Fluticasone and vilanterol preparations and inhalers

Abstract

A composition comprising fluticasone and vilanterol is provided. [Solution] A composition comprising fluticasone particles or a pharmaceutically acceptable salt or solvate thereof, vilanterol particles or a pharmaceutically acceptable salt or solvate thereof, and 1,1-difluoroethane.

Description

[Technical Field]

[0001] This disclosure generally relates to formulations used in inhalation forms and inhalers, such as aerosol canisters and metered-dose inhalers containing them. In particular, this disclosure relates to formulations containing fluticasone and vilanterol. [Background technology]

[0002] In recent years, dry powder inhalers (DPIs) containing fluticasone furoate and vilanterol triphenylacetate have become commercially available. These include GlaxoSmithKline's Relvar® Ellipta® and Breo® Ellipta® DPI. [Overview of the project]

[0003] Pressurized metered-dose inhalers (pMDIs) offer several advantages over direct-to-administer (DPIs). For example, controlling the stability of micronized medication in DPIs to deliver a consistent volume to the patient can be challenging. Additionally, in some cases, pMDIs can be manufactured at a lower cost than DPI products.

[0004] The present disclosure provides compositions comprising fluticasone particles or a pharmaceutically acceptable salt or solvate thereof, vilanterol particles or a pharmaceutically acceptable salt or solvate thereof, and 1,1-difluoroethane (HFA-152a).

[0005] In embodiments, fluticasone or a pharmaceutically acceptable salt or solvate thereof may be fluticasone furoate.

[0006] In the embodiment, vilanterol or a pharmaceutically acceptable salt or solvate thereof is vilanterol triphenylacetate.

[0007] In an embodiment, the propellant may include 1,1-difluoroethane (HFA-152a) or may consist essentially of 1,1-difluoroethane (HFA-152a).

[0008] In an embodiment, the canister size of fluticasone may be between about 2 micrometers and 4 micrometers.

[0009] In an embodiment, the canister size of vilanterol triphenylacetate may be between about 1 micrometer and 2 micrometers.

[0010] In an embodiment, the concentration of fluticasone may be between about 1.0 mg / g and 2.5 mg / g.

[0011] In an embodiment, the concentration of fluticasone may be between about 2.0 mg / g and 4.5 mg / g.

[0012] In an embodiment, the concentration of vilanterol triphenylacetate may be between about 0.2 mg / g and 1.0 mg / g.

[0013] Furthermore, according to the present disclosure, there is provided a composition comprising fluticasone particles or a pharmaceutically acceptable salt or solvate thereof, vilanterol particles or a pharmaceutically acceptable salt or solvate thereof, and 1,1-difluoroethane (HFA-152a), wherein fluticasone and vilanterol or their pharmaceutically acceptable salts or solvates are the only active ingredients in the composition.

[0014] In an embodiment, fluticasone or a pharmaceutically acceptable salt or solvate thereof may be fluticasone furoate.

[0015] In an embodiment, vilanterol or a pharmaceutically acceptable salt or solvate thereof is vilanterol triphenylacetate.

[0016] In some embodiments, the propellant may contain 1,1-difluoroethane (HFA-152a) or may consist substantially of 1,1-difluoroethane (HFA-152a).

[0017] In the embodiment, the canister size of fluticasone may be between approximately 2 micrometers and 4 micrometers.

[0018] In the embodiment, the canister size for vilanterol triphenylacetate may be between about 1 micrometer and 2 micrometers.

[0019] In the embodiment, the concentration of fluticasone may be between approximately 1.0 mg / g and 2.5 mg / g.

[0020] In the embodiment, the concentration of fluticasone may be between approximately 2.0 mg / g and 4.5 mg / g.

[0021] In the embodiment, the concentration of vilanterol triphenylacetate may be between approximately 0.2 mg / g and 1.0 mg / g.

[0022] Furthermore, the present disclosure provides an aerosol canister comprising the composition of the disclosed embodiment.

[0023] In embodiments, the aerosol canister may encompass at least one surface having a primer composition comprising a silane having two or more reactive silane groups separated by organic linking groups, wherein the primer composition has a coating composition comprising at least a partially fluorinated compound.

[0024] In the embodiment, the at least partially fluorinated compound is a polyfluoropolyethersilane.

[0025] In this embodiment, at least one surface is at least a portion of the valve surface.

