Pressurized metered dose inhaler comprising a buffered pharmaceutical formulation

Abstract

To provide a can in a pressurized metered dose inhaler for the treatment of respiratory diseases which ensures good stability of the chemical components over a long period of time, excellent aerosolization performance and low GWP.SOLUTION: A can for use in a pMDI device containing a formulation comprising at least a corticosteroid, a LABA drug and a HFA or HFO propellant, wherein the can is internally coated with a coating comprising a compound selected from at least an epoxy phenolic resin, a perfluorinated polymer, a perfluoroalkoxy alkane polymer, a perfluoroalkoxy alkylene polymer, a perfluoroalkylene polymer, a polytetrafluoroethylene polymer (Teflon), a fluorinated ethylene propylene polymer (FEP), a polyethersulfone polymer (PES), etc., mixtures or combinations thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates generally to an aerosol formulation comprising at least a LABA, a corticosteroid, and a propellant, the formulation being contained in a coated canister and particularly useful for use in pressurized metered dose inhalers for the respiratory tract. [Background technology]

[0002] Pressurized metered-dose inhalers (pMDIs) are well-known devices for administering medications to the respiratory tract via inhalation. pMDI devices typically include a medication-containing canister (also referred to herein as a "canister") and an actuator housing with a mouthpiece. The canister is usually crimped onto a metering valve assembly. Depending on the active ingredient and additional components, such as additives and acids, the final pMDI formulation may be in the form of a solution or a suspension. A solution generally refers to one that is substantially free of sediment or particles, while a suspension typically refers to a formulation that contains undissolved material or sediment. pMDI devices may use a propellant to expel medication-containing droplets into the respiratory tract as an aerosol. For many years, the preferred propellants used in this regard have been chlorofluorocarbons or CFCs, such as CCl3F (Freon 11 or CFC-11), CCl2F2 (Freon 12 or CFC-12), and the chlorofluorocarbon derivative commonly referred to as CClF2-CClF2 (Freon 114 or CFC-114). International concern that fully or partially halogenated chlorofluorocarbons have critical global warming potentials (GWPs) that impact the Earth's protective ozone layer led many countries to sign the Montreal Protocol, which requires that their production and use be severely restricted and eventually phased out entirely. As a result, hydrofluoroalkanes (HFAs), specifically 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227a), have been identified and accepted as alternatives to CFCs in the pharmaceutical sector. Since then, the hydrofluoroalkane propellants HFA134a and HFA227a have been widely used in the respiratory field, especially given their efficacy and compatibility with many active ingredients, such as corticosteroids, LABAs, or antimuscarinics.

[0003] However, despite the effectiveness of HFA propellants and their widespread application in many pharmaceutical products already on the market, the possibility of having alternative classes of propellants and alternative means for obtaining effective pMDI devices is constantly being explored. For general references in this regard, see, for example, "Pharmaceutical Inhalation Aerosol Technology", Third Edition 2019, Anthony J. Hickey et al., where, in Table 18.3 on page 440, several propellants potentially suitable for medical use are compared in terms of their global warming potential.

[0004] This relates, for example, to the optimization of the mechanical elements of the pMDI device, such as the valve or the can, or also to the possibility of having propellant-free spray devices, spray-drying systems, or devices characterized by a more environmentally friendly impact.

[0005] Further characteristics to consider when discussing pMDI devices are the apparent pH and water content of the formulation aerosolized by the device - for general references in this regard see, for example, WO01 / 89480 and WO03 / 074024.

[0006] Fluorocarbon polymers are commonly used to coat the interior surface of pMDI cans and, for suspension formulations, to eliminate particle adhesion or deposition on the can wall, i.e., avoid sticking, and to avoid the formation of by-products.

[0007] EP0820323 describes a pMDI having some or all of its internal surfaces coated with one or more fluorocarbon polymers for dispensing inhalable drug formulations comprising salmeterol and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents, such that the internal surface of the can significantly reduces or essentially eliminates the problem of salmeterol adhesion or deposition.

[0008] WO 2015 / 101576 describes a pMDI device particularly suitable for use with a solution of formoterol, beclomethasone propionate, and glycopyrronium bromide contained in an FEP-coated can. As disclosed therein, the formulation contained in the FEP-coated can has improved stability and reduced amounts of degradation products, primarily with respect to N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide. In fact, this product (identified as DP3) is a specific degradation product resulting from the interaction of formoterol with bromide ions from glycopyrronium bromide when the two active ingredients are dissolved in an HFA-ethanol system in the presence of acid, particularly hydrochloric acid.

