Pressurized dispensing vessel

Abstract

To provide a pressurized dispensing container which can be used with propellants based on 1,1-difluoroethane.SOLUTION: A pressurized dispensing container comprises a container for a product to be dispensed, and a valve fixed to the container, where the container contains a propellant comprising 1,1-difluoroethane or a derivative thereof and optionally ethanol. The valve comprises a valve stem, a valve body, and one or more seals. The valve stem is slidable within the valve body. The one or more seals cooperate 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. The one or more seals is / are formed from (i) an elastomeric composition, preferably an elastomeric composition comprising an ethylene-propylene-diene terpolymer. The sealing gasket is formed from (ii) an elastomeric composition comprising an isobutylene polymer or a copolymer thereof.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a pressurized dispensing container and an elastomeric sealing material for use therein. The pressurized dispensing container may be used to dispense a pressurized fluid in the form of an aerosol. The pressurized dispensing container finds use as a pharmaceutical dispensing device such as a pressurized metered dose inhaler device (pMDI) and in a diagnostic device suitable for dispensing pharmaceuticals.

Background Art

[0002] It is known from, for example, GB1201918 to provide a dispensing device in which fluid from a pressurized dispensing container is discharged by a valve in a controlled manner, the valve including an elastomeric seal which is annular and which cooperates with a sliding valve shaft to open and close a fluid port. Each of FR-A-2,549,568, WO95 / 02651, and GB2148912, and PCT / GB96 / 01551 discloses yet another example of such a dispensing device.

[0003] The required material properties necessary for good seal performance for pharmaceutical use include chemical compatibility (swelling), tensile strength, compression set, stress relaxation, modulus of elasticity, regulatory compliance, low permeability to fluids and gases, low levels of extracts and leachables, and stability of properties after extraction.

[0004] As well as the requirements for good engineering properties, there are requirements regarding hygienic properties which may otherwise increase impurities in the formulation to unacceptable levels and which also include low levels of extracts and leachables which may potentially react with the formulation, excipient, or additive. In this regard, the products to be dispensed from a pMDI are generally provided as solutions or suspensions in a propellant solvent, which is particularly common in the dispensing of pharmaceutical compounds for inhalation therapy. The throttle valves used in dispensing devices such as pMDIs are typically composed of a mixture of metal and / or thermoplastic parts and elastomeric parts.

[0005] Known rubber compounds for sealing pharmaceutical quantitative aerosol inhalers include those based on conventional techniques for vulcanizing synthetic or natural rubber polymers.

[0006] The products to be dispensed are generally supplied as solutions or suspensions in alcohol or non-alcoholic solvents, which is particularly common for dispensing pharmaceutical compounds for inhalation therapy.

[0007] A typical apparatus contains a hydrofluoroalkane (HFA) volatile propellant, such as a conventional propellant like HFA134a, and has a liquid phase in which the product is readily soluble in the container together with an alcohol carrier. A typical material for use in valve seals is synthetic rubber such as chloroprene rubber. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] GB1201918 [Patent Document 2] FR-A-2,549,568 [Patent Document 3] WO95 / 02651 [Patent Document 4] GB2148912 [Patent Document 5] PCT / GB96 / 01551 [Patent Document 6] WO03 / 078538 A1 [Patent Document 7] WO2017 / 021698 A1 [Patent Document 8] US6,095,182 [Patent Document 9] GB2401099 [Patent Document 10] GB2340477 [Patent Document 11] EP0803449 [Patent Document 12] EP0801009 [Overview of the project] [Problems that the invention aims to solve]

[0009] The object of the present invention is to provide a pressurized dispensing vessel that can be used with propellants based on 1,1-difluoroethane. In addition, the pressurized dispensing vessel can also be used with other low-global-warming propellants or combinations thereof. Furthermore, the pressurized dispensing vessel can also be used 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. [Means for solving the problem]

[0010] Accordingly, in a first aspect, the present invention provides a pressurized dispensing vessel comprising a container for a product to be dispensed and a valve fixed to the container, the container containing a propellant comprising 1,1-difluoroethane or a derivative thereof and optionally an alcohol such as ethanol, the valve comprising 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 to regulate the discharge of fluid, the valve further comprising a sealing gasket for sealing the valve to the dispensing vessel, the one or more seals being formed from (i) an elastomer composition, preferably an elastomer composition comprising an ethylene-propylene-diene polymer, and the sealing gasket being formed from (ii) an elastomer composition comprising an isobutylene polymer or a copolymer thereof.