[0026] Furthermore, the present disclosure provides an inhaler comprising a composition of any one of the disclosed embodiments, or an aerosol canister of any one of the disclosed embodiments.

[0027] Other features and aspects of this disclosure will become apparent upon consideration of the detailed description. [Modes for carrying out the invention]

[0028] Throughout this disclosure, singular nouns such as “a,” “an,” and “the” are used for convenience; singular nouns include plural nouns unless explicitly specified or clearly indicated by the context. Numerical ranges, such as “between x and y” or “to x and y,” encompass the values ​​of the endpoints x and y.

[0029] Some terms used in this application have specific meanings as set forth herein. All other terms are known to those skilled in the art and are given the meanings that those skilled in the art would have given them at the time of the invention.

[0030] Elements referred to as “common” and “commonly used” in this specification, and similar phrases, should be understood as common in the context of the compositions, inhalers and metered-dose inhalers and other articles and methods of this disclosure, and this term is not used to mean that these features exist in the prior art, much less are common. Unless otherwise specified, only the background art portions of this application relate to the prior art.

[0031] The "particle diameter" of a single particle is the size of the smallest hypothetical hollow sphere that can enclose the particle.

[0032] The "median mass diameter" or MMD of multiple particles refers to the particle diameter value at which 50% of the particles have a particle diameter smaller than that value, and 50% of the particles have a particle diameter larger than that value.

[0033] The "canister size" of multiple particles refers to the mass-average particle diameter of the multiple particles when the formulation is prepared.

[0034] The "outside actuator size" of multiple particles is defined in the United States Pharmacopeia. <601> This refers to the aerodynamic median mass diameter (MMAD) of multiple particles after they have passed through the actuator of an inhaler, such as a metered-dose inhaler, as measured by the procedure described above.

[0035] Where the concentration of fluticasone is discussed in this application, for convenience, the most commonly used form of fluticasone in this disclosure, namely fluticasone furoate, is referred to. Therefore, it should be understood that if another form of fluticasone or a salt of fluticasone is used, the concentration of that other form or salt should be calculated based on fluticasone furoate. Those skilled in the art can easily perform this calculation by comparing the molecular weight of the form of fluticasone or salt used with the molecular weight of fluticasone furoate.

[0036] Where the concentration of vilanterol is discussed in this application, for convenience, unless otherwise specified, the concentration of the most commonly used form of vilanterol in this disclosure, namely vilanterol triphenylacetate, is referred to. Therefore, it should be understood that if another form or salt of vilanterol is used, the concentration of that other form or salt should be calculated based on vilanterol triphenylacetate. Those skilled in the art can easily perform this calculation by comparing the molecular weight of the form or salt of vilanterol used with the molecular weight of vilanterol triphenylacetate.

[0037] formulation The pharmaceutical preparation contains fluticasone particles. Fluticasone may be a free base, but may also be in the form of one or more pharmaceutically acceptable salts or solvates of fluticasone furoate, fluticasone propionate, etc.

[0038] Fluticasone, such as fluticasone furoate, may be in the form of particles. The canister size for fluticasone particles, such as fluticasone furoate, may be any suitable canister size. Exemplary suitable canister sizes may be 1 micrometer or more, 1.5 micrometers or more, 2 micrometers or more, 2.5 micrometers or more, 3 micrometers or more, 3.5 micrometers or more, 4 micrometers or more, or 4.5 micrometers or more. Exemplary suitable canister sizes may also be 5 micrometers or less, 4.5 micrometers or less, 4.0 micrometers or less, 3.5 micrometers or less, 3.0 micrometers or less, 2.5 micrometers or less, 2.0 micrometers or less, or 1.5 micrometers or less. Sizes from 1 micrometer to 5 micrometers are common. In embodiments, the canister size may be between 2.0 and 4.0 micrometers. In embodiments, the canister size may be between 2.0 and 3.0 micrometers.

