Method of filling a pressurised dispensing container and filled pressurised dispensing container

Abstract

Method of filling a pressurised dispensing container (10) with a product to be dispensed; wherein the pressurised dispensing container comprises a container (11) for the product (12) to be dispensed, and a valve fixed to the container; wherein the valve comprises a valve stem (15), 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; the valve further comprises a sealing gasket for sealing the valve to the dispensing container; and each of the one or more seals and the sealing gasket (14) comprises a polymer material comprising bromobutyl rubber; wherein the product to be dispensed comprises a propellant comprising 1,1-difluoroethane or a derivative thereof and / or 1,3,3,3-tetrafluoroprop-1-ene or a derivative thereof; and wherein the method comprises filling the container with the product to be dispensed through the valve.

Description

[0001] METHOD OF FILLING A PRESSURISED DISPENSING CONTAINER AND FILLED PRESSURISED DISPENSING CONTAINER

[0002] The present disclosure relates to a method of filling a pressurised dispensing container with a product to be dispensed, a pressurised dispensing container filled using the method and the use of a specific valve to seal a pressurised dispensing container, and in particular the high filling accuracy achieved by the use of a particular valve.

[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. Accurately and consistently filling the pressurised dispensing containers allows the pressurised dispensing containers to contain predictable and controlled total doses of the product, in particular when produced on a large scale.

[0004] 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. However, these propellants may exhibit higher diffusion rates through known sealing materials. This may affect filling accuracies.

[0005] Accordingly, there is a desire to develop pressurised dispensing containers that can be filled with a product to be dispensed, in particular those which comprise such lower GWP propellants, consistently and with high accuracy, and also the associated methods of filing the pressurised dispensing containers. As such, there is also a desire to limit the amount of product that is wasted during the filling process.

[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 a method of filling a pressurised dispensing container with a product to be dispensed, a pressurised dispensing container filled using the method, the use of a specific valve to seal a pressurised dispensing container and a method of using a nasal spray according to the claims appended hereto.

[0007] Specifically, the present disclosure provides method of filling a pressurised dispensing container with a product to be dispensed; wherein the pressurised dispensing container comprises a container for the 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; the valve further comprises a sealing gasket for sealing the valve to the dispensing container; and each of the one or more seals and the sealing gasket comprises a polymer material comprising bromobutyl rubber; wherein the product to be dispensed comprises a propellant comprising 1 ,1 -difluoroethane or a derivative thereof and / or 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof; and wherein the method comprises: filling the container with the product to be dispensed through the valve.

[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 the use of an all-bromobutyl valve, i.e. one in which each of the one or more seals and the sealing gasket comprises a polymer material comprising bromobutyl rubber, may improve the filling accuracy of the pressurised dispensing container, in particular when lower GWP propellants are used, in comparison to other valves such as those comprising ethylene propylene diene monomer rubber (EPDM) seals and / or gaskets. In other words, less product may be lost or wasted during the filling process by achieving closer to the correct fill weight more repeatably, thereby providing a more consistent concentration. This is highly desirable in practice. In particular, with a move in the industry towards lower doses and smaller canisters, it is becoming harder to accurately fill canisters. This may particularly be the case for the lower GWP propellants, which may be lighter gases. A method of filling canisters having improved filling accuracy may therefore substantially reduce the number of rejects (i.e. those canisters filled with amounts outside an acceptable quality control range) when the canisters are filled on a large scale.

[0010] Typically, the propellants described herein, such as 1 ,1 -difluoroethane or a derivative thereof and / or 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof, are pharmaceutical grade propellants.

[0011] Bromobutyl rubber is typically derived from halogenating butyl rubber with bromine in a continuous process. The term “butyl rubber” as used herein may encompass an isobutylene polymer or co-polymer thereof, typically a copolymer of isobutylene and isoprene. The copolymer of isobutylene and isoprene may typically comprise from 95 to 99 wt.% isobutylene and from 1 to 5 wt.% isoprene, typically about 98 wt.% isobutylene and about 2 wt.% isoprene.

