Pressurized dispensing container

Abstract

PRESSURIZED DISPENSING CONTAINER. The present invention relates to a pressurized dispensing container (10) comprising a container (11) for product to be dispensed, and a valve attached to the container, wherein the container contains a propellant comprising 1,1-difluoroethane or a derivative thereof and optionally ethanol. The valve comprises a valve stem (15), a valve body (16, 18) and one or more seals (20, 21), the valve stem being sliding within a valve body, the one or more seals cooperating with the valve stem to regulate the discharge of a fluid. The valve further comprises a sealing gasket (14) for sealing the valve to the discharge container. The one or more seals (20, 21) is / are formed from (i) an elastomeric composition, preferably an elastomeric composition comprising an ethylene-propylene-diene terpolymer.The sealing gasket (14) is formed from (ii) an elastomeric composition comprising an isobutylene polymer or copolymer thereof.

Description

1 / 20 “PRESSURIZED DISPENSING CONTAINER”

[001] The present invention relates to a pressurized dispensing container and elastomeric sealing materials for use therein. The pressurized dispensing container can be used to dispense pressurized fluid in the form of an aerosol. The pressurized dispensing container finds application as a pharmaceutical dispensing device, such as a pressurized metered-dose inhaler (pMDI) and in medical verification devices suitable for dispensing a pharmaceutical product.

[002] It is known from GB 1201918, for example, to provide a dispensing apparatus in which fluid from a pressurized dispensing container is released by a valve in a controlled manner, the valve including elastomeric seals which are annular and which cooperate with a sliding valve stem to open and close the fluid ports. FR-A-2,549,568, WO 95 / 02651 and GB 2148912 and PCT / GB96 / 01551 each disclose further examples of such a dispensing apparatus.

[003] The required material properties needed for good sealing performance for pharmaceutical applications include: chemical compatibility (swelling), ten silo resistance, permanent compression fit, stress relaxation, elastic modulus, regulatory compliance, low fluid and gas permeability, low levels of extractables and leachables, and stable properties after extraction.

[004] In addition to the requirement for good engineering properties, there is a requirement for sanitary properties, including low levels of extractables and leachables, which can increase drug impurities to unacceptable levels, as well as potentially react with the drug, vehicle, or excipients. In this context, the products to be dispensed from a pMDI are commonly Petition 870220074443, dated 08 / 18 / 2022, page 8 / 32 2 / 20 dispensed in solution or suspension in a propellant base, this being particularly common in the dispensing of medicinal compounds for inhalation therapy. The metering valves used in dispensing devices, such as pMDIs, are typically constructed from a mixture of metal and / or thermoplastic parts and elastomeric rubber parts.

[005] Rubber compounds known for sealing pharmaceutical metered-dose aerosol inhalers include those based on the traditional vulcanization technology of a synthetic or natural rubber polymer.

[006] The products to be dispensed are commonly supplied in solution or suspension in an alcoholic or non-alcoholic base, this being particularly common in the dispensing of medicinal compounds for inhalation therapy.

[007] A typical apparatus includes a volatile hydrofluoroalkane (HFA) propellant, for example, conventional propellants such as HFA134a, and having a liquid phase in which the product together with the alcohol carrier is readily soluble within the container. A typical material for use in the valve seal is a synthetic rubber, such as chloroprene rubber.

[008] It is an object of the present invention to provide a pressurized dispensing container that can be used with 1,1-difluoroethane-based propellants. In addition, the pressurized dispensing container may also be suitable for use with other low global warming propellants or combinations thereof. Furthermore, the pressurized dispensing container may also be suitable for use with propellants such as 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227), for example, when one or more of HFA134a and HFA227 are used in combination with 1,1-difluoroethane.

[009] Accordingly, in a first aspect, the present invention provides a pressurized dispensing container comprising a container for product Petition 870220074443, dated 08 / 18 / 2022, page 9 / 32 3 / 20 to be dispensed, and a valve fixed to the container, wherein the container contains a propellant comprising 1,1-difluoroethane or a derivative thereof and optionally an alcohol such as ethanol, wherein the valve comprises a valve stem, a valve body and one or more seals, the valve stem being sliding within a valve body, the one or more seals cooperating with the valve stem to regulate the discharge of a fluid, wherein the valve further comprises a sealing gasket to seal the valve to the discharge container, wherein the one or more seals is / are formed from (i) an elastomeric composition, preferably an elastomeric composition comprising an ethylene-propylene-diene terpolymer, and the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or copolymer thereof.

