Pressurized metered dose inhaler comprising buffered pharmaceutical formulation

Abstract

The present invention generally relates to an aerosol formulation comprising formoterol, beclomethasone dipropionate and glycopyrronium bromide, the formulation being contained in a coated canister, which formulation is particularly useful for use in pressurized metered dose inhalers for the treatment of respiratory diseases.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of February 18, 2021, an application number of 202110189931.0, and an invention title of "Pressurized Metered Inhaler Containing Buffered Pharmaceutical Formulation". Technical Field

[0002] The present invention generally relates to an aerosol formulation comprising at least a LABA, a LAMA, a corticosteroid, and a propellant, which formulation is contained in a coated can and is particularly useful for use in a pressurized metered inhaler for the respiratory field. Background Art

[0003] Pressurized metered inhalers (pMDIs) are well-known devices for administering pharmaceutical products to the respiratory tract by inhalation. A pMDI device typically presents a canister (or "can" as referred to herein) containing the drug and an actuator housing having a mouthpiece. The canister is typically crimped to a metering valve assembly. Depending on the active ingredient and additional components such as excipients, acids, and the like, the final pMDI formulation can be in the form of a solution or a suspension. A solution generally means substantially free of precipitates or particles, while a suspension generally represents a formulation having some insoluble material or precipitate. pMDI devices can use a propellant to expel droplets containing the pharmaceutical product as an aerosol into the respiratory tract. For many years, the preferred propellants used in this regard have been chlorofluorocarbon derivatives, which are commonly referred to as Freon or CFCs, such as CCl3F (Freon 11 or CFC-11), CCl2F2 (Freon 12 or CFC-12), and CClF2-CClF2 (Freon 114 or CFC-114). Due to international concerns about the critical values of the global warming potential (GWP) of fully and partially halogenated chlorofluorocarbons that affect the earth's protective ozone layer, many countries have joined the "Montreal Protocol" agreement, which stipulates that their manufacture and application should be strictly restricted and ultimately phased out completely. As a result, hydrofluoroalkanes (HFAs), especially 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227a), have been identified and accepted in the pharmaceutical sector as alternatives to CFCs. Since then, the hydrofluoroalkane propellants HFA 134a and HFA227a have been widely used in the respiratory field, especially considering their efficacy and compatibility with many active ingredients such as corticosteroids, LABAs, or anticholinergic drugs.

[0004] Although the HFA propellants are effective and although they are widely used in many pharmaceutical drugs already on the market, the possibility of obtaining alternative classes of propellants and alternative ways of obtaining effective pMDI devices has been under consideration. As a general reference in this sense, see, for example, "Pharmaceutical Inhalation Aerosol Technology", 3rd Edition, 2019, Anthony J. Hickey et al., where on page 440, Table 18.3, several propellants that might be suitable for pharmaceutical use have been compared in terms of their global warming potential.

[0005] This involves, for example, the optimization of mechanical components of the pMDI device such as valves or cans, or even the possibility of obtaining spray devices, spray drying systems or devices characterized by a more environmentally friendly impact that are free of propellants.

[0006] Another feature worth considering when discussing pMDI devices is the apparent pH and water content of the formulation sprayed by the device. As general references in this sense, see, for example, WO 01 / 89480 and WO 03 / 074024.

[0007] Fluorocarbon polymers are often used to coat the inner surface of the pMDI can to eliminate particle adhesion or deposition on the can wall, i.e., to avoid adhesion (for suspension formulations) and to avoid the formation of by-products.

[0008] EP0820323 describes a pMDI having a part or all of its inner surface coated with one or more fluorocarbon polymers, which is used for dispensing an inhalation pharmaceutical formulation comprising salmeterol and a fluorocarbon propellant optionally combined with one or more other pharmacological active agents, wherein the coating of the inner surface of the can significantly reduces or substantially eliminates the problem of adhesion or deposition of salmeterol.

[0009] WO 2015 / 101576 describes a pMDI device that is particularly suitable for use with a solution of formoterol, beclomethasone dipropionate and glycopyrronium bromide contained in an FEP-coated can. As disclosed therein, the formulation contained in the FEP-coated can is given improved stability and a reduced amount of degradation products, mainly with respect to N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide. This product (identified as DP3) is actually a specific degradation product resulting from the interaction of formoterol and bromide ions from glycopyrronium bromide when the two active ingredients are dissolved in an HFA ethanol system in the presence of an acid, especially hydrochloric acid.

[0010] EP2706987 describes a formulation for use in a pMDI device that is particularly suitable for treating respiratory diseases, which comprises beclomethasone dipropionate and HFA152.

