EA046192B1 - MEDIZED AEROSOL INHALERS CONTAINING A BUFFERED PHARMACEUTICAL COMPOSITION - Google Patents

Description

Field of invention

The invention relates primarily to an aerosol composition comprising at least LABA, LAMA, a corticosteroid and a propellant, said composition being contained in a covered container, particularly suitable for use in a metered dose inhaler in the field of respiratory diseases.

BACKGROUND OF THE INVENTION

Metered dose inhalers (pMDIs) are well-known devices for delivering pharmaceutical products to the respiratory tract via inhalation. The pMDI device typically has a drug-containing container (or container as referred to herein) and a dispensing device having a mouthpiece. A metering valve system is usually attached to the container. Depending on the active ingredients and additional components such as excipients, acids and others, the final pMDI formulation can be in the form of a solution or suspension. A solution is generally considered to be free of sediment or particles, while a suspension generally refers to a composition having some undissolved material or precipitate. pMDI devices can use a propellant to inject droplets containing pharmaceutical products into the respiratory tract as an aerosol. For many years, the preferred propellants used for this purpose have been derivatives of chlorofluorocarbons, which go by the commercial names Freons 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 that fully and partially halogenated chlorofluorocarbons have a critical global warming potential (GWP) effect on the protective ozone layer, many countries have entered into an agreement, the Montreal Protocol, mandating significant restrictions on their production and use and eventual phase-out. Consequently, hydrofluoroalkanes (HFAs), particularly 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3heptafluoropropane (HFA 227a), have been identified and accepted as CFC substitutes in pharmaceutical applications. sector. Since then, hydrofluoroalkane propellants HFA 134a and HFA 227a have been widely used in the respiratory field, particularly given their effectiveness and compatibility with many active ingredients such as corticosteroids, LABAs or antimuscarinics.

However, despite the effectiveness of these HFA propellants and despite their widespread use in many pharmaceutical drugs already on the market, the possibility of having an alternative class of propellants and alternative methods for producing effective pMDI devices is always relevant. As a general reference in this regard, see, for example, Pharmaceutical Inhalation Aerosol Technology, Third Edition 2019, Anthony J. Hickey et Al. where on page 440, in table. 18.3 compares several propellants with potential medical applications from a global warming potential perspective.

This concerns, for example, the optimization of the mechanical components of the pMDI device, such as valves and containers, or even the possibility of having propellant-free spray devices, spray drying systems or devices with a more favorable impact on the environment.

An additional feature to consider when considering a pMDI device is the apparent pH and water content of the formulation sprayed through the device. For general reference in this regard, see, for example, WO 01/89480 and WO 03/074024.

Fluorocarbon polymers are often used to coat the interior surfaces of pMDI containers to prevent particle adhesion, or deposition on the container walls, i.e. to avoid caking, in the case of suspension formulations, and to avoid the formation of by-products.

EP0820323 describes a pMDI having part or all of its internal surface coated with one or more fluorocarbon polymers for dispensing an inhalation medicinal composition containing salmeterol and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active substances, where coating the internal surface of the container significantly reduces or substantially eliminates the problem of salmeterol adhesion or deposition.

WO 2015/101576 describes a pMDI device, in particular suitable for use with a solution of formoterol, beclomethasone dipropionate and glycopyrronium bromide contained in a FEP-lined container. As described therein, the composition contained in the FEP-coated container has increased stability and reduced amounts of degradation products, mainly Na(3-bromo)-[2hydroxy-5-[1-hydroxy-2-[1-(4 -methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide. This product (identified as DP3) is actually a specific degradation product formed by the reaction of formoterol and bromine ions from glycopyrronium bromide when these two active ingredients are dissolved in an HFA-ethanol system in the presence of an acid, particularly hydrochloric acid.

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EP2706987 describes a composition for use in a pMDI device containing beclomethasone dipropionate and HFA152, particularly suitable for the treatment of respiratory diseases.

WO2018/051131 Example 1, Table 4 describes a pharmaceutical composition containing beclomethasone dipropionate and formoterol fumarate dihydrate, a propellant containing 1,1-difluoroethane (HFA 152a), optionally a LAMA agent such as glycopyrronium bromide and glycerol. However, WO2018/051131 does not describe a coated container suitable for use with the composition described above.

