Pressurised dispensing container and formulation contained therein

Abstract

Pressurised dispensing container (10) comprising a container for product to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem (15), a valve body (16) and one or more seals (20, 21), the valve stem being slidable within the valve body, the one or more seals co-operating with the valve stem for regulating discharge of a fluid; wherein the valve further comprises a sealing gasket (14) for sealing the valve to the dispensing container; wherein the one or more seals is / are formed from an elastomeric composition comprising an ethylene-propylene-diene terpolymer; wherein the sealing gasket is formed from an elastomeric composition comprising an isobutylene polymer or co-polymer thereof; and wherein the container contains a formulation comprising: a propellant comprising HFO-1234ze; salbutamol and / or a salt thereof; and from 1 to 2 wt.% of a monohydric alcohol, based on the total weight of the formulation.

Description

[0001] FORMULATION CONTAINED IN PRESSURISED DISPENSING CONTAINER

[0002] The present disclosure relates to a pressurised dispensing container, a pharmaceutical dispensing device and a method of treating bronchospasm and / or asthma, and in particular to a pharmaceutical metered dose aerosol inhaler device containing a formulation to be dispensed.

[0003] Pressurised dispensing containers, such as those used in pharmaceutical metered dose aerosol inhaler devices, are filled with the product, e.g. pharmaceutical composition, to be dispensed. There is a trend in the field to move towards lower global warming potential (GWP) propellants in the product, e.g. pharmaceutical composition, to be dispensed, such as HFC 152a and HFO 1234ze, and research into providing suitable compositions to be dispensed comprising such propellants is ongoing. An important factor for such a pressurised dispensing container filled with the product to be dispensed is achieving consistent delivered dose (DD) performance (i.e., dose of the particular active pharmaceutical ingredient (API) that is delivered) across the lifetime of the device.

[0004] Ethanol is typically present as an excipient in such formulations. It is known, in general, that the inclusion of higher concentrations of ethanol may improve the DD performance of the composition, such as increasing the delivered dose weight per actuation. For example, it has been described that ethanol concentrations of, for example, 5 wt.% may exhibit acceptable DD performance.

[0005] There is a desire to further develop such formulations to provide pressurised dispensing containers that can provide acceptably consistent DD performance, while not compromising on other performance characteristics.

[0006] The present disclosure seeks to tackle at least some of the problems associated with the prior art or at least to provide a commercially acceptable alternative solution thereto. The present disclosure provides at least a pressurised dispensing container, a pharmaceutical dispensing device, a method of treating bronchospasm and / or asthma and a method of using a nasal spray according to the claims appended hereto.

[0007] Specifically, the present disclosure provides a pressurised dispensing container comprising a container for product to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem, a valve body and one or more seals, the valve stem being slidable within the valve body, the one or more seals co-operating with the valve stem for regulating discharge of a fluid; wherein the valve further comprises a sealing gasket for sealing the valve to the dispensing container; wherein the one or more seals is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer; wherein the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or co-polymer thereof; and wherein the container contains a formulation comprising: a propellant comprising HFO-1234ze; salbutamol and / or a salt thereof; and from 1 to 2 wt.% of a monohydric alcohol, based on the total weight of the formulation.

[0008] The skilled reader will appreciate that one or more features of one aspect or embodiment of the present disclosure may be combined with one or more features of another aspect or embodiment of the present disclosure unless the immediate context teaches otherwise.

[0009] The inventors have surprisingly found that, when using a pressurised dispensing container comprising a valve as required herein, good consistency of DD of salbutamol can be achieved by use of the pressurised dispensing container, even when the product to be dispensed comprises relatively low monohydric alcohol (ethanol) concentrations, such as from 1 to 2 wt.%. The inventors have also surprisingly found that this can be achieved without compromising on aerodynamic particle size distribution (APSD) properties, for example. An acceptable balance of DD and APSD performance can be achieved, even when the product to be dispensed comprises relatively low monohydric alcohol (ethanol) concentrations, such as from 1 to 2 wt.%. However, if the monohydric alcohol (ethanol) concentration is too low, then the through inhaler life DD may be too inconsistent for commercialisation.

[0010] By contrast, the currently available teaching in the field of the present disclosure simply suggests, in general, that higher ethanol concentrations, such as 5 wt.% ethanol, for example, may be necessary for acceptable or improved DD performance, in particular when using HFO 1234ze as a propellant, for example.

[0011] Without wishing to be bound by theory, it is thought that higher ethanol concentrations in the product to be dispensed may help to achieve consistent DD performance by “washing” the API, such as salbutamol sulfate, off of the container’s internal surfaces (i.e. reducing deposition) and keeping it in suspension or bulk formulation. As such, particles of the API may therefore stay and uniformly disperse in the bulk formulation, enabling a consistent dose of the API to be delivered when delivering a consistent amount of formulation through the life of the pressurised dispensing container. By contrast, it is thought that the presence of moisture (water) can have the opposite effect, such as increasing the deposition of the API on the canister’s internal surfaces. However, when using a pressurised dispensing container comprising a valve as required herein, it has been found that good DD performance can be achieved, even when the product to be dispensed comprises relatively low monohydric alcohol (ethanol) concentrations, such as from 1 to 2 wt.%. Without wishing to be bound by theory, it is thought that the valve as required herein may reduce moisture ingress and increase seal integrity, meaning that less monohydric alcohol (ethanol) is required to provide the same effect as the higher monohydric alcohol (ethanol) content suggested in the prior art when using other valves, where higher moisture concentrations may be present in the product to be dispensed by ingress of moisture.

[0012] In other words, the combination of the formulation of the disclosure with the pressurised dispensing container mechanical arrangement described herein may enable a lower concentration of monohydric alcohol (ethanol) to be used while still exhibiting suitable “washing” properties. By contrast, it has previously been accepted that higher monohydric alcohol (ethanol) concentrations may typically be required to achieve acceptable DD performance, with any pressurised dispensing container mechanical arrangement.

[0013] Advantageously, the pressurised dispensing container described herein therefore enables such a low monohydric alcohol (ethanol) concentration formulation to be commercialised. This may be specific to the particular combination of propellant, API and pressurised dispensing container mechanical arrangement described herein. However, use of other propellants, such as 1 ,1 -difluoroethane (HFC 152a) is also contemplated herein.

[0014] In the present disclosure, the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or co-polymer thereof.

[0015] The sealing gasket may also be referred to as a static seal, in contrast to the one or more seals co-operating with the valve stem, which may be referred to as a dynamic seal or seals. In other words, in one embodiment, the sealing gasket is defined as being static, in that it seals between non-moving parts of the valve. Moreover, in one embodiment, the one or more seals is / are defined as being dynamic, in that it or they seal between moving parts of the valve.