[0011] WO2018 / 051131 describes in Example 1, Table 4, a pharmaceutical formulation that comprises beclomethasone dipropionate and formoterol fumarate dihydrate, a propellant containing 1,1-difluoroethane (HFA 152a), an optional LAMA agent such as glycopyrronium bromide, and glycerol. However, WO2018 / 051131 does not disclose a coated canister suitable for use with the above formulation.

[0012] WO2018 / 051130 describes a pharmaceutical formulation that comprises a pharmaceutical component containing at least one pharmaceutically acceptable salt of glycopyrrolate and a propellant component containing HFA 152a, wherein the formulation exhibits satisfactory stability without the use of an acid stabilizer.

[0013] WO2019236559, published on December 12, 2019, describes a pharmaceutical composition for use in a pMDI device that comprises beclomethasone dipropionate, formoterol fumarate dihydrate, glycopyrronium, a propellant selected from HFA134a, 227a, and 152a, a co-solvent, an organic acid, and optionally water.

[0014] US20160324778 describes a pharmaceutical composition for use in a pressurized pharmaceutical composition that comprises a propellant selected from HFO-1234yf (2,3,3,3-tetrafluoropropene) and HFO-1234ze (1,3,3,3-tetrafluoropropene) and one or more active ingredients such as formoterol and beclomethasone dipropionate, wherein the active ingredients are in the form of a suspension or solution containing the propellant.

[0015] Although the above prior art provides effective formulation and device technical arrangements, there is still a need to find a suitable pMDI device for use in the respiratory field for treating, for example, asthma and / or COPD, which not only takes into account the reduction of the global warming potential (GWP), but also conveniently provides a good stability system, especially with respect to the calibration and maintenance of the apparent pH of the formulation contained in the device. In fact, it has been noted that the prior art does not mention an appropriate and practical way to buffer the apparent pH of a formulation suitable for a pMDI device, which formulation contains at least corticosteroids, LABA agents, LAMA agents, and a propellant. The apparent pH is actually a key parameter that can affect many aspects of a pMDI formulation, especially when in solution form. For example, the stability of LABA and / or LAMA agents, shelf life, consistent delivery of the drug in the aerosol from the MDI, reproducibility of the final formulation, and maintenance of optimal chemical conditions in the canister.

[0016] We have unexpectedly found that, by means of an internally coated canister provided with a dedicated metering valve system, it is possible to stabilize the apparent pH of a formulation suitable for a pMDI device, which formulation contains at least corticosteroids, LABA, LAMA, and a suitable HFA or HFO propellant.

[0017] We have surprisingly found that the application of an internally coated canister provided with a dedicated metering valve system can avoid the presence of a buffer to maintain the stability of the apparent pH of a pMDI formulation. In fact, the internally coated canister according to the present invention is capable of stabilizing the apparent pH, even for an extended period of time, as demonstrated in the experimental section below. In this sense, the coated canister of the present invention can act as an apparent pH buffer system, and the application of the dedicated metering valve further increases the apparent pH buffering effect of the coated canister.

[0018] Advantageously, the coated canister provided with an appropriate valve system and containing at least corticosteroids, LABA, LAMA, and the selected HFA or HFO propellant of the present invention can be easily used in a pMDI device for treating respiratory diseases such as asthma and / or COPD, also ensuring good stability of the chemical components over time, excellent aerosolization performance, and low GWP. Summary of the Invention

[0019] In one aspect, the present invention relates to a canister for use in a pMDI device, the canister containing a formulation comprising at least a corticosteroid, a LABA agent, a LAMA agent, and an HFA 152a or HFO propellant, the canister being internally coated with a coating comprising at least a compound selected from: epoxy-phenol resin, perfluorinated polymer, perfluoroalkoxyalkane polymer, perfluoroalkoxyalkylene polymer, perfluoroalkylene polymer, polytetrafluoroethylene polymer (Teflon), fluorinated-ethylene-propylene polymer (FEP), polyethersulfone polymer (PES), fluorinated-ethylene-propylene polyethersulfone polymer (FEP-PES), polyamide, polyimide, polyamideimide, polyphenylene sulfide, plasma, mixtures or combinations thereof, wherein the canister is provided with a valve having at least one gasket, the gasket being made of a material comprising at least one polymer selected from: low density polyethylene, butyl polymers such as chlorobutyl or bromobutyl polymers, butadiene-acrylonitrile, chloroprene, EPDM (a polymer of ethylenepropylenediene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC), or combinations thereof.

[0020] In an additional aspect, the present invention relates to the coated canister as indicated above, wherein the formulation comprising at least a corticosteroid, a LABA, a LAMA agent, and an HFA or HFO propellant is a solution, preferably also comprising an inorganic or organic acid and / or a co-solvent.