WO2018/051130 describes a pharmaceutical composition comprising a drug component containing at least one pharmaceutically acceptable glycopyrrolate salt and a propellant component containing HFA 152a, wherein said composition exhibits satisfactory stability without the use of acid stabilizers.

WO2019236559, published December 12, 2019, describes pharmaceutical compositions for use in a pMDI device containing beclomethasone dipropionate, formoterol fumarate dihydrate, glycopyrronium, a propellant selected from HFA 134a, 227a and 152a, a co-solvent, organic acid(s) and optionally water.

US20160324778 describes a medical composition for use under pressure containing 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 such as formoterol and beclomethasone dipropionate, where the active ingredient is in the form of a suspension or solution with a propellant.

Although the prior art described above relates to effective technical solutions for compositions and devices, there is still a need to find a suitable pMDI device for use in the field of respiratory diseases for the treatment of, for example, asthma and/or COPD, which not only involves the reduction of global warming potential (GWP) ), but also conveniently provides a good stabilization system, in particular with regard to the calibration and maintenance of the apparent pH value of the composition contained in said device. In fact, it is noted that the prior art lacks a suitable and practical method for buffering the apparent pH of a composition suitable for a pMDI device containing at least a corticosteroid, a LABA agent, a LAMA agent, and a propellant. Apparent pH is in fact a key parameter that can influence many aspects of pMDI formulation, particularly when in solution form, such as stability of LABA and/or LAMA formulations, shelf life, consistent drug delivery in aerosol form from MDI, reproducibility of the final composition and maintenance of optimal chemical conditions in the tank.

The inventors have surprisingly discovered that it is possible to stabilize the apparent pH of a formulation suitable for a pMDI device containing at least a corticosteroid, LABA, LAMA and a suitable HFA or HFO propellant by means of an internally lined container equipped with a dedicated metering valve system.

The inventors have surprisingly discovered that the use of an internally lined container equipped with a dedicated metering valve system allows the presence of a buffer to be avoided to maintain a stable apparent pH of the pMDI formulation. In fact, the inner lined container according to the invention is capable of stabilizing the apparent pH value, even over a long period of time, as demonstrated in the experimental section below in the present description. In this regard, the coated container of the invention can act as an apparent pH buffering system and the use of a dedicated metering valve further enhances the apparent pH buffering effect of the coated container.

Advantageously, said coated container equipped with a suitable valve system containing at least a corticosteroid, LABA, LAMA and a certain HFA or HFO propellant according to the invention is readily used in a pMDI device for the treatment of respiratory diseases such as asthma and/or COPD, also ensuring good stability of chemical components over time, excellent atomization characteristics, and at the same time low GWP.

The essence of the invention

In one aspect, the present invention provides a container for use in a pMDI device, wherein the container contains at least a corticosteroid, a LABA agent, a LAMA agent, and an HFA 152a or HFO propellant, wherein the container is coated with a coating containing at least a compound selected from: epoxyphenol resin, perforated polymer, perfo-blockkanic polymer, perforcoxial polymer, perfetorcalene polymer, poly-tetraftoroethylene polymer (Teflon), fluorine ethylene-profile (FEP) polymer, polyesphone polymer (PES), fluorine ethylene-perpiolene polyeshulus Vogo (FEP-ps) polymer, polyamide, polyimide, polyamideimide, polyphenylene sulfide, plasma, mixtures thereof or combinations thereof, where said container is equipped with a valve having at least one sealing gasket made of a material

- 2 046192 containing: at least one polymer selected from low density polyethylene, butyl polymer such as chlorobutyl or bromobutyl polymer, acrylonitrile butadiene, neoprene, EPDM (ethylene propylene diene monomer polymer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) ) or a combination thereof.

In one further aspect, the present invention relates to the above coated container, wherein said composition comprising at least a corticosteroid, a LABA agent, a LAMA agent and an HFA or HFO propellant is a solution, preferably also containing a mineral or organic acid and/or a co-solvent.

In a further aspect, the invention relates to a pMDI device for use in the field of respiratory diseases, in particular for the treatment of asthma and/or COPD, containing the above-mentioned coated container.