[0039] The actuator outer size of fluticasone particles, such as fluticasone furoate particles, may be any suitable actuator outer size. Exemplary suitable actuator outer sizes may be 1 micrometer or more, 1.5 micrometers or more, 2 micrometers or more, 2.5 micrometers or more, 3 micrometers or more, 3.5 micrometers or more, 4 micrometers or more, or 4.5 micrometers or more. Exemplary suitable actuator sizes may also be 5 micrometers or less, 4.5 micrometers or less, 4.0 micrometers or less, 3.5 micrometers or less, 3.0 micrometers or less, 2.5 micrometers or less, 2.0 micrometers or less, or 1.5 micrometers or less. Sizes from 1 micrometer to 5 micrometers are common. In embodiments, the actuator outer size may be between 2.0 and 4.0 micrometers. In embodiments, the actuator outer size may be between 2.5 and 3.5 micrometers.

[0040] Fluticasone, such as fluticasone furoate, may be present in the formulation at any appropriate concentration. When the concentration of fluticasone is expressed in mg / g units, the concentration of fluticasone may be 0.1 or higher, 0.2 or higher, 0.3 or higher, 0.4 or higher, 0.5 or higher, 0.6 or higher, 0.7 or higher, 0.8 or higher, 0.9 or higher, 1.0 or higher, 1.5 or higher, or 2.0 or higher. Alternatively, based on mg / g, the concentration of fluticasone may be 10.0 or lower, 8.0 or lower, 6.0 or lower, 5.0 or lower, 4.0 or lower, 3.0 or lower, 2.5 or lower, 2.2 or lower, or 2.0 or lower. One exemplary range is from 1.0 mg / g to 2.5 mg / g. Another exemplary range is from 2.0 mg / g to 4.5 mg / g. Another exemplary range is from 1.0 mg / g to 5 mg / g. Another exemplary range is from 2.0 mg / g to 10.0 mg / g. For some applications, a concentration of approximately 1.7 mg / g is used. For other applications, a concentration of approximately 3.5 mg / g is used.

[0041] The composition also contains vilanterol, such as vilanterol triphenylacetate. The vilanterol, such as vilanterol triphenylacetate, may also be in the form of particles. The canister size of the vilanterol particles may be any suitable canister size. Exemplary preferred canister sizes may be 1 micrometer or larger, 1.5 micrometers or larger, 2 micrometers or larger, 2.5 micrometers or larger, 3 micrometers or larger, 3.5 micrometers or larger, 4 micrometers or larger, or 4.5 micrometers or larger. Exemplary preferred canister sizes may also be 5 micrometers or smaller, 4.5 micrometers or smaller, 4.0 micrometers or smaller, 3.5 micrometers or smaller, 3.0 micrometers or smaller, 2.5 micrometers or smaller, 2.0 micrometers or smaller, or 1.5 micrometers or smaller. 1 to 5 micrometers is common. In embodiments, the canister size may be between 3.0 and 4.5 micrometers. In embodiments, the canister size may be between 1.0 and 2.0 micrometers.

[0042] The actuator outer size of vilanterol particles such as vilanterol triphenylacetate may be any suitable actuator outer size. Exemplary suitable actuator outer sizes may be 1 micrometer or more, 1.5 micrometers or more, 2 micrometers or more, 2.5 micrometers or more, 3 micrometers or more, 3.5 micrometers or more, 4 micrometers or more, or 4.5 micrometers or more. Exemplary suitable actuator sizes may also be 5 micrometers or less, 4.5 micrometers or less, 4.0 micrometers or less, 3.5 micrometers or less, 3.0 micrometers or less, 2.5 micrometers or less, 2.0 micrometers or less, or 1.5 micrometers or less. 1 micrometer to 5 micrometers is common. In embodiments, the actuator outer size may be between 1.0 and 4.0 micrometers. In embodiments, the actuator outer size may be between 1.5 and 2.5 micrometers.

[0043] Vilanterol may be used at any appropriate concentration. Based on mg / g, exemplary concentrations are 0.05 or higher, 0.10 or higher, 0.15 or higher, 0.20 or higher, 0.25 or higher, 0.30 or higher, 0.35 or higher, 0.40 or higher, 0.45 or higher, or 0.5 or higher. Exemplary concentrations are also 2.0 or lower, 1.9 or lower, 1.8 or lower, 1.7 or lower, 1.6 or lower, 1.5 or lower, 1.4 or lower, 1.3 or lower, 1.2 or lower, 1.1 or lower, 1.0 or lower, 0.9 or lower, 0.8 or lower, 0.7 or lower, 0.6 or lower, or 0.5 or lower. Typical concentrations range from 0.2 mg / g to 2.0 mg / g, for example, 0.2 mg / g to 1.0 mg / g, or 0.4 mg / g to 0.8 mg / g. A concentration of 0.4 mg / g is used in some applications. For other applications, a concentration of 0.7 mg / g is used. For yet another application, a concentration of 0.9 mg / g is used.