[0012] As will be appreciated by the skilled reader, 1 ,1 -difluoroethane is also known as HFC 152a and 1 ,3,3,3-tetrafluoroprop-1 -ene is also known as HFO 1234ze (an HFO being a hydrofluroolefin, which is a type of hydrofluorocarbon). 1 ,3,3,3- tetrafluoroprop-1 -ene is typically present as the trans isomer HFO 1234ze(E).

[0013] In one embodiment, filling the container with the product to be dispensed comprises: when the propellant comprises 1 ,1 -difluoroethane or a derivative thereof, filling the container with the product to be dispensed such that the container contains a mass of the product to be dispensed within 1 .25 wt.% of the target mass of the product to be dispensed; and / or when the propellant comprises 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof, filling the container with the product to be dispensed such that the container contains a mass of the product to be dispensed within 0.11 wt.% of the target mass of the product to be dispensed.

[0014] In further embodiments, when the propellant comprises 1 ,1 -difluoroethane or a derivative thereof, filling the container with the product to be dispensed comprises filling the container with the product to be dispensed such that the container contains a mass of the product to be dispensed within 1 .20 wt.%, within 1.17 wt.%, within 1.15 wt.%, within 1 .12 wt.%, within 1.10 wt.% or even within 1 .08 wt.%, of the target mass of the product to be dispensed.

[0015] In further embodiments, when the propellant comprises 1 ,3,3,3-tetrafluoroprop-1 - ene or a derivative thereof, filling the container with the product to be dispensed comprises filling the container with the product to be dispensed such that the container contains a mass of the product to be dispensed within 0.10 wt.%, within 0.09 wt.%, within 0.08 wt.%, within 0.07 wt.%, within 0.05 wt.% or even within 0.03 wt.%, of the target mass of the product to be dispensed.

[0016] Use of the valve described herein may enable such filling accuracies to be achieved.

[0017] In some embodiments, it is the mean mass of the product to be dispensed of a set of, for example, 30 containers that is within the specified wt.% of the target mass of the product to be dispensed. In other words, for example, in one embodiment, when the method is used to fill a set of 30 pressurised dispensing containers, filling the container with the product to be dispensed comprises, when the propellant comprises 1 ,1 -difluoroethane or a derivative thereof, filling the container with the product to be dispensed such that the mean mass of the product to be dispensed in the filled containers over the 30 containers is within 1 .25 wt.% of the target mass of the product to be dispensed.

[0018] The term “target mass” as used herein may encompass a pre-determined mass of the product to be dispensed with which the method aims to fill the container.

[0019] In one embodiment, when the method is used to fill a set of 30 pressurised dispensing containers: the standard deviation of the mass of the product contained in the container is less than 0.1 wt.% of the target mass of the product to be dispensed when the propellant comprises 1 ,1 -difluoroethane or a derivative thereof; and / or the standard deviation of the mass of the product contained in the container is less than 0.05 wt.% of the target mass of the product to be dispensed when the propellant comprises 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof.

[0020] In further embodiments, when the method is used to fill a set of 30 pressurised dispensing containers, the standard deviation of the mass of the product contained in the container is less than 0.09 wt.%, less than 0.08 wt.% or even less than 0.07 wt.%, of the target mass of the product to be dispensed when the propellant comprises 1 ,1 -difluoroethane or a derivative thereof.

[0021] In further embodiments, when the method is used to fill a set of 30 pressurised dispensing containers, the standard deviation of the mass of the product contained in the container is less than 0.04 wt.%, less than 0.03 wt.% or even less than 0.02 wt.%, of the target mass of the product to be dispensed when the propellant comprises 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof.

[0022] Use of the valve described herein may enable such filling precision to be achieved. In one embodiment, the polymer material consists of the bromobutyl rubber. Use of such a valve may further enhance the advantages described herein.

[0023] In one embodiment, in the pressurised dispensing container, the one or more seals of the valve consists of one seal. In an alternative embodiment, in the pressurised dispensing container, the one or more seals of the valve consists of two seals.

