month and 3 months © 40°C/75 % RH Time % Assay (LC) Initial time, t = 0 98.5 t = 5 days @50/75 98.6 t = 10 days @50/75 98.4 t = 15 days @ 50/75 97.6 t = 30 days @50/75 97.2 t = 1 month @ 40/75 95.8 t = 3 months @ 40/75 94.3 Table 4. Chemical stability of fluticasone furoate in HFA-134a in uncoated aluminium canisters based on percentage assay at time t = 0 and after storage for 5, 10, 15 and 30 days 10 § 50°C/75 % RH; and after storage for 1 month and 3 months 40°C/75 % RH Time % Assay (LC) Initial time, t = 0 99.8 t = 5 days @50/75 92.9 t= 10 days @ 50/75 88.9 t= 15 days @ 50/75 83.8 t= 30 days @ 50/75 73.8 t = 1 month @ 40/75 87.5 t = 3 months @ 40/75 68.9 Table 5. Chemical stability of fluticasone furoate in HFA-152a in uncoated aluminium canisters based on percentage assay at time t = 0 and after storage for 5, 10, 15 and 30 days g 50°C/75 % RH; and after storage for 1 month and 3 months g 40°C/75 % RH Time % Assay (LC) Initial time, t = 0 101.5 t = 5 days @ 50/75 98.5 t = 10 days @50175 96.8 t = 15 days @50175 93.2 t = 30 days @ 50/75 89.4 t = 1 month @ 40/75 95.5 t = 3 months @ 40/75 78.9 It can be seen from the data in Tables 2 to 5 above that the vilanterol trifenatate and the fluticasone furoate both exhibit superior chemical stability under both normal and accelerated test conditions when HFA-152a is used as the aerosolization propellant rather than HFA-134a.

Example 2

A number of experiments were conducted to investigate the in vitro aerosolization performance of combination drug formulations of vilanterol trifenatate and fluticasone furoate in metered dose inhalers (MDIs) using HFA-152a as the propellant.

The drug formulations were prepared as described in Example 1 above.

The in vitro aerosolization performance of the pharmaceutical formulations of vilanterol trifenatate and fluticasone furoate was studied immediately after preparation with a Next Generation Impactor (NGI, Copley Scientific, Nottingham UK). The Next Generation Impactor was connected to a vacuum pump (GE Motors, NJ, USA). Prior to testing, the cups of the NGI system were coated with 1 cro v/v silicone oil in hexane to eliminate particle bounce. For each experiment, three actuations of the valve were discharged into the NGI at 30 L.min-1 as per pharmacopeia guidelines. Following aerosolization, the NGI apparatus was dismantled and the actuator and each part of the NGI was washed down into known volumes of the HPLC mobile phase. The mass of drug deposited on each part of the NGI was determined by HPLC. This protocol was repeated three times for each canister, following which, the fine particle dose (FPD) and fine particle fraction of the emitted dose (FPFED) were determined.

The drug formulations were analysed using the HPLC technique described in Example 1 above.

The results of investigating the in vitro aerosolization performance of the combination drug formulations of vilanterol trifenatate and fluticasone furoate in HFA-152a are shown in Figure 1.

Claims

Claims: 1. A pharmaceutical composition comprising: (iii) a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof; and (iv) a propellant component comprising 1,1-difluoroethane (HFA-152a).
2. The pharmaceutical composition of claim 1, wherein the composition contains less than 500 ppm, preferably less than 100 ppm, more preferably less than 50 ppm, still more preferably less than 10 ppm and especially less than 5 ppm of water based on the total weight of the pharmaceutical composition and less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm and particularly less than 50 ppm of dissolved oxygen based on the total weight of the pharmaceutical composition.
3. The pharmaceutical composition of claim 1 or 2, wherein the at least one vilanterol compound is selected from vilanterol and vilanterol trifenatate.
4. The pharmaceutical composition of claim 3, wherein the at least one vilanterol compound is vilanterol trifenatate.
5. The pharmaceutical composition of any one of the preceding claims, wherein the drug component additionally comprises at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof.
6. The pharmaceutical composition of claim 5, wherein the at least one fluticasone compound is selected from fluticasone and fluticasone furoate.
7. The pharmaceutical composition of claim 6, wherein the at least one fluticasone compound is fluticasone furoate.
8. The pharmaceutical composition of any one of the preceding claims, wherein at least 90 weight %, preferably at least 95 weight % and more preferably at least 99 weight % of the propellant component is 1,1-difluoroethane (HFA-152a).
9. The pharmaceutical composition of claim 8, wherein the propellant component contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities.
10. The pharmaceutical composition of any one of the preceding claims, wherein at least 95 weight %, preferably at least 98 weight % and more preferably at least 99 weight % of the composition consists of the two components (i) and (h).
11. The pharmaceutical composition of any one of claims 1 to 9 which consists entirely of the two components (i) and (ii).
12. The pharmaceutical composition of any one of claims 1 to 10 further comprising a surfactant component comprising at least one surfactant compound, preferably at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid, ethyl oleate, sorbitan monooleate, sorbitan trioleate, isopropyl myristate and lecithin.
13. The pharmaceutical composition of any one of claims 1 to 10 and 12 further comprising a polar excipient, preferably ethanol.
14. The pharmaceutical composition of any one of claims 1 to 10 and 12 which is free of polar excipients.
15. The pharmaceutical composition of any one of the preceding claims which after storage in uncoated aluminium containers at 40°C and 75% relative humidity for 3 months will produce less than 4 % by weight, preferably less than 3 % by weight, even more preferably less than 2 % by weight of impurities from the degradation of the at least one vilanterol compound based on the total weight of the at least one vilanterol compound and the impurities.
16. The pharmaceutical composition of any one of the preceding claims, wherein at least 90 % by weight, preferably at least 92 c/ci by weight and more preferably at least 94 % by weight of the at least one vilanterol compound that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage in uncoated aluminium containers at 40°C and 75 % relative humidity for 3 months.
17. The pharmaceutical composition of any one of the preceding claims in the form of a suspension.
18. The pharmaceutical composition of any one of claims 1 to 16 in the form of a solution.
19. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is free of one or more of (i) perforated microstructures; (i) polymers having amide and/or carboxylic acid ester repeating structural units; (iii) acid stabilisers; and (iv) pharmaceutically acceptable salts of both cromoglycic acid and nedocromil.
20. The pharmaceutical composition of any one of the preceding claims, wherein the stated compounds of the drug component are the only pharmaceutically active ingredients in the pharmaceutical composition.
21. A metered dose inhaler (M DI) fitted with a sealed and pressurised aerosol container that contains a pharmaceutical composition as claimed in any one of claims 1 to 20.
22. A method of improving the stability of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA152a).
23. The method of claim 22, further comprising selecting the components and conditions for the preparation of the pharmaceutical composition to maintain the water content of the pharmaceutical composition below 500 ppm, preferably below 100 ppm, more preferably below 50 ppm, still more preferably below 10 ppm and particularly below 5 ppm based on the total weight of the pharmaceutical composition.
24. The method of claim 22, wherein the pharmaceutical composition is as claimed in any one of claims 1 to 20.
25. The method of any one of claims 22 to 24, wherein the pharmaceutical composition is stabilised compared to a pharmaceutical composition that uses 1,1,1,2-tetrafluoroethane (H FA-134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) as the propellant but which is otherwise identical.