WO2022029403A1

WO2022029403A1 - Pharmaceutical composition

Info

Publication number: WO2022029403A1
Application number: PCT/GB2021/051749
Authority: WO
Inventors: Stuart Corr
Original assignee: Mexichem Uk Limited; Mexichem Fluor S.A. De C.V.
Priority date: 2020-08-03
Filing date: 2021-07-08
Publication date: 2022-02-10
Also published as: GB2597758A; GB202012057D0

Abstract

A pharmaceutical composition is described. The composition comprises: (i) a drug component comprising at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof, at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof and at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a).

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 mouthpiece. 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

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SUBSTITUTE SHEET (RULE 26) 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 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 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-1 14) in the MDI sector and is sometimes used alone or blended with HFA -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 HFA-134a has come under regulatory control as a result of the European Mobile Air Conditioning Directive (2006/40/EC). Industry has developed 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 (HFO-1234yf) and 1 ,3,3,3-tetrafluoropropene (HFO-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.

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SUBSTITUTE SHEET (RULE 26) Umechdimum and its salt umechdinium bromide are long acting muscarinic antagonists (LAMA) that are used in the treatment of chronic obstructive pulmonary disease (COPD). They are typically used as part of a combination therapy in which the drug component also includes a long acting beta-2 agonist (LABA).

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

We have found that a propellant comprising 1 ,1 -difluoroethane (HFA-152a) can be used to successfully deliver umeclidinium-based drug formulations using a MDI. These formulations can exhibit improved chemical stability, improved aerosolization 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 umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof, particularly umeclidinium bromide; 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

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SUBSTITUTE SHEET (RULE 26) 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:

(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.

(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 dissolved oxygen based on the total weight of the pharmaceutical composition.

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SUBSTITUTE SHEET (RULE 26) 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 umeclidinium 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 umeclidinium 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 umeclidinium compound dissolved in the propellant, e.g. with the assistance of a polar excipient, such as ethanol. In yet a further embodiment, the at least one umeclidinium compound is partially dispersed or suspended in the propellant and partially dissolved in the propellant, e.g. with the assistance of a polar excipient, such as ethanol. Preferably, the at least one umeclidinium compound is dispersed or suspended in the propellant.

The most preferred pharmaceutically acceptable salt of umeclidinium is umeclidinium bromide. Accordingly, in a preferred embodiment the pharmaceutical composition of the first aspect of the present invention includes at least one umeclidinium compound selected from umeclidinium and umeclidinium bromide. In a particularly preferred embodiment, the pharmaceutical composition of the first aspect of the present invention includes umeclidinium bromide.

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.

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SUBSTITUTE SHEET (RULE 26) The drug component may consist essentially of or consist entirely of the at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts 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 umeclidinium compound. When the drug component consists entirely of the at least one umeclidinium compound, the pharmaceutical composition does not contain any other active pharmaceutical ingredients, such as other long acting muscarinic antagonists (LAMA), corticosteroids, long acting beta-2-agonists (LABA) or short acting beta-2-agonists (SABA).

Alternatively, the drug component may contain other drugs, such as at least one long acting beta-2 agonist (LABA) and/or at least one corticosteroid.

The propellant component in the pharmaceutical composition of the first aspect of the present invention comprises 1 ,1 -difluoroethane (HFA-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 HFA-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 %, 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 % of the propellant component.

In a preferred embodiment, the propellant component has a global warming potential (GWP) 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

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SUBSTITUTE SHEET (RULE 26) 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 (ii) 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 preferred embodiment, the pharmaceutical composition of the present invention is free of polar excipients such as ethanol.

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SUBSTITUTE SHEET (RULE 26) 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 %, 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, it is preferably 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 % 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 a long acting beta-2- agonist (LABA) in addition to the at least one umeclidinium compound. Any of the long

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SUBSTITUTE SHEET (RULE 26) acting beta-2-agonists 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 beta-2-agonists include formoterol, arformoterol, bambuterol, clenbuterol, salmeterol, indacaterol, olodaterol and vilanterol as well as their pharmaceutically acceptable derivatives, such as their pharmaceutically acceptable salts and esters. Preferred long acting beta-2-agonists are vilanterol and the pharmaceutically acceptable salts and esters thereof, particularly vilanterol trifenatate.

Accordingly, in a second 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 umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof, particularly umeclidinium bromide, and at least one long acting beta-2-agonist (LABA); and

(ii) a propellant component comprising 1 ,1 -difluoroethane (HFA-152a).

In an especially preferred embodiment of the second 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 umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof, particularly umeclidinium bromide, and at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, especially vilanterol trifenatate; and

(ii) a propellant component comprising 1 ,1 -difluoroethane (HFA-152a).

The at least one long acting beta-2-agonist (LABA), such as vilanterol and/or vilanterol trifenatate, in the pharmaceutical composition of the invention in all aspects and embodiments disclosed herein is preferably in a micronized form.