[0016] In one embodiment, the one or more seals is / are mounted on the valve body. In one embodiment, the one or more seals is / are mounted on the valve stem. In one embodiment, a first seal is mounted on the valve body and a second seal is mounted on the valve stem.

[0017] In one embodiment, the valve is a continuous spray valve. In one embodiment, the valve further comprises a metering chamber, and the valve is a metering valve. In one embodiment, the metering chamber of the metering valve is permanent. In one embodiment, the metering chamber is constructed wholly from rigid components, such as components formed from one or more materials selected from polyester, nylon, acetal, or the like, stainless steel, ceramics, glass, or the like.

[0018] The purpose of the sealing gasket is to provide a seal between the valve and the dispensing container, thereby preventing the escape of the contents of the dispensing container, for example leakage of the propellant. Arguably as important, if not more so, the sealing gasket prevents the ingress of unwanted constituents, e.g. moisture, into the container, which can have a deleterious effect on the product, e.g. drug or pharmaceutical, to be dispensed. For example, the presence of excess moisture in propellant suspensions can lead to a reduction in fine particle mass through drug particle agglomeration, reducing the therapeutic effect of the API. Moisture can also result in hydrolysis of the API formulation.

[0019] The (ii) elastomeric composition comprises an isobutylene polymer or co-polymer thereof, for example one or more of polyisobutylene, polybutene, butyl rubber, halogenated butyl rubber, including derivatives thereof. In one embodiment, the elastomeric composition comprises butyl rubber or bromobutyl rubber. Butyl rubber is a copolymer made from isobutylene and a small amount of a diolefin such as, for example, isoprene (2-methylbuta-1 ,3-diene).

[0020] Typically, butyl rubber comprises approximately 97 wt.% (such as from 95 to 99 wt.%) isobutylene and approximately 3 wt.% (such as from 1 to 5 wt.%) isoprene, and it may be polymerized using an aluminium chloride catalyst.

[0021] Halogenated butyl rubbers such as bromobutyl rubber and chlorobutyl rubber may be made by treating isoprene-isobutylene rubber with bromine / chlorine. It will be understood that the term isobutylene polymer as used herein is intended to cover halogenated polymers.

[0022] The (ii) elastomeric composition may further comprise (a) a cross-linking agent for the isobutylene polymer or co-polymer thereof; and optionally (b) an accelerator for the cross-linking agent.

[0023] It will be appreciated that the (ii) elastomeric composition may comprise a blend of an isobutylene polymer or co-polymer thereof with another polymer, such as a chlorine-substituted diene polymer. For example, a blend of butyl rubber (e.g. bromobutyl rubber) and polychloroprene may be used. Blending of polychloroprene with the non-polar butyl is advantageous as it allows dissipation of static charge. Static charge builds up during the automated valve assembly process and or during storage in plastic bags can cause seals to self-adhere and pose problems in valve assembly.

[0024] If present, the crosslinking agent (also known as a curing agent) provides or facilitates network formation to result in a three-dimensional polymer network structure. The crosslinking agent may act by reacting with the functional groups on the polymer chain. The cross-linking agent will typically comprise sulfur or a sulfur-containing compound. The cross-linking agent may be substantially free of any peroxide curing agents such as, for example, dicumyl peroxide.

[0025] In one embodiment, the accelerator, if present, includes a polysulfide compound derived from a substituted dithiocarbonic acid or derivative thereof. The polysulfide compound may be derived from a substituted xanthic acid or derivative thereof, such as of the type ROC (S) SH, in which R is typically an alkyl radical. The substituted group in the polysulfide compound typically comprises an isopropyl group. In one embodiment, the polysulfide compound comprises three or more bridging sulfur atoms, such as 3,4 or 5 bridging sulfur atoms. In one embodiment, the polysulfide compound is substantially free from nitrogen, phosphorus and metallic elements. Advantageously, the polysulfide compound comprises or consists of diisopropyl xanthogen polysulfide.

[0026] The elastomeric composition (ii) typically comprises up to 3 wt.% of the accelerator based on the total weight of the accelerator and polymer in the composition, more typically up to 1 .5 wt.% of the accelerator based on the total weight of the accelerator and polymer in the composition, still more typically up to 1 wt.% of the accelerator based on the total weight of the accelerator and polymer.

[0027] In one embodiment, the weight ratio of the accelerator to the cross-linking agent in the elastomeric composition (ii) is in the range of from 1 :1 to 3:1 , such as from 1 :1 to 2:1.

[0028] It will be understood that the (ii) elastomeric composition may further contain one or more additives, process aids, crosslinking agents, accelerators, and / or fillers. It may also be blended with additional polymer(s) or copolymer(s).

[0029] The sealing gasket comprising the (ii) elastomeric composition may be produced by conventional forming techniques such as, for example, compression moulding and / or extrusion.

[0030] The initiation of the cross-linking reaction may be achieved by any of the known conventional techniques, for example heating the formulation to at least the curing reaction temperature, which is typically in the range of from 130 to 200°C. A typical process may involve forming rubber compound strips (typically of approximately 1 mm thickness) by compression moulding. The moulding temperature is typically in the range 160-180°C. The cure time is typically in the range 1 -10 minutes. The moulded strips may be post cured in an air oven for typically 1 hour at 150°C.

[0031] The strips may then be made into gaskets using a punching device. The use of the accelerator as herein described in the (ii) elastomeric composition according to the present disclosure can eliminate the need for free sulfur in the cross-linking process. The accelerator as herein described may be provided as a liquid and may be miscible with the polymer to provide a homogeneous dispersion. It has been found that the use of such an accelerator facilitates filler dispersion and can obviate the need for a separate plasticiser. The presence of plasticisers is undesirable in that they tend to leach out of the material. In contrast, the accelerator as herein described forms or is part of the cross-linked network and therefore does not leach out into the drug media. In the seal compositions according to the present disclosure the accelerator is typically almost totally consumed during the cross-linking reaction. This results in a cleaner rubber and the extractables are reduced. Typically, substantially no nitrosamines are generated during the cross-linking reaction.

[0032] Elastomeric compositions comprising an isobutylene polymer or co-polymer thereof are described in, for example, US20050241636A1 which is hereby incorporated by reference.

[0033] The one or more seals is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer.

[0034] Because the one or more seals co-operate with the valve stem, which is slidable within the valve body, such seals may also be referred to as dynamic seals. The mechanical properties of these seals are important to provide durability and consistent metering of product and propellant. Butyl rubbers may show inferior compression set properties compared to ethylene-propylene-diene terpolymer (EPDM), thus rendering them sub-optimal when used as a dynamic seal in pressurised dispensing containers of the type described herein. By contrast, the elastomeric composition (i), comprising ethylene-propylene-diene terpolymer, has very good mechanical properties and exhibits reduced compression set making it more effective as a dynamic seal. In one embodiment, an ethylene-propylene-diene terpolymer for use in the (i) elastomeric composition comprises from 40 to 70 wt.% ethylene, from 30 to 50 wt.% propylene, and ENB (ethylidenenorbornene) in an amount of 0.5 to 9 wt.%.