[0024] In one embodiment, the propellant consists of 1 ,1 -difluoroethane or a derivative thereof. In an alternative embodiment, the propellant consists of 1 ,3,3,3- tetrafluoroprop-1 -ene or a derivative thereof.

[0025] In one embodiment, the product to be dispensed comprises at least 80 wt.%, at least 85 wt.% or at least 90 wt.% of the propellant, based on the total weight of the product to be dispensed.

[0026] In one embodiment, at least one of the one or more seals and the sealing gasket further comprises a filler, optionally a mineral filler. In a further embodiment, each of the one or more seals and the sealing gasket further comprises a filler, optionally a mineral filler.

[0027] In a further embodiment, the mineral filler comprises one or more of magnesium silicate, aluminium silicate, silica, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide magnesium carbonate, magnesium aluminium silicate, aluminium hydroxide, talc, kaolin, clay and amino silane coated clay. Typically, the mineral filler comprises talc and / or clay.

[0028] In one embodiment, at least one of the one or more seals and the sealing gasket further comprises a process aid, optionally wherein the process aid comprises, or is, stearic acid. In a further embodiment, each of the one or more seals and the sealing gasket further comprises a process aid, optionally wherein the process aid comprises, or is, stearic acid. In one embodiment, at least one of the one or more seals and the sealing gasket further comprises one or more of a reinforcement agent, a plasticizer, a binder, a stabilizer, a retarder, a bonding agent, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonant, a secondary accelerator and an activator. In a further embodiment, each of the one or more seals and the sealing gasket further comprises one or more of a reinforcement agent, a plasticizer, a binder, a stabilizer, a retarder, a bonding agent, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonant, a secondary accelerator and an activator.

[0029] In one embodiment, in the pressurised dispensing container, each of the one or more seals and the sealing gasket consists of the polymer material and optionally a filler.

[0030] In one embodiment, the product to be dispensed further comprises ethanol.

[0031] In one embodiment, the product to be dispensed further comprises an active pharmaceutical ingredient (API).

[0032] 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, salbutamol, 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.

[0033] The API may be used as either the free base or as one or more salts conventional in the art, such as, for example, acetate, benzenesulphonate, 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, methylsulphate, mucate, napsylate, nitrate, pamoate, (embonate), pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, 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-l ,3-diol, and 1 -(3,4-dihydroxyphenyl)-2 isopropylaminoethanol.

[0034] 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.

[0035] The API may, for example, be one which is suitable for the treatment of asthma. Examples include salbutamol, beclomethasone, salmeterol, fluticasone, formoterol, terbutaline, sodium chromoglycate, budesonide and flunisolide, and physiologically acceptable salts (for example salbutamol sulphate, salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate, and terbutaline sulphate), solvates and esters, including combinations of two or more thereof. Individual isomers such as, for example, R-salbutamol, may also be used. As will be appreciated, the 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.

[0036] The term “seal” as used herein is intended to encompass a wide variety of suitable sealing members or portions 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 co-moulded. The term sealing gasket as used herein is primarily used to refer to a static seal.

[0037] In certain pharmaceutical applications it is also possible to extract or wash the cured elastomer in order to remove surface residues and by-products resulting from the cure reaction and moulding process. In one embodiment, the seal and / or gasket is therefore subjected to a wash and / or an extraction to reduce or eliminate extractives and / or leachables. For example, a solvent-extraction and / or a supercritical fluid-extraction. An alcohol extraction (for example an ethanol extraction) of the seal and / 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.

[0038] In one embodiment, in the pressurised dispensing container, the sealing gasket is defined as being static, in that it seals between non-moving parts of the valve.

[0039] In one embodiment, in the pressurised dispensing container, the one or more seals is / are defined as being dynamic, in that it or they seal between moving parts of the valve.