In one embodiment, the pharmaceutical composition of the second 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

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SUBSTITUTE SHEET (RULE 26) compounds that may be used as part of the drug component. In a 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 another 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 a 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 umeclidinium 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 umeclidinium compound and the at least one long acting beta-2-agonist. 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 umeclidinium compound and the at least one long acting beta-2-agonist. When the drug component consists entirely of the at least one umeclidinium compound and the at least one long acting beta-2-agonist, the pharmaceutical composition does not contain any other active pharmaceutical ingredients.

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SUBSTITUTE SHEET (RULE 26) A preferred drug component comprises and preferably consists entirely of a combination of umeclidinium bromide and either vilanterol or vilanterol trifenatate, especially vilanterol trifenatate.

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 %, 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.

If a surfactant component is used, preferably it is free from fluorinated surfactant compounds.

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 a further 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 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, in addition to the at least one umeclidinium compound. Preferred compounds include fluticasone and fluticasone furoate, especially fluticasone furoate.

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SUBSTITUTE SHEET (RULE 26) Accordingly, a third 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 umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof, especially umeclidinium bromide, 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 invention in all aspects and embodiments disclosed herein is preferably in a micronized form.

In one embodiment, the pharmaceutical composition of the third 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 a preferred embodiment, the pharmaceutical composition of the third aspect of the present invention is water-free. Alternatively, the pharmaceutical composition of the third 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 another embodiment, the pharmaceutical composition 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 a 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

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SUBSTITUTE SHEET (RULE 26) because they tend to reduce the degradation of drug compounds resulting in a composition with higher chemical stability.

Suitable and preferred umeclidinium compounds in the pharmaceutical composition of the third 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 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 may consist essentially of or consist entirely of the at least one umeclidinium 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 umeclidinium compound and the at least one fluticasone compound. When the drug component consists entirely of the at least one umeclidinium compound and the at least one fluticasone compound, the pharmaceutical composition does not contain any other active pharmaceutical ingredients.

A preferred drug component comprises and preferably consists entirely of a combination of umeclidinium bromide and fluticasone furoate.

In one embodiment, the pharmaceutical composition of the third 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 %, 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 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.

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SUBSTITUTE SHEET (RULE 26) If a surfactant component is used, preferably it is free from fluorinated surfactant compounds.

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

In a further embodiment, the pharmaceutical composition of the third 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 composition of the invention may also include at least one long acting beta-2-agonist and at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof, such as fluticasone furoate and fluticasone propionate, in addition to the at least one umeclidinium compound.

Accordingly, a fourth 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 umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof, especially umeclidinium bromide, at least one long acting beta-2-agonist 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).

In one embodiment, the pharmaceutical composition of the fourth 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 a preferred embodiment, the pharmaceutical composition of the fourth aspect of the present invention is water-free. Alternatively, the pharmaceutical composition of the fourth 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

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SUBSTITUTE SHEET (RULE 26) 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 another embodiment, the pharmaceutical composition of the fourth 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 a preferred embodiment, the pharmaceutical composition is free of dissolved oxygen. Alternatively, the pharmaceutical composition of the fourth 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 umeclidinium compounds are as discussed above for the pharmaceutical composition of the first aspect of the present invention. Suitable and preferred long acting beta-2-agonists are as discussed above for the pharmaceutical composition of the second aspect of the present invention. Preferably, the long acting beta- 2-agonist is a vilanterol compound selected from vilanterol and/or the pharmaceutically acceptable salts and esters thereof, particularly vilanterol trifenatate. Suitable and preferred fluticasone compounds are as discussed above for the pharmaceutical composition of the third aspect of the present invention.

Typical and preferred amounts of the drug component and the propellant component in the pharmaceutical composition of the fourth 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 umeclidinium compound, the at least one long acting beta-2-agonist 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 umeclidinium compound, the at least one long acting beta-2-agonist and the at least one fluticasone compound. When the drug component consists entirely of the at least one umeclidinium compound, the at least one long acting beta-2-agonist and the at least one fluticasone compound, the pharmaceutical composition does not contain any other active pharmaceutical ingredients.

15

SUBSTITUTE SHEET (RULE 26) A preferred drug component comprises and preferably consists entirely of a combination of umeclidinium bromide, vilanterol or vilanterol trifenatate and fluticasone furoate.

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

In a further embodiment, the pharmaceutical composition of the fourth 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 invention may comprise one or more other additives of the type that are conventionally used 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 containing an umeclidinium compound, such as umeclidinium bromide, and the propellant can unexpectedly improve the chemical stability

16

SUBSTITUTE SHEET (RULE 26) of the umeclidinium compound compared to the stability it exhibits in formulations containing either HFA-134a or HFA-227ea as the propellant, but which are otherwise identical.

Accordingly, in a fifth 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 umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof, said method comprising using a propellant component comprising 1 , 1 -difluoroethane (HFA-152a).

The pharmaceutical composition in the stabilisation method of the fifth 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 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 a 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 fifth 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 umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts 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,

17

SUBSTITUTE SHEET (RULE 26) 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 fifth 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 a preferred embodiment, the pharmaceutical composition is free of dissolved oxygen. Alternatively, the pharmaceutical composition of the fifth 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 fifth aspect of the present invention suitable and preferred umeclidinium 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 fifth 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.