Detailed Description of the Invention

Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one skilled in the art.

The molar ratio between formoterol, or a salt thereof, or a solvate of said salt, and an acid is calculated taking into account the number of moles of formoterol, or its salt, or solvate of said salt in the composition and the number of moles of the selected acid in the composition.

Unless otherwise specified, the term formoterol fumarate or FF refers to (R,R)(±)formoterol fumarate or its dihydrate.

Unless otherwise indicated, the term LABA or LABA agent includes a long-acting beta-2 agonist as known in the art.

Unless otherwise indicated, the term LAMA or LAMA agent includes a muscarinic receptor antagonist as is known in the art.

The term % w/w means the percentage by weight of a component relative to the total weight of the composition.

Term % w/v means the percentage by weight of a component relative to the total volume of the composition.

A stable composition, as defined herein, means that the residual active ingredient content is at least about 90% w/w. (which is the percentage by weight relative to the initial content at time 0), preferably at least about 95% w/w, and that the total degradation product content does not exceed about 10% by weight relative to the initial active ingredient content at time 0, preferably no more than about 5% by weight, at a given time as determined by HPLC/UV-VIS.

With respect to the term apparent pH value as defined herein, it should be noted that the pH calculation is typically representative of an aqueous liquid, for example, where water is the predominant component. In relatively aprotic solvents, such as the HFA system of the present invention, the protons are unhydrated and their activity coefficients may differ from those in aqueous solution. Although the Nerst equation (describing the potential of an electrochemical cell as a function of the concentrations of ions participating in the reaction) with respect to the electromagnetic field (EMF) applies and the glass electrode pH metric system generates a variable millivolt output depending on the proton concentration and the polarity of the carrier, pH meter data reflect the apparent pH value in accordance with the present invention. In this regard, the apparent pH value in accordance with the invention can be measured by methods known in the art, for example, as stated 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.

As mentioned above, the present invention surprisingly demonstrates that when a coated container equipped with a specialized valve system, as detailed herein, which is suitable for a pMDI device, is used to contain an appropriate formulation containing at least a corticosteroid, a LABA agent, an LAMA and HFA or HFO propellant, the apparent pH of such a composition may be conveniently buffered between about 2.5 and 5, preferably between about 3 and 4.5, depending, for example, on the components of the composition and/or on their amounts, such as described herein below. The presence of such a buffer system provides several advantages such as increased stability of the formulation over time, particularly with regard to the amount of formoterol, good shelf life, reproducibility of the final formulation, maintenance of optimal chemical conditions in the container and stable delivery of the aerosolized drug from the MDI.

In particular, the presence of a stable apparent pH value through an internally lined container equipped with a specialized valve system avoids the addition of an external conventional acid-base buffer system, which would lead to a more complex composition; the combined use of a coated container along with a specialized metering valve further increases the stability of the formulation by acting as a system

- 3 046192 buffering the apparent pH value. In contrast, unlined containers do not demonstrate the effect of maintaining an apparent pH value constant over time for the pMDI solution composition, as demonstrated in the comparative examples herein below.

Thus, in one embodiment, the invention relates to a container equipped with a specialized valve system for use in a pMDI device containing a composition as described herein and claimed in the claims, characterized in that the apparent pH of said composition is stabilized at values from 2.5 to 5, preferably from about 3 to 4.5. In other words, the invention also relates to a container as described herein and claimed for use in buffering the apparent pH of a formulation containing at least a corticosteroid, LABA, LAMA and an HFA or HFO propellant of about 2.5 to 5, preferably approximately 3 to 4.5.

The apparent pH of a pMDI formulation is influenced by the composition of the formulation, for example, with respect to acid concentration and the like, and the appropriate value can be achieved by selecting the appropriate amount and type of LABA, LAMA and/or corticosteroid agent, or by adding additional components to the formulation, such as described herein below.