[0040] In one embodiment, in the pressurised dispensing container, the one or more seals is / are mounted on the valve body. In one embodiment, in the pressurised dispensing container, the one or more seals is / are mounted on the valve stem. In a further embodiment, in the pressurised dispensing container, a first seal is mounted on the valve body and a second seal is mounted on the valve stem.

[0041] In one embodiment, in the pressurised dispensing container, the valve is a continuous spray valve.

[0042] In one embodiment, in the pressurised dispensing container, the valve further comprises a metering chamber, and the valve is a metering valve. In a further embodiment, in the pressurised dispensing container, the metering chamber of the metering valve is permanent. In a further embodiment, in the pressurised dispensing container, 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.

[0043] In one embodiment, the pressurised dispensing container is a pharmaceutical dispensing device; and optionally, the pharmaceutical dispensing device is a pharmaceutical metered dose aerosol inhaler device.

[0044] In a further aspect provided is a pressurised dispensing container filled using the method of the above aspect.

[0045] In a further aspect provided is a pharmaceutical dispensing device comprising the pressurised dispensing container of the above aspect, optionally wherein the pharmaceutical dispensing device is a pharmaceutical metered dose aerosol inhaler device. In a further aspect provided is the use of a valve to seal a pressurised dispensing 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 cooperating with the valve stem for regulating discharge of a fluid; the valve further comprises a sealing gasket for sealing the valve to the dispensing container; and each of the one or more seals and the sealing gasket comprises a polymer material comprises bromobutyl rubber; wherein the use of the valve is for improving the filling accuracy of a method of filling the pressurised dispensing container with a product to be dispensed.

[0046] In one embodiment, the use of the valve is also for improving the filling precision of a method of filling the pressurised dispensing container with a product to be dispensed.

[0047] The improvements in filling accuracy and precision may be in comparison with conventional valves, such as those comprising EPDM-based seals and gaskets.

[0048] In one embodiment of this aspect, the method of filling the pressurised dispensing container with a product to be dispensed comprises the method of the first aspect described herein.

[0049] 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. The disclosure will now be described in relation to the following non-limiting drawings in which:

[0050] Figure 1 shows, by way of example only, a pressurised dispensing container.

[0051] Figure 2 shows the results of testing in Example 1 .

[0052] Figure 3 shows the results of testing in Example 1 .

[0053] Figure 4 shows the results of testing in Example 2.

[0054] Figure 5 shows the results of testing in Example 2.

[0055] Figure 6a shows the results of Monte Carlo simulations described in Example 3.

[0056] Figure 6b shows the results of Monte Carlo simulations described in Example 3.

[0057] Figure 6c shows the results of Monte Carlo simulations described in Example 3.

[0058] Figure 6d shows the results of Monte Carlo simulations described in Example 3.

[0059] 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.

[0060] In the example embodiment of Figure 1 , the pressurised dispensing container 10 comprises a dispensing container 1 1 in which a product 12 is stored to be dispensed in metered doses. A valve is held in position to seal the dispensing container 1 1 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] The present disclosure is directed to a pressurised dispensing container. Examples include a pharmaceutical metered dose aerosol inhaler device, a syringe, and an auto injector. An exemplary use of the seal and gaskets described herein is in a pressurised pharmaceutical metered dose aerosol inhaler device for dispensing a pharmaceutical.

[0065] 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. The disclosure will now be described in relation to the following non-limiting examples.

[0066] Example 1 - HFO 1234ze propellant

[0067] Canisters comprising a valve in which each seal and gasket comprises a polymer material consisting of EPDM were filled with HFO 1234ze(E). Canisters having the same properties except that each seal and gasket of the valve comprised a polymer material consisting of bromobutyl rubber (BUR) were also filled with HFO 1234ze(E).

[0068] The target fill weight of the HFO 1234ze(E) was 18,300 mg. 30 of each canister were filled in total and the results are shown in Table 1 and Figure 2.

[0069] Table 1

[0070] As can be seen in Table 1 , the mean fill weight for the BUR valve was surprisingly much more accurate than when the EPDM valves were used, within 0.02 wt.% of the target fill weight, for a comparable standard deviation.