18

SUBSTITUTE SHEET (RULE 26) The drug component in the stabilisation method of the fifth aspect of the present invention may consist essentially of or consist entirely of the at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts 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 umeclidinium compound. When the drug component consists entirely of the at least one umeclidinium compound, the pharmaceutical composition does not contain any other active pharmaceutical ingredients.

Alternatively, the drug component may additionally comprise at least one long acting beta- 2-agonist, e.g. at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, and/or at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof as described above for the pharmaceutical compositions of the second and third aspects of the present invention, respectively.

The improved chemical stability may also be observed when the pharmaceutical composition, in addition to the at least one umeclidinium compound, also comprises at least one long acting beta-2-agonist, e.g. at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, and/or at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof.

Accordingly, in one embodiment of the fifth 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 umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof together with at least one long acting beta-2-agonist and/or at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof, said method comprising using a propellant component comprising 1 ,1- difluoroethane (HFA-152a). In this embodiment, the at least one long acting beta-2-agonist is preferably a vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof.

In one embodiment, the pharmaceutical composition in the fifth aspect of the present invention consists essentially of and more preferably consists entirely of the drug

19

SUBSTITUTE SHEET (RULE 26) component and the propellant component as defined 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 components.

In an alternative embodiment, the pharmaceutical composition in the fifth 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, (ii) 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 50°C and 75 % relative humidity for 30 days will produce less than 2 % by weight, preferably less than 1 .5 % by weight and more preferably less than 1 % by weight, of impurities from the degradation of the one or more drug compounds making up the drug component based on the total weight of the one or more drug compounds and the impurities. This performance can apply even if the drug component comprises at least one long acting beta-2-agonist, such as at least one vilanterol compound, and/or at least one fluticasone compound as specified herein in addition to the at least one umeclidinium compound.

In one preferred stabilisation method in which the pharmaceutical composition comprises at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof in addition to the at least one umeclidinium compound, the resulting pharmaceutical composition after storage at 50°C and 75 % relative humidity for 30 days will produce less than 2 % by weight, preferably less than 1 .5 % by weight and more preferably less than 1 % by weight, of impurities from the degradation of the at least one umeclidinium compound and the at least one vilanterol compound based on the total

20

SUBSTITUTE SHEET (RULE 26) weight of the at least one umeclidinium compound, the at least one vilanterol compound and the impurities.

In another preferred stabilisation method in which the pharmaceutical composition comprises at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof and at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof in addition to the at least one umeclidinium compound, the resulting pharmaceutical composition after storage at 50°C and 75 % relative humidity for 30 days will produce less than 2 % by weight, preferably less than 1.5 % by weight and more preferably less than 1 % by weight, of impurities from the degradation of the at least one umeclidinium compound, the at least one vilanterol compound and the at least one fluticasone compound based on the total weight of the at least one umeclidinium compound, the at least one vilanterol compound, the at least one fluticasone compound and the impurities.

In yet another preferred stabilisation method, at least 90 % by weight, preferably at least 93 % by weight, and more preferably at least 96 % by weight of the at least one umeclidinium compound that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage at 50°C and 75 % relative humidity for 30 days.

This performance can apply even if the drug component comprises at least one long acting beta-2-agonist, such as at least one vilanterol compound, and/or at least one fluticasone compound as specified herein in addition to the at least one umeclidinium compound.

In one preferred stabilisation method in which the drug component comprises at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof and at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium compound and the at least one vilanterol compound that are contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage at 50°C and 75 % relative humidity for 30 days.

In another preferred stabilisation method in which the drug component comprises at least one umeclidinium compound selected from umeclidinium and the pharmaceutically

21

SUBSTITUTE SHEET (RULE 26) acceptable salts thereof, at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof and at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium compound, the at least one vilanterol compound and the at least one fluticasone compound that are contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage at 50°C and 75 % relative humidity for 30 days.

One preferred pharmaceutical composition of the first, second, third and fourth aspects of the present invention will produce less than 2 % by weight, preferably less than 1 .5 % by weight and more preferably less than 1 % by weight of impurities from the degradation of the one or more drug compounds making up the drug component based on the total weight of the one or more drug compounds and the impurities after storage at 50°C and 75 % relative humidity for 30 days.

A preferred pharmaceutical composition of the second and fourth aspects of the present will produce less than 2 % by weight, preferably less than 1.5 % by weight and more preferably less than 1 % by weight, of impurities from the degradation of the at least one umeclidinium compound and the at least one vilanterol compound based on the total weight of the at least one umeclidinium compound, the at least one vilanterol compound and the impurities after storage at 50°C and 75 % relative humidity for 30 days.

Another preferred pharmaceutical composition of the fourth aspect of the present invention will produce less than 2 % by weight, preferably less than 1 .5 % by weight and more preferably less than 1 % by weight, of impurities from the degradation of the at least one umeclidinium compound, the at least one vilanterol compound and the at least one fluticasone compound based on the total weight of the at least one umeclidinium compound, the at least one vilanterol compound, the at least one fluticasone compound and the impurities after storage at 50°C and 75 % relative humidity for 30 days.