Regarding the container, a coated container known in the art can be used within the scope of the present invention. Thus, the container may be made of metal, such as aluminum or metal alloys, stainless steel or anodized aluminum, fluoro-passivated aluminum, and the like. Alternatively, the container may be made of plastic or any other suitable material. Preferably the container is made of aluminum, optionally anodized, or stainless steel, suitably coated. The coating is typically applied to the interior surface of the container, thereby providing an interior layer that acts as a contact surface between the interior surface of the container and the composition contained therein. Thus, the inner coating will prevent adhesion of the formulation component to the surface of the container, also providing a pH buffering system. Typically, the inner coating forms a coating layer having a thickness that satisfies the requirements of uniformity and homogeneity when tested using, for example, a WACO enamel grading device, for example, commercially available. The inner coating covers at least 50% of the interior surface of the container, preferably at least 95%, even more preferably at least 99%.

In this regard, a suitable coating container according to the invention may have part or all of its internal surfaces coated with an inert organic or inorganic coating, preferably containing: epoxyphenol resin, perfluorinated polymer, perfluoroalkoxyalkane polymer, perfluoroalkoxyalkylene polymer (PFA), perfluoroalkylene polymer, poly-tetrafluoroethylene polymer (PTFE or Teflon), fluorinated ethylene propylene (FEP) polymer, polyether sulfone polymer (PES), fluorinated ethylene propylene polyether sulfone (FEP-PES) polymer, polyamide, polyimide, polyamideimide, polyphenylene sulfide, plasma, mixtures thereof or combinations thereof.

As an example, the term coated FEP refers to a coating layer containing FEP, and optionally additional components, including additives, adhesives, aggregators such as PES, isobutyl ketone, and the like.

The above polymers can be used in combination with additional components or as part of a polymer mixture obtained, for example, by mixing together two or more polymer compounds. In this regard, the inner coating of the container according to the invention is designed to also contain the mixtures or combinations mentioned. In one embodiment, the coated container of the invention is a FEP or PTFE coated container, or more preferably a FEP-PES coated container. When coated with FEP-PES, the PES acts as an intermediate layer between the inner surface and the FEP polymer, thus providing an even more uniform and consistent coating. In fact, it should be noted that, when suitable, more than one coating can be applied to the interior surface of the container, thereby forming a two-layer or multi-layer coating having increased uniformity and stability.

In one embodiment of the invention, the container is an aluminum container characterized by an internal coating containing a FEP-PES polymer. Suitable aluminum FEP-coated containers within the scope of the invention are those, for example, commercially available and used in the art.

As demonstrated herein below in the experimental portion, when the formulation in the form of a solution containing beclomethasone dipropionate (BDP), formoterol fumarate dihydrate, glycopyrronium bromide and HFA152a propellant is contained in a FEP-lined container equipped with a specialized valve system according to the invention, the apparent pH value of the specified composition is conveniently maintained at a certain level, even over a long period of time.

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In one embodiment, the corticosteroid component of the formulation contained in a coated container equipped with a specialized valve system according to the invention is selected from the group consisting of: budesonide, beclomethasone (BDP), for example, as an ester of monopropionic or dipropionic acid, flunisolide, flucatisone, for example, as an ester of propionic acid or furancarboxylic acid, ciclesonide, mometasone, for example, as an ester of furancarboxylic acid, mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocionide, clocortolone, tipredane, prednicarbate, alklometasone dipropionate, halomethasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, deoxycorticosterone, rofleponide, ethiprednol dicloacetate, where beclomethasone dipropionate (BDP) and budesonide are particularly preferred. In an even more preferred embodiment, the corticosteroid component is beclomethasone dipropionate (BDP).

According to another embodiment, the amount of the corticosteroid component in accordance with the present invention is 0.01-0.7% w/w, more preferably 0.05-0.5% w/w, even more preferably 0.1-0.3 % w/w

As for the LABA component in the composition contained in the coated container according to the invention, it is preferably selected from the group consisting of: fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol (TA-2005), indacaterol, milveterol, bambuterol, clenbuterol, vilanterol , olodaterol, abediterol, terbutaline, salmeterol, diastereoisomeric mixtures thereof and pharmaceutically acceptable salts or hydrates thereof. In one embodiment, LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

Alternatively, the composition of the present invention may contain salbutamol, β-salbutamol (levalbuterol) and a pharmaceutically acceptable salt or hydrate thereof.