[0044] In some embodiments, fluticasone and vilanterol may be the sole active ingredients in the composition.

[0045] A propellant is also included in the formulation. The propellant may be 1,1-difluoroethane (also known as HFA-152a). In certain embodiments, the propellant may further include 1,1,1,2,3,3,3-heptafluoropropane (also known as HFA-227 or HFC-227) and / or 1,1,1,2-tetrafluoroethane (also known as HFA-134 or HFC-134) in combination with 1,1-difluoroethane (HFA-152a). In some embodiments, the propellant consists substantially of 1,1-difluoroethane (HFA-152a). The propellant may also function as a dispersant for particles of fluticasone, such as fluticasone furoate, and vilanterol, such as vilanterol triphenylacetate.

[0046] Fluticasone particles, such as fluticasone furoate, and vilanterol particles, such as vilanterol triphenylacetate, do not need to be dissolved in the formulation. Instead, fluticasone particles, such as fluticasone furoate, and vilanterol particles, such as vilanterol triphenylacetate, are suspended in the propellant.

[0047] In some embodiments, the composition comprises substantially fluticasone, vilanterol, and one or more propellants.

[0048] To facilitate this suspension, additional components may be added to the formulation. One such additional component is ethanol. Another such additional component is a surfactant. These additional components are not essential unless otherwise specified.

[0049] If ethanol is used, it may be used at a relatively low concentration. Based on mass percentage, the amount of ethanol used, if used, may be 5 or less, 4.5 or less, 4.0 or less, 3.5 or less, 3.0 or less, 2.5 or less, 2.0 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, or 0.5 or less. Based on mass percentage, the amount of ethanol used, if used, may be 0.5 or more, 0.6 or more, 0.7 or more, 0.8 or more, 0.9 or more, 1.0 or more, 1.1 or more, 1.1 or more, 1.2 or more, 1.3 or more, 1.4 or more, 1.5 or more, 2.0 or more, 2.5 or more, 3.0 or more, 3.5 or more, 4.0 or more, 4.5 or more, or 5.0 or more. When ethanol is included, the exemplary range of ethanol concentration is from 0.1% by mass to 5% by mass, for example, from 0.5% by mass to 4% by mass. In some cases, an ethanol concentration of 1% by mass may be used.

[0050] One or more surfactants may be used to promote the suspension of particles in the formulation. However, formulations without surfactants may be advantageous for some purposes, and surfactants are not required unless otherwise specified.

[0051] Any pharmaceutically acceptable surfactant may be used. Most such surfactants are suitable for use in inhalers. Exemplary surfactants include oleic acid, sorbitan monooleate, sorbitan trioleate, soy lecithin, polyethylene glycol, polyvinylpyrrolidone, or combinations thereof. Oleic acid, polyvinylpyrrolidone, or combinations thereof are the most common. A combination of polyvinylpyrrolidone and polyethylene glycol is also commonly used. When using polyvinylpyrrolidone, it can have any suitable molecular weight. Examples of suitable weight-average molecular weights are from 10 to 100 kilodaltons, and may be from 10 to 50, 10 to 40, 10 to 30, or 10 to 20 kilodaltons. When using polyethylene glycol, it can be any suitable grade. PEG1000 and PEG300 are the most commonly used.

[0052] When used, the surfactant may be present in an amount of 0.0001 or more, 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more, 0.09 or more, 0.10 or more, 0.15 or more, 0.20 or more, 0.25 or more, 0.3 or more, 0.4 or more, 0.5 or more, 0.6 or more, 0.7 or more, 0.8 or more, 0.9 or more, or 1 or more, based on mass percentage. The surfactant may be present in amounts of 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.25% or less, 0.20% or less, 0.15% or less, 0.14% or less, 0.13% or less, 0.12% or less, 0.11% or less, 0.10% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, or 0.01% or less, based on mass percentage. The concentration range may be from 0.0001% by mass to 1% by mass, for example, from 0.001% by mass to 0.1% by mass. For specific applications, 0.01% by mass of the surfactant may be used.