In a further preferred pharmaceutical composition of the first, second, third and fourth aspects of the present invention at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium compound that is contained originally in the pharmaceutical composition of the invention immediately following preparation will be present in the composition after storage at 50°C and 75 % relative humidity for 30 days.

22

SUBSTITUTE SHEET (RULE 26) In yet another preferred pharmaceutical composition of the second and fourth aspects of the present invention at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium compound and the at least one vilanterol compound that are contained originally in the pharmaceutical composition of the invention immediately following preparation will be present in the composition after storage at 50°C and 75 % relative humidity for 30 days.

In a further preferred pharmaceutical composition of the third and fourth aspects of the present invention at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium compound and the at least one fluticasone compound that are contained originally in the pharmaceutical composition of the invention immediately following preparation will be present in the composition after storage at 50°C and 75 % relative humidity for 30 days.

In a still further preferred pharmaceutical composition of the fourth aspect of the present invention at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium compound, the at least one vilanterol compound and the at least one fluticasone compound that are contained originally in the pharmaceutical composition of the invention immediately following preparation will be present in the composition after storage at 50°C and 75 % relative humidity for 30 days.

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.

Preferred umeclidinium compounds in the stabilisation method of the fifth aspect of the present invention are umeclidinium and umeclidinium bromide. Preferred vilanterol compounds in the stabilisation method of the fifth aspect of the present invention are vilanterol and vilanterol trifenatate. Preferred fluticasone compounds in the stabilisation method of the fifth aspect of the present invention are fluticasone and fluticasone furoate.

It has been found that the use of a propellant comprising 1 ,1 -difluoroethane (HFA-152a) in a pharmaceutical composition comprising an umeclidinium compound, such as

23

SUBSTITUTE SHEET (RULE 26) umechdinium bromide, and the propellant can unexpectedly improve the aerosohzation performance of the pharmaceutical composition when that composition is delivered from a metered dose inhaler compared to the performance that is observed for a composition that uses either HFA-134a or HFA-227ea as the propellant but which is otherwise identical.

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

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

The fine particle fraction is a widely recognised term in the art. It is a measure of the mass fraction of emitted aerosol particles having a diameter below 5 pm which is generally accepted as being the most desirable particle size range for effective alveolar drug delivery.

Increasing the fine particle fraction of the emitted dose is highly beneficial, because it is the fine drug particles that are able to penetrate into the deep bronchiole passages and the alveolar passages of the lung to maximise relief from the effects of an asthma attack or COPD.

In the method of the sixth aspect of the present invention suitable and preferred umeclidinium 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 method of the sixth 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 method of the sixth aspect of the present invention may consist essentially of or consist entirely of the at least one umeclidinium compound, such as umeclidinium bromide. 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

24

SUBSTITUTE SHEET (RULE 26) the drug component consists of the least one umeclidinium compound. When the drug component consists entirely of the at least one umeclidinium compound, the pharmaceutical composition does not contain any other active pharmaceutical ingredients.

Alternatively, the drug component may additionally comprise at least one long acting beta- 2-agonist and/or at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof as described above for the pharmaceutical compositions of the second and third aspects of the present invention, respectively. If the drug component additionally comprises at least one long acting beta-2- agonist, it is preferably selected from vilanterol and the pharmaceutically acceptable salts and esters thereof, especially vilanterol trifenatate.

It has also been observed that the use of a propellant comprising 1 ,1 -difluoroethane (HFA- 152a) can improve the aerosolization performance of a pharmaceutical composition which comprises at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof in addition to the at least one umeclidinium compound. The improved aerosolization performance results in higher fine particle fractions of the at least one umeclidinium compound and the at least one vilanterol compound in the emitted doses of the drugs compared to the fine particle fractions that are attainable when either HFA-134a or HFA-227ea are used as the propellant.

Accordingly, in one embodiment of the sixth aspect of the present invention there is provided a method of improving the aerosolization performance of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof and 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).

In one embodiment, the pharmaceutical composition in the sixth 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 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 components.

25

SUBSTITUTE SHEET (RULE 26) In an alternative embodiment, the pharmaceutical composition in the sixth 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.

Preferred umeclidinium compounds in the method of the sixth aspect of the present invention are umeclidinium and umeclidinium bromide. Preferred vilanterol compounds in the method of the sixth aspect of the present invention are vilanterol and vilanterol trifenatate. Preferred fluticasone compounds in the method of the sixth aspect of the present invention are fluticasone and fluticasone furoate.

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 umeclidinium compounds, and where included the long acting beta-2-agonists and fluticasone compounds, from a pressurised aerosol container using a metered dose inhaler (MDI). 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 seventh aspect of the present invention provides a pressurised container holding the pharmaceutical composition of the first, second, third or fourth aspect of the present invention. In an eighth 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, second, third or fourth 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

26

SUBSTITUTE SHEET (RULE 26) 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 umeclidinium 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 MDIs.