[010] In the first aspect, the propellant preferably comprises or consists of HFA152a and optionally an alcohol such as ethanol. Compared to conventional chlorofluorocarbon propellants, HFA152a is reported to have a zero ozone depletion potential, a lower global warming potential and a shorter atmospheric lifetime.

[011] In the first aspect, the propellant may alternatively comprise or consist of a combination of HFA152a and HFA134a and optionally an alcohol such as ethanol. In the first aspect, the propellant may alternatively comprise or consist of a combination of HFA152a and HFA227ea and optionally an alcohol such as ethanol. Designs

[012] The following drawings are provided by way of example only to help understand certain aspects of the present invention: Petition 870220074443, dated 08 / 18 / 2022, p. 10 / 32 4 / 20 Figure 1 shows, as an example only, the pressurized dispensing container; Figure 2 shows moisture content data (ppm) which refers to the storage stability of a filled container where the sealing gasket comprises ethylene-propylene-diene terpolymer (EPDM); Figure 3 shows data demonstrating that a smaller amount of static leakage can be achieved with a hybrid valve configuration according to the present invention containing a bromobutyl gasket (typically, for example, an isobutylene polymer) compared with a similar valve configuration containing only EPDM as the primary atmospheric gasket seal; and Figure 4 shows data demonstrating that a smaller amount of moisture ingress can be achieved with a hybrid valve configuration according to the present invention containing a bromobutyl gasket (typically, for example, an isobutylene polymer) compared with a similar valve configuration containing only EPDM as the primary atmospheric gasket seal. Gasket seal (also known as a static seal)

[013] In the present invention, the sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or copolymer thereof.

[014] The sealing gasket may also be referred to as the static seal, in contrast to the one or more seals cooperating with the valve stem, which may be referred to as a dynamic seal or seals.

[015] The purpose of the sealing gasket is to provide a seal between the valve and the dispensing container, thus preventing leakage of the contents of the dispensing container, for example, leakage from the propellant. Undeniably so Petition 870220074443, dated 08 / 18 / 2022, p. 11 / 32 5 / 20 Importantly, if not more so, the sealing gasket prevents the entry 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 the mass of fine particles through the agglomeration of drug particles, reducing the therapeutic effect of the active pharmaceutical ingredient (API). Moisture can also result in the oxidation of the API formulation.

[016] The inventors discovered that (ii) an elastomeric composition comprising an isobutylene polymer or copolymer thereof provides a particularly effective seal when the propellant is or comprises 1,1-difluoroethane (e.g., HFA152a) or a derivative thereof. While not wishing to be limited by theory, HFA152a has a higher dipole moment than conventional propellants such as HFA134a and may therefore be more hygroscopic, leading to greater moisture ingress into the container. Surprisingly, the inventors found that conventional EPDM polymers did not perform well in moisture ingress tests for 1,1-difluoroethane-based propellants. The propellant is often provided in conjunction with an alcohol, such as ethanol. The inventors further found that moisture ingress into the container was exacerbated when alcohol was present.The elastomeric composition (ii) described here surprisingly provides an effective moisture barrier when the propellant includes an alcohol such as ethanol.

[017] The sealing gasket according to the present invention may also be compatible with the propellants described herein in terms of helium gas permeability, low dipole moment, low change in permeability and creep behavior with temperature, resistance to dissolution in the propellant and low water absorption. Petition 870220074443, dated 08 / 18 / 2022, page 12 / 32 6 / 20 (ii) an elastomeric composition comprising an isobutylene polymer or copolymer thereof

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

[019] Typically, butyl rubber comprises approximately 97% isobutylene and approximately 3% isoprene, and it can be polymerized using an aluminum chloride catalyst.

[020] Halogenated butyl rubbers such as bromobutyl rubber and chlorobutyl rubber can be produced by treating isoprene-isobutylene rubber with bromine / chlorine. It will be understood that the term isobutylene polymer as used in this document is intended to cover halogenated polymers.