[0053] In particular, oleic acid may be used at any of the above concentrations. In particular, polyvinylpyrrolidone may be used at any of the above concentrations. In particular, a combination of polyethylene glycol and polyvinylpyrrolidone may be used at any of the above concentrations. In particular, sorbitan trioleate may be used at any of the above concentrations.

[0054] The above formulations may be used in metered-dose inhalers known in the art.

[0055] An exemplary metered-dose inhaler for a pharmaceutical formulation described herein comprises an aerosol canister with a valve. The canister may have any suitable volume. The maximum volume of the canister depends on the amount of formulation used to fill the canister. In exemplary applications, the canister may have volumes of 5 mL to 500 mL, e.g., 10 mL to 500 mL, 25 mL to 400 mL, 5 mL to 50 mL, 8 mL to 30 mL, 10 mL to 25 mL, or 5 to 20 mL. The canister may usually have a volume sufficient to contain enough drug for a suitable number of doses. The appropriate number of doses is discussed herein. The valve may be attached to or crimpled on the canister via a cap or ferrule. The cap or ferrule is often made of aluminum or an aluminum alloy and may be part of the valve assembly. One or more seals may be located between the canister and the ferrule. The seals may be one or more O-ring seals or gasket seals. The valve may be a metering valve. Exemplary valve size ranges from 20 microliters to 100 microliters. Commonly used specific valve sizes include 25, 50, 60, and 63 microliter valve sizes.

[0056] The container and valve may include an actuator. Most actuators have a patient port for delivering the formulation contained in the canister, which may be a mouthpiece. The patient port may be configured in various ways depending on the intended administration site of the formulation. For example, a patient port designed for nasal administration may generally have an upward inclination to direct the formulation towards the nose. The actuator is most commonly made of plastic material. Exemplary plastic materials for this purpose include at least one of polyethylene and polypropylene. An exemplary MDI has an actuator with an orifice diameter. Any suitable orifice diameter may be used. Exemplary orifice diameters range from 0.2 mm to 0.65 mm. Exemplary orifice ejection lengths range from 0.5 mm to 1.5 mm. Specific examples include orifice diameters of 0.2 mm, 0.25 mm, 0.3 mm, 0.4 mm, 0.5 mm, or 0.6 mm, all of which may have orifice ejection lengths of 0.8 mm, 1.0 mm, or 1.5 mm.

[0057] A metering valve may be present, and is usually located at least partially within the canister and in at least partially communication with an actuator. An exemplary metering valve includes a metering chamber, at least partially defined by an inner valve body through which a valve stem passes. The valve stem may be biased outward by a compression spring to slide-seal-engage with an inner tank seal and an outer diaphragm seal. The valve may also include a second valve body in the shape of a body emptier. The inner valve body, sometimes called the main valve body, partially defines the metering chamber. The second valve body, sometimes called the secondary valve body, in addition to serving as a bottle emptier, partially defines a pre-metering area (sometimes called a pre-metering chamber). The outer wall of the portion of the metering valve located inside the canister, and the inner wall of the canister, define a formulation chamber containing the pharmaceutical formulation.

[0058] During use, the pharmaceutical formulation enters the metering chamber from the formulation chamber. In moving to the metering chamber, the formulation can enter the pre-metering chamber by passing through the annular space between the secondary valve body (or the flange of the secondary valve body) and the main valve body. The valve is activated by pushing the valve stem inward into the container, thereby allowing the pharmaceutical formulation to pass from the pre-metering chamber through the side hole of the valve stem, through the outlet of the valve stem, to the actuator nozzle, and finally to the patient through the patient port. When the valve stem is released, the pharmaceutical formulation passes through the annular space into the valve, for example, the pre-metering chamber, and then moves to the metering chamber.

[0059] The pharmaceutical formulation may be placed in a canister by any known method. The two most common methods are cold filling and pressurized injection. In the cold filling process, the pharmaceutical formulation is cooled to a suitable temperature and injected into the canister. Here, for formulations using propellants HFA 152a, HFA 134a, HFA 227, or combinations thereof, the temperature may be between -40°C and -60°C. Subsequently, a metering valve is crimpled into the canister. As the canister warms to room temperature, the vapor pressure associated with the pharmaceutical formulation increases, thereby providing the appropriate pressure within the canister.