[0009] EP2706987 describes a formulation for use in a pMDI device comprising beclomethasone propionate and HFA152, which is particularly suitable for the treatment of respiratory disorders.

[0010] WO2018 / 051131 describes a pharmaceutical formulation containing beclomethasone propionate and formoterol fumarate dihydrate, a propellant containing 1,1-difluoroethane (HFA152a), and glycerol, which has good chemical stability, in Table 4 of Example 1. Indeed, the exemplified formulation of WO2018 / 051131 is characterized by the absence of acid and the presence of glycerol.

[0011] WO2018 / 051130 describes a pharmaceutical formulation comprising a drug component comprising at least one pharmaceutically acceptable salt of glycopyrrolate and a propellant component comprising HFA152a, wherein the formulation exhibits satisfactory stability without the use of an acid stabilizer.

[0012] US20160324778 describes a pharmaceutical composition for use in pressurized pharmaceutical compositions comprising 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 propionate, wherein the active ingredients are in the form of a suspension or solution with the propellant.

[0013] While the above-mentioned prior art provides technical arrangements for effective formulations and devices, there remains a need to find a suitable pMDI device for use in the respiratory field, for example for the treatment of asthma and / or COPD, that not only attempts to reduce the Greenhouse Warming Potential (GWP), but also advantageously provides a good stabilization system, particularly with regard to adjusting and maintaining the apparent pH of the formulation contained in the device. Indeed, it should be noted that the prior art is silent about suitable and practical methods for buffering the apparent pH of formulations suitable for pMDI devices, including at least a corticosteroid, a LABA, and a propellant. Apparent pH is indeed an important parameter, especially when in the form of a solution, that can affect many aspects of pMDI formulations, such as the stability of LABA drugs, shelf life, consistent delivery of the drug in the aerosol from the MDI, reproducibility of the final formulation, and maintaining optimal chemical conditions within the can.

[0014] It has been unexpectedly discovered that the apparent pH of a formulation suitable for a pMDI device containing at least a corticosteroid, a LABA and an appropriate HFA or HFO propellant can be stabilized by an inner coated canister.

[0015] It has surprisingly been found that the use of an internally coated canister can avoid the presence of a buffering agent and maintain a stable apparent pH of a pMDI formulation. Indeed, the internally coated canister of the present invention can stabilize the apparent pH even over long periods of time, as shown in the experimental part of this specification below. In this sense, the coated canister of the present invention can act as an apparent pH buffer system.

[0016] Advantageously, the coated canisters containing at least a corticosteroid, a LABA and a selected HFA or HFO propellant of the present invention can be crimped with a suitable valve system and easily used in pDMI devices for the treatment of respiratory disorders, such as asthma and / or COPD, and ensure good chemical stability over time, excellent aerosolization performance, and low GWP. Summary of the Invention

[0017] In one aspect, the invention refers to a canister for use in a pMDI device containing a formulation comprising at least a corticosteroid, a LABA drug and an HFA or HFO propellant, wherein the canister is internally coated with a coating comprising a compound selected from at least an epoxy phenolic resin, a perfluorinated polymer, a perfluoroalkoxyalkane polymer, a perfluoroalkoxyalkylene polymer, a perfluoroalkylene polymer, a polytetrafluoroethylene polymer (Teflon), a fluorinated ethylene propylene polymer (FEP), a polyethersulfone polymer (PES), a fluorinated ethylene propylene polyethersulfone polymer (FEP-PES), a polyamide, a polyimide, a polyamideimide, a polyphenylene sulfide, a plasma, a mixture or combination thereof.

[0018] In a further embodiment, the present invention refers to a can as described above, comprising a metering valve system having at least a gasket made of an elastomeric material comprising low density polyethylene, butyl rubber, such as chlorobutyl or bromobutyl rubber, butadiene-acrylonitrile rubber, neoprene, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC), or mixtures thereof.

[0019] In a further aspect, the present invention relates to a coated can as described above, wherein the formulation comprising at least a corticosteroid, a LABA drug and an HFA propellant is a solution that preferably also comprises an inorganic or organic acid and / or a cosolvent.