[0021] In another aspect, the present invention relates to a pMDI device for use in the respiratory field, particularly for the treatment of asthma and / or COPD, comprising the coated canister as indicated above. DETAILED DESCRIPTION OF THE INVENTION

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0024] The "molar ratio" between formoterol or a salt thereof or a solvate of the salt and the selected acid is calculated considering the number of moles of formoterol or a salt thereof or a solvate of the salt in the formulation and the number of moles of the selected acid in the formulation.

[0025] Unless otherwise provided, the term "formoterol fumarate" or "FF" means (R,R)-(±) formoterol fumarate or its dihydrate.

[0026] Unless otherwise indicated, the term "LABA" or "LABA agent" includes in its meaning long-acting β2 agonists known in the art.

[0027] Unless otherwise indicated, the term "LAMA" or "LAMA agent" includes in its meaning long-acting muscarinic receptor antagonists known in the art.

[0028] The term "% w / w" refers to the weight percentage of a component relative to the total weight of the formulation.

[0029] The term "% w / v" refers to the weight percentage of a component relative to the total volume of the formulation.

[0030] A "stable" composition as defined herein means that, at a given point in time, the residual active ingredient content is at least about 90% w / w (which is the weight percentage content relative to its starting content at time 0), preferably at least about 95% w / w, and the total content of degradation products is not more than about 10% by weight, preferably not more than about 5% by weight, relative to the starting content of the active ingredient at time 0, as measured by HPLC / UV-VIS.

[0031] Regarding the term "apparent pH" mentioned herein, it should be noted that the calculation of pH is generally characteristic of aqueous liquids, such as in cases where water is the main component. In relatively non-protic solvents such as the HFA systems of the present invention, protons are non-hydrated and their activity coefficients can be different from those in aqueous solutions. Although the Nerst equation regarding the electromagnetic field (EMF) (which describes the potential of an electrochemical cell as a function of the concentration of ions participating in the reaction) is applied and the pH meter glass electrode system will produce a variable millivolt output depending on the proton concentration and the polarity of the medium, the pH meter reading represents the "apparent pH" according to the present invention. In this direction, the apparent pH according to the present invention can be measured by techniques known in the art, as indicated, for example, in "Correlation between Apparent pH and Acid or Base Concentration in ASTM Medium" Orest Popovych, Analytical Chemistry 1964, 36, 4, 878-882; Analytical Standard Test Method (ASTM) D6423-19 "Standard Test Method for Determination of pH of Denatured Fuel Ethanol and Ethanol Fuel Blends".

[0032] As mentioned above, the present invention surprisingly shows that when a coated can suitable for use in a pMDI device (which is provided with a dedicated valve system as detailed herein) is used to contain a suitable formulation comprising at least a corticosteroid, a LABA agent, a LAMA agent, and an HFA or HFO propellant, the apparent pH of such a formulation can be conveniently buffered between about 2.5 and 5, preferably between about 3 and 4.5, depending on, for example, the components of the formulation and / or their amounts, as described below. Such a buffering system provides several advantages such as increased stability of the formulation over time, particularly with respect to the amount of formoterol, good shelf life, reproducibility of the final formulation, maintenance of optimal chemical conditions within the can, and consistent delivery of the drug in the aerosol from the MDI.

[0033] Specifically, obtaining a stable apparent pH by means of an internally coated can provided with a dedicated valve system avoids the addition of an external conventional acid-base buffering system, which would result in a more complex formulation; the combined use of the coated can with a dedicated metering valve further increases the stability of the formulation acting as an apparent pH buffering system. In contrast, an uncoated can internally does not exhibit the effect of keeping the apparent pH of a pMDI solution formulation constant over time, as demonstrated in the comparative examples below.

[0034] Thus, in one embodiment, the present invention relates to a can provided with a dedicated valve system for use in a pMDI device, which contains a formulation as described and claimed herein, characterized by the fact that the apparent pH of the formulation is stabilized at a value between about 2.5 and 5, preferably between about 3 and 4.5. In other words, the present invention also relates to a coated can described and claimed herein, which is suitable for buffering the apparent pH of a formulation comprising at least a corticosteroid, a LABA, a LAMA, and an HFA or HFO propellant between about 2.5 and 5, preferably between about 3 and 4.5.

[0035] The apparent pH of a pMDI formulation is affected by the composition of the formulation, for example with respect to the concentration of acids, etc., and by selecting the appropriate amounts and types of LABA, LAMA, and / or corticosteroid agents, or by adding additional components to the formulation, an appropriate value can be set, as described below.