[0060] In the pressurized injection method, the metering valve may first be crimped onto an empty canister. Subsequently, the formulation may be injected into the container through the valve by pressurization. Alternatively, all non-volatile components may first be injected into an empty canister before the valve is crimped onto the canister. The propellant may then be added into the canister through the valve by pressurization.

[0061] When in operation, an exemplary metered-dose inhaler filled with any of the formulations described herein can produce particulate matter masses of 5 mcg to 20 mcg of vilanterol, in particular vilanterol triphenylacetate, and particulate matter masses of 10 mcg to 40 mcg of fluticasone, in particular fluticasone furoate, per operation. In specific cases, an inhaler such as a metered-dose inhaler can produce particulate matter masses of 6 mcg to 12 mcg of vilanterol, in particular vilanterol triphenylacetate, and particulate matter masses of 15 mcg to 25 mcg of fluticasone, in particular fluticasone furoate, per operation. In certain cases, inhalers such as metered-dose inhalers can produce particulate matter masses of vilanterol from 6 mcg to 12 mcg per action, particularly particulate matter masses of vilanterol triphenylacetate, and particulate matter masses of fluticasone from 25 mcg to 35 mcg per action, particularly particulate matter masses of fluticasone furoate. The particulate matter masses can be calculated by the procedures described in the examples section of this disclosure.

[0062] The particulate matter mass discussed above may correspond to the particulate matter fraction of vilanterol, in particular vilanterol triphenylacetate, and the particulate matter fraction of fluticasone, in particular fluticasone furoate, and the particulate matter fraction may be from 20% to 65%, in particular from 20% to 40%, and in more particular from 25% to 35%. The particulate matter fraction can be calculated by the procedure described in the examples section of this disclosure.

[0063] Exemplary metered-dose inhalers are designed to deliver a specific number of doses of a pharmaceutical formulation. In most cases, the specific number of doses ranges from 15 to 400, for example, from 120 to 250, or for example, from 15 to 60. One commonly used metered-dose inhaler is designed to provide 120 doses, which may be used with any of the formulations or types of inhalers described herein. Another commonly used metered-dose inhaler is designed to provide 240 doses, which may be used with any of the formulations or types of inhalers described herein. In another embodiment, a metered-dose inhaler may provide 30 doses.

[0064] A metered-dose inhaler may be equipped with a dose counter for counting the number of doses. Suitable dose counters are known in the art and are described, for example, in U.S. Patent Nos. 8740014, 8479732, and 8814035, and U.S. Patent Application Publication 2012 / 0234317, all of which are incorporated in their entirety by reference to the disclosure of dose counters.

[0065] An exemplary dose counter, detailed in U.S. Patent No. 8740014 (the entire disclosure of that dose counter is incorporated herein by reference), has a fixed ratchet element and a trigger element that are constructed and positioned to perform a reciprocal movement in conjunction with a reciprocal movement between an actuarial element in an inhaler and the dose counter. The reciprocal movement may include a forward stroke (outward relative to the inhaler) and a return stroke. The return stroke returns the trigger element to its position prior to the forward stroke. A counter element is also included in this type of dose counter. The counter element is constructed and positioned to perform a predetermined counting action each time a dose is administered. The counter element is biased toward the fixed ratchet and trigger elements and can count movements in a direction substantially perpendicular to the direction of the reciprocal movement of the trigger element.

[0066] The counter element in the above-described dose counter includes a first region that interacts with a trigger member. The first region includes at least one inclined surface that engages with the trigger member during the forward stroke of the trigger member. This engagement during the forward stroke causes the counter element to perform a counter action. The counter element also has a second region that interacts with a ratchet member. The second region includes at least one inclined surface that engages with the ratchet element during the return stroke of the trigger element, causing the counter element to perform a further counting action, thereby ending the counting action. The counter element is typically in the shape of a counter ring and partially advances during the forward and return strokes of the trigger element. The forward stroke of the trigger can be linked to the pressing of the valve stem, which causes the valve to fire (and, in the case of a metering inhaler, also to measure the contents), and the return stroke can be linked to the return of the valve stem to the resting position, so that the dose counter can count accurate doses.