[0011] In the first embodiment, the propellant preferably comprises or consists of HFA152a and optionally an alcohol such as ethanol. Compared to conventional chlorofluorocarbon propellants, HFA152a has been reported to have zero ozone depletion potential, a low global warming potential, and a shorter atmospheric lifetime.

[0012] In a first aspect, the propellant may instead comprise or consist of a combination of HFA152a and HFA134a and optionally an alcohol such as ethanol. In a first aspect, the propellant may instead comprise or consist of a combination of HFA152a and HFA227ea and optionally an alcohol such as ethanol.

[0013] The following drawings are provided by way of example to assist in the understanding of certain aspects of the present invention.

Brief Description of the Drawings

[0014] [Figure 1] A diagram showing a pressurized dispensing container by way of example only. [Figure 2] A diagram showing moisture content (ppm) data related to the stable storage of a filled canister with a sealing gasket comprising ethylene-propylene-diene terpolymer (EPDM). [Figure 3] A diagram showing data demonstrating that a hybrid valve configuration according to the present invention containing a bromobutyl (typically, for example, an isobutylene polymer) gasket can achieve lower levels of static leakage compared to a similar valve configuration containing only EPDM as a primary atmospheric gas gasket seal. [Figure 4] A diagram showing data demonstrating that a hybrid valve configuration according to the present invention containing a bromobutyl (typically, for example, an isobutylene polymer) gasket can achieve lower levels of moisture ingress compared to a similar valve configuration containing only EPDM as a primary atmospheric gas gasket seal.

Modes for Carrying Out the Invention

[0015] Sealing gasket (also known as static seal) In the present invention, the sealing gasket is formed from an elastomeric composition comprising (ii) an isobutylene polymer or a copolymer thereof.

[0016] A sealing gasket is sometimes called a static seal, in contrast to one or more seals that work with the valve stem, which may be called one or more dynamic seals.

[0017] The purpose of a 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, such as the leakage of propellant. Almost certainly importantly, the sealing gasket prevents the ingress of undesirable components, such as moisture, into the container, which could potentially adversely affect the product to be dispensed, such as a drug or pharmaceutical. For example, the presence of excess moisture in a propellant suspension can lead to a reduction in particulate matter through drug particle aggregation, thereby reducing the therapeutic effect of the active pharmaceutical ingredient (API). Moisture can also lead to oxidation of the API formulation.

[0018] The inventors have found that (ii) an elastomer 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 we do not wish to be bound by theory, HFA152a has a higher dipole moment than conventional propellants such as HFA134a and can therefore be more hygroscopic, thereby leading to greater moisture penetration into the container. Surprisingly, the inventors have found that conventional EPDM polymers did not perform adequately in moisture penetration tests against propellants based on 1,1-difluoroethane. Propellant is often supplied with an alcohol such as ethanol. The inventors have further found that the degree of moisture penetration into the container increased when alcohol was present. Surprisingly, the elastomer composition (ii) described herein provides an effective moisture barrier when the propellant contains an alcohol such as ethanol.

[0019] The sealing gasket according to the present invention is also considered suitable for the propellants described herein in terms of helium gas permeability, low dipole moment, low change in permeability and creep behavior with respect to temperature, resistance to dissolution in the propellant, and low water absorption.

[0020] (ii) Elastomer composition comprising an isobutylene polymer or its copolymer (ii) The elastomer composition comprises one or more of the following: polyisobutylene, polybutene, butyl rubber, and halogenated butyl rubber, including an isobutylene polymer or copolymer thereof, for example, a derivative thereof. More preferably, the elastomer composition comprises butyl rubber or bromobutyl rubber. Butyl rubber is a copolymer made from isobutylene and a small amount of diolefin, such as isoprene (2-methylbuta-1,3-diene).