[0036] In terms of cans, coated cans known in the art can be suitably used in the present invention. Thus, the can can be made of a metal such as aluminum or a metal alloy, stainless steel or anodized aluminum, fluorine passivated aluminum, etc. Alternatively, the can can be made of plastic or any other suitable material. Preferably, the can is made of aluminum (optionally anodized) or stainless steel (suitably coated). The coating is generally applied to the inner surface of the can, thereby providing an inner layer that serves as an interface between the inner surface of the can and the preparation contained therein. Thus, the inner coating will prevent the components of the preparation from adhering to the can surface and also set up a pH buffering system. Generally, the inner coating will form a coating characterized by having a thickness that meets the requirements of uniformity and homogeneity, as tested using, for example, a WACO enamel rating instrument (such as commercially available). The inner coating will cover at least 50%, preferably at least 95%, and even more preferably at least 99% of the inner surface of the can.

[0037] In this regard, suitable coated cans of the present invention can have some or all of their inner surfaces coated with an inert organic or inorganic coating, which preferably comprises: epoxy-phenol resin, perfluoropolymer, perfluoroalkoxyalkane polymer, perfluoroalkoxyalkylene polymer (PFA), perfluoroalkylene polymer, polytetrafluoroethylene polymer (PTFE or Teflon), fluorinated-ethylene-propylene polymer (FEP), polyethersulfone polymer (PES), fluorinated-ethylene-propylene polyethersulfone polymer (FEP-PES), polyamide, polyimide, polyamideimide, polyphenylene sulfide, plasma, mixtures or combinations thereof.

[0038] As an example, the term "FEP-coated" means a coating that contains FEP and optionally contains additional components, including additives, binders, aggregating agents such as PES, isobutyl ketone, etc.

[0039] The polymers listed above can be used in combination with additional components or as part of a polymer mixture, such as a polymer mixture obtained by blending two or more polymeric compounds together. In this direction, the inner coating of the can according to the present invention is also intended to include such mixtures or combinations. In one embodiment, the coated can of the present invention is an FEP or PTFE-coated can, or more preferably an FEP-PES-coated can. In the case of FEP-PES coating, PES serves as an intermediate layer between the inner surface and the FEP polymer, thereby ensuring an even more uniform and homogeneous coating. It has actually been noted that when appropriate, more than one coating can be applied to the inner surface of the can to form a bilayer or multilayer coating with improved homogeneity and stability.

[0040] In one embodiment of the present invention, the can is an aluminum can, characterized by having an inner coating comprising an FEP-PES polymer. Suitable FEP-coated aluminum cans of the present invention are, for example, those commercially available and used in the art.

[0041] As demonstrated in the experimental section below, when a formulation comprising beclomethasone dipropionate (BDP), formoterol fumarate dihydrate, glycopyrronium bromide, and HFA152a propellant in solution form is contained in an FEP-coated can provided with a dedicated valve system according to the present invention, the apparent pH of the formulation is conveniently maintained at a selected value, even for an extended period of time.

[0042] In one embodiment, the corticosteroid component of the formulation contained in the coated can according to the present invention is selected from: budesonide, beclomethasone (BDP), for example as the mono- or dipropionate, flunisolide, fluticasone, for example as the propionate or furoate, ciclesonide, mometasone, for example as the furoate, mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinolone acetonide acetate, clocortolone, tixocortol pivalate, prednicarbate, alclometasone dipropionate, halometasone, lomefloxacin, desonide propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, rofleponide, etiprednol dicloacetate, wherein beclomethasone dipropionate (BDP) and budesonide are particularly preferred. In another preferred embodiment, the corticosteroid component is beclomethasone dipropionate (BDP).

[0043] According to another embodiment, the amount of the corticosteroid component according to the present invention is between 0.01 - 0.7% w / w, more preferably between 0.05 - 0.5% w / w, even more preferably between 0.1 - 0.3% w / w.

[0044] Regarding the LABA component of the formulation contained in the coated can according to the present invention, it is preferably selected from: fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol (TA-2005), indacaterol, milveterol, bambuterol, clenbuterol, vilanterol, olodaterol, abediterol, terbutaline, salmeterol, diastereoisomer mixture, and pharmaceutically acceptable salts or hydrates thereof. In one embodiment, the LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

[0045] Alternatively, the formulation of the present invention may comprise salbutamol, (R)-salbutamol (levosalbutamol) and pharmaceutically acceptable salts or hydrates thereof.

[0046] Preferably, the amount of LABA according to the present invention is between 0.0005 - 0.04% w / w, more preferably between 0.001 - 0.03% w / w, and even more preferably between 0.005 - 0.02% w / w.

[0047] In one embodiment, the LAMA pharmaceutical component of the formulation contained within the coated can according to the present invention is selected from: glycopyrronium, methscopolamine, ipratropium, oxitropium, trospium, tiotropium, aclidinium, and umeclidinium or pharmaceutically acceptable salts. In a preferred embodiment, the LAMA pharmaceutical is glycopyrronium bromide. Preferably, the amount of LAMA according to the present invention is between 0.001 - 0.08% (w / w), preferably 0.005 - 0.06% (w / w), and more preferably 0.01 - 0.04% (w / w).