[0020] In a further aspect, the present invention relates to a pMDI device for use in the respiratory field, in particular for the treatment of asthma and / or COPD, comprising a coated can as shown above. DETAILED DESCRIPTION OF THE INVENTION

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0022] The "molar ratio" between formoterol, or a salt thereof, or a solvate of the salt thereof, and an acid is calculated taking into account the number of moles of formoterol, or a salt thereof, or a solvate of the salt thereof in the formulation and the number of moles of the selected acid in the formulation.

[0023] Unless otherwise specified, the term "formoterol fumarate" or "FF" refers to (R,R)-(±) formoterol fumarate or its dihydrate.

[0024] Unless otherwise specified, the term "LABA" or "LABA drug" includes within its meaning long-acting beta-2 agonists known in the art.

[0025] The term "% w / w" refers to the weight percent of the ingredient relative to the total weight of the formulation.

[0026] The term "% w / v" refers to the weight percent of a component relative to the total volume of the formulation.

[0027] A "stable" composition, as defined herein, means one having a residual active ingredient content at a given time point of at least about 90% w / w (as a weight percent of the content relative to the initial content at time 0), preferably at least about 95% w / w, as measured by HPLC / UV-VIS, and a total content of degradation products of no more than about 10% w / w, preferably no more than about 5% w / w, relative to the initial content of active ingredient at time 0.

[0028] With respect to the term "apparent pH" as intended herein, it should be noted that pH calculations are generally characteristic of aqueous liquids, for example, when water is the predominant component. In relatively aprotic solvents, such as the HFA systems of the present invention, protons are not hydrated, and their activity coefficients may differ from those in aqueous solutions. The Nernst equation for the electromagnetic field (EMF) (which describes the potential of an electrochemical cell as a function of the concentration of ions participating in a reaction) is applied, and the glass electrode system of the pH meter produces a variable millivolt output according to the proton concentration and the polarity of the vehicle, and the pH meter reading represents the "apparent pH" according to the present invention. In this regard, the apparent pH according to the present invention can be measured by techniques known in the art, for example, as set forth 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."

[0029] As noted above, the present invention unexpectedly demonstrates that when a coated can suitable for a pMDI device is used to contain a suitable formulation comprising at least a corticosteroid, a LABA drug, and an HFA or HFO propellant, the apparent pH of such a formulation can be advantageously buffered to between about 2.5 and 5, preferably between about 3 and 4.5, depending, for example, on the formulation's ingredients and / or their amounts, as described herein below. Having such a buffering system provides several advantages, including increased formulation stability over time, 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, particularly with respect to the formoterol amount.

[0030] In particular, having a stable apparent pH with an internally coated can avoids the addition of an external conventional acid-base buffer system, which leads to more complex formulations. In contrast, cans without an internal coating are not as effective at maintaining a constant apparent pH over time for pMDI solution formulations, as shown in the comparative example below.

[0031] Thus, in one embodiment, the invention relates to a canister for use in a pMDI device, comprising a formulation as described and claimed herein, wherein the apparent pH of the formulation has been stabilized at a value of about 2.5 to 5, preferably about 3 to 4.5. In other words, the invention also relates to a canister as described and claimed herein, suitable for buffering the apparent pH of a formulation comprising at least a corticosteroid, a LABA, and an HFA or HFO propellant to a value of about 2.5 to 5, preferably about 3 to 4.5.

[0032] The apparent pH of a pMDI formulation is affected by the composition of the formulation, for example with reference to the acid concentration, and setting an appropriate value may be achieved by selecting the appropriate amount and type of LABA and / or corticosteroid drug or by adding further ingredients to the formulation, as described herein below.

[0033] Regarding cans, coated cans known in the art can be suitable for use in the present invention. Thus, cans can be made of metal, such as aluminum, or metal alloys, stainless steel, anodized aluminum, fluorine-passivated aluminum, etc. Alternatively, cans can be made of plastic or other suitable materials. Preferably, cans can be made of appropriately coated, optionally anodized, aluminum or stainless steel. The coating is typically applied to the interior surface of the can, thus providing an inner layer that serves as an interface between the interior surface of the can and the formulation contained therein. The inner surface coating thereby prevents the adhesion of formulation components to the can surface and also establishes a pH buffer system. Typically, the inner coating forms a coating layer characterized by a thickness that meets requirements for uniformity and homogeneity, as tested, for example, using a commercially available WACO enamel evaluation device. The inner coating covers at least 90%, preferably at least 95%, and even more preferably at least 99% of the interior surface of the can.