[0035] In one embodiment, the terpolymer comprises from 45 to 65 wt.% ethylene, from 35 to 45 wt.% propylene, and from 2 to 8 wt.% ENB. In one embodiment, the terpolymer comprises 50 to 60 wt.% ethylene, from 38 to 43 wt.% propylene, and from 3 to 7 wt.% ENB. In one embodiment, the terpolymer comprises approximately 50 wt.% ethylene, approximately 45 wt.% propylene, and approximately 5 wt.% ENB.

[0036] The ethylene content may be determined by ASTM D3900. The propylene content may be determined by ASTM D3900. The ENB content may be determined by ASTM D6047.

[0037] The terpolymer may be manufactured using a constrained geometry catalyst system. For example, a metallocene constrained geometry catalyst system, such as one based on titanium monocyclopentadienyl, optionally with a silane group incorporated therein.

[0038] In one embodiment, the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 90, such as from 20 to 80, from 30 to 70, or from 30 to 50. In one embodiment, the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of approximately 40. The Mooney Viscosity may be determined by ASTM D1646. The unit for Mooney Viscosity is Mooney units, MU.

[0039] In one embodiment, the (i) elastomeric composition comprises an ethylene- propylene-diene terpolymer, which terpolymer comprises from 45 to 65 wt.% ethylene, from 40 to 50 wt.% propylene, and ENB (ethylidenenorbornene) in an amount of 0.5 to 9 wt.%, wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 90. In one embodiment, the terpolymer has a density of from 0.84 to 0.90 g / cm3, such as from 0.85 to 0.87 g / cm3, or approximately 0.86 g / cm3. The density may be determined by ASTM D297.

[0040] In one embodiment, the terpolymer has an ash content of < 0.1 wt.%, and a total volatiles content of < 0.4 wt.%.

[0041] In one embodiment, the terpolymer has a medium molecular weight distribution.

[0042] It will be understood that the (i) elastomeric composition, e.g. an ethylene- propylene-diene terpolymer, may further contain one or more additives, process aids, crosslinking agents, accelerators, and / or fillers. It may also be blended with additional polymer(s) or copolymer(s).

[0043] The seal comprising the (i) elastomeric composition, e.g. an ethylene-propylene- diene terpolymer, may be produced by conventional forming techniques such as, for example, compression moulding and / or extrusion.

[0044] Elastomeric compositions comprising an ethylene-propylene-diene terpolymer are described in, for example, WO2017021698A1 which is hereby incorporated by reference.

[0045] The term “seal” as used herein is intended to encompass any sealing member or portion thereof present in, e.g., a pharmaceutical dispensing device, such as a metered dose inhaler, including, but not limited to, gaskets and seals whether static or dynamic. It will be appreciated that the seal may be provided as a separate component or may be formed integrally with the valve, i.e. be comoulded. The term sealing gasket as used herein is primarily used to refer to a static seal. The seal or gasket may further include a filler, such as a mineral and / or inorganic filler. Mineral fillers may be preferable to carbon black in order to minimise the formation of polynuclear aromatic hydrocarbon compounds. Suitable examples include any of magnesium silicate, aluminium silicate, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide, magnesium carbonate, magnesium aluminium silicate, aluminium hydroxide, talc, kaolin and clay, including combinations of two or more thereof. In one embodiment, the filler is or comprises one or more of magnesium silicate, talc, calcined clay, nano particle clays, kaolin and / or amino silane coated clay or clay coated with a titanium or zirconate coupling agent. The filler is typically present in the seal material in an amount of from 1 to 65 wt.%, such as from 2 to 60 wt.%, or from 5 to 55 wt.%.

[0046] In one embodiment, the one or more seals and / or the sealing gasket further comprise(s) a mineral and / or inorganic filler, such as in an amount of from 1 to 10 wt.%.

[0047] Where appropriate, the seal or gasket may further include a process aid, such as a low molecular weight polyethylene, stearic acid or an organic or non-organic stearate. The process aid, for example stearic acid, may be provided in the gasket seal in an amount of up to 1 wt.%.

[0048] Where appropriate, the seal or gasket may further include a curing or crosslinking agent. For example, the seal or gasket may further include a peroxide curing agent, sulfur or a sulfur-containing compound. A peroxide curing agent such as, for example, dialkyl peroxide is, however, preferable to other curing agents such as sulfur since its use minimises the formation of extractives (e.g. 2- mercaptobenzothiazole, N-nitrosamines, mercaptobenzothiazole disulfide) resulting from contact between the material and alcohol in use. The curing or cross-linking agent (for example a dialkyl peroxide) may be provided in the seal in an amount of up to 7 wt.%. The (i) elastomeric composition and / or the (ii) elastomeric composition may typically be cured, or cross-linked.

[0049] The seal or gasket may further comprise one or more of a reinforcement agent, a plasticizer, a binder, a stabilizer, a process aid, a retarder, a bonding agent, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonants, a primary accelerator, a secondary accelerator and / or a crosslink activator. One or more of these may be provided in the seal in an amount of up to 1 wt.%. For example, an antioxidant, such as, for example, octylated diphenylamine, may be included in an amount of up to 0.7 wt.%.

[0050] It will be appreciated that certain constituents may have more than one effect. For example, zinc oxide may act as an activator and as a filler. Similarly, magnesium oxide may act as an acid absorber and as a filler.

[0051] In most pharmaceutical applications it is also necessary to extract or wash the cured elastomer in order to remove surface residues and by-products resulting from the cure reaction and moulding process. The seal or gasket may therefore be subjected to a wash and / or an extraction to reduce or eliminate extractives and / or leachables. For example, a solvent-extraction and I a supercritical fluidextraction. An alcohol extraction is typical. An alcohol extraction (for example an ethanol extraction) of the seal or gasket may be performed after the seal or gasket has been manufactured and before the valve is assembled. This step reduces or eliminates extractives and / or leachables. In this process, the seal I gasket components are loaded into a glass column and washed by refluxing ethanol.

[0052] Where appropriate, the seal or gasket may also be co-moulded if desired with thermoplastics such as PBT, nylon and / or polyacetal. The container may be made, for example, from any suitable plastic or metal or glass material which is essentially gas and water impermeable. An example of a suitable plastic material is polyester.

[0053] As will be appreciated by the skilled reader, HFO 1234ze (an HFO being a hydrofluroolefin) is also known as 1 ,3,3,3-tetrafluoroprop-1 -ene. 1 , 3,3,3- tetrafluoroprop-1 -ene is typically present as the trans isomer HFO 1234ze(E). Typically, the propellants described herein, such as HFO-1234ze, are pharmaceutical grade propellants.