Preferably, the amount of LABA according to the present invention is 0.00050.04% w/w, more preferably 0.001-0.03% w/w, even more preferably 0.005-0.02% w/w.

In one embodiment, the LAMA agent component of the formulation contained in the coated container of the invention is selected from the group consisting of glycopyrronium, methscopolamine, ipratropium, oxitropium, trospium, tiotropium, aclidinium and umeclidinium, or pharmaceutically acceptable salts. In one preferred embodiment, the LAMA agent is glycopyrronium bromide. Preferably, the amount of LAMA according to the present invention is from 0.001 to 0.08% w/w, preferably from 0.005 to 0.06% w/w, more preferably from 0.01 to 0.04% w/w. /wt.

The propellant composition contained in the coated container according to the invention is selected from HFA 152a and hydrofluoroolefins (HFO).

In one embodiment, the HFO propellant composition contained in the coated container of 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 propellant is HFO-1234ze.

In one preferred embodiment, the propellant is HFA152a.

The composition contained in the coated container according to the invention may be in the form of a suspension or solution. In one embodiment, certain corticosteroids and LABA and LAMA components are preferably dissolved in the HFA or HFO propellant as defined above, thereby providing a solution. Thus, in one particular preferred embodiment, the invention relates to a FEP-coated container for use in a pMDI device, wherein said FEP-coated container contains a solution containing at least beclomethasone dipropionate, formoterol fumarate dihydrate, glycopyrronium bromide and HFA 152a.

As stated above, in one embodiment, the composition contained in the coated container according to the invention may optionally further contain components such as excipients, additives, solvents, co-solvents, acids, low volatile components or even active ingredients. The addition of these components can be suitably calibrated to modulate, for example, the physicochemical properties of the composition and/or to provide the proper apparent pH, which is desirably kept constant, in accordance with the present invention. In this regard, in one preferred embodiment, the invention relates to a coated container for use in a pMDI device as described above, wherein said coated container contains a composition 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 volatile component.

Preferably, said co-solvent is a polar compound capable of increasing the solubility of the components in the composition. Examples of suitable co-solvents are

- 5 046192 aliphatic alcohols having from 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol and the like, preferably ethanol, more preferably anhydrous ethanol.

When present, said co-solvent is used in an amount ranging from 5% w/w. up to 20% w/w, more preferably 10% to 15%.

In one embodiment, the acid may be a mineral or 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, 2methylpropionic acid acid, malic acid, butanoic acid, tartaric acid, propionic 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, with hydrochloric acid being particularly preferred. In an even more preferred embodiment, the acid is hydrochloric acid, concentrated or dilute, preferably 1 M. Preferably, when the acid is 1 M HCl, it is used in an amount of 0.001-0.08% w/w. preferably 0.005-0.06%, more preferably 0.01-0.04%.

In general, the amount of acid selected is preferably selected such that the final pH of the solution is approximately 2.5 to 5, preferably 3 to 4.5, as stated above. According to the invention, using a coated container equipped with a dedicated valve system, the selected apparent pH value remains stable and substantially unchanged over time, even when said pH value is adjusted by the presence of an acid, thereby solving the problem of how to control and stabilize the apparent pH of a formulation suitable for use in a pMDI containing at least a corticosteroid, a LABA agent, a LAMA agent, and a propellant, in the presence of an inorganic or organic acid.

In an even more preferred embodiment, the pMDI solution of the invention consists of LABA, LAMA, a corticosteroid, dissolved in a system containing or consisting of HFA152a, HCl 1 M and EtOH. According to this even more preferred embodiment, the LABA, LAMA and the corticosteroid are, respectively, formoterol fumarate dihydrate glycopyrronium bromide and beclomethasone dipropionate.

As will be understood, it is also to be understood that these latter described embodiments are included within the scope of the present invention, also in any possible combination with all other preferred embodiments as set forth herein above and below.

In one embodiment of the invention, the molar ratio between LABA and acid, when present, is from 0.50 to 1.50, preferably from 0.9 to 1.1. In fact, it should be noted that in this range the stability of the final composition is increased to a particularly convenient extent.