[0034] In this regard, suitable coated cans of the present invention may have some or all of their interior surfaces coated with an inert organic or inorganic coating, preferably including epoxy phenolic resins, perfluorinated polymers, perfluoroalkoxyalkane polymers, perfluoroalkoxyalkylene polymers (PFA), perfluoroalkylene polymers, polytetrafluoroethylene polymers (PTFE or Teflon), fluorinated ethylene propylene polymers (FEP), polyethersulfone polymers (PES), fluorinated ethylene propylene polyethersulfone polymers (FEP-PES), polyamides, polyimides, polyamideimides, polyphenylene sulfides, plasma, mixtures or combinations thereof.

[0035] As an example, the term "FEP coated" refers to a coating layer that includes FEP and any additional components, including additives, adhesives, cohesives, e.g., PES, isobutyl ketone.

[0036] The polymers listed above can be used in combination with additional components or as part of a polymer blend, for example, obtained by mixing two or more polymer compounds together. In this regard, the internal can coating of the present invention is intended to include such blends or combinations. In one embodiment, the coated can of the present invention is a can coated with FEP or PTFE, or more preferably, a can coated with FEP-PES. In the case of an FEP-PES coating, the PES acts as an intermediate layer between the internal surface and the FEP polymer, ensuring a more uniform and homogeneous coating. It should be noted that, in appropriate cases, multiple coatings can be applied to the internal surface of the can to form a two- or multi-layer coating with improved homogeneity and stability.

[0037] In one embodiment of the present invention, the can is an aluminum can characterized by having an inner surface coating containing an FEP-PES polymer. Aluminum FEP-coated cans suitable for the present invention are, for example, those commercially available and in use in the field.

[0038] As shown in the experimental part below, when a formulation in solution form containing at least beclomethasone propionate (BDP), formoterol fumarate dihydrate, and an HFA propellant selected from HFA134a and HFA152a is contained in an FEP-coated can according to the present invention, the apparent pH of the formulation is favorably maintained at a selected value, even over an extended period of time. In contrast, when an uncoated aluminum can (whether anodized or not) is used as a comparative experiment, the apparent pH of the same solution exhibits an unstable profile over time, as shown in Tables 1 and 2 (comparison) below.

[0039] In one embodiment, the corticosteroid component of the formulation contained in the coated can according to the invention is budesonide, beclomethasone (BDP), e.g. the mono- or dipropionate ester, flunisolide, fluticasone, e.g. the propionate or furoate ester, ciclesonide, mometasone, e.g. the furoate ester, mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, flucloxone, fluticas ... In a further preferred embodiment, the corticosteroid component is selected from the group consisting of ocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone propionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, rofleponide, etiprednol dicloacetate, with beclomethasone propionate (BDP) and budesonide being particularly preferred.

[0040] The propellant for the formulation contained in the coated can according to the invention is selected from hydrofluoroalkanes (HFAs) and hydrofluoroolefins (HFOs).

[0041] In one preferred embodiment, the HFA propellant of the formulation contained in the coating can according to the invention is selected from the group consisting of 1,1,1,2-tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA227a), 1,1-difluoroethane (HFA152a) and mixtures thereof.

[0042] In a further preferred embodiment, the HFA propellant is selected from HFA134a and HFA152a or mixtures thereof.

[0043] In one preferred embodiment, the HFA propellant is HFA134a.

[0044] In one equally preferred embodiment, the HFA propellant is HFA152a.

[0045] In one embodiment, the HFO propellant of the formulation contained in the coated can according to the invention is selected from the group consisting of 1,3,3,3-tetrafluoropropene (HFO-1234ze) and 2,3,3,3-tetrafluoropropene (HFO-1234yf). Preferably, the HFO propellant is HFO-1234ze.

[0046] Preferably, when the propellant is HFA134a, the amount of corticosteroid component according to the invention is comprised between 0.1 and 0.5% w / w, more preferably between 0.1 and 0.3% w / w, even more preferably between 0.1 and 0.2% w / w.