[0021] Typically, butyl rubber consists of about 97% isobutylene and about 3% isoprene, and it can be polymerized using an aluminum chloride catalyst.

[0022] 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 herein, is intended to encompass halogenated polymers.

[0023] (ii) The elastomer composition may further comprise (a) a crosslinking agent for an isobutylene polymer or copolymer thereof and optionally (b) an accelerator for the crosslinking agent.

[0024] (ii) It will be acknowledged that the elastomer composition may comprise a compound with another polymer, such as a chlorine-substituted diene polymer of isobutylene polymer or its copolymer. For example, a compound of butyl rubber (e.g., bromobutyl rubber) and polychloroprene can be used. Compounding polychloroprene with nonpolar butyl is advantageous because it allows for the dissipation of static charge. Static charge accumulation during the automatic valve assembly process and / or storage in plastic bags can cause seals to self-adhere and present problems in valve assembly.

[0025] Where present, crosslinking agents (also known as curing agents) provide or facilitate network formation to result in a three-dimensional polymer network structure. Crosslinking agents can act by reacting with functional groups on polymer chains. Crosslinking agents typically comprise sulfur or sulfur-containing compounds. Crosslinking agents are preferably substantially free of any peroxide curing agents, such as dicumyl peroxide.

[0026] The accelerator, if present, preferably comprises a polysulfide compound derived from a substituted dithiocarbonate or its derivative. The polysulfide compound is preferably derived from a substituted xanthogenic acid or its derivative, preferably of the ROC(S)SH type, where R is typically an alkyl group. The substituents in the polysulfide compound typically comprise an isopropyl group. The polysulfide compound preferably comprises 3 or 4 or more crosslinked sulfur atoms, more preferably 3, 4, or 5 crosslinked sulfur atoms. The polysulfide compound is preferably substantially free of nitrogen, phosphorus, and metal elements. Significantly, the polysulfide compound comprises or is composed of a diisopropyl xanthogenic polysulfide.

[0027] The elastomer composition (ii) typically comprises up to 3% by weight of an accelerator based on the total weight of the accelerator and polymer in the composition, more typically up to 1.5% by weight of an accelerator based on the total weight of the accelerator and polymer in the composition, and even more typically up to 1% by weight of an accelerator based on the total weight of the accelerator and polymer.

[0028] The weight ratio of accelerator to crosslinking agent in the elastomer composition (ii) is preferably in the range of 1:1 to 3:1, more preferably in the range of 1:1 to 2:1.

[0029] (ii) It will be understood that the elastomer composition may further contain one or more additives, processing aids, crosslinking agents, accelerators, and / or fillers. It may also be compounded with additional polymers or copolymers.

[0030] (ii) A sealing gasket comprising an elastomer composition can be produced, for example, by conventional forming techniques such as compression molding and / or extrusion.

[0031] The initiation of the crosslinking reaction can be achieved by any known prior art, for example, by heating the formulation to at least a curing reaction temperature, typically in the range of 130 to 200°C. A preferred step involves forming rubber compound strips (typically about 1 mm thick) by compression molding. The molding temperature is typically in the range of 160-180°C. The curing time is typically in the range of 1-10 minutes. The molded strips are preferably post-cured in an air dryer at 150°C for typically 1 hour.

[0032] Next, the strips can be made into gaskets using a punching device.

[0033] (ii) The use of accelerators as described herein in elastomer compositions according to the present invention can eliminate the need for free sulfur in the crosslinking process. Accelerators as described herein are preferably supplied as liquids and preferably miscible with the polymer to provide a uniform dispersion. The use of such accelerators has been found to facilitate filler dispersion and eliminate the need for separate plasticizers. The presence of plasticizers is undesirable because they tend to leach out of the material. In contrast, accelerators as described herein form or are part of the crosslinking network and therefore do not leach into the drug medium. In the sealing compositions according to the present invention, the accelerator is typically consumed almost completely during the crosslinking reaction. This results in cleaner rubber and reduced extractability. Typically, substantially no nitrosamines are generated during the crosslinking reaction.