[021] The (ii) elastomeric composition may further comprise (a) a crosslinking agent for the isobutylene polymer or copolymer thereof; and optionally (b) an accelerator for the crosslinking agent.

[022] It will be noted that (ii) the elastomeric composition may comprise a mixture of an isobutylene polymer or copolymer thereof with another polymer, such as a chlorine-substituted diene polymer. For example, a mixture of butyl rubber (e.g., bromobutyl rubber) and polychloroprene may be used. The mixture of polychloroprene with non-polar butyl is advantageous as it allows for the dissipation of static charge. Static charge accumulated during the automated valve assembly process and / or during storage in plastic bags may cause self-adhesion of the seals and cause problems in Petition 870220074443, dated 08 / 18 / 2022, page 13 / 32 7 / 20 valve assembly.

[023] 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 functional groups in the polymer chain. The crosslinking agent will typically comprise sulfur or a sulfur-containing compound. The crosslinking agent is preferably substantially free of any peroxide curing agents such as, for example, dicumyl peroxide.

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

[025] The elastomeric composition (ii) typically comprises up to 3% by weight of the accelerator based on the total weight of the accelerator and polymer in the composition, more typically up to 1.5% by weight of the accelerator based on the total weight of the accelerator and polymer in the composition, even more typically up to 1% by weight of the accelerator based on the total weight of the accelerator and polymer.

[026] The weight ratio of the accelerator to the crosslinking agent in the elastomeric composition (ii) is preferably in the range of 1:1 to 3:1, more preferably 1:1 to 2:1. Petition 870220074443, dated 08 / 18 / 2022, page 14 / 32 8 / 20

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

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

[029] The initiation of the crosslinking reaction can be achieved by any of the known conventional techniques, for example, by heating the formulation to at least the curing reaction temperature, which is typically in the range of 130 to 200°C. A preferred process involves forming strips of rubber compound (typically approximately 1 mm thick) by compression molding. The molding temperature is typically in the range of 160-180°C.

[030] The curing time is typically in the range of 1 to 10 minutes. The molded strips are preferably post-cured in an air oven for typically 1 hour at 150°C.

[031] The strips can then be made into gaskets using a punching device.

[032] The use of the accelerator as described herein in the (ii) elastomeric composition according to the present invention can eliminate the need for free sulfur in the crosslinking process. The accelerator as described herein is preferably provided as a liquid and is preferably miscible with the polymer to provide a homogeneous dispersion. It has been found that the use of such an accelerator facilitates the dispersion of the filler and can avoid the need for a separate plasticizer. The presence of plasticizers is undesirable insofar as they tend to leach out of the material. In contrast, the accelerator as described herein forms or is part of the crosslinked network and, Petition 870220074443, dated 08 / 18 / 2022, page 15 / 32 9 / 20 therefore, it does not infiltrate the drug medium. In the sealing compositions according to the present invention, the accelerator is typically almost entirely consumed during the crosslinking reaction. This results in a cleaner rubber and reduced extractables. Typically, substantially no nitrosamines are generated during the crosslinking reaction.

[033] Elastomeric compositions comprising an isobutylene polymer or copolymer thereof are described, for example, in WO 03 / 078538 A1. One or more seals (also known as dynamic seals or seals)

[034] One or more seals is / are formed from (i) an elastomeric composition, preferably an elastomeric composition comprising an ethylene-propylene-diene terpolymer.

[035] As one or more seals cooperate with the valve stem, which is sliding within the valve body, these seals may also be called dynamic seals. The mechanical properties of these seals are important for providing durability and consistent product and propellant dosing. Butyl rubbers may exhibit inferior compression set properties compared to ethylene-propylene-diene terpolymer (EPDM), making them suboptimal when used as dynamic seals in pressurized dispensing vessels of the type described in this document. In contrast, the elastomeric composition (i), comprising ethylene-propylene-diene terpolymer, has very good mechanical properties and exhibits a reduced compression set, making it more effective as a dynamic seal.Furthermore, the inventors discovered that an elastomeric composition comprising an isobutylene polymer or copolymer thereof provides an effective leak- and moisture-proof seal (i.e., a static seal) when in use. Petition 870220074443, dated 08 / 18 / 2022, page 16 / 32 10 / 20 a propellant comprising or consisting of 1,1-difluoroethane (e.g., HFA152a).