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 umeclidinium 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-152a- containing propellant component, in liquid form, introduced through the valve into the

27

SUBSTITUTE SHEET (RULE 26) 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 (GWP) of a pharmaceutical composition comprising a drug component comprising at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts 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 (GWP) 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:

(i) a drug component comprising at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof; and

(ii) a propellant component comprising 1 ,1 -difluoroethane (HFA-152a).

28

SUBSTITUTE SHEET (RULE 26) 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 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 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 umeclidinium compound is selected from umeclidinium and umeclidinium bromide and preferably is umeclidinium bromide.

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

8. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein the drug component additionally comprises at least one long acting beta-2-agonist selected from the group consisting of formoterol, arformoterol, bambuterol, clenbuterol, salmeterol, indacaterol, olodaterol, vilanterol and the pharmaceutically acceptable salts and esters thereof, preferably at least one long acting beta-2-agonist selected from vilanterol and the pharmaceutically acceptable salts and esters thereof.

9. The pharmaceutical composition of numbered paragraph 8, wherein at least one long acting beta-2-agonist is selected from vilanterol and vilanterol trifenatate.

10. The pharmaceutical composition of numbered paragraph 9, wherein the at least one long acting beta-2-agonist is vilanterol trifenatate.

29

SUBSTITUTE SHEET (RULE 26) 11. The pharmaceutical composition of any one of numbered paragraphs 8 to 10, wherein the at least one long acting beta-2-agonist is in a micronized form.

12. 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.

13. The pharmaceutical composition of numbered paragraph 12, wherein the at least one fluticasone compound is selected from fluticasone, fluticasone propionate and fluticasone furoate.

14. The pharmaceutical composition of numbered paragraph 13, wherein the at least one fluticasone compound is fluticasone furoate.

15. The pharmaceutical composition of any one of numbered paragraphs 12 to 14, wherein the at least one fluticasone compound is in a micronized form.

16. The pharmaceutical composition of any one of numbered paragraphs 1 to 7, wherein the drug component consists entirely of the at least one umeclidinium compound.

17. 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.

18. 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 %, 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.

19. The pharmaceutical composition of any one of the preceding numbered paragraphs, 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).

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

30

SUBSTITUTE SHEET (RULE 26) 21. The pharmaceutical composition of numbered paragraph 19 or 20, wherein the propellant component contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities.

22. The pharmaceutical composition of any one of the preceding numbered paragraphs, 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 (ii).

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

24. The pharmaceutical composition of numbered paragraph 23, wherein the surfactant component comprises at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin.

25. The pharmaceutical composition of numbered paragraph 23 or 24, wherein the surfactant component is free of fluorinated surfactant compounds.

26. The pharmaceutical composition of numbered paragraph 25, wherein the surfactant component is free of fluorinated surfactant compounds and free of surfactant compounds selected from Cg- fatty acids or salts, bile salts, phospholipids and alkyl saccharides.

27. The pharmaceutical composition of any one of the preceding numbered paragraphs further comprising a polar excipient.

28. The pharmaceutical composition of numbered paragraph 27, wherein the polar excipient is ethanol.

29. The pharmaceutical composition of any one of numbered paragraphs 1 to 26 which is free of polar excipients.

30. The pharmaceutical composition of any one of numbered paragraphs 1 to 26 which is free of ethanol.

31. The pharmaceutical composition of any one of numbered paragraphs 1 to 22 which consists entirely of the two components (i) and (ii).

31

SUBSTITUTE SHEET (RULE 26) 32. The pharmaceutical composition of any one of the preceding numbered paragraphs which after storage in uncoated aluminium containers at 50°C and 75 % relative humidity for 30 days will produce less than 2 % by weight, preferably less than 1 .5 % by weight and more preferably less than 1 % by weight of impurities from the degradation of the one or more drug compounds making up the drug component based on the total weight of the one or more drug compounds and the impurities.

33. The pharmaceutical composition of any one of the preceding numbered paragraphs, wherein at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium 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 50°C and 75 % relative humidity for 30 days.

34. The pharmaceutical composition of any one of numbered paragraphs 1 to 32, wherein at least 90 %, preferably at least 93 % and more preferably at least 96 % of the original pharmaceutical activity of the composition is retained after storage in uncoated aluminium containers at 50°C and 75 % relative humidity for 30 days.

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

36. The pharmaceutical composition of any one of numbered paragraphs 23 to 26 and any one of numbered paragraphs 27 to 30 and 32 to 34 when dependent on any one of numbered paragraphs 23 to 26, 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.

37. The pharmaceutical composition of any one of numbered paragraphs 1 to 34 in the form of a solution.

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

39. 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.

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SUBSTITUTE SHEET (RULE 26) 40. The pharmaceutical composition of any one of the preceding numbered paragraphs which is free of pharmaceutically acceptable salts of both cromoglycic acid and nedocromil.

41. 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.