[0048] The propellant of the formulation contained within the coated can according to the present invention is selected from HFA 152a and hydrofluoroolefins (HFO).

[0049] In one embodiment, the HFO propellant of the formulation contained within the coated can according to the present invention is selected from: 1,3,3,3 - tetrafluoropropene (HFO - 1234ze) and 2,3,3,3 - tetrafluoropropene (HFO - 1234yf). Preferably, the propellant is HFO - 1234ze.

[0050] In a preferred embodiment, the propellant is HFA152a.

[0051] The formulation contained within the coated can according to the present invention may be in the form of a suspension or a solution. In one embodiment, the selected corticosteroid, LABA, and LAMA components are preferably dissolved in the HFA or HFO propellant as defined above, thereby providing a solution. Thus, in a particularly preferred embodiment, the present invention relates to an FEP - coated can for use in a pMDI device, the FEP - coated can containing a solution that comprises at least beclomethasone dipropionate, formoterol fumarate dihydrate, glycopyrronium bromide, and HFA 152a.

[0052] As described above, in one embodiment, the formulation contained in the coated can according to the present invention may optionally further comprise additional components such as excipients, additives, solvents, co-solvents, acids, low volatility components or even active ingredients. The addition of said components can be appropriately calibrated in order to modularize for example the chemo-physical properties of the formulation and / or to set an appropriate apparent pH that is desired to remain constant according to the present invention. In this regard, in a preferred embodiment, the present invention relates to a coated can for use in a pMDI device as described above, said coated can containing a formulation comprising a corticosteroid, a LABA agent, a LAMA agent, an HFA or HFO propellant and optionally a co-solvent and / or an acid and / or a low volatility component.

[0053] Preferably, the co-solvent is a polar compound capable of increasing the solubility of the components in the formulation. Examples of suitable co-solvents are aliphatic alcohols having 1-4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, etc., preferably ethanol, more preferably absolute ethanol.

[0054] When present, the co-solvent is used in an amount between 5% w / w and 20% w / w, more preferably between 10% and 15%.

[0055] In one embodiment, the acid can be an inorganic acid or an organic acid, preferably selected from: hydrochloric acid, hydrobromic acid, nitric acid, fumaric acid, phosphoric acid and citric acid, maleic acid, acetic acid, xinafoic acid, oxalic acid, lactic acid, 2-methylpropanoic acid, malic acid, butyric acid, tartaric acid, propanoic acid, pentanoic acid, succinic acid, glycolic acid, hexanoic acid, malonic acid, glutaric acid, formic acid, adipic acid, ascorbic acid, benzoic acid, glucuronic acid or mixtures thereof, where hydrochloric acid is particularly preferred. According to a still preferred embodiment, the acid is concentrated hydrochloric acid or dilute hydrochloric acid, preferably 1M. Preferably, when the acid is 1M HCl, it is used in an amount between 0.001-0.08% w / w, preferably between 0.005-0.06%, more preferably between 0.01-0.04%.

[0056] Generally, the amount of the selected acid is preferably chosen so as to have a final apparent pH of the solution between about 2.5 and 5, preferably between 3 and 4.5, as described above. According to the present invention, by using a coated can provided with a dedicated valve system, the selected apparent pH is maintained stable and substantially does not vary over time, even when the pH is set by the presence of an acid, thus solving the problem of how to control and stabilize the apparent pH of a formulation suitable for pMDI applications, said formulation comprising at least a corticosteroid, a LABA agent, a LAMA agent and a propellant, in the presence of an inorganic or organic acid.

[0057] In a still preferred embodiment, the pMDI solution of the present invention consists of a LABA, a LAMA, and a corticosteroid dissolved in a system comprising HFA152a, 1 M HCl, and EtOH or consisting of them. According to this still preferred embodiment, the LABA, LAMA, and corticosteroid are formoterol fumarate dihydrate, glycopyrronium bromide, and beclomethasone dipropionate, respectively.

[0058] As will be appreciated, these last-described embodiments are also intended to be included within the scope of the present invention, also in any possible combination with all other preferred embodiments set forth above and below.

[0059] In one embodiment of the present invention, when present, the molar ratio between the LABA and the acid is between 0.50 and 1.50, preferably between 0.9 and 1.1. It has actually been noted that within this range, the stability of the final formulation is increased to a particularly convenient degree.

[0060] When present, the low volatility component has a vapor pressure at 25 °C of less than 0.1 kPa, preferably less than 0.05 kPa, and is preferably selected from: diols, propylene glycol, polyethylene glycol, glycerol or its esters, ascorbyl palmitate, isopropyl myristate, etc., where isopropyl myristate and glycerol are particularly preferred.

[0061] According to one embodiment, based on the total weight of the formulation, the formulation of the present invention contains preferably less than 3000 ppm, more preferably less than 2000 ppm, even more preferably less than 1500 ppm of water.