[0054] As will be appreciated by the skilled reader, the salbutamol and / or a salt thereof is an / the API of the formulation. The salbutamol may typically be present as a physiologically acceptable salt thereof, for example.

[0055] As will be appreciated by the skilled reader, conventional salbutamol may be provided as a racemic mixture of the R and S enantiomers. As will also be appreciated, salbutamol may also be known as albuterol. Conventional albuterol is a racemic mixture of (S)-albuterol and (F?)-albuterol (levalbuterol). Without wishing to be bound by theory, it is thought that levalbuterol may be the therapeutically active component of albuterol whereas (S)-albuterol is considered inert with some unwanted effects. However, it is common in the field to use albuterol.

[0056] The formulation may be provided in the form of a suspension. In other words, the salbutamol and / or a salt thereof, such as salbutamol sulfate, may typically be suspended in the propellant and monohydric alcohol.

[0057] In one embodiment, the salbutamol and / or a salt thereof is micronized. In other words, in one embodiment, the salbutamol and / or a salt thereof comprises, consists essentially of, or consists of, micronized salbutamol and / or a salt thereof. As will be appreciated, the term “consists essentially of” or “consisting essentially of” as used herein may encompass that further components other than those listed may be present, provided that they do not materially affect the essential characteristics of the formulation.

[0058] The container of the pressurised dispensing container contains a formulation as described herein. As will be appreciated, the formulation contained in the container may therefore be understood as the product to be dispensed.

[0059] The formulation may typically be (substantially) anhydrous, such as comprising less than 0.02 wt.% water, for example, based on the total weight of the formulation.

[0060] In one embodiment, the monohydric alcohol comprises a C1 -C3 monohydric alcohol, i.e. a monohydric alcohol comprising from one to three carbon atoms. In one embodiment, the monohydric alcohol comprises, consists essentially of, or consists of, ethanol.

[0061] In other words, in one embodiment, the present disclosure provides a pressurised dispensing container comprising a container for product to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem, a valve body and one or more seals, the valve stem being slidable within the valve body, the one or more seals co-operating with the valve stem for regulating discharge of a fluid; wherein the valve further comprises a sealing gasket for sealing the valve to the dispensing container; wherein the one or more seals is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer; wherein the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or co-polymer thereof; and wherein the container contains a formulation comprising, optionally consisting essentially of or consisting of: a propellant comprising HFO-1234ze; salbutamol and / or a salt thereof; and from 1 to 2 wt.% ethanol, based on the total weight of the formulation.

[0062] The formulation comprises from 1 to 2 wt.% (such as from 1 .0 to 2.0 wt.%) of a monohydric alcohol, based on the total weight of the formulation. In one embodiment, the formulation comprises from 1 .1 to 1 .9 wt.% of the monohydric alcohol, from 1 .2 to 1 .8 wt.% of the monohydric alcohol, from 1 .25 to 1 .75 wt.% of the monohydric alcohol, from 1 .3 to 1 .7 wt.% of the monohydric alcohol, or from 1 .4 to 1 .6 wt.% of the monohydric alcohol, based on the total weight of the formulation. In one embodiment, the formulation comprises from 1 .5 (such as 1 .50) to 1 .95 wt.% of the monohydric alcohol, such as from 1 .7 to 1 .9 wt.% of the monohydric alcohol, based on the total weight of the formulation. Such monohydric alcohol (ethanol) concentrations may exhibit a particularly good balance of properties as described herein.

[0063] In one embodiment, the formulation comprises from 0.05 to 0.5 wt.% (such as from 0.05 to 0.50 wt.%) of the salbutamol and / or a salt thereof, based on the total weight of the formulation. In one embodiment, the formulation comprises from 0.07 to 0.4 wt.% (such as from 0.07 to 0.40 wt.%) of the salbutamol and / or a salt thereof, from 0.09 to 0.3 wt.% (such as from 0.09 to 0.30 wt.%) of the salbutamol and / or a salt thereof, from 0.1 to 0.2 wt.% (such as from 0.10 to 0.20 wt.%) of the salbutamol and / or a salt thereof, from 0.12 to 0.18 wt.% of the salbutamol and / or a salt thereof, from 0.13 to 0.17 wt.% of the salbutamol and / or a salt thereof, or from 0.14 to 0.16 wt.% of the salbutamol and / or a salt thereof, based on the total weight of the formulation. Such concentrations of the salbutamol and / or a salt thereof may assist in providing a suitable DD.

[0064] In one embodiment, in the formulation, the weight ratio of the salbutamol and / or a salt thereof (salbutamol sulfate) relative to the monohydric alcohol (ethanol) is from 5 to 20 wt.% (i.e., in other words, the amount of salbutamol and / or a salt thereof (salbutamol sulfate) present in the formulation may be from 5 to 20 wt.% of the amount of monohydric alcohol (ethanol) present in the formulation). In one embodiment, in the formulation, the weight ratio of the salbutamol and / or a salt thereof (salbutamol sulfate) relative to the monohydric alcohol (ethanol) is from 7.5 to 15 wt.%, or from 8.5 to 10 wt.%.

[0065] In one embodiment, the salbutamol and / or a salt thereof comprises salbutamol sulfate.

[0066] In one embodiment, the formulation further comprises one or more further APIs. The term “API” as used herein is intended to encompass a wide variety of suitable pharmaceuticals, compounds, compositions, medicaments, agents or products which can be delivered or administered to a human being or animal, for example pharmaceuticals, drugs, biological and medicinal products. Examples include antiallergics, analgesics, bronchodilators, antihistamines, therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, antiinflammatory preparations, hormones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, an alkaloid, or a steroid, including combinations of two or more thereof. In particular, examples include isoproterenol [alpha- (isopropylaminomethyl) protocatechuyl alcohol], phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline, adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, hydrocortisone, hydrocortisone acetate and prednisolone, insulin, cromolyn sodium, and mometasone, including combinations of two or more thereof.

[0067] The salbutamol and / or a salt thereof and / or further API may be used as either the free base or as one or more salts conventional in the art, such as, for example, acetate, benzenesulfonate, benzoate, bircarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, (embonate), pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, and triethiodide, including combinations of two or more thereof. Cationic salts may also be used, for example the alkali metals, e.g. Na and K, and ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, for example glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1 - amino-2- propanol-amino-2-(hydroxymethyl)propane-1 ,3-diol, and 1 -(3,4- dihydroxyphenyl)-2 isopropylaminoethanol.

[0068] The API will typically be one which is suitable for inhalation and may be provided in a suitable form for this purpose, for example as a powder or as a solution or suspension in a solvent or carrier liquid, for example ethanol.

[0069] The further API may, for example, be one which is suitable for the treatment of asthma. Examples include beclomethasone, salmeterol, fluticasone, formoterol, terbutaline, sodium chromoglycate, budesonide and flunisolide, and physiologically acceptable salts (for example salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate, and terbutaline sulfate), solvates and esters, including combinations of two or more thereof. As will be appreciated, the further API may comprise of one or more active ingredients, an example of which is flutiform, and may optionally be provided together with a suitable carrier, for example a liquid carrier. One or more surfactants may be included if desired.