[036] A preferred ethylene-propylene-diene terpolymer for use in (i) elastomeric composition comprises 40 to 70% by weight of ethylene, 30 to 50% by weight of propylene and ENB (ethylidenonorbornene) in an amount of 0.5 to 9% by weight

[037] More preferably, the terpolymer preferably comprises 45 to 65% by weight of ethylene, 35 to 45% by weight of propylene and 2 to 8% by weight of ENB. More preferably, the terpolymer comprises 50 to 60% by weight of ethylene, 38 to 43% by weight of propylene and 3 to 7% by weight of ENB. More preferably, the terpolymer comprises approximately 50% by weight of ethylene, approximately 45% by weight of propylene and approximately 5% by weight of ENB.

[038] Ethylene content can be determined by ASTM D3900. Propylene content can be determined by ASTM D3900. ENB content can be determined by ASTM D6047.

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

[040] The terpolymer preferably has a Mooney viscosity (ML 1 + 4, 125 °C) of 10 to 90, more preferably 20 to 80, more preferably 30 to 70, even more preferably 30 to 50. Most preferably, the terpolymer has a Mooney viscosity (ML 1 + 4, 125 °C) of approximately 40. Mooney viscosity can be determined by ASTM D1646. The unit for Mooney viscosity is Mooney units, MU.

[041] Preferably, the terpolymer has a density of 0.84 to 0.90 Petition 870220074443, dated 08 / 18 / 2022, p. 17 / 32 11 / 20 g / cm3, more preferably 0.85 to 0.87 g / cm3, even more preferably approximately 0.86 g / cm3. Density can be determined by ASTM D297.

[042] Preferably, the terpolymer has an ash content < 0.1% by weight and a total volatile content < 0.4% by weight.

[043] Preferably, the terpolymer has an average molecular weight distribution.

[044] It should be understood that (i) the elastomeric composition, for example, an ethylene-propylene-diene terpolymer, may contain one or more additives, processing aids, crosslinking agents, accelerators and / or fillers. It may also be blended with additional polymer(s) or copolymer(s).

[045] seals comprising (i) an elastomeric composition, for example an ethylene-propylene-diene terpolymer, may be produced by conventional forming techniques such as, for example, compression molding and / or extrusion.

[046] Elastomeric compositions comprising an ethylene-propylene-diene terpolymer are described, for example, in WO 2017 / 021698 A1. General

[047] The following description applies to all aspects of the present invention, unless otherwise indicated.

[048] The present invention will now be described in more detail. In the following passages, different aspects of the present invention are defined in greater detail. Each aspect thus defined can be combined with any other aspect or aspects, unless clearly indicated otherwise. In particular, any feature indicated as preferred or advantageous can be combined with any other feature or features indicated as being preferred or advantageous.

[049] The term fence, as used in this document, is intended to encompass any fence member or portion thereof present, for example, Petition 870220074443, dated 08 / 18 / 2022, p. 18 / 32 12 / 20 in a pharmaceutical dispensing device, such as a metered-dose inhaler, including but not limited to static or dynamic gaskets and seals. 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-molded. The term sealing gasket, as used in this document, is primarily used to refer to a static seal.

[050] The seal or gasket may further include a filler, preferably a mineral and / or inorganic filler. Mineral fillers are preferable to carbon black to minimize the formation of polynuclear aromatic hydrocarbon compounds. Suitable examples include any magnesium silicate, aluminum silicate, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide, magnesium carbonate, magnesium and aluminum silicate, aluminum hydroxide, talc, kaolin, and clay, including combinations of two or more of these. Preferably, the filler is or comprises one or more of magnesium silicate, talc, calcined clay, nanoparticle clays, clay coated with kaolin and / or aminosilane, or clay coated with a titanium or zirconate coupling agent. The filler is typically present in the sealing material in an amount of 1 to 65% by weight, preferably 2 to 60% by weight, more preferably 5 to 55% by weight.

[051] When appropriate, the seal or gasket may also include a process aid, preferably a low molecular weight polyethylene, stearic acid or an organic or inorganic stearate. The process aid, for example stearic acid, may be provided in the gasket seal in an amount of up to 1% by weight.