[0047] According to another embodiment, when the propellant is HFA152a, the amount of corticosteroid component according to the invention is comprised between 0.1 and 0.7% w / w, more preferably between 0.1 and 0.5% w / w, even more preferably between 0.2 and 0.4% w / w.

[0048] The LABA component of the formulation contained in the coated can according to the present invention is preferably selected from the group consisting of salbutamol, (R)-salbutamol (levalbuterol), fenoterol, formoterol fumarate, arformoterol, carmoterol (TA-2005), indacaterol, mirveterol, bambuterol, clenbuterol, vilanterol, olodaterol, abesiterol, terbutaline, salmeterol, diastereomeric mixtures, and pharmaceutically acceptable salts or hydrates thereof. In one embodiment, the LABA is formoterol fumarate, preferably formoterol fumarate dihydrate. Preferably, when the propellant is HFA134a, the amount of the LABA according to the present invention is 0.005-0.020% w / w, more preferably 0.010-0.020% w / w, and even more preferably 0.010-0.016% w / w. In another embodiment, when the propellant is HFA152a, the amount of LABA according to the invention is comprised between 0.005 and 0.030% w / w, more preferably between 0.010 and 0.027% w / w, even more preferably between 0.012 and 0.022% w / w.

[0049] The formulation contained in the coated can according to the present invention can be in the form of a suspension or solution. In one embodiment, the selected corticosteroid and LABA components are preferably dissolved in the HFA or HFO propellant defined above, thus providing a solution. Thus, in a particularly preferred embodiment, the present invention relates to an FEP-coated can for use in a pMDI device, containing a solution comprising at least beclomethasone propionate, formoterol fumarate dihydrate, and HFA134a and / or HFA152a.

[0050] As described above, the formulation contained in the coated can according to the present invention may optionally further comprise further components, such as additives, additives, solvents, co-solvents, acids, low-volatility components or further active ingredients. The addition of such components may be adjusted appropriately in accordance with the present invention, for example to modulate the chemical and physical properties of the formulation and / or to set an appropriate apparent pH that is desired to be kept constant. In this regard, in a preferred embodiment, the present invention relates to a coated can for use in a pMDI device, which contains a formulation comprising a corticosteroid, a LABA drug, an HFA or HFO propellant, and optionally a co-solvent and / or an acid and / or a low-volatility component.

[0051] Preferably, the co-solvent is a polar compound that can increase the solubility of the ingredients in the formulation. Examples of suitable co-solvents include aliphatic alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, etc., preferably ethanol, more preferably absolute ethanol.

[0052] When present, the co-solvent is used in an amount of 5% to 20% w / w, more preferably 10% to 15%.

[0053] In one embodiment, the acid may be an inorganic acid or an organic acid, preferably selected from hydrochloric acid, hydrobromic acid, nitric acid, fumaric acid, phosphoric acid, and citric acid, with hydrochloric acid being particularly preferred. In a more preferred embodiment, the acid is concentrated or diluted hydrochloric acid, preferably 1 M. When the acid is HCl 1 M and the propellant is HFA134a, it is used in an amount of 0.010 to 0.050% w / w, preferably 0.012 to 0.025% w / w, and even more preferably 0.015 to 0.025% w / w.

[0054] According to another embodiment, when the acid is HCl 1M and the propellant is HFA152a, it is used in an amount of 0.014 to 0.070% w / w, preferably 0.016 to 0.035% w / w, even more preferably 0.020 to 0.035% w / w.

[0055] Generally, the amount of acid selected is preferably selected to have a final apparent pH of the solution comprised as above between about 2.5 and 5, preferably between 3 and 4.5. According to the present invention, by using a coated can, the selected apparent pH remains stable and substantially unchanged 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 pH of a formulation suitable for pMDI application, comprising at least a corticosteroid, a LABA drug, and a propellant, in the presence of an inorganic or organic acid.

[0056] In one embodiment of the invention, the molar ratio between the LABA and the acid, if present, is between 0.50 and 1.50, preferably between 0.9 and 1.1. It should be noted that in this range, in fact, the stability of the final formulation is increased to a particularly advantageous extent.

[0057] When present, the low volatility component has a vapor pressure of less than 0.1 kPa, preferably less than 0.05 kPa at 25°C, and is preferably selected from the group consisting of glycol, propylene glycol, polyethylene glycol, glycerol or esters thereof, ascorbyl palmitate, isopropyl myristate, etc., with isopropyl myristate and glycerol being particularly preferred.