[0034] Elastomer compositions comprising isobutylene polymers or copolymers thereof are described, for example, in WO03 / 078538 A1.

[0035] One or more seals (also known as one or more dynamic seals) One or more seals are formed from (i) an elastomer composition, preferably an elastomer composition comprising an ethylene-propylene-diene polymer.

[0036] One or more seals cooperate with a slidable valve stem within the valve body, and such seals may therefore also be called dynamic seals. The mechanical properties of these seals are important for providing durability and consistent metering of the product and propellant. Butyl rubber may exhibit inferior compression set properties compared to ethylene-propylene-diene polymer (EPDM), and therefore makes them unsuitable when used as dynamic seals in the type of pressurized dispensing vessels described herein. In contrast, elastomer compositions (i) comprising ethylene-propylene-diene polymer have very good mechanical properties and exhibit reduced compression set, which makes them more effective as dynamic seals. Furthermore, the inventors have found that elastomer compositions comprising isobutylene polymer or copolymers thereof provide effective leak and moisture seals (i.e., static seals) when using propellants comprising or composed of 1,1-difluoroethane (e.g., HFA152a).

[0037] (i) An ethylene-propylene-diene polymer suitable for use in an elastomer composition comprises 40 to 70% by weight of ethylene, 30 to 50% by weight of propylene, and 0.5 to 9% by weight of ENB (ethylidene norbornene).

[0038] More preferably, the terpolymer 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. Most preferably, the terpolymer comprises about 50% by weight of ethylene, about 45% by weight of propylene, and about 5% by weight of ENB.

[0039] The ethylene content can be determined by ASTM D3900. The propylene content can be determined by ASTM D3900. The ENB content can be determined by ASTM D6047.

[0040] Turpolymers can be produced using shape-constrained catalyst systems. For example, there are metallocene-constrained shape catalyst systems, such as those based on titanium monocyclopentadienyl incorporating silane groups.

[0041] 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, and more preferably 30 to 50. Most preferably, the terpolymer has a Mooney viscosity (ML 1+4,125°C) of about 40. The Mooney viscosity can be determined by ASTM D1646. The unit of Mooney viscosity is the Mooney unit, MU.

[0042] Preferably, the terpolymer is 0.84 to 0.90 g / cm³. 3 , more preferably 0.85 to 0.87 g / cm³ 3 More preferably, about 0.86 g / cm³ 3 It has a density of [density]. The density can be determined by ASTM D297.

[0043] Preferably, the terpolymer has an ash content of <0.1% by weight and a total volatile matter content of <0.4% by weight.

[0044] Preferably, the terpolymer has an intermediate molecular weight distribution.

[0045] (i) It will be understood that the elastomer composition, for example, ethylene-propylene-diene polymer, may further contain one or more additives, processing aids, crosslinking agents, accelerators, and / or fillers. It may also be compounded with additional polymers or copolymers.

[0046] (i) Seals comprising an elastomer composition, for example, an ethylene-propylene-diene polymer, can be produced by conventional forming techniques such as compression molding and / or extrusion.

[0047] Elastomer compositions comprising ethylene-propylene-diene polymers are described, for example, in WO2017 / 021698A1.

[0048] overview The following description is applicable to all aspects of the present invention unless otherwise indicated.

[0049] The present invention will now be described further below. The following sections will define various aspects of the present invention in more detail. Each of the aspects defined therein can be combined with any one or more other aspects unless the opposite is explicitly stated. In particular, any feature indicated as preferred or advantageous can be combined with any one or more other features indicated as preferred or advantageous.

[0050] As used herein, the term seal is intended to encompass, but is not limited to, any sealing component or part thereof present in a pharmaceutical dispensing device, such as a metering inhaler, including gaskets and seals, whether static or dynamic. Seals may be supplied as separate components or formed integrally with a valve, i.e., co-molded. As used herein, the term sealing gasket is primarily used to refer to static seals.