[0062] It is worth noting that by the present invention, the problem of how to effectively buffer the apparent pH of a pMDI formulation for commercial purposes containing a corticosteroid, a LABA agent, a LAMA agent, and an HFA or HFO propellant is surprisingly solved in the absence of additional buffering components or agents, which would otherwise compromise the stability and / or efficacy of the formulation contained in the canister. Also from a manufacturing point of view, the present invention allows for the preparation of a ready-to-use pMDI device with a simple and consolidated manufacturing process, which includes the coated canisters detailed herein. Even further, the application of a green propellant such as HFA 152a allows the present invention not only to solve the problems stated above, but also to address potential environmental concerns caused by the long-term application of other fluorinated propellants.

[0063] As pointed out above, the coated can for use according to the present invention is characterized by a dedicated metering valve system. It has actually surprisingly been found that the application of a dedicated metering valve further increases the apparent pH buffering of the coated can according to the present invention and is also beneficial with respect to residual formoterol, the overall stability and potency of the formulation. Generally, the can of a pMDI device is crimped with a metering valve for delivering a therapeutically effective dose of an active ingredient. The metering valve assembly comprises at least a gasket seal. Preferably, the valve comprises 2 or 3 gaskets made of the same or different materials. In this regard, according to the present invention, the valve is provided with 2 or 3 gaskets made of the same or different materials. Thus, according to the present invention, at least one gasket is made of a suitable elastomeric material, which elastomeric material comprises at least one polymer selected from the following: low density polyethylene, butyl such as chlorobutyl or bromobutyl, butadiene-acrylonitrile, chloroprene, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or combinations thereof.

[0064] Preferably, the valve is provided with 3 gaskets, and even more preferably they are all made of EPDM and are referred to herein as B-valves.

[0065] In a preferred embodiment, the valve is provided with one gasket made of COC and two gaskets made of EPDM and is referred to herein as A-valve.

[0066] In an equally preferred embodiment, the valve is provided with two gaskets, preferably both made of chlorobutyl polymer, and is referred to herein as V-valve.

[0067] In another preferred embodiment, the valve is provided with one gasket made of butyl rubber and two gaskets made of EPDM.

[0068] In an additional embodiment, the valve is provided with two gaskets preferably made of bromobutyl polymer, and one gasket made of a material selected from the following: chlorobutyl polymer, butadiene-acrylonitrile, chloroprene, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or combinations thereof. Preferably, the valve is provided with two gaskets made of bromobutyl polymer and one gasket made of EPDM.

[0069] The metering valve according to the present invention is generally capable of delivering a volume in the range of 25 - 150 μl, preferably in the range of 50 - 100 μl and more preferably 50 μl or 70 μl per actuation. Suitable valves of the present invention are commercially available, for example from factories well known in the art.

[0070] As a further advantage, we have surprisingly found that the choice of valve can conveniently improve the efficacy and reliability of the final pMDI device. For example, when using the HFA152a propellant in a coated can according to the present invention, an A-valve or a V-valve provides an even further improvement in the stability of the final formulation, for example relative to a B-valve provided with three washers made of EPDM.

[0071] As pointed out in the experimental section of the present invention, if the formulation is in the form of a solution, this improvement in stability is further enhanced. In fact, when used in combination with the HFA152a propellant, a B-valve can cause leakage of the propellant, which may lead to unwanted product loss and may impair the efficacy of the pMDI device over time. Surprisingly, when an A-valve or a V-valve is used in combination with the HFA152a propellant in a coated can according to the present invention, not only is the apparent pH buffering maximized, but leakage of the formulation is substantially avoided. This results in an effective and convenient system being readily adopted in the final pMDI device. This versatility confers a wide range of applications and customization possibilities for the final pMDI device containing the can according to the present invention, thus fulfilling the various needs and requirements of patients and / or the market.

[0072] According to a preferred embodiment, the valve is selected from an A-valve and a V-valve, with the A-valve being even more preferred.

[0073] Thus, in a preferred embodiment, the present invention relates to an FEP-coated can for use in a pMDI device, the FEP-coated can containing a formulation that at least comprises BDP, formoterol fumarate dihydrate, glycopyrronium bromide, HCl and an HFA152a propellant, the FEP-coated can having a valve selected from an A-valve or a V-valve. According to this embodiment, the can optionally further comprises ethanol, preferably anhydrous ethanol.

[0074] By means of common methodologies used in the art, a selected formulation can be filled into the coated can for use in a pMDI device according to the present invention. As a general example, the methodology can include the following steps:

[0075] a) Prepare a solution that comprises: formoterol fumarate, BDP, glycopyrronium bromide and ethanol;

[0076] b) Fill the FEP-coated can with the solution;

[0077] c) Add a quantity of HCl that produces a molar ratio of formoterol fumarate dihydrate to the acid that is between 0.50 and 1.50;

[0078] d) Add 1,1-difluoroethane (HFA 152a) propellant;

[0079] e) Crimp and inflate with an Aptar valve.