[0058] According to one embodiment, the formulation of the present invention preferably contains water in an amount less than 3000 ppm, more preferably less than 2000 ppm, even more preferably less than 1500 ppm, relative to the total weight of the formulation.

[0059] It is noteworthy that the present invention surprisingly solves the problem of how to effectively buffer the apparent pH of commercial pMDI formulations containing a corticosteroid, a LABA drug, and an HFA or HFO propellant without the addition of additional components or substances that, while buffering, may nevertheless impair the stability and / or efficacy of the formulation contained in the can. Also, from a manufacturing perspective, the present invention enables the production of ready-to-use pMDI devices containing the coated cans described herein using a simple, integrated manufacturing process. Furthermore, through the use of green propellants such as HFA152a or HFO-1234ze, the present invention not only solves the above-mentioned problems, but also addresses potential environmental concerns arising from the long-term use of other fluorinated propellants.

[0060] As indicated above, coated cans for use according to the present invention can also be characterized by additional technical features, such as a metering valve system. Indeed, it has surprisingly been found that the use of a specialized metering valve further increases the apparent pH buffering effect of the coated cans according to the present invention, which is also beneficial in terms of residual formoterol and the overall stability and efficacy of the formulation. Generally, the can of a pMDI device is crimped onto a metering valve for delivering a therapeutically effective dose of the active ingredient. The metering valve assembly includes at least a gasket seal. Preferably, the valve includes two or three gaskets made of the same or different materials. In this regard, according to the present invention, the valve comprises two or three 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, including at least one polymer selected from low-density polyethylene, butyl, e.g., chlorobutyl or bromobutyl, butadiene-acrylonitrile, neoprene, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC), or a combination thereof.

[0061] Preferably, the valve comprises three gaskets, even more preferably all of which are made from EPDM, and is referred to herein as a B-valve.

[0062] In one equally preferred embodiment, the valve comprises a gasket made of COC together with two gaskets made of EPDM, and is referred to herein as an A-valve.

[0063] In a further preferred embodiment, the valve comprises two gaskets, preferably both of which are made from chlorobutyl polymer, and is referred to herein as a V-valve.

[0064] In a further preferred embodiment, the valve comprises a gasket made of butyl rubber together with two gaskets made of EPDM.

[0065] Metering valves according to the invention are typically capable of delivering volumes in the range of 25-150 μl per actuation, preferably in the range of 50-100 μl, and more preferably 50 μl or 70 μl. Valves suitable for the present invention are commercially available, for example from manufacturers well known in the art.

[0066] Furthermore, we have found that, depending on the HFA propellant selected, valve selection can advantageously improve the effectiveness and reliability of the final pMDI device. For example, when HFA152a propellant is used in a coated can according to the present invention, A-valves or V-valves improve the stability of the final formulation over, for example, B-valves. This stability improvement is further enhanced when the formulation is in the form of a solution, as shown in the experimental part of this application. In fact, when used in combination with HFA152 propellant, B-valves can lead to leakage of the propellant, which can result in undesirable loss of product and potentially impair the effectiveness of the pMDI device over time. Surprisingly, when A-valves or V-valves are used in combination with HFA152a propellant in a coated can according to the present invention, not only is the apparent pH buffering effect maximized, but leakage of the formulation is also substantially avoided. This results in an effective and convenient system that is easily used in the final pMDI device. Advantageously, when HFA134a propellant is used in a coated can according to the present invention, either B-valves, A-valves, or V-valves can be advantageously used. This versatility allows for a wide range of applications and customization possibilities for the final pMDI device comprising the canister according to the invention, thus meeting the various needs and requirements of patients and / or markets.

[0067] According to a preferred embodiment, when the propellant is HFA152a, the valve is selected from A-valves and V-valves, with A-valves being even more preferred.

[0068] In another embodiment, when the propellant is HFA134a, the valve is selected from B-bulbs, A-bulbs and V-bulbs, with B-bulbs and A-bulbs being more preferred.

[0069] Thus, in one preferred embodiment, the present invention relates to an FEP-coated can for use in a pMDI device containing a formulation comprising at least BDP, formoterol fumarate dihydrate, HCl, and 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 absolute ethanol.