[0051] The seal or gasket may further contain a filler, preferably a mineral and / or inorganic filler. Mineral fillers are preferred over carbon black to minimize the formation of polynuclear aromatic hydrocarbon compounds. Suitable examples include any of the following, including two or more combinations thereof: magnesium silicate, aluminum silicate, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide, magnesium carbonate, aluminum magnesium silicate, aluminum hydroxide, talc, kaolin, and clay. Preferably, the filler is one or more of the following, or comprises them: magnesium silicate, talc, calcined clay, nanoparticle clay, kaolin and / or aminosilane coated clay, or clay coated with titanium or zirconate coupling agent. The filler is typically present in the seal material in an amount of 1 to 65% by weight, preferably 2 to 60% by weight, and more preferably 5 to 55% by weight.

[0052] Where appropriate, the seal or gasket may further contain processing aids, preferably low molecular weight polyethylene, stearic acid, or organic or non-organic stearates. Processing aids, such as stearic acid, may be provided to the gasket seal in amounts up to 1% by weight.

[0053] Where appropriate, the seal or gasket may further contain a curing or crosslinking agent. For example, the seal or gasket may further contain a peroxide curing agent, sulfur, or a sulfur-containing compound. However, peroxide curing agents such as dialkyl peroxides are preferred over other curing agents such as sulfur because their use minimizes the formation of extracts (e.g., 2-mercaptobenzothiazole, N-nitrosamine, mercaptobenzothiazole disulfide) derived from contact between the material and the alcohol during use. The curing or crosslinking agent (e.g., dialkyl peroxide) may be provided in the seal in an amount of up to 7% by weight.

[0054] The seal or gasket may further comprise one or more of the following: reinforcing agents, plasticizers, binders, stabilizers, processing aids, retarders, binders, antioxidants, lubricants, pigments, waxes, resins, ozone degradation inhibitors, primary accelerators, secondary accelerators, and / or crosslinking activators. One or more of these may be provided in the seal in amounts up to 1% by weight. For example, antioxidants such as octylated diphenylamine may be included in amounts up to 0.7% by weight.

[0055] It can be acknowledged that certain components may have more than one effect. For example, zinc oxide can act as both an activator and a filler. Similarly, magnesium oxide can act as both an acid absorber and a filler.

[0056] In most pharmaceutical applications, it is also necessary to extract or wash the cured elastomer to remove surface residues and by-products resulting from the curing reaction and molding process. Therefore, seals or gaskets are preferably washed and / or extracted to reduce or eliminate extracts and / or leaches. Examples include solvent extraction and / or supercritical fluid extraction. Alcohol extraction is preferred. Alcohol extraction of seals or gaskets (e.g., ethanol extraction) is preferably performed after the seals or gaskets are manufactured and before the valves are assembled. This step reduces or eliminates extracts and / or leaches. In this step, the seal / gasket components are loaded into a glass cylinder and washed by refluxing ethanol.

[0057] Where appropriate, the seal or gasket may also be co-molded with thermoplastics such as PBT, nylon, and / or polyacetal, as needed.

[0058] The present invention relates to pressurized dispensing vessels. Examples include pharmaceutical metering aerosol inhalation devices, syringes, and auto-injectors. A preferred use of the seals and gaskets described herein is in pressurized pharmaceutical metering aerosol inhalation devices for dispensing pharmaceuticals.

[0059] The container can be made 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.

[0060] Figure 1 shows a pressurized dispensing vessel 10 as merely an example. The pressurized dispensing vessel 10 is shown merely as an example of a possible application of the present invention. It is expected that a skilled reader will understand that other applications of the present invention are possible, and therefore the following description of the pressurized dispensing vessel 10 should not be taken as limiting.

[0061] The pressurized dispensing container 10 may include a dispensing container 11 in which a product 12 to be dispensed in a fixed quantity is stored. A valve can be held in place to seal the dispensing container 11 by a ferrule 13 crimped onto the open neck portion of the dispensing container 11. The valve further includes a sealing gasket 14 to seal the valve to the dispensing container 11. The sealing gasket 14 may be a static seal.

[0062] The valve comprises a valve stem 15, valve bodies 16, 18, and one or more seals 20, 21, wherein the valve stem 15 is slidable within the valve bodies 16, 18, and the one or more seals 20, 21 cooperate with the valve stem 15 to regulate the discharge of fluid.