[0070] In one embodiment, the propellant comprises at least 50 wt.% HFO-1234ze, at least 60 wt.% HFO-1234ze, at least 70 wt.% HFO-1234ze, at least 80 wt.% HFO- 1234ze, at least 90 wt.% HFO-1234ze, or at least 95 wt.% HFO-1234ze, based on the total weight of the propellant. Typically, the propellant consists essentially of, or consists of, HFO-1234ze, in particular HFO 1234ze(E).

[0071] In other words, in one embodiment, the present disclosure provides a pressurised dispensing container comprising a container for product to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem, a valve body and one or more seals, the valve stem being slidable within the valve body, the one or more seals co-operating with the valve stem for regulating discharge of a fluid; wherein the valve further comprises a sealing gasket for sealing the valve to the dispensing container; wherein the one or more seals is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer; wherein the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or co-polymer thereof; and wherein the container contains a formulation comprising, optionally consisting essentially of or consisting of:

[0072] HFO-1234ze; salbutamol and / or a salt thereof; and from 1 to 2 wt.% of a monohydric alcohol, based on the total weight of the formulation.

[0073] Moreover, in one embodiment, the present disclosure provides a pressurised dispensing container comprising a container for product to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem, a valve body and one or more seals, the valve stem being slidable within the valve body, the one or more seals co-operating with the valve stem for regulating discharge of a fluid; wherein the valve further comprises a sealing gasket for sealing the valve to the dispensing container; wherein the one or more seals is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer; wherein the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or co-polymer thereof; and wherein the container contains a formulation comprising, optionally consisting essentially of or consisting of:

[0074] HFO-1234ze; salbutamol and / or a salt thereof, such as salbutamol sulfate; and from 1 to 2 wt.% ethanol, based on the total weight of the formulation.

[0075] In one embodiment, the formulation comprises at least 95 wt.% of the propellant, at least 97.5 wt.% of the propellant, at least 97.8 wt.% of the propellant, or at least 98 (such as 98.0) wt.% of the propellant, based on the total weight of the formulation. In one embodiment, the formulation comprises from 97.5 to 98.95 wt.% of the propellant, or from 97.85 to 98.85 wt.% of the propellant, based on the total weight of the formulation.

[0076] In other words, in one embodiment, provided is a pressurised dispensing container comprising a container for product to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem, a valve body and one or more seals, the valve stem being slidable within the valve body, the one or more seals co-operating with the valve stem for regulating discharge of a fluid; wherein the valve further comprises a sealing gasket for sealing the valve to the dispensing container; wherein the one or more seals is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer; wherein the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or co-polymer thereof; and wherein the container contains a formulation comprising, based on the total weight of the formulation: at least 95 wt.%, optionally from 97.5 to 98.95 wt.%, of a propellant a propellant comprising HFO-1234ze; from 0.05 to 0.5 wt.% salbutamol and / or a salt thereof; and from 1 to 2 wt.% of a monohydric alcohol.

[0077] Moreover, in one embodiment, provided is a pressurised dispensing container comprising a container for product to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem, a valve body and one or more seals, the valve stem being slidable within the valve body, the one or more seals co-operating with the valve stem for regulating discharge of a fluid; wherein the valve further comprises a sealing gasket for sealing the valve to the dispensing container; wherein the one or more seals is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer; wherein the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or co-polymer thereof; and wherein the container contains a formulation consisting essentially of or consisting of, based on the total weight of the formulation: at least 95 wt.%, optionally from 97.5 to 98.95 wt.%, of a propellant a propellant comprising HFO-1234ze; from 0.05 to 0.5 wt.% salbutamol and / or a salt thereof; and from 1 to 2 wt.% of a monohydric alcohol.

[0078] In one embodiment, the formulation comprises, consists essentially of, or consists of: from 0.05 to 0.5 wt.% of the salbutamol and / or a salt thereof, based on the total weight of the formulation; from 1 to 2 wt.% of a monohydric alcohol, such as ethanol, based on the total weight of the formulation; optionally, a surfactant; and the balance being the propellant, together with any unavoidable impurities. In one embodiment, the surfactant comprises one or more of oleic acid, polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, propoxylated polyethylene glycol and polyoxyethylene. In one embodiment, the surfactant comprises, or is, oleic acid.

[0079] In one embodiment, if present, the formulation comprises less than 2 wt.% of the surfactant, such as less than 1 wt.% of the surfactant or less than 0.5 wt.% of the surfactant, based on the total weight of the formulation. For example, if present, the formulation may comprise from 0.01 to 2 wt.% of the surfactant, such as from 0.05 wt.% to 1 wt.% of the surfactant or from 0.1 to 0.5 wt.% of the surfactant, based on the total weight of the formulation.

[0080] In one embodiment, at least a portion of, optionally all of, an internal surface of the container comprises a fluorocarbon polymer coating. Typically, such coatings may be hydrophobic. Without wishing to be bound by theory, it is thought that such coatings may also contribute to the reduced API (salbutamol and / or a salt thereof) deposition on the container walls and therefore improved DD consistency. Such a combination of features may therefore assist in providing the desirable balance of properties described herein.

[0081] The term “internal surface” as used herein may encompass an interior surface of the container that in use is contacted by the formulation contained within the pressurised dispensing container.

[0082] In one embodiment, the fluorocarbon polymer coating is a fluorinated ethylene propylene coating. Suitable coatings are known to the skilled reader. Such an embodiment may assist in providing the desirable balance of properties described herein. In one embodiment, the container contains from 15 to 25 g of the formulation, such as from 16 to 20 g, from 18 to 19 g, or from 18 to 18.5 g.

[0083] In one embodiment, the container contains a volume of from 10 to 30 mL, optionally from 15 to 25 mL, such as about 19 mL. A 19 mL canister may typically contain from 18 to 18.5 g of the formulation, for example.

[0084] In one embodiment, the pressurised dispensing container is pressurised to a pressure of from 300 kPa to 15 MPa, such as from 400 kPa to 5 MPa or from 500 kPa to 3.5 MPa.

[0085] The container may be made, for example, from a wide variety of suitable plastic or metal or glass materials which are effectively gas and water impermeable. An example of a suitable plastic material is polyester.

[0086] In one embodiment, the pressurised dispensing container is for use in the treatment of bronchospasm and / or asthma. In one embodiment, the formulation, i.e. the formulation contained in the container, is for use in the treatment of bronchospasm and / or asthma.

[0087] In a further aspect, the present disclosure provides a pharmaceutical dispensing device comprising the pressurised dispensing container described herein, optionally wherein the pharmaceutical dispensing device is a pharmaceutical metered dose aerosol inhaler device. Other examples of pharmaceutical dispensing devices include a syringe and an auto injector.