When present, the low volatile component has a vapor pressure at 25°C below 0.1 kPa, preferably below 0.05 kPa, preferably selected from the group consisting of glycols, propylene glycol, polyethylene glycol, glycerol or its esters, ascorbyl palmitate, isopropyl myristate and the like, where isopropyl myristate and glycerol are particularly preferred.

In accordance with one embodiment, the composition of the present invention contains an amount of water preferably below 3000 ppm, more preferably below 2000 ppm, even more preferably below 1500 ppm. based on the total mass of the composition.

It should be noted that by means of the present invention, the problem of how to effectively buffer the apparent pH of a commercial pMDI formulation containing a corticosteroid, a LABA agent, a LAMA agent, and an HFA or HFO propellant is surprisingly solved in the absence of additional buffering ingredients or agents that may still reduce the stability and/or effectiveness of the formulation contained in the container. Also, from a manufacturing standpoint, the present invention provides a ready-to-use pMDI device containing a coated container, as detailed herein, with a simple and uniform manufacturing process. Moreover, the use of a green propellant such as HFA 152a allows the present invention not only to solve the above problems, but also eliminates the potential environmental hazards resulting from long-term use of other fluorinated propellants.

As stated above, the coated container for use in accordance with the present invention is characterized by a dedicated metering valve system. In fact, it has surprisingly been found that the use of a dedicated metering valve further enhances the apparent pH buffering effect of the coated container according to the invention, which is also beneficial in terms of residual formoterol, overall stability and efficacy of the formulation. As a rule, the pMDI device is attached to the capacitance

- 6 046192 dosing valve for delivering a therapeutically effective dose of active ingredients. The metering valve system contains at least a sealing gasket. Preferably, the valve contains 2 or 3 sealing gaskets made of the same or different materials. In this regard, according to the present invention, a valve is provided with 2 or 3 sealing gaskets made from the same material or from different materials. Thus, in accordance with the present invention, at least one sealing gasket is made from a suitable elastomeric material containing at least one of polymers selected from: low-density polyethylene, butyl such as chlorobutyl or bromobutyl, acrylonitrile butadiene, neoprene, EPDM (polymer of ethylene propylene diene monomers), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or a combination thereof.

Preferably, a valve is provided with 3 sealing gaskets, even more preferably all of them are made of EPDM, and is referred to herein as a B valve.

In one preferred embodiment, a valve is provided with a seal made of COC together with two seals made of EPDM, and is referred to herein as an A-valve.

One equally preferred embodiment provides a valve with two sealing gaskets, preferably both of chlorobutyl polymer, and is referred to herein as a V-valve. A further preferred embodiment provides a valve with two sealing gaskets, preferably both of chlorobutyl polymer, and is referred to herein as a V-valve.

In one further preferred embodiment, the valve is provided with a sealing gasket made of butyl rubber together with two sealing gaskets made of EPDM.

In one further embodiment, the valve has two sealing gaskets, preferably made of bromobutyl polymer, and one sealing gasket made of a material selected from the group consisting of chlorobutyl polymer, butadiene acrylonitrile, neoprene, EPDM (ethylene propylene diene monomer polymer), TPE ( thermoplastic elastomer), cycloolefin copolymer (COC), or combinations thereof. Preferably, the valve is equipped with two sealing gaskets made of bromobutyl polymer and one sealing gasket made of EPDM.

The metering valve of the invention is typically capable of delivering a volume in the range of 25 to 150 μL, preferably in the range of 50 to 100 μL, and more preferably 50 μL to 70 μL per actuation. Suitable valves within the scope of the present invention are commercially available, for example from manufacturers well known in the art.

As a further advantage, the inventors have unexpectedly discovered that, depending on the selected HFA propellant, the choice of valve can conveniently improve the efficiency and reliability of the final pMDI device. For example, when HFA152a propellant is used in a coated container in accordance with the present invention, the A-valve or V-valve provides an even greater increase in the stability of the final composition, for example, relative to the B-valve, which has 3 sealing gaskets made of EPDM.

This increase in stability is further enhanced if the formulation is in solution form, as indicated in the experimental portion of this specification. The B-valve, in fact, when used in combination with HFA152a propellant, may result in leakage of said propellant, which may result in unwanted product loss and possibly reduce the effectiveness 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 container according to the invention, not only is the apparent pH buffering effect maximized, but also the leakage of the formulation is substantially prevented. This results in an efficient and user-friendly system that can be easily used in a final pMDI device. This versatility allows for broad application and customization of the final pMDI device containing the container according to the invention, thereby satisfying various patient and/or market needs and demands.