[052] When appropriate, the seal or gasket may also include a curing or crosslinking agent. For example, the seal or gasket may also include a peroxide, sulfur, or sulfur-containing compound curing agent. An agent Petition 870220074443, dated 08 / 18 / 2022, page 19 / 32 13 / 20 peroxide curing, such as dialkyl peroxide, is, however, preferable to other curing agents, such as sulfur, since its use minimizes 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 crosslinking agent (e.g., a dialkyl peroxide) may be provided in the seal in an amount of up to 7% by weight.

[053] The seal or gasket may further comprise one or more reinforcing agents, a plasticizer, a binder, a stabilizer, a processing aid, a retarder, a bonding agent, an antioxidant, a lubricant, a pigment, a wax, a resin, antiozonants, a primary accelerator, a secondary accelerator and / or a crosslinking activator. One or more of these may be supplied in the seal in an amount of up to 1% by weight. For example, an antioxidant, such as, for example, octyl diphenylamine, may be included in an amount of up to 0.7% by weight.

[054] 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.

[055] In most pharmaceutical applications, it is also necessary to extract or wash the cured elastomer to remove surface residues and byproducts resulting from the curing reaction and molding process. The seal or gasket is therefore preferably subjected to washing and / or extraction to reduce or eliminate extractives and / or leachables. For example, solvent extraction and / or supercritical fluid extraction. Alcohol extraction is preferred. Alcohol extraction (e.g., ethanol extraction) of the seal or gasket is preferably performed after the seal or gasket is manufactured and before valve assembly. This step reduces or eliminates extractives and / or leachables. In this Petition 870220074443, dated 08 / 18 / 2022, page 20 / 32 In the 14 / 20 process, the seal / gasket components are loaded into a glass column and washed by refluxing ethanol.

[056] When appropriate, the seal or gasket may also be molded if desired with thermoplastics such as PBT, nylon and / or polyacetal.

[057] The present invention is directed to a pressurized dispensing container. Examples include a pharmaceutical metered-dose aerosol inhaler device, a syringe, and an autoinjector. A preferred use of the seals and gaskets described herein is in a pressurized pharmaceutical metered-dose aerosol inhaler device for dispensing a pharmaceutical product.

[058] The container can be produced, for example, from any suitable plastic, metal or glass material that is essentially impermeable to gas and water. An example of a suitable plastic material is polyester.

[059] Figure 1 shows, by way of example only, a pressurized dispensing container 10. The pressurized dispensing container 10 is illustrated only as an example of a possible application of the present invention. The discerning reader will understand that other applications of the present invention are possible and, as such, the description of the pressurized dispensing container 10 that follows should not be taken as limiting.

[060] The pressurized dispensing container 10 may comprise a dispensing container 11 in which a product 12 is stored for dispensing in measured doses. A valve may be held in position to seal the dispensing container 11 by a ferrule 13 that is crimped into the open neck portion of the dispensing container 11. The valve further comprises a gasket 14 for sealing the valve to the dispensing container 11. The gasket seal 14 may be a static seal.

[061] The valve comprises a valve stem 15, a valve body Petition 870220074443, dated 08 / 18 / 2022, page 21 / 32 15 / 20 16, 18 and one or more seals 20, 21, the valve stem 15 being sliding within the valve body 16, 18, one or more seals 20, 21 cooperating with the valve stem 15 to regulate the discharge of a fluid.

[062] One or more seals 20, 21 may comprise an inner seal 20 and an outer seal 21. Both the inner seal 20 and the outer seal 21 may form a dynamic sliding seal with the valve stem 15.

[063] The present invention is suitable for use with a variety of metering valves and the example in Figure 1 is only one possible design. The present invention is suitable for use with metering valves including, but not limited to, capillary check valves and quick-fill and quick-empty valves. The 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 these publications for a more complete understanding of the operation of metering valves and MDIs in general.