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

43. A sealed container that contains a pharmaceutical composition as defined in any one of numbered paragraphs 1 to 42.

44. The sealed container of numbered paragraph 43 which is an uncoated aluminium can.

45. The sealed container of numbered paragraph 43 or 44 which is a pressurized aerosol container for use with a metered dose inhaler (MDI).

46. A metered dose inhaler (MDI) fitted with a sealed container as defined in numbered paragraph 45.

47. The metered dose inhaler of numbered paragraph 46 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.

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

49. The method of numbered paragraph 48, 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

33

SUBSTITUTE SHEET (RULE 26) 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.

50. The method of numbered paragraph 49, wherein the water 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.

51. The method of any one of numbered paragraphs 48 to 50, wherein the 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.

52. The method of numbered paragraph 51 , wherein the 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.

53. The method of any one of numbered paragraphs 48 to 52, wherein the at least one umeclidinium compound is selected from umeclidinium and umeclidinium bromide and preferably is umeclidinium bromide.

54. The method of any one of numbered paragraphs 48 to 53, wherein the at least one umeclidinium compound is in a micronized form.

55. The method of any one of numbered paragraphs 48 to 54, wherein the drug component additionally comprises at least one long acting beta-2-agonist selected from the group consisting of formoterol, arformoterol, bambuterol, clenbuterol, salmeterol, indacaterol, olodaterol, vilanterol and the pharmaceutically acceptable salts and esters thereof, preferably at least one long acting beta-2-agonist selected from vilanterol and the pharmaceutically acceptable salts and esters thereof.

56. The method of numbered paragraph 55, wherein the at least one long acting beta- 2-agonist is selected from vilanterol and vilanterol trifenatate.

57. The method of numbered paragraph 56, wherein the at least one long acting beta- 2-agonist is vilanterol trifenatate.

58. The method of any one of numbered paragraphs 55 to 57, wherein the at least one long acting beta-2-agonist is in a micronized form.

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SUBSTITUTE SHEET (RULE 26) 59. The method of any one of numbered paragraphs 48 to 58, wherein the drug component additionally comprises at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof.

60. The method of numbered paragraph 59, wherein the at least one fluticasone compound is selected from fluticasone, fluticasone propionate and fluticasone furoate.

61. The method of numbered paragraph 60, wherein the at least one fluticasone compound is fluticasone furoate.

62. The method of any one of numbered paragraphs 59 to 61 , wherein the at least one fluticasone compound is in a micronized form.

63. The method of any one of numbered paragraphs 48 to 54, wherein the drug component consists essentially of the at least one umeclidinium compound.

64. The method of any one of numbered paragraphs 48 to 63, 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.

65. The method of any one of numbered paragraphs 48 to 64, wherein the propellant component comprises from 80.0 to 99.99 weight %, 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.

66. The method of any one of numbered paragraphs 48 to 65, 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).

67. The method of any one of numbered paragraphs 48 to 65, wherein the propellant component is entirely 1 ,1 -difluoroethane (HFA-152a).

68. The method of numbered paragraph 66 or 67, wherein the propellant component contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities.

69. The method of any one of numbered paragraphs 48 to 68, 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 component.

35

SUBSTITUTE SHEET (RULE 26) 70. The method of any one of numbered paragraphs 48 to 69, wherein the pharmaceutical composition further comprises a surfactant component comprising at least one surfactant compound.

71. The method of numbered paragraph 70, wherein the surfactant component comprises at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin.

72. The method of any one of numbered paragraphs 48 to 71 , wherein the pharmaceutical composition further comprises a polar excipient.

73. The method of numbered paragraph 72, wherein the polar excipient is ethanol.

74. The method of any one of numbered paragraphs 48 to 71 , wherein the pharmaceutical composition is free of polar excipients.

75. The method of any one of numbered paragraphs 48 to 71 , wherein the pharmaceutical composition is free of ethanol.

76. The method of any one of numbered paragraphs 48 to 69, wherein the pharmaceutical composition consists entirely of the drug component and the propellant component.

77. The method of any one of numbered paragraphs 48 to 76, wherein the pharmaceutical composition after storage in uncoated aluminium containers at 50°C and 75 % relative humidity for 30 days will produce less than 2 % by weight, preferably less than 1 .5 % by weight and more preferably less than 1 % by weight of impurities from the degradation of the one or more drug compounds making up the drug component based on the total weight of the one or more drug compounds and the impurities.

78. The method of any one of numbered paragraphs 48 to 77, wherein at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium 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 50°C and 75 % relative humidity for 30 days.

79. The method of any one of numbered paragraphs 48 to 77, wherein at least 90 %, preferably at least 93 % and more preferably at least 96 % of the original pharmaceutical

36

SUBSTITUTE SHEET (RULE 26) activity of the composition is retained after storage in uncoated aluminium containers at 50°C and 75 % relative humidity for 30 days.

80. The method of any one of numbered paragraphs 48 to 79, wherein the pharmaceutical composition is in the form of a suspension.