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

Thus, in one preferred embodiment, the invention relates to a FEP-coated container for use in a pMDI device, wherein said FEP-coated container comprises a composition comprising at least BDP, formoterol fumarate dihydrate, glycopyrronium bromide, HCl propellant and HFA152a, wherein said FEP-coated the container has a valve selected from an A-valve or a V-valve. In accordance with this embodiment, the container optionally further contains ethanol, preferably anhydrous.

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A coated container for use in a pMDI device in accordance with the present invention can be filled with the selected composition through standard methodologies used in the art.

As a general example, said methodology may include the steps of:

a) obtaining a solution containing: formoterol fumarate, BDP, glycopyrronium bromide and ethanol;

b) filling the FEP-coated container with said solution;

c) adding an amount of HCl resulting in a molar ratio between formoterol fumarate dihydrate and acid of from 0.50 to 1.50;

d) adding 1,1-difluoroethane propellant (HFA 152a);

e) plugging with the Aptar valve and filling with gas.

A pMDI containing a coated container according to the invention may have the configuration and components of a commonly used pMDI device, such as components already on the market for well known formulations for the treatment of, for example, asthma and/or COPD.

Unless otherwise stated, it is contemplated that all of the above embodiments may be combined together and are considered part of the scope of the present invention.

The invention is further described by means of the following non-limiting examples.

experimental part

In Examples 1 and 2 below, the apparent pH was measured using a standard LiCl electrode commonly used for measuring pH in organic media. For an aerosol MDI product, the following procedure is used to measure the apparent pH of the formulation:

- Cool the container to at least -50°C (immerse the container in a dry ice bath or liquid nitrogen to ensure the internal pressure is reduced to atmospheric pressure).

- Open the container by cutting the valve and allow the propellant to evaporate at room temperature.

- Transfer the remaining ethanol solution (containing API) into a glass vial and dilute with 10 ml anhydrous ethanol to a volume sufficient for measurement with a standard LiCl electrode.

- Measure the apparent pH of the reduced solution using a LiCl electrode.

Example 1

An aluminum FEP coated container according to the invention was filled with a solution containing FF (0.011% w/w), BDP (0.18% w/w), glycopyrronium bromide (0.022% w/w), 1M HCl (0 .02% w/w) and ethanol (12% w/w), in the presence of HFA152a.

Aluminum FEP-lined containers filled with solutions 1 or 2 and equipped with valves A, B or V were placed in stability chambers at 25°C, 60% R.H. (relative humidity). The apparent pH value (App pH) and the residual percentage of formoterol fumarate dihydrate (FF% w/w) relative to the initial content (100% at T=0) in the solution were measured at T=0 after 1, 3 and 6 months, respectively.

The results are summarized in table. 1 below.

Table 1

Apparent pH value (App pH) and FF% in FEP coated container at T=0 and T=1 month (1M); T=3 months (3M) and 6 months (6M), measured at 25°C/60% R.H.

Propellant Capacity Valve T=0 (App pH) T=1M (App pH) T=3M FF% w/w (App pH) T=6M FF% w/w (App pH) 152a FEP A-valve 100.0 (4.5) 98.9 (4.5) 96.9 (4.5) 97.7 (4.4) 152a FEP V-valve 100.0 (4.4) 98.0 (4.4) 95.5 (4.3) 94.4 (4.3) 152a FEP B-valve 100 (4.5) 99.1 (4.4) 97.5 (4.5) 96.7 (4.3)

A-valve: A valve provided with a seal made of COC together with two seals made of EPDM, for example, as available from Aptar.

V-valve: A valve equipped with two sealing gaskets, both of which are made of chlorobutyl polymer, for example, as available from Vari.

B-valve: A valve fitted with 3 sealing gaskets, all made of EPDM, for example as available from Bespak.

- 8 046192

Example 2 (comparative)

The same analysis as in Example 1 was carried out using an uncoated aluminum container equipped with valves A, B or V.