[064] The term pharmaceutical, as used in this document, is intended to encompass any pharmaceutical product, compound, composition, medicine, agent or product that 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, angina preparations, antibiotics, anti-inflammatory preparations, hormones or sulfonamides, such as, for example, a vasoconstrictor amine, an enzyme, an alkaloid or a steroid, including combinations of two or more thereof. In particular, examples include isoproterenol [alpha-(isopropylaminomethyl)protocatechuic alcohol], phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, ergotamine, Petition 870220074443, dated 08 / 18 / 2022, page 22 / 32 16 / 20 scopolamine, metapyrylene, cyanocobalamin, terbutaline, rimiterol, salbutamol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl and diamorphine, streptomycin, penicillin, procaine penicillin, tetracycline, chlortetracycline and hydroxytetracycline, adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, hydrocortisone, hydrocortisone acetate and prednisolone, insulin, sodium cromoglycate and mometasone, including combinations of two or more thereof.

[065] The pharmaceutical product may be used as a free base or as one or more conventional salts in the art, such as, for example, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esilate, fumarate, fluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, 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 of these.Cationic salts can also be used, for example, alkali metals, for example, Na and K, and ammonium salts and amine salts known in the art to be pharmaceutically acceptable, for example, glycine, ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol-amino-2-(hydroxymethyl)propane-1,3-diol and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.

[066] The pharmaceutical product will typically be one that is suitable for inhalation and can be provided in any form suitable for this purpose, for example, as a powder or as a solution or suspension in a solvent or carrier liquid, for example, ethanol. Petition 870220074443, dated 08 / 18 / 2022, page 23 / 32 17 / 20

[067] The pharmaceutical product may, for example, be suitable for the treatment of asthma. Examples include salbutamol, beclomethasone, salmeterol, fluticasone, formoterol, terbutaline, sodium cromoglycate, budesonide and flunisolide and physiologically acceptable salts (e.g., salbutamol sulfate, salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate and terbutaline sulfate), 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 pharmaceutical product may comprise one or more active ingredients, an example of which is flutiform, and may optionally be provided in conjunction with a suitable carrier, for example, a liquid carrier. One or more surfactants may be included, if desired.

[068] Other examples of formulations that include two active ingredients include: beclomethasone and formoterol; budesonide and formoterol; salmeterol and fluticasone; salbutamol and ipratropium bromide; and formoterol and mometasone. Examples of formulations that include three active ingredients include: formoterol, glycopyrrolate and mometasone; and beclomethasone, glycopyrrolate and formoterol.

[069] In the pressurized dispensing container described herein, the fluid to be dispensed typically comprises a liquid or particulate product such as a solution or suspension in a carrier liquid. The carrier liquid may preferably comprise an alcohol, for example ethanol. One or more surfactants may be present. One or both of oleic acid and / or glycerol may also be included in the carrier liquid.

[070] The present invention will now be described with reference to the following examples. Examples

[071] Figure 2 shows the moisture content (ppm) data relating to the storage stability of a filled container where the sealing gasket Petition 870220074443, dated 08 / 18 / 2022, p. 24 / 32 18 / 20 comprises EPDM. Time: T03 = 3 months; and T06 = 6 months. Condition: 40 / 75 = temperature of 40 °C and 75% relative humidity.

[072] After storage for 3 months and 6 months at 40 °C / 75% RH, moisture ingress is greater than would be expected when using a conventional HFA134a propellant. This may suggest that HFA152a is more hygroscopic than HFA134a, perhaps due to its higher dipole moment. The results indicate that conventional EPDM polymers do not perform well in moisture ingress tests for this propellant.

[073] In contrast, the inventors found that if the sealing gasket comprises (ii) an elastomeric composition comprising an isobutylene polymer or copolymer thereof as described herein, then the moisture content is reduced under similar conditions. The sealing gasket according to the present invention may also be compatible with the propellants described herein in terms of low permeability to helium gas, low dipole moment, low change in permeability and creep behavior with temperature, resistance to dissolution in the propellant and low water absorption.

[074] The following additional example is based on 6 months of analysis of two main performance requirements: 1. Static leakage - containment of the propellant vapor within the container throughout the product's lifespan, minimizing leakage through the main atmospheric seal; and 2. Moisture ingress - preventing atmospheric moisture from entering the container during the product's lifespan by minimizing ingress through the main atmospheric seal.