[0070] In yet a further embodiment, the present invention relates to an FEP-coated can for use in a pMDI device containing a formulation comprising at least BDP, formoterol fumarate dihydrate, HCl, and HFA134a propellant, the FEP-coated can having a valve selected from a B-valve, an A-valve, and a V-valve, preferably a V-valve or an A-valve. According to this embodiment, the can optionally further comprises ethanol, preferably absolute ethanol.

[0071] Coated canisters for use in pMDI devices according to the present invention can be filled with a formulation of choice by conventional methods used in the art.

[0072] In a general example, the method comprises the following steps: a) preparing a solution comprising formoterol fumarate, BDP and ethanol; b) filling an FEP coated can with the solution; c) adding HCl in an amount such that the molar ratio between formoterol fumarate dihydrate and the acid is 0.50 to 1.50; d) adding 1,1-difluoroethane (HFA152a) propellant; e) crimping and gassing the Aptar valve; and may include:

[0073] pMDIs containing coated canisters according to the present invention may have the configuration and construction of commonly used pMDI devices, such as those already on the market as known formulations for treating asthma and / or COPD.

[0074] Unless otherwise stated, it is intended that all of the above embodiments may be combined together and be considered part of the scope of the present invention.

[0075] The invention will now be illustrated by the following non-limiting examples. [Example]

[0076] (Experimental part) In the following Examples 1 and 2, the apparent pH was measured using a standard LiCl electrode commonly used to measure pH in organic media. Being an MDI pressurized product, the following procedure was applied to measure the apparent pH of the formulation: 1. Cool the canister to at least -50°C (immerse the canister in a dry ice bath or liquid nitrogen to reduce the internal pressure to atmospheric pressure). 2. Cut the valve to open the canister and allow the propellant to evaporate at room temperature. 3. Pour the remaining ethanol solution (containing the API) into a glass vial and make up to a volume of 10 ml with absolute ethanol, sufficient for measurement with a standard LiCl electrode. 4. Measure the apparent pH of the reconstituted solution using a LiCl electrode.

[0077] Example 1 Aluminum FEP coated cans according to the present invention were filled with a solution containing formoterol fumarate dihydrate (0.010% w / w), BDP (0.172% w / w), HCl 1M (0.024% w / w) and ethanol (12% w / w) in the presence of HFA134a (Solution 1).

[0078] Similarly, aluminum FEP-coated cans according to the present invention were filled with a solution containing FF (0.011% w / w), BDP (0.18% w / w), HCl 1M (0.026% w / w) and ethanol (12% w / w) in the presence of HFA152a (Solution 2).

[0079] Aluminum FEP-coated cans filled with Solution 1 or 2 and fitted with valves A, B, or V were placed in a stability chamber at 25°C and 60% RH (relative humidity). The apparent pH (App pH) of both Solutions 1 and 2, and the percentage of formoterol fumarate dihydrate remaining relative to the initial content (FF % w / w) were measured at T = 0, 1, 3, and 6 months, respectively.

[0080] The results are summarized in Table 1 below. [Table 1]

[0081] Example 2 (Comparative) The same analysis as in Example 1 was carried out using uncoated aluminum cans.

[0082] The apparent pH (App pH) of both solutions 1 and 2 was measured using the various bulbs at T=0, 1, 3 and 6 months, respectively.

[0083] The results are summarized in Table 2. [Table 2]

[0084] As is evident from Tables 1 and 2 above, the use of FEP-coated cans according to the invention with the indicated valves ensures favourable stabilisation of the pH of the solutions contained therein, even over long periods of time, e.g. after 6 months, when compared to T=0.

[0085] Conversely, the use of uncoated cans (comparison) can result in a significant increase in pH and a decrease in FF %w / w relative to the value measured at T=0, even after just one month of storage at 25°C, which can be considered room temperature.

Claims

1. 1. A canister for use in a pMDI device containing a formulation comprising at least a corticosteroid, a LABA drug, and an HFA or HFO propellant, the canister being internally coated with a coating comprising a compound selected from at least an epoxy phenolic resin, a perfluorinated polymer, a perfluoroalkoxyalkane polymer, a perfluoroalkoxyalkylene polymer, a perfluoroalkylene polymer, a polytetrafluoroethylene polymer (Teflon), a fluorinated ethylene propylene polymer (FEP), a polyethersulfone polymer (PES), a fluorinated ethylene propylene polyethersulfone polymer (FEP-PES), a polyamide, a polyimide, a polyamideimide, a polyphenylene sulfide, a plasma, a mixture or a combination thereof.