[0088] The pharmaceutical dispensing device may comprise an actuator. Suitable actuator designs are known to the skilled reader. The actuator may be configured, for example, for oral or nasal delivery. The actuator may comprise a sump configured to initially receive the formulation when discharged from the pressurised dispensing container. In one embodiment the sump has a volume of from 15 to 20 pl, from 16 to 19 pl, or 18 pl. The actuator may typically comprise a spray orifice through which the formulation may flow during use from the sump to a delivery piece, e.g. a mouthpiece or nasal piece, during dispensing of the formulation. Typically, the spray orifice may be substantially circular, such as having a substantially circular cross section at its narrowest point. In one embodiment, the spray orifice has a critical dimension (e.g., smallest diameter in the case of a circular spray orifice) of from 0.2 to 0.6 mm (such as from 0.20 to 0.60 mm), from 0.25 to 0.5 mm (such as from 0.25 to 0.50 mm), from 0.3 to 0.45 mm (such as from 0.30 to 0.45 mm), or from 0.3 to 0.4 mm (such as from 0.30 to 0.40 mm). In one embodiment a land length of the spray orifice is from 0.5 to 1 mm (such as from 0.50 to 1 .00 mm), from 0.5 to 0.8 mm (such as from 0.55 to 0.75 mm), from 0.6 to 0.7 mm (such as from 0.60 to 0.70 mm), or 0.65 mm. Advantageously, such spray orifice sizes when used in combination with the pressurised dispensing container disclosed herein may decrease the amount of deposition on the induction port and increase the deposition on next generation impactor (NG I) stages 4 to 6. Such a combination of features may therefore assist in providing the desirable balance of properties described herein, i.e. providing a good combination of consistent DD throughout inhaler life and good APSD NGI properties.

[0089] In one embodiment, the pharmaceutical dispensing device is configured to deliver a target dose of from 76.5 to 103.5 pg, such as 90 pg, of the salbutamol and / or a salt thereof per actuation. The term “target dose” as used herein may encompass a pre-determined mass of the salbutamol and / or a salt thereof of which each actuation aims to emit. The target dose may be calculated as a mean target dose, the mean being calculated over the life of the pharmaceutical dispensing device, such as for the first 200 actuations of the pharmaceutical dispensing device. In one embodiment, the pharmaceutical dispensing device is capable of delivering a dose of the salbutamol and / or a salt thereof within ±20% of the target dose, such as within ±15% of the target dose, for at least 90% (such as at least 95%, or even 100%) of the actuations of the pharmaceutical dispensing device throughout the life of the pharmaceutical dispensing device, such as for the first 200 actuations of the pharmaceutical dispensing device. In one embodiment, the pharmaceutical dispensing device may be capable of delivering comparable DD performance, such as having a mean delivered dose of the salbutamol and / or a salt thereof measured over 200 actuations of the pharmaceutical dispensing device within ±20% or ±15% of that of an identical pharmaceutical dispensing device except that the formulation comprises 5 wt.% ethanol and optionally wherein the pressurised dispensing container contains an alternative valve.

[0090] In a further aspect, the present disclosure provides a method of treating bronchospasm and / or asthma comprising using the pharmaceutical dispensing device described herein to administer to a subject an effective amount of the formulation, i.e. the formulation contained in the container. In one embodiment, the subject is a human.

[0091] In a further aspect provided is a method of using a nasal spray wherein the nasal spray comprises the pressurised dispensing container of the above aspect or the pharmaceutical dispensing device of the above aspect, the method comprising: administering a first dose of fluid in a first nostril and after a delay administering a second dose of fluid in a second nostril, wherein the delay is between 2 seconds and 24 hours or as advised by a healthcare professional.

[0092] The disclosure will now be described in relation to the following non-limiting drawings in which:

[0093] Figure 1 shows, by way of example only, a pressurised dispensing container.

[0094] Figure 2 shows results of the DD testing in Example 1 .

[0095] Figure 3a shows results of the through inhaler life shot weight testing of Example 2. Figure 3b shows results of the through inhaler life DD testing of Example 2.

[0096] Figure 4 shows results of the through inhaler life APSD NGI stage deposition testing of Example 2.

[0097] Figure 5 shows results of the spray orifice diameter testing of Example 2.

[0098] In particular, Figure 1 shows, by way of example only, a pressurised dispensing container 10. The pressurised dispensing container 10 is illustrated merely as one example of a possible application of the present disclosure. The skilled reader will understand that other applications of the present disclosure are possible and, as such, the following description of the pressurised dispensing container 10 should not be taken as limiting.

[0099] In the example embodiment of Figure 1 , the pressurised dispensing container 10 comprises a dispensing container 11 in which a product 12 is stored to be dispensed in metered doses. A valve is held in position to seal the dispensing container 11 by a ferrule 13 which is crimped to the open neck of the dispensing container 11 . The valve further comprises a sealing gasket 14 for sealing the valve to the dispensing container 11 . The sealing gasket 14 is a static seal.

[0100] In the example embodiment of Figure 1 , the valve comprises a valve stem 15, a valve body 16, 18 and one or more seals 20, 21 , the valve stem 15 being slidable within the valve body 16, 18, the one or more seals 20, 21 co-operating with the valve stem 15 for regulating discharge of a fluid.

[0101] In the example embodiment of Figure 1 , the one or more seals 20, 21 comprises an inner seal 20 and an outer seal 21 . Both the inner seal 20 and the outer seal 21 form a dynamic, sliding seal with the valve stem 15.

[0102] The present disclosure is suitable for use with a range of metering valves and the example of Figure 1 is just one possible design. The present disclosure is suitable for use with metering valves including, but not limited to, capillaryretention valves and fast-fill, fast-empty valves. Operation of such metering valves is described in more detail in publications US 6,095,182, GB 2401099, GB 2340477, EP 0803449 and EP 0801009 and the reader is directed to those publications for a fuller understanding of the operation of metering valves and metered dose inhalers in general.

[0103] The disclosure will now be described in relation to the following non-limiting examples.

[0104] Example 1

[0105] Each of the formulations disclosed in Table 1 were filled into three Presspart 19 mL fluorocarbon-polymer coated canisters sealed with a valve as described herein and fitted with a Bespak actuator having a 0.42 mm spray orifice diameter. The valve comprised a seal comprising EPDM and a sealing gasket comprising bromobutyl rubber.

[0106] Table 1

[0107] Each canister was tested for DD. Each canister was tested at the beginning, middle and end of inhaler life (BOL, i.e. shot no. 3 or 4, MOL, i.e. shot no. 99 or 100, and EOL, i.e. shot no. 199 or 200, respectively). United States Pharmacopeia (USP) equipment was used to the collect DD at 30 L / min, which were then analysed by high performance liquid chromatography (HPLC). The target delivered dose was 90 pL. The results of the DD testing are shown in Figure 2.