[0080] The pMDI containing the coated can according to the present invention can have the configuration and components of a conventional pMDI device, such as those already on the market for well-known formulations used to treat, for example, asthma and / or COPD.

[0081] Unless otherwise provided, all of the above embodiments are intended to be combinable and considered part of the scope of the present invention.

[0082] The present invention will now be described by the following non-limiting examples.

[0083] Experimental Section

[0084] In Examples 1 and 2 below, the apparent pH was measured using a standard LiCl electrode commonly used to measure pH in organic media. For MDI pressurized products, in order to measure the apparent pH of the formulation, the following protocol was applied:

[0085] 1 - Cool the can to at least -50 °C (immerse the can in a dry ice bath or liquid nitrogen to allow the internal pressure to be reduced to atmospheric pressure).

[0086] 2 - Open the can by cutting the valve and allow the propellant to evaporate at room temperature.

[0087] 3 - Pour the remaining ethanol solution (containing API) into a glass bottle and adjust the volume to 10 ml with anhydrous ethanol to have a sufficient volume for measurement via a standard LiCl electrode.

[0088] 4 - Measure the apparent pH of the reconstituted solution using a LiCl electrode.

[0089] Example 1

[0090] In the presence of HFA 152a, an FEP-coated aluminum can according to the present invention was filled with a solution containing FF (0.011% w / w), BDP (0.18% w / w), glycopyrronium bromide (0.022% w / w), 1 M HCl (0.02% w / w), and ethanol (12% w / w).

[0091] The FEP-coated aluminum cans filled with the above solution and provided with valve A, B, or V were placed in a stability chamber at 25 °C and 60% R.H. (relative humidity).

[0092] At T = 0, 1, 3, and 6 months respectively, the apparent pH (App pH) of the solution and the residual percentage (FF% w / w) of formoterol fumarate dihydrate relative to the starting content (100% at T = 0) were measured.

[0093] The results are collected in Table 1 below.

[0094] Table 1: Apparent pH values (App pH) and FF% measured in an FEP-coated can at 25 °C / 60% R.H. at T = 0 and T = 1 month (1M), T = 3 months (3M), and 6 months (6M)

[0095]

[0096] A-valve: The valve is provided with a gasket made of COC and two gaskets made of EPDM, such as those available from Aptar, for example.

[0097] V-valve: The valve is provided with two gaskets, both made of chlorobutyl polymer, such as those available from Vari, for example.

[0098] B-valve: The valve is provided with 3 gaskets, all made of EPDM, such as those available from Bespak, for example.

[0099] Example 2 (Comparison)

[0100] The same analysis as in Example 1 has been carried out using uncoated aluminum cans provided with valve A, B, or V.

[0101] The apparent pH (App pH) of the solution according to Example 1 was measured at T = 0, 1, 3, and 6 months respectively. The results are collected in Table 2.

[0102] Table 2: Apparent pH values (App pH) and FF% w / w measured in an uncoated can at 25 °C / 60% R.H. at T = 0 and T = 1 month (1M), T = 3 months (3M), and 6 months (6M)

[0103]

[0104]

[0105] B-valve: The valve is provided with 3 gaskets, all made of EPDM, such as those available from Bespak, for example.

[0106] A-valve: The valve is provided with a gasket made of COC and two gaskets made of EPDM, such as those available from Aptar, for example.

[0107] V-valve: The valve is provided with two gaskets, both of which are made of neoprene polymer, such as, for example, available from Vari.

[0108] As is evident from Tables 1 and 2 above, the application of an FEP-coated can according to the invention provided with the specified valve (filled with a solution in the presence of HFA152a propellant) ensures a convenient stabilization of the pH of the solution contained therein, even over an extended period of time, for example, even after 6 months compared to T = 0.

[0109] In contrast, by using an uncoated can (comparison), the pH increases significantly relative to the measured value at T = 0, also resulting in a potential decrease in FF% w / w, even after storage at 25 °C (which can be assumed to be room temperature) for only 1 month.

Claims

1. A canister for use in a pMDI device, the canister containing a formulation comprising at least a corticosteroid, a LABA agent, a LAMA agent, and an HFA152a or HFO propellant, the canister being internally coated with a coating comprising at least a compound selected from: epoxy-phenol resin, perfluoropolymer, perfluoroalkoxyalkane polymer, perfluoroalkoxyalkylene polymer, perfluoroalkylene polymer, polytetrafluoroethylene polymer (Teflon), fluorinated-ethylene-propylene polymer (FEP), polyethersulfone polymer (PES), fluorinated-ethylene-propylene polyethersulfone polymer (FEP-PES), polyamide, polyimide, polyamideimide, polyphenylene sulfide, plasma, mixtures or combinations thereof, wherein the canister is provided with a valve having at least one gasket, the gasket being made of a material comprising at least one polymer selected from: low density polyethylene, butyl polymers such as chlorobutyl or bromobutyl polymers, butadiene-acrylonitrile, chloroprene, EPDM (ethylene propylene diene monomer polymer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or combinations thereof.