[0063] 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 having a valve stem 15.

[0064] The present invention is suitable for use in conjunction with a series of throttle valves, and the example in Figure 1 is merely one possible design. The present invention is suitable for use in conjunction with throttle valves including, but is not limited to, capillary retention valves and fast-filling, fast-release valves. The operation of such throttle valves is described in detail in references US6,095,182, GB2401099, GB2340477, EP0803449, and EP0801009, and readers are encouraged to refer to these references for a more complete understanding of the operation of throttle valves and MDI in general.

[0065] As used herein, the term "pharmaceutical" is intended to encompass all pharmaceuticals, compounds, compositions, agents, drugs, or products that can be delivered or administered to humans or animals, such as pharmaceuticals, drugs, biological and medicinal products. Examples include, for example, vasoconstrictive amines, enzymes, alkaloids, or steroids, as well as anti-allergic agents, analgesics, bronchodilators, antihistamines, therapeutic proteins and peptides, cough suppressants, angina preparations, antibiotics, anti-inflammatory preparations, hormones, or sulfonamides. In particular, examples include adrenocorticotropic and adrenocortical hormones such as isoproterenol [α-(isopropylaminomethyl)protocatecylic alcohol], phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotin, codeine, atropine, heparin, morphine, dihydromorphinone, ergotamine, scopolamine, metapyrylene, cyanocobalamin, terbutaline, limiterol, salbutamol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine, streptomycin, penicillin, procainepenicillin, tetracycline, chlorotetracycline and hydroxytetracycline, cortisone, hydrocortisone, hydrocortisone acetate and prednisolone, insulin, cromolyn sodium, and mometasone.

[0066] Pharmaceuticals include, for example, acetates, benzenesulfonates, benzoates, bicarbonates, hydrogen tartrates, bromides, calcium edetate, camusylates, carbonates, chlorides, citrates, dihydrochlorides, edetates, edisylates, estrates, esylates, fumarates, fluceptate, gluconates, glutamates, glycolyl arsanilates, hexylresorcinates, hydrobromides, hydrochlorides, hydroxynaphthoates, iodides, isethionates, and lactic acid, which include two or more combinations thereof. These can be used in the present art as either a conventional free base or one or more salts, such as salts, lactobionates, malates, maleates, mandelates, mesylates, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylates, nitrates, pamoates, (embonates), pantothenates, phosphates, diphosphates, polygalacturonates, salicylates, stearates, basic acetates, succinates, sulfates, tannates, tartrates, and triethiodides. For example, alkali metals, such as Na and K, and ammonium salts and salts of pharmaceutically acceptable amines known in the art, such as glycine, ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol-amino-2-(hydroxymethyl)propane-1,3-diol, and cationic salts of 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol can also be used.

[0067] Pharmaceuticals are typically suitable for inhalation and can be provided in any suitable form for this purpose, for example, as a powder or as a solvent or carrier liquid, such as a solution or suspension in ethanol.

[0068] Pharmaceuticals may be suitable, for example, for the treatment of asthma. Examples include salbutamol, beclomethasone, salmeterol, fluticasone, formoterol, terbutaline, sodium cromoglycate, budesonide, and flunisolide, including two or more combinations thereof, as well as physiologically acceptable salts (e.g., salbutamol sulfate, salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate, and terbutaline sulfate), solvates, and esters. Individual isomers, such as R-salbutamol, may also be used. As recognized, pharmaceuticals may comprise one or more active ingredients, an example of which is flutiform, and may optionally be provided with a suitable carrier, such as a liquid carrier. One or more surfactants may be included as needed.

[0069] Further examples of formulations containing two active ingredients include beclomethasone and formoterol, budesonide and formoterol, salmeterol and fluticasone, salbutamol and ipratropium bromide, and formoterol and mometasone. Examples of formulations containing three active ingredients include formoterol, glycopyrrolate, and mometasone, and beclomethasone, glycopyrrolate, and formoterol.

[0070] In the pressurized dispensing vessels described herein, the fluid to be dispensed typically comprises a liquid or particulate product as a solution or suspension in a carrier liquid. The carrier liquid may preferably comprise an alcohol, such as ethanol. One or more surfactants may be present. Oleic acid and / or glycerol, or both, may also be present in the carrier liquid.