[0108] As can be seen, each canister, and in particular those containing Formulations 2, 3 and 4, are capable of providing good consistency of DD (such as within ±20% of the mean overall DD) across inhaler life.

[0109] Example 2

[0110] Materials and equipment used in this Example included micronised salbutamol sulfate (SS), HFO-1234ze (Honeywell, USA), 19 mL aluminium canisters (H&T Presspart, UK), 63pL valves as described herein and actuators with different spray orifice diameters (Bespak, UK), metered dose inhaler (MDI) unit dose sampling apparatus (DUSA) and NGI (Copley Scientific Ltd, UK), HPLC (Agilent Technologies, Inc., USA). The valves comprised a seal comprising EPDM and a sealing gasket comprising bromobutyl rubber.

[0111] Canisters were filled manually by weighing micronized SS and ethanol into canisters which were then sealed by crimping on valves. The sealed canisters were filled with HFO-1234ze through the valve. The filled canisters were sonicated for 15 minutes, followed by 24 hour shaking and then quarantined valve down for at least 14 days before testing. Actuators with different spray orifice diameters (0.30mm, 0.33mm, 0.42mm, 0.48mm) and a Ventolin actuator (spray orifice diameter: 0.51 mm) were used for testing. The composition of each Formulation is summarised in Table 2. Table 2

[0112] Through inhaler life (TIL) DD and APSD testing: Two actuations were collected at 30 L / min using USP equipment for both DD and APSD tests and the sample solutions were analysed using HPLC. For the TIL tests, 5 canisters from each Formulation were tested for DD over 10 days and 3 canisters were tested for APSD at day 1 , 5 and 9. Testing was also conducted for a commercial Ventolin inhaler as a comparative example.

[0113] Figures 3a and 3b present TIL individual shot weight (SW) and DD (mean from 5 canisters for each Formulation) over 10 days against the target of 90 pg salbutamol base per actuation. Total recovered doses from NG I tests at day 1 , 5 and 9 APSD were also included in the chart. Figure 4 shows a comparison of percentage stage deposition and fine particle fraction (< 5pm) from the NG I tests performed on day 1 (mean from 3 canisters from each Formulation).

[0114] It was found that increase of ethanol concentration from 0% to 2% did not affect TIL SW (Figure 3a) but improved the TIL DD consistency and the mean of the TIL doses became closer to the target value of 90pg per actuation (Figure 3b). The mean SW was 77.1 mg, 79.0 mg, 78.7 mg and 72.3 mg, respectively, while the overall mean DD was 60.2 pg, 65.9 pg, 77.2 pg and 88.0 pg for Formulation 5, 6, 7 and Ventolin, respectively. The standard deviation of the DD across the inhaler life was about 10 pg, 8.3 pg, 2.5 pg and 5.6 pg for Formulation 5, 6, 7 and Ventolin, respectively, showing that the TIL DD was most consistent for Formulation 7. For the Formulation 5 with 0% ethanol, an increase in the DD was measured towards end of inhaler life (EOL). Without wishing to be bound by theory, it is likely that more SS particles were deposited on the canister wall without ethanol in the formulation, which resulted in high SS concentration and high DD at EOL.

[0115] As can be seen in Figure 4, Formulations 5 and 6 without and with only 0.5 wt.% ethanol, respectively, matched Ventolin well on the APSD at BOL but gave inconsistent and low TIL DD (Figure 3b). As the ethanol concentration increased to 2 wt.%, the TIL DD improved but the APSD profile shifted towards larger size with a reduced FPF (Figure 4).

[0116] In addition, the effect of different spray orifice diameters (OD) was measured for the canisters filled with Formulation 7. The results are shown in Figure 5. In particular, Figure 5 presents the NG I stage deposition (mean from 2 measurements) at different actuator ODs. Each spray orifice had the same shape, except for its diameter.

[0117] It was found in this study that reducing the OD from 0.51 mm to 0.3 mm led to a noticeable reduction in the percentage deposition on the induction port and an increase in stages 4-6 deposition (Figure 5). Without wishing to be bound by theory, it is thought that reducing the OD may produce smaller aerosol droplets and increase the time for aerosols to exit the device and hence more propellant evaporation. This may also lead to a reduced droplet size of the aerosols reaching the induction port, hence less deposition. As a result, aerosols passing through the induction port may further break into primary particles.

[0118] In summary, it has been found that good consistency of DD of salbutamol can be achieved by use of the pressurised dispensing container having the valve described herein, even when the product to be dispensed comprises relatively low monohydric alcohol (ethanol) concentrations, such as from 1 to 2 wt.% (whereas it has previously been thought that, in general, higher ethanol concentrations may be required). Such a device can provide comparable performance to commercial Ventolin. However, if the monohydric alcohol (ethanol) concentration is too low, then the TIL DD may be too inconsistent for commercialisation. Surprisingly, while the performance may be acceptable for any actuator OD, further improvements to the combination of TIL DD and APSD NG I performance can be made by reducing the actuator OD.

[0119] Example 3

[0120] Four filled canisters were prepared. Two canisters were prepared according to a “canister A” batch and two canisters were prepared according to a “canister B” batch as follows, to provide two replications for each batch. Canister A comprised an uncoated can sealed with a valve comprising a seal comprising EPDM and a sealing gasket comprising EPDM. Canister B comprised an uncoated can sealed with a valve comprising a seal comprising EPDM and a sealing gasket comprising bromobutyl rubber. Each of canister A and canister B were filled with 18 g of a formulation of 0.148 wt.% albuterol sulfate, 2 wt.% ethanol and the balance HFO-1234ze.

[0121] Each of canister A and canister B were tested for DD in a similar manner to the testing in Example 1 and the results are shown in Table 3. The target DD was 90 pg. The top entry in each row corresponds to canister replication 1 and the bottom entry in each row corresponds to the canister replication 2 for each of canisters A and B.

[0122] Table 3

[0123] As can be seen from Table 3, canister B sealed with a valve comprising a seal comprising EPDM and a sealing gasket comprising bromobutyl rubber and containing a formulation comprising 2 wt.% ethanol demonstrated more consistent DD across and at each stage of inhaler life, as compared with canister A sealed with a valve comprising a seal comprising EPDM and a sealing gasket comprising EPDM and also containing a formulation comprising 2 wt.% ethanol.

[0124] In a separate test, TIL DD was measured for canisters C and D using a Bespak actuator. Three canisters were tested in a batch according to canister C and three canisters were tested in a batch according to canister D. Canister C comprised a fluorocarbon polymer coated can sealed with a valve comprising a seal comprising EPDM and a sealing gasket comprising EPDM. Canister D comprised a fluorocarbon polymer coated can sealed with a valve comprising a seal comprising bromobutyl rubber and a sealing gasket comprising bromobutyl rubber. Each of canister C and canister D were filled with 18 g of a formulation of 0.158 wt.% salbutamol sulfate, 2.0 wt.% ethanol and the balance HFO-1234ze.