[0071] For completeness, further canisters were filled in the same manner as above, except that the canister itself (i.e. the canister having the valve attached) was manufactured using a different method to test whether the results due to the differences in the valves were repeatable. The results are shown in Table 2 and Figure 3.

[0072] Table 2

[0073] As can be seen in Table 2, the mean fill weight for the BUR valve was still surprisingly much more accurate than when the EPDM valves were used, within 0.07 wt.% of the target fill weight. However, the standard deviation for the canister sealed with the EPDM valve was higher by a factor of almost three.

[0074] Example 2 - HFC 152a propellant

[0075] Canisters comprising a valve in which each seal and gasket comprises a polymer material consisting of EPDM were filled with HFC 152a. Canisters having the same properties except that each seal and gasket of the valve comprised a polymer material consisting of BUR were also filled with HFC 152a.

[0076] The target fill weight of the HFC 152a was 10,000 mg. 30 of each canister were filled in total and the results are shown in Table 3 and Figure 4. Table 3

[0077] As can be seen in Table 3, the mean fill weight for the BUR valve was still surprisingly much more accurate than when the EPDM valves were used, within 1.12 wt.% of the target fill weight. The standard deviation for the canister sealed with the BUR valve was also much lower.

[0078] For completeness, further canisters were filled in the same manner as above, except that the canister itself (i.e. the canister having the valve attached) was manufactured using a different method to test whether the results due to the differences in the valves were repeatable. The results are shown in Table 4 and Figure 5.

[0079] Table 4 As can be seen in Table 4, the mean fill weight for the BUR valve was still surprisingly much more accurate than when the EPDM valves were used, within 1 .05 wt.% of the target fill weight. The standard deviation for the canister sealed with the BUR valve was also much lower.

[0080] In Figures 2-5, the y-axis represents the measured fill weight in mg and the x-axis represents the canister sample number. The solid line represents the BUR valve and the dashed line represents the EPDM valve in each case.

[0081] Example 3 - simulations

[0082] Based on the testing data obtained, Monte Carlo simulations were performed to predict the accuracy performance of the method according to an aspect of the invention (using BUR valves) as compared to a method of filling a canister in which the each of the one or more seals and the sealing gasket comprises a polymer material comprising EPDM.

[0083] 1 ,000,000 canister fills were simulated for each combination of: HFO 1234ze(E) with a “BUR valve”, HFO 1234ze(E) with an “EPDM valve”, HFC 152a with a “BUR valve” and HFC 152a with an “EPDM valve”. The simulation results are shown in Figures 6a-6d, respectively. Figures 6a-d are histograms having an x- axis indicating the predicted fill weight as a percentage of the target fill weight and a y-axis indicating the frequency. The summary data are shown in Table 5, the upper value being the mean, the middle value being the standard deviation and the lower value being the percentage of the canisters predicted to be filled outside of the target fill weight range of ±1 .1%. Table 5

[0084] The simulations therefore predicted that, with a ±1 .1% fill weight target and a sample of 1 ,000,000 canisters, almost 10000 more rejects may be expected when filling canisters with HFO 1234ze(E) having an EPDM-based valve compared to using the method of an aspect of the invention, and 1600 more rejects may be expected when filling canisters with HFC 152a having an EPDM- based valve compared to using the method of an aspect of the invention. 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

Claims:1 . A method of filling a pressurised dispensing container with a product to be dispensed; wherein the pressurised dispensing container comprises a container for the 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; the valve further comprises a sealing gasket for sealing the valve to the dispensing container; and each of the one or more seals and the sealing gasket comprises a polymer material comprising bromobutyl rubber; wherein the product to be dispensed comprises a propellant comprising1 ,1 -difluoroethane or a derivative thereof and / or 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof; and wherein the method comprises: filling the container with the product to be dispensed through the valve.