[075] Although a fully EPDM valve is capable of meeting the leakage specifications required by the USP (United States Pharmacopeia), with the alternative low GWP (global warming potential) propellant (HFA 152a), Petition 870220074443, dated 08 / 18 / 2022, p. 25 / 32 19 / 20 A hybrid EPDM / bromobutyl valve option has been developed in the present invention to (i) provide superior static leak performance and (ii) reduce the amount of moisture ingress that is typically associated with the use of hygroscopic materials, such as HFA 152a and HFA 152a propellant mixtures containing excipients, for example ethanol.

[076] The study data provided in Figure 3 show that a smaller amount of static leakage can be achieved with a hybrid valve configuration according to the present invention containing a bromobutyl gasket (typically, for example, an isobutylene polymer) compared with a similar valve configuration containing only EPDM as the primary atmospheric gasket seal. Data are provided for the HFA 152a propellant alone and in combination with ethanol.

[077] The study data provided in Figure 4 show that a smaller amount of moisture ingress can be achieved with a hybrid valve configuration according to the present invention containing a bromobutyl gasket (typically, for example, an isobutylene polymer) compared with a similar valve configuration containing only EPDM as the primary atmospheric gasket seal. Data are provided for the HFA 152a propellant alone and in combination with ethanol.

[078] With HFA 152a being a significantly different molecule (molecular size, diffusion coefficient and dipole moment) from previous propellants used in pMDI applications, the present invention has identified through analysis and experimentation an advantageous combination of pMDI valve elastomers to meet the challenging performance characteristics associated with the HFA 152a propellant. Methods Used Filling: Petition 870220074443, dated 08 / 18 / 2022, page 26 / 32 20 / 20 Target fill weights for packaging: 10g (with and without ethanol) Packaging containing ethanol: 15% Test: Leak test n = 30 packets / time point Moisture test n = 3 packages / time point Storage:

[079] All packages stored under ambient conditions for 2 weeks of quarantine, followed by 40 °C / 75% RH for the listed test periods.

[080] Leakage and moisture ingress tests are conducted in accordance with the European Medicines Agency standard ICH Topic Q 1 A (R2) / Step 5 / Stability testing of new substances and drug products / NOTE FOR GUIDANCE ON STABILITY TESTING: STABILITY TESTING OF NEW DRUGS AND PRODUCTS (CPMP / ICH / 2736 / 99) (August 2003). Leak: T0 = ​​Packages tested after 2 weeks of storage at room temperature. T6 = Packages tested after 6 months at 40°C / 75RH. Initial weights taken after 24 hours of stability, then the second weights after 7 days of ambient storage. Moisture Entry: Karl Fischer titration method using a coulometer. T3 = Test performed after 3 months in an oven at 40 °C / 75% RH. T6 = Test performed after 6 months in an oven at 40°C / 75% RH Petition 870220074443, dated 08 / 18 / 2022, page 27 / 32

Claims

1 / 4 CLAIMS 1. Pressurized dispensing container (10) comprising a dispensing container (11) for product (12) to be dispensed, and a valve fixed to the container, wherein the container (11) contains a propellant comprising 1,1-difluoroethane or a derivative thereof and optionally ethanol, wherein the valve comprises a valve stem (15), a valve body (16, 18) and one or more seals (20, 21), the valve stem (15) being sliding within the valve body (16, 18), the one or more seals (20, 21) cooperating with the valve stem (15) to regulate the discharge of a fluid, wherein the valve further comprises a sealing gasket (14) for sealing the valve to the discharge container (11), CHARACTERIZED in that the one or more seals (20, 21) is / are formed from (i) an elastomeric composition comprising an ethylene-propylene-diene terpolymer, said terpolymer comprising 40 to 70% by weight of ethylene,30 to 50% by weight of propylene and ENB (ethylidenonorbornene) in an amount of 0.5 to 9% by weight, wherein the terpolymer preferably has a Mooney viscosity (ML 1 + 4, 125 °C) of 10 to 90, and the sealing gasket (14) is formed from (ii) an elastomeric composition comprising an isobutylene polymer or copolymer thereof.

2. Pressurized dispensing container (10), according to claim 1, CHARACTERIZED in that the propellant comprises: a) HFA152a and optionally ethanol; b) a combination of HFA152a and HFA134a and optionally ethanol; or c) a combination of HFA152a and HFA227ea and optionally ethanol.