[0071] The present invention will be further described below with reference to the following examples.

[0072] Examples Figure 2 shows moisture content (ppm) data related to stable storage of filled canisters with EPDM sealing gaskets. Time: T03 = 3 months, and T06 = 6 months. Conditions: 40 / 75 = 40°C temperature and 75% relative humidity.

[0073] After storage at 40°C / 75%RH for 3 and 6 months, moisture ingress was higher than expected when using conventional HFA134a propellant. This suggests that HFA152a is potentially more hygroscopic than HFA134a due to its larger dipole moment. The results indicate that conventional EPDM polymers do not perform adequately in moisture ingress tests for this propellant.

[0074] In contrast, the inventors have found that the moisture content is reduced under similar conditions when the sealing gasket comprises (ii) an elastomer composition comprising an isobutylene polymer or copolymer thereof, as described herein. The sealing gasket according to the present invention is also considered suitable for the propellants described herein in terms of low 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.

[0075] The following further example is based on a 6-month analysis of two key performance requirements: 1. Static leakage - Propellant vapor contamination in the canister over the product's storage period by minimizing leakage through the main atmospheric gasket seal, and 2. Moisture Intrusion - Prevents atmospheric moisture from penetrating the canister over the product's storage period by minimizing intrusion through the main atmospheric gasket seal.

[0076] While all EPDM valves can satisfy the required USP (United States Pharmacopeia) leakage specifications with alternative low GWP (Global Warming Potential) propellants (HFA152a), the EPDM / bromobutyl hybrid valve option developed in this invention (i) provides superior static leakage performance and (ii) reduces the amount of moisture ingress typically associated with the use of hygroscopic materials such as propellants HFA152a and HFA152a mixtures containing additives, e.g., ethanol.

[0077] The research data provided in Figure 3 demonstrate that the hybrid valve configuration according to the present invention, which includes a bromobutyl (typically, e.g., isobutylene polymer) gasket, can achieve lower static leakage compared to a similar valve configuration containing only EPDM as the primary atmospheric gasket seal. Data are shown for the propellant HFA152a itself and in combination with ethanol.

[0078] The research data provided in Figure 4 shows that the hybrid valve configuration according to the present invention, which includes a bromobutyl (typically, e.g., isobutylene polymer) gasket, can achieve lower levels of moisture ingress compared to a similar valve configuration containing only EPDM as the primary atmospheric gasket seal. Data for the propellant HFA152a alone and in combination with ethanol are shown.

[0079] Taking advantage of the fact that HFA152a is a significantly different molecule (molecular size, diffusion coefficient, and dipole moment) from previous propellants used in pMDI applications, the present invention identified, through analysis and experimentation, favorable combinations of pMDI valve elastomers to address the performance characteristics of the challenges associated with HFA propellant 152a.

[0080] Method used filling: Pack target filling weight: 10g (with or without ethanol) Ethanol-containing pack: 15%

[0081] test: Leakage test n=30 packs / time point Moisture test n=3 packs / time point

[0082] storage: All packs were stored under ambient conditions for two weeks of isolation, followed by storage at 40°C / 75%RH for the subsequent test periods listed. Leakage and water ingress tests shall be conducted in accordance with the European Medicines Agency standard ICH Topic Q 1A(R2) / Stage 5 / Stability testing of new drug substances and products / Notes for guidance on stability testing: Stability testing of new drug substances and products (CPMP / ICH / 2736 / 99) (August 2003).

[0083] Leakage: T0=Pack was tested after 2 weeks of ambient storage. The T6 pack was tested after 6 months at 40°C / 75RH. The initial weight was taken after 24 hours of stabilization, and the second weight was taken after 7 days of ambient storage.