[0125] Prior to testing, canisters were sonicated for 3 minutes and then shaken for 12 hours, and were stored valve-down for not less than 14 days at ambient conditions before use. The TIL DD results are shown in Table 4.

[0126] Table 4

[0127] As can be seen from Table 4, canister C sealed with a valve comprising a seal comprising EPDM and a sealing gasket comprising EPDM and containing a formulation comprising 2.0 wt.% ethanol demonstrated comparable or more consistent DD across and at each stage of inhaler life, as compared with canister D sealed with a valve comprising a seal comprising bromobutyl rubber and a sealing gasket comprising bromobutyl rubber and also containing a formulation comprising 2 wt.% ethanol. These results may be compared with the results shown for canisters A and B to predict the relative TIL DD consistency of a canister sealed with a valve comprising a seal comprising EPDM and a sealing gasket comprising bromobutyl rubber, a canister sealed with a valve comprising a seal comprising EPDM and a sealing gasket comprising EPDM and a canister sealed with a valve comprising a seal comprising bromobutyl rubber and a sealing gasket comprising bromobutyl rubber at ethanol concentrations of from 1 to 2 wt.%, such as 2 wt.%.

[0128] The foregoing detailed description has been provided by way of explanation and illustration, and is not intended to limit the scope of the appended claims. Numerous variations in the embodiments illustrated herein will be apparent to one of ordinary skill in the art and remain within the scope of the appended claims and their equivalents.

Claims

33Claims:1 . A pressurised dispensing container comprising a container for product to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem, a valve body and one or more seals, the valve stem being slidable within the valve body, the one or more seals co-operating with the valve stem for regulating discharge of a fluid; wherein the valve further comprises a sealing gasket for sealing the valve to the dispensing container; wherein the one or more seals is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer; wherein the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or co-polymer thereof; and wherein the container contains a formulation comprising: a propellant comprising HFO-1234ze; salbutamol and / or a salt thereof; and from 1 to 2 wt.% of a monohydric alcohol, based on the total weight of the formulation.

2. The pressurised dispensing container of claim 1 , wherein the monohydric alcohol comprises a C1 -C3 monohydric alcohol, optionally wherein the monohydric alcohol comprises ethanol.

3. The pressurised dispensing container of claim 1 or claim 2, wherein the formulation comprises from 1 .1 to 1 .9 wt.% of the monohydric alcohol, optionally from 1 .2 to 1 .8 wt.% of the monohydric alcohol, based on the total weight of the formulation.

4. The pressurised dispensing container of any preceding claim, wherein the formulation comprises from 0.05 to 0.5 wt.% of the salbutamol and / or a salt thereof, based on the total weight of the formulation.

345. The pressurised dispensing container of any preceding claim, wherein the salbutamol and / or a salt thereof comprises salbutamol sulfate.

6. The pressurised dispensing container of any preceding claim, wherein the formulation comprises at least 95 wt.% of the propellant, optionally at least 97.5 wt.% of the propellant, based on the total weight of the formulation.

7. The pressurised dispensing container of any preceding claim, wherein the formulation comprises: from 0.05 to 0.5 wt.% of the salbutamol and / or a salt thereof, based on the total weight of the formulation; from 1 to 2 wt.% of a monohydric alcohol, based on the total weight of the formulation; optionally, a surfactant; and the balance being the propellant, together with any unavoidable impurities.

8. The pressurised dispensing container of any preceding claim, wherein at least a portion of, optionally all of, an internal surface of the container comprises a fluorocarbon polymer coating.

9. The pressurised dispensing container of any preceding claim, wherein the (ii) elastomeric composition comprises one or more of polyisobutylene, polybutene, butyl rubber, halogenated butyl rubber, including derivatives thereof.

10. The pressurised dispensing container of claim 9, wherein the (ii) elastomeric composition comprises a bromobutyl rubber.11 . The pressurised dispensing container of any preceding claim, wherein the (i) elastomeric composition comprises an ethylene-propylene-diene terpolymer, which terpolymer comprises from 45 to 65 wt.% ethylene, from 40 to 50 wt.% propylene, and ENB (ethylidenenorbornene) in an amount of 0.5 to 9 wt.%,wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 90.

12. The pressurised dispensing container of any preceding claim, wherein the sealing gasket is defined as being static, in that it seals between non-moving parts of the valve; and / or wherein the one or more seals is / are defined as being dynamic, in that it or they seal between moving parts of the valve.

13. The pressurised dispensing container of any preceding claim, wherein the one or more seals is / are mounted on the valve body; and / or wherein the one or more seals is / are mounted on the valve stem, optionally wherein a first seal is mounted on the valve body and a second seal is mounted on the valve stem.

14. The pressurised dispensing container of any preceding claim, wherein the valve is a continuous spray valve.

15. The pressurised dispensing container of any preceding claim, wherein the valve further comprises a metering chamber, and the valve is a metering valve.

16. The pressurised dispensing container of claim 15, wherein the metering chamber of the metering valve is permanent.

17. The pressurised dispensing container of claim 15 or claim 16, wherein the metering chamber is constructed wholly from rigid components, such as components formed from one or more materials selected from polyester, nylon, acetal, or the like, stainless steel, ceramics, glass, or the like.

18. The pressurised dispensing container of any preceding claim, for use in the treatment of bronchospasm and / or asthma.

19. A pharmaceutical dispensing device comprising the pressurised dispensing container of any of claims 1 to 17, optionally wherein the pharmaceutical dispensing device is a pharmaceutical metered dose aerosol inhaler device.

20. The pharmaceutical dispensing device of claim 19, wherein the pharmaceutical dispensing device comprises an actuator comprising: a sump configured to initially receive the formulation when discharged from the pressurised dispensing container; and a spray orifice through which the formulation may flow during use from the sump to a delivery piece during dispensing of the formulation; wherein the spray orifice has a critical dimension of from 0.2 to 0.6 mm.21 . The pharmaceutical dispensing device of claim 20, wherein the spray orifice has a critical dimension of from 0.25 to 0.5 mm or from 0.3 to 0.45 mm.

22. A method of treating bronchospasm and / or asthma comprising using the pharmaceutical dispensing device of any of claims 19 to 21 to administer to a subject an effective amount of the formulation.

23. A method of using a nasal spray wherein the nasal spray comprises the pressurised dispensing container of any of claims 1 to 18 or the pharmaceutical dispensing device of any of claims 19 to 21 , the method comprising: administering a first dose of fluid in a first nostril and after a delay administering a second dose of fluid in a second nostril, wherein the delay is between 2 seconds and 24 hours or as advised by a healthcare professional.

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