81. The method of numbered paragraph 70 or 71 and any one of numbered paragraphs 72 to 75 and 77 to 80 when dependent on numbered paragraph 70 or 71 , 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.

82. The method of any one of numbered paragraphs 48 to 79, wherein the pharmaceutical composition is in the form of a solution.

83. The method of any one of numbered paragraphs 48 to 82, wherein the pharmaceutical composition is free of perforated microstructures.

84. The method of any one of numbered paragraphs 48 to 83, wherein the propellant component has a global warming potential (GWP) of less than 250, preferably less than 200 and more preferably less than 150.

85. The method of any one of numbered paragraphs 48 to 84, wherein the stated components of the drug component are the only pharmaceutically active ingredients in the pharmaceutical composition.

86. A method of improving the aerosolization performance of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable derivatives thereof, said method comprising using a propellant component comprising 1 ,1 -difluoroethane (HFA-152a).

87. The method of numbered paragraph 86, wherein the pharmaceutical composition is a composition as described in any one of numbered paragraphs 1 to 42.

88. The pharmaceutical composition of any one of numbered paragraphs 8 to 15 and any one of numbered paragraphs 16 to 42 when dependent on any one of numbered paragraphs 8 to 15 which is adapted to deliver the compounds making up the drug component in approximately the same proportions that they occur in the pharmaceutical composition.

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SUBSTITUTE SHEET (RULE 26) 89. 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 described in any one of numbered paragraphs 1 to 42 and 88.

90. The method of numbered paragraph 89, wherein the respiratory disorder is asthma or a chronic obstructive pulmonary disease.

91. The method of numbered paragraph 89 or 90, wherein the pharmaceutical composition is delivered to the patient using a metered dose inhaler (MDI).

92. The pharmaceutical composition of any one of numbered paragraphs 1 to 42 and 88 for use in the treatment of a respiratory disorder.

93. The pharmaceutical composition for use of numbered paragraph 92, wherein the respiratory disorder is asthma or a chronic obstructive pulmonary disease.

94. The pharmaceutical composition for use of numbered paragraph 92 or 93, wherein the pharmaceutical composition is delivered to the patient using a metered dose inhaler (MDI).

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 umeclidinium bromide and vilanterol trifenatate in either HFA-134a or HFA- 152a.

Pharmaceutical formulations of umeclidinium bromide and vilanterol trifenatate were prepared in either HFA-134a or HFA-152a (Mexichem, UK). Micronized umeclidinium bromide and vilanterol trifenatate were weighed directly into standard uncoated 14 ml aluminium canisters. The canisters were then crimped with a 50 pL 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 umeclidinium bromide was 65 pg and the nominal dose of vilanterol trifenatate was 22 pg.

38

SUBSTITUTE SHEET (RULE 26) The stability of the two drugs in the propellants was investigated immediately after preparation, i.e. at time t = 0, and after storage, valve down and valve up, for 5 days (t = 5 days), 15 days (t = 15 days) and 30 days (t = 30 days) at 50°C and 75 % relative humidity (RH).

Reverse-phase high performance liquid chromatography (HPLC) 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 the umeclidinium bromide and vilanterol trifenatate.

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

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 umeclidinium bromide and vilanterol trifenatate binary drug formulations in HFA-134a and HFA-152a in uncoated aluminium canisters are shown in Tables 2 and 3 below.

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SUBSTITUTE SHEET (RULE 26) Table 2. Chemical stability of umeclidinium bromide and vilanterol trifenatate in HFA-134a in uncoated aluminium cans based on percentage assay at time t = 0 and after storage for 5, 15 and 30 days @ 50°C/75 % RH.

Table 3. Chemical stability of umeclidinium bromide and vilanterol trifenatate in HFA-152a in uncoated aluminium cans based on percentage assay at time t = 0 and after storage for 5, 15 and 30 days @ 50°C/75 % RH.

It can be seen from the data in Tables 2 and 3 above that the umeclidinium bromide and vilanterol trifenatate 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 stability of combination drug formulations of umeclidinium bromide, vilanterol trifenatate and fluticasone furoate in either HFA-134a or HFA-152a.

40

SUBSTITUTE SHEET (RULE 26) Pharmaceutical formulations of umeclidinium bromide, vilanterol trifenatate and fluticasone furoate were prepared in either HFA-134a or HFA-152a (Mexichem, UK). Micronized umeclidinium bromide (0.175 w/w), vilanterol trifenatate (0.021 % w/w) and fluticasone furoate (0.021 % w/w) were weighed directly into standard uncoated 14 ml aluminium canisters. The canisters were then crimped with a 50 pL 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 stability of the three drugs in the propellants was investigated immediately after preparation, i.e. at time t - 0, and after storage, valve down and valve up, for 5 days (t = 5 days), 15 days (t = 15 days) and 30 days (t = 30 days) at 50°C and 75 % relative humidity (RH).

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

The results of investigating the chemical stability of the umeclidinium bromide, vilanterol trifenatate and fluticasone furoate combination drug formulations in HFA-134a and HFA- 152a in uncoated aluminium canisters are shown, respectively in Tables 4 and 5 below.