The apparent pH value (App pH) of the solution according to example 1 was measured at T=0, after 1, 3 and 6 months, respectively. The results are summarized in table. 2.

table 2

Apparent pH value (App pH) and FF% w/w. in an uncovered container at T=0 and T=1 month (1M); T=3 months (3M) and 6 months (6M), measured at 25°C/60% R.H.

Propellant Uncovered container Valve T=0 (App pH) T=1M (App pH) T=3M (App pH) T=6M (App pH) 152a Al B-valve (4.5) (4.9) (5.3) (5.3) 152a Al A-valve (4.5) (5.1) (5.6) (5.7) 152a Al V-valve (4.7) (5.0) (5.6) (5.5)

B-valve: A valve fitted with 3 sealing gaskets, all made of EPDM, for example as available from Bespak.

A-valve: A valve provided with a seal made of COC together with two seals made of EPDM, for example, as available from Aptar.

V-valve: A valve equipped with two sealing gaskets, both of which are made of chlorobutyl polymer, for example, as available from Vari.

As is evident from Tables 1 and 2, the use of a FEP-coated container filled with a solution in the presence of the HFA152a propellant according to the invention, equipped with the said valves, guarantees convenient stabilization of the pH of the solution contained therein, even over a long period of time, for example even after 6 months. compared to T=0.

In contrast, when using an uncoated container (comparative), the pH substantially increases relative to that at T=0, also providing a potential reduction in FF% w/w, even after storage for only one month at 25°C, which can be taken as room temperature.

Claims (14)

1. A container for use in a pressurized metered dose inhaler (pMDI) device, the container comprising a formulation comprising at least a corticosteroid selected from beclomethasone dipropionate or budesonide, a LABA agent selected from formoterol fumarate or formoterol fumarate dihydrate, a LAMA agent , which is glycopyrronium, and HFA 152a or 1,3,3,3-tetrafluoropropene (HFO-1234ze) propellant, the container being internally coated with a coating containing at least a fluorinated ethylene propylene (FEP) polymer, and equipped with a valve, wherein the valve equipped with a sealing gasket made of cycloolefin copolymer (COC), and two sealing gaskets made of ethylene propylene diene monomer polymer (EPDM), or the valve is equipped with two sealing gaskets, both made of chlorobutyl polymer. 2. The container according to claim 1, where the LABA agent is formoterol fumarate dihydrate. 3. Container according to claim 1, where the LAMA agent is glycopyrrhonium bromide. 4. A container as claimed in any one of the preceding claims, comprising a composition further comprising one or more excipients, co-solvents and acids. 5. The container according to claim 4, where the co-solvent is an aliphatic alcohol having from 1 to 4 carbon atoms. 6. The container according to claim 5, wherein the aliphatic alcohol is ethanol, preferably anhydrous. 7. A container according to claims 4-7, containing a composition additionally containing a mineral or organic acid selected from the group consisting of: hydrochloric, hydrobromic, nitric, fumaric, phosphoric and citric acid, maleic acid, acetic acid, xinafoic acid, oxalic acid, lactic acid, 2-methylpropionic acid, malic acid, butanoic acid, tartaric acid, propionic acid, pentanoic acid, succinic acid, glycolic acid, hexanoic acid, malonic acid, glutaric acid, formic acid, adipic acid, ascorbic acid, benzoic acid acid and glucuronic acid. 8. The container according to claim 7, wherein the acid is hydrochloric acid. 9. The container according to any of the preceding claims, containing a composition further containing a low-volatile component selected from the group consisting of glycols, propylene glycol, polyethylene glycol, glycerin or its esters, ascorbyl palmitate, isopropyl myristate. 10. A container according to any of the preceding claims, containing the composition in the form of a solution. 11. A container according to any one of the preceding claims, containing a composition having an apparent pH value buffered to from 2.5 to 5. 12. The container according to claim 11, containing a composition having an apparent pH value buffered to from 3 to 4.5. 13. A device comprising a pressurized metered dose inhaler (pMDI) comprising a container as defined in any one of the preceding claims. 14. The pMDI device according to claim 13 for the treatment of a respiratory disease selected from asthma and/or COPD.