2. 2. The can of claim 1, wherein the corticosteroid is selected from the group consisting of budesonide, beclomethasone propionate, flunisolide, fluticasone, ciclesonide, mometasone, mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone propionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, rofleponide, and etiprednol dicloacetate.

3. 3. The method of claim 2, wherein the corticosteroid is beclomethasone propionate or budesonide.

4. 4. The can according to any one of claims 1 to 3, wherein the LABA drug is selected from the group consisting of salbutamol, (R)-salbutamol, fenoterol, formoterol fumarate, arformoterol, carmoterol, indacaterol, mirveterol, bambuterol, clenbuterol, vilanterol, olodaterol, abesiterol, terbutaline, and salmeterol.

5. 5. The can of claim 4, wherein the LABA drug is formoterol fumarate dihydrate.

6. 6. The can according to any one of claims 1 to 5, wherein the HFA propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA227ea), 1,1-difluoroethane (HFA152a), and mixtures thereof.

7. 7. The can according to any one of claims 1 to 6, wherein the HFO propellant is selected from the group consisting of 1,3,3,3-tetrafluoropropene (HFO-1234ze) and 2,3,3,3-tetrafluoropropene (HFO-1234yf).

8. 7. The can of claim 6, wherein the propellant is 1,1,1,2-tetrafluoroethane (HFA134a).

9. 7. The can of claim 6, wherein the propellant is 1,1-difluoroethane (HFA152a).

10. 8. The can of claim 7, wherein the propellant is 1,3,3,3-tetrafluoropropene (HFO-1234ze).

11. A can according to any one of claims 1 to 10, which is internally coated with a coating comprising a fluorinated ethylene propylene (FEP) polymer.

12. A can according to any one of claims 1 to 11, containing a formulation further comprising one or more additives, co-solvents or acids.

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

14. 14. Can according to claim 13, wherein the aliphatic alcohol is ethanol, preferably absolute ethanol.

15. 15. The can according to any one of claims 12 to 14, containing a formulation further comprising an inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, fumaric acid, phosphoric acid and citric acid.

16. 16. The can of claim 15, wherein the acid is hydrochloric acid.

17. 17. The can according to any one of claims 1 to 16, containing a formulation further comprising a low-volatility component selected from the group consisting of glycol, propylene glycol, polyethylene glycol, glycerol or esters thereof, ascorbyl palmitate, isopropyl myristate.

18. A can according to any one of claims 1 to 17, containing the formulation in the form of a solution.

19. 19. The can according to any one of claims 1 to 18, comprising a valve having at least one gasket made of a material comprising at least one polymer selected from low density polyethylene, butyl, such as chlorobutyl or bromobutyl, butadiene-acrylonitrile, neoprene, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC), or combinations thereof.

20. 20. Can according to claim 19, wherein the valve comprises a gasket made of COC together with two gaskets made of EPDM.

21. 20. The can of claim 19, wherein the valve comprises two gaskets, both made of chlorobutyl polymer.

22. 20. The can of claim 19, wherein the valve comprises three gaskets, all made of EPDM.

23. 20. The can according to claim 19, wherein the valve comprises a gasket made of butyl rubber together with two gaskets made of EPDM.

24. 22. Can according to any one of the preceding claims, wherein the propellant is HFA152a and the valve comprises a gasket made of COC together with two gaskets made of EPDM; or the valve comprises two gaskets, both made of chlorobutyl polymer.

25. 23. A can according to any one of claims 1 to 20 and 22, wherein the propellant is HFA134a and the valve comprises a gasket made of COC together with two gaskets made of EPDM; or the valve comprises three gaskets all made of EPDM; or the valve comprises two gaskets both made of chlorobutyl polymer.

26. 26. A can according to any one of claims 1 to 25, containing a formulation having an apparent pH buffered between 2.5 and 5.

27. 27. The can according to claim 26, containing a formulation having an apparent pH buffered between 3 and 4.

5.

28. A PMDI device comprising a canister according to any one of claims 1 to 27.

29. 29. A pMDI device according to claim 28 for the treatment of a respiratory disease selected from asthma and / or COPD.

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