2. The canister according to claim 1, wherein the corticosteroid is selected from: budesonide, beclomethasone dipropionate, flunisolide, fluticasone, ciclesonide, mometasone, mometasone furoate, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, teprenone, prednicarbate, alclometasone dipropionate, halometasone, lymecycline, desonide propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, rofleponide, and eprodisate.

3. The canister according to claim 2, wherein the corticosteroid is beclomethasone dipropionate or budesonide.

4. The canister according to any one of the preceding claims, wherein the LABA agent is selected from: fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol, indacaterol, mivacurium, bambuterol, clenbuterol, vilanterol, olodaterol, abediterol, terbutaline, and salmeterol.

5. The canister according to claim 4, wherein the LABA agent is formoterol fumarate dihydrate.

6. The canister according to claim 1, wherein the formulation agent alternatively comprises an agent selected from salbutamol and (R)-salbutamol.

7. The canister according to one of the preceding claims, wherein the LAMA agent is selected from glycopyrronium, methscopolamine, ipratropium, oxitropium, tropicamide, tiotropium, aclidinium, umeclidinium or a pharmaceutically acceptable salt.

8. The canister according to claim 7, wherein the LAMA agent is glycopyrronium bromide.

9. The canister according to any one of the preceding claims, wherein the HFO propellant is selected from 1,3,3,3-tetrafluoropropene (HFO-1234ze) and 2,3,3,3-tetrafluoropropene (HFO-1234yf).

10. The can according to any one of the preceding claims, wherein the can is internally coated with a coating comprising a fluorinated ethylene-propylene (FEP) polymer.

11. The can according to any one of the preceding claims, wherein the can contains a formulation which further comprises one or more excipients, co-solvents and acids.

12. The can according to claim 11, wherein the co-solvent is an aliphatic alcohol having 1 to 4 carbon atoms.

13. The can according to claim 12, wherein the aliphatic alcohol is ethanol, preferably absolute ethanol.

14. The can according to claims 11-13, wherein the can contains a formulation which further comprises an inorganic or organic acid selected from hydrochloric acid, hydrobromic acid, nitric acid, fumaric acid, phosphoric acid, citric acid, maleic acid, acetic acid, hydroxynaphthoic acid, oxalic acid, lactic acid, 2-methylpropanoic acid, malic acid, butyric acid, tartaric acid, propanoic acid, pentanoic acid, succinic acid, glycolic acid, hexanoic acid, malonic acid, glutaric acid, formic acid, adipic acid, ascorbic acid, benzoic acid and glucuronic acid.

15. The can according to claim 14, wherein the acid is hydrochloric acid.

16. The can according to any one of the preceding claims, wherein the can contains a formulation which further comprises a low volatility component selected from diols, propylene glycols, polyethylene glycols, glycerol or its esters, ascorbyl palmitate, isopropyl myristate.

17. The can according to any one of the preceding claims, wherein the can contains the formulation in solution form.

18. The can according to claims 1-17, wherein the valve is provided with 3 gaskets all made of EPDM.

19. The can according to claims 1-17, wherein the valve is provided with a gasket made of COC and two gaskets made of EPDM.

20. The can according to claims 1-17, wherein the valve is provided with two gaskets both made of chlorobutyl polymer.

21. The can according to claims 1-17, wherein the valve is provided with a gasket made of butyl rubber and two gaskets made of EPDM.

22. The can according to claims 1-17, wherein the valve is provided with two gaskets made of bromobutyl and one gasket made of a material selected from: chlorobutyl, butadiene-acrylonitrile, chloroprene, EPDM (ethylene propylene diene monomer polymer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or combinations thereof.

23. The can according to any one of claims 1-22, wherein the propellant is HFA152a and the valve is provided with a gasket made of COC and two gaskets made of EPDM; or the valve is provided with two gaskets, both of which are made of chlorobutyl polymer.

24. The can according to any one of the preceding claims, wherein the can contains a formulation having an apparent pH buffered between 2.5 and 5.

25. The can according to claim 24, wherein the can contains a formulation having an apparent pH buffered between 3 and 4.

5.

26. A pMDI device comprising the can according to any one of the preceding claims.

27. The pMDI device according to claim 26, which is used for treating respiratory diseases selected from asthma and / or COPD.

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