Table 4. Chemical stability of umeclidinium bromide, vilanterol trifenatate and fluticasone furoate in HFA-134a in uncoated aluminium cans based on percentage assay at time t = 0 and after storage for 5, 15 and 30 days @ 50°C/75 % RH.

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SUBSTITUTE SHEET (RULE 26) Table 5. Chemical stability of umeclidinium bromide, vilanterol trifenatate and fluticasone furoate in HFA-152a in uncoated aluminium cans based on percentage assay at time t = 0 and after storage for 5, 15 and 30 days @ 50°C/75 % RH.

It can be seen from the data in Tables 4 and 5 that the umeclidinium bromide, vilanterol trifenatate and fluticasone furoate all exhibit superior chemical stability under both normal and accelerated test conditions when HFA-152a is used as the propellant rather than HFA- 134a.

Example 3

A number of experiments were conducted to investigate the in vitro aerosolization performance of combination drug formulations of umeclidinium bromide and vilanterol trifenatate 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 umeclidinium bromide and vilanterol trifenatate was studied immediately after preparation, i.e. at time t = 0, with a Next Generation Impactor (NGI, Copley Scientific, Nottingham UK) using the method described below. The formulations were then stored under stress storage conditions (valve up and valve down) at 50°C and 75 % relative humidity for 5 days, 15 days and 30 days. After storing under the stress storage conditions, the in vitro aerosolization performance of the pharmaceutical formulations was tested again as before with a Next Generation Impactor using the method described below.

42

SUBSTITUTE SHEET (RULE 26) 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 % 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.mim¹ 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 high performance liquid chromatography (HPLC) technique described in Example 1 above was used to determined drug content following aerosolization studies (see below).

The results of investigating the in vitro aerosolization performance of the combination drug formulations of umeclidinium bromide (UMEC) and vilanterol trifenatate (VIL) in HFA-152a are shown in Table 6 below and in Figure 1.

Table 6

¹MMAD = mass median aerodynamic diameter

²ED = emitted does in pg

³FPD = fine particle dose in pg

⁴FPF = fine particle fraction of the total emitted dose (%)

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SUBSTITUTE SHEET (RULE 26)

Claims

CLAIMS:

1. A pharmaceutical composition comprising:

(i) a drug component comprising at least one umeclidinium compound selected from umeclidinium and the pharmaceutically acceptable salts thereof, at least one vilanterol compound selected from vilanterol and the pharmaceutically acceptable salts and esters thereof and at least one fluticasone compound selected from fluticasone and the pharmaceutically acceptable salts and esters thereof; and

(ii) 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 oxygen based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition of claim 1 or 2, wherein the at least one umeclidinium compound is selected from umeclidinium and umeclidinium bromide.

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

5. The pharmaceutical composition of any one of the preceding claims, wherein the at least one fluticasone compound is selected from fluticasone and fluticasone furoate.

6. 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).

7. The pharmaceutical composition of any one of the preceding claims, wherein the propellant component is entirely 1 ,1 -difluoroethane (HFA-152a).

8. The pharmaceutical composition of claim 6, wherein the propellant component contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities.

9. The pharmaceutical composition of any one of the preceding claims, wherein the composition further comprises a surfactant component comprising at least one surfactant

44

SUBSTITUTE SHEET (RULE 26) compound, preferably at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin.

10. The pharmaceutical composition of any one of the preceding claims, wherein the composition further comprises a polar excipient, preferably wherein the polar excipient is ethanol.

11. The pharmaceutical composition of any one of claims 1 to 9, wherein the composition is free from polar excipients.

12. The pharmaceutical composition of any one of the preceding claims, wherein the composition is in the form of a suspension or a solution.

13. The pharmaceutical composition of any one of the preceding claims, wherein the stated components of the drug component are the only pharmaceutically active ingredients in the pharmaceutical composition.

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

15. The method of claim 14, 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.

16. The method of claim 14 or 15, wherein the pharmaceutical composition after storage in uncoated aluminium containers at 50°C and 75 % relative humidity for 30 days will produce less than 2 % by weight, preferably less than 1 .5 % by weight and more preferably less than 1 % by weight of impurities from the degradation of the one or more drug compounds making up the drug component based on the total weight of the one or more drug compounds and the impurities.

45

SUBSTITUTE SHEET (RULE 26)

17. The method of any one of claims 14 to 16, wherein at least 90 % by weight, preferably at least 93 % by weight and more preferably at least 96 % by weight of the at least one umeclidinium 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 50°C and 75 % relative humidity for 30 days.

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

19. A sealed container that contains a pharmaceutical composition as claimed in any one of claims 1 to 13, preferably wherein the sealed container is a pressurized aerosol container for use with a metered dose inhaler (MDI).

20. A metered dose inhaler (MDI) fitted with a sealed container as claimed in claim 19, preferably wherein the metered dose inhaler comprises a nozzle and valve assembly attached to the sealed 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.

46

SUBSTITUTE SHEET (RULE 26)