3. Pressurized dispensing container (10), according to claim 1 or 2, CHARACTERIZED in that the (ii) elastomeric composition Petition 870260064085, dated 06 / 29 / 2026, p. 8 / 15 2 / 4 comprises one or more of polyisobutylene, polybutene, butyl rubber, halogenated butyl rubber, including derivatives thereof.

4. Pressurized dispensing container (10), according to claim 3, CHARACTERIZED in that (ii) the elastomeric composition comprises a bromobutyl rubber.

5. Pressurized dispensing container (10), according to any one of claims 1 to 4, CHARACTERIZED in that (i) the elastomeric composition comprises an ethylene-propylene-diene terpolymer, wherein the terpolymer comprises from 45 to 65% by weight of ethylene, from 40 to 50% by weight of propylene, and ENB (ethylidenonorbornene) in an amount of 0.5 to 9% by weight, wherein the terpolymer has a Mooney viscosity (ML 1 + 4, 125°C) of from 10 to 90.

6. Pressurized dispensing container (10), according to any one of claims 1 to 5, CHARACTERIZED in that one or more seals (20, 21) and / or the sealing gasket (14) additionally comprise a mineral and / or inorganic filler, preferably in an amount from 1 to 10% by weight.

7. Pressurized dispensing container (10), according to claim 6, CHARACTERIZED in that the mineral and / or inorganic filler is selected from one or more of magnesium silicate, aluminum silicate, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide, magnesium carbonate, magnesium and aluminum silicate, aluminum hydroxide, talc, kaolin and clay.

8. Pressurized dispensing container, according to any one of claims 1 to 7, CHARACTERIZED in that one or more seals (20, 21) and / or the sealing gasket (14) further comprise a process aid, preferably a low molecular weight polyethylene, stearic acid or an organic or non-organic stearate.

9. Pressurized dispensing container (10), according to any one of claims 1 to 8, CHARACTERIZED in that one or more seals (20, 21) and / or the sealing gasket (14) further comprise a curing agent.

10. Pressurized dispensing container (10), according to any one of claims 1 to 9, CHARACTERIZED in that one or more seals (20, 21) and / or the sealing gasket (14) further comprise one or more of a reinforcing agent, a plasticizer, a binder, a stabilizer, a retarder, a linking agent, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonant, a primary accelerator, a secondary accelerator or an activator.

11. Pressurized dispensing container, according to any one of claims 1 to 10, CHARACTERIZED in that the sealing gasket (14) is defined as being static, sealing between non-moving parts of the valve.

12. Pressurized dispensing container (10), according to any one of claims 1 to 11, CHARACTERIZED in that one or more seals (20, 21) are defined as being dynamic, as they seal between moving parts of the valve.

13. Pressurized dispensing container, according to any one of claims 1 to 12, CHARACTERIZED in that one or more seals (20, 21) are mounted on the valve body (16, 18).

14. Pressurized dispensing container (10), according to any one of claims 1 to 13, CHARACTERIZED in that one or more seals (20, 21) are mounted on the valve stem (15).

15. Pressurized dispensing container (10), according to claim 14, CHARACTERIZED in that a first seal is mounted on the valve body (16, 18) and a second seal is mounted on the valve stem (15).

16. Pressurized dispensing container (10), according to any one of claims 1 to 15, CHARACTERIZED in that the valve is a continuous spray valve.

17. Pressurized dispensing container (10), according to any one of claims 1 to 16, CHARACTERIZED in that the valve further comprises a measuring chamber and the valve is a measuring valve.

18. Pressurized dispensing container (10), according to claim 17, CHARACTERIZED in that the measuring chamber of the measuring valve is permanent.

19. Pressurized dispensing container (10), according to claim 18, CHARACTERIZED in that the dispensing chamber is constructed entirely from rigid components, such as components formed from one or more materials selected from polyester, nylon, acetal or similar materials, stainless steel, ceramic, glass or similar materials.

20. Pressurized dispensing container (10), according to any one of claims 1 to 19, CHARACTERIZED in that it is a pharmaceutical dispensing device; and, optionally, wherein the pharmaceutical dispensing device is a pharmaceutical metered dose aerosol inhaler device. Petition 870260064085, dated 06 / 29 / 2026, p. 11 / 15

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