2. The method of claim 1 , wherein filling the container with the product to be dispensed comprises: when the propellant comprises 1 ,1 -difluoroethane or a derivative thereof, filling the container with the product to be dispensed such that the container contains a mass of the product to be dispensed within 1 .25 wt.% of the target mass of the product to be dispensed; and / or when the propellant comprises 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof, filling the container with the product to be dispensed such that the container contains a mass of the product to be dispensed within 0.11 wt.% of the target mass of the product to be dispensed.

3. The method of claim 1 or claim 2, wherein when the method is used to fill a set of 30 pressurised dispensing containers: the standard deviation of the mass of the product contained in the container is less than 0.1 wt.% of the target mass of the product to be dispensed when the propellant comprises 1 ,1 -difluoroethane or a derivative thereof; and / or the standard deviation of the mass of the product contained in the container is less than 0.05 wt.% of the target mass of the product to be dispensed when the propellant comprises 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof.

4. The method of any preceding claim, wherein the polymer material consists of the bromobutyl rubber.

5. The method of any preceding claim, wherein in the pressurised dispensing container, the one or more seals of the valve consists of one seal.

6. The method of any of claims 1 to 4, wherein in the pressurised dispensing container, the one or more seals of the valve consists of two seals.

7. The method of any preceding claim, wherein the propellant consists of 1 ,1 - difluoroethane or a derivative thereof.

8. The method of any of claims 1 to 6, wherein the propellant consists of 1 ,3,3,3-tetrafluoroprop-1 -ene or a derivative thereof.

9. The method of any preceding claim, wherein at least one of the one or more seals and the sealing gasket further comprises a filler, optionally a mineral filler.

10. The method of claim 9, wherein the mineral filler comprises one or more of magnesium silicate, aluminium silicate, silica, titanium oxide, zinc oxide, calciumcarbonate, magnesium oxide magnesium carbonate, magnesium aluminium silicate, aluminium hydroxide, talc, kaolin, clay and amino silane coated clay.11 . The method of any preceding claim, wherein the product to be dispensed further comprises ethanol.

12. The method of any preceding claim, wherein in the pressurised dispensing container, the sealing gasket is defined as being static, in that it seals between non-moving parts of the valve.

13. The method of any preceding claim, wherein in the pressurised dispensing container, the one or more seals is / are defined as being dynamic, in that it or they seal between moving parts of the valve.

14. The method of any preceding claim, wherein in the pressurised dispensing container, the one or more seals is / are mounted on the valve body.

15. The method of any preceding claim, wherein in the pressurised dispensing container, the one or more seals is / are mounted on the valve stem.

16. The method of claim 15, wherein in the pressurised dispensing container, a first seal is mounted on the valve body and a second seal is mounted on the valve stem.

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

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

19. The method of claim 18, wherein in the pressurised dispensing container,the metering chamber of the metering valve is permanent.

20. The method of claim 18 or 19, wherein in the pressurised dispensing container, 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.21 . The method of any preceding claim, wherein the pressurised dispensing container is a pharmaceutical dispensing device; and optionally, wherein the pharmaceutical dispensing device is a pharmaceutical metered dose aerosol inhaler device.

22. A pressurised dispensing container filled using the method of any preceding claim.

23. A pharmaceutical dispensing device comprising the pressurised dispensing container of claim 22, optionally wherein the pharmaceutical dispensing device is a pharmaceutical metered dose aerosol inhaler device.

24. Use of a valve to seal a pressurised dispensing 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 cooperating with the valve stem for regulating discharge of a fluid; the valve further comprises a sealing gasket for sealing the valve to the dispensing container; and each of the one or more seals and the sealing gasket comprises a polymer material comprises bromobutyl rubber; wherein the use of the valve is for improving the filling accuracy of a method of filling the pressurised dispensing container with a product to be dispensed.

25. The use of claim 24, wherein the method of filling the pressurised dispensing container with a product to be dispensed comprises the method of any of claims 1 to 21 .

26. A method of using a nasal spray wherein the nasal spray comprises the pressurised dispensing container of claim 22 or the pharmaceutical dispensing device of claim 23, 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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