[0084] Moisture intrusion: Karl Fischer titration method using a coulometer. T3 = The test was conducted after 3 months in an oven at 40°C / 75%RH. T6 = The test was conducted after 6 months in an oven at 40°C / 75%RH. [Explanation of Symbols]

[0085] 10 Pressurized dispensing vessel 12 products 14. Sealing gasket 16, 18 Valve body 20, 21 Seals

Claims

1. A pressurized dispensing container, which is a pharmaceutical dispensing device, comprises a container for the product 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 ethanol, The valve comprises a valve stem, a valve body, and one or more seals, the valve stem being slidable within the valve body, and the one or more seals cooperating with the valve stem to regulate the discharge of fluid. The valve further comprises a sealing gasket for sealing the valve to the dispensing container. The one or more seals are formed from (i) an elastomer composition comprising an ethylene-propylene-diene polymer, The sealing gasket is formed from an elastomer composition comprising (ii) an isobutylene polymer or a copolymer thereof, The ethylene-propylene-diene polymer is present in a concentration of 0.84 to 0.90 g / cm³. 3 Having a density of, A pressurized dispensing container characterized by the following features.

2. The aforementioned propellant is (a) HFA152a and optionally ethanol, (b) A combination of HFA152a and HFA134a and optionally ethanol, (c) A combination of HFA152a and HFA227ea and optionally ethanol, Equipped with, The pressurized dispensing vessel according to feature 1.

3. The (ii) elastomer composition comprises one or more of polyisobutylene, polybutene, butyl rubber, and halogenated butyl rubber, including a derivative thereof, as described in claim 1 or 2 of the pressurized dispensing container.

4. The (ii) elastomer composition is characterized by comprising bromobutyl rubber, as described in claim 3.

5. The (i) elastomer composition comprises an ethylene-propylene-diene polymer comprising 45 to 65% by weight of ethylene, 40 to 50% by weight of propylene, and 0.5 to 9% by weight of ENB (ethylidene norbornene), The terpolymer has a Mooney viscosity of 10 to 90 (ML 1 + 4, 125°C). A pressurized dispensing vessel according to any one of claims 1 to 4.

6. The pressurized dispensing container according to any one of claims 1 to 5, characterized in that the one or more seals and / or the sealing gasket further comprises 1 to 10% by weight of a mineral filler and / or an inorganic filler.

7. The pressurized dispensing vessel according to claim 6, characterized in that the mineral filler 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, aluminum magnesium silicate, aluminum hydroxide, talc, kaolin, and clay.

8. The pressurized dispensing container according to any one of claims 1 to 7, characterized in that the one or more seals and / or the sealing gasket further comprises low molecular weight polyethylene, stearic acid, or an organic or non-organic stearate.

9. The pressurized dispensing container according to any one of claims 1 to 8, characterized in that the one or more seals and / or the sealing gasket further comprises a curing agent.

10. The pressurized dispensing container according to any one of claims 1 to 9, characterized in that the one or more seals and / or the sealing gasket further comprises one or more of the following: reinforcing agents, plasticizers, binders, stabilizers, retarders, binders, antioxidants, lubricants, pigments, waxes, resins, ozone degradation inhibitors, primary accelerators, secondary accelerators, or activators.

11. The pressurized dispensing container according to any one of claims 1 to 10, characterized in that the one or more seals are one or more dynamic seals that seal between the movable parts of the valve.

12. The pressurized dispensing container according to any one of claims 1 to 11, characterized in that the one or more seals are mounted on the valve body.

13. The pressurized dispensing container according to any one of claims 1 to 12, characterized in that the one or more seals are mounted on the valve shaft.

14. The pressurized dispensing container according to claim 13, characterized in that a first seal is mounted on the valve body and a second seal is mounted on the valve shaft.

15. The pressurized dispensing container according to any one of claims 1 to 14, characterized in that the valve is a continuous spray valve.

16. The pressurized dispensing vessel according to any one of claims 1 to 15, wherein the valve further comprises a metering chamber, and the valve is a throttle valve.

17. The pressurized dispensing vessel according to claim 16, characterized in that the measuring chamber is entirely composed of rigid components formed from one or more materials selected from polyester, nylon, or acetal, stainless steel, ceramic, or glass.

18. A pressurized dispensing container according to any one of claims 1 to 17, characterized in that it is a pharmaceutical quantitative aerosol inhaler device.

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