[0067] Another preferred dose counter, detailed in U.S. Patent No. 8,479,732 (the entire disclosure of that dose counter is incorporated herein by reference), is particularly adapted for use in metered-dose inhalers. This dose counter includes a first count indicator having a first indicator support surface. The first count indicator is rotatable about a first axis. The dose counter also includes a second count indicator having a second indicator support surface. The second count indicator is rotatable about a second axis. The first and second axes are positioned such that they form an obtuse angle. The above obtuse angle may be any obtuse angle, but advantageously it is between 125° and 145°. The obtuse angle aligns in a common viewing area so that the first and second indicator support surfaces collectively display at least a portion of the dose count. One or both of the first and second indicator support surfaces may be marked with numbers so that when viewed together through the viewing area, the numbers provide the dose. For example, one of the first and second display support surfaces may have the hundreds and tens digits and the other the ones digit, so that when the two display support surfaces are read together, a number between 000 and 999 representing the number of doses is provided.

[0068] Another preferred dose counter is described in detail in U.S. Patent Application Publication No. 2012 / 0234317 (the entire disclosure of that dose counter is incorporated herein by reference). Such a dose counter includes a counter element that performs a predetermined counting action each time a dose is administered. The counting action may be vertical or substantially vertical. A count display element is also included. The count display element that performs a predetermined count display action each time a dose is administered includes a first region that interacts with the counter element.

[0069] The counter element has a region that interacts with the count display element. In particular, the count element includes a first region that interacts with the count display element. The first region includes at least one surface that engages with at least one surface of the first region of the count display element. The first region of the counter element and the first surface of the count display element are arranged so that the counter display member completes a count display operation that is linked to the count operation of the counter element, and so that during and induced by the operation of the counter element, the count inducing element performs a rotational motion or substantial rotational motion. In practice, the first region of the counter element or the counter display element may include, for example, one or more channels. The first region of other elements may include one or more projections adapted to engage with the one or more channels.

[0070] Further preferred dose counters are described in detail in U.S. Patent No. 8,814,035 (the entire disclosure of that dose counter is incorporated herein by reference). Such dose counters are particularly adapted for use in inhalers equipped with mutual actuators operating along a first axis. The dose counter includes a display element rotatable around a second axis. The display element is adapted to perform one or more predetermined count display actions when one or more doses are administered. The second axis is positioned at an obtuse angle to the first axis. The dose counter also includes a worm rotatable around a worm axis. The worm is adapted to drive the display element. This may be done, for example, by having a region that interacts with and wraps around a region of the display element. The worm axis and the second axis do not intersect and are not aligned perpendicularly. The worm axis is also, in most cases, not aligned in a column coaxial with the first axis. However, the first and second axes may intersect.

[0071] At least one of the various internal components of an inhaler, such as a metered-dose inhaler as described herein, for example, one or more of the canister, valve, gasket, seal, or O-ring, may be coated with one or more types of coatings. Some of these coatings provide low surface energy. Such coatings are not required as they are not essential for the normal operation of all inhalers.

[0072] Several available coatings are described in U.S. Patent No. 8,414,956 and 8,815,325, and U.S. Patent Application Publication No. 2012 / 0097159, all of which are incorporated herein by reference as a whole disclosure of coatings for inhalers and inhaler components. Other coatings, such as fluorinated ethylene propylene resin, or FEP, are also suitable. FEP is particularly suitable for use in coating canisters.

[0073] The first acceptable coating may be provided by the following method: a) To provide one or more components of an inhaler, such as a metered-dose inhaler. b) To provide a primer composition comprising a silane having two or more reactive silane groups separated by an organic linking group, c) To provide a coating composition comprising at least a partially fluorinated compound, d) Applying the primer composition to at least a portion of the surface of the component, e) Applying the coating composition to the portion of the surface of the component after applying the primer composition.

[0074] Compounds that are at least partially fluorinated typically have one or more reactive functional groups, which are usually reactive silane groups, such as hydrolyzable silane groups or hydroxysilane groups. Such reactive silane groups enable the reaction between the partially fluorinated compound and one or more reactive silane groups of the primer. Such reactions are often condensation reactions.

[0075] An example of a silane that can be used has the following formula X 3-m (R 1 ) m Si-Q-Si(R 2 ) k X 3-k Here R 1 and R 2 A is an independently selected monovalent group, X is a hydrolyzable group or a hydroxyl group, m and k are independently numerical values ​​of 0, 1, or 2, and Q is a divalent organic linking group.

[0076] Useful examples of such silanes include one, two or more mixtures of 1,2-bis(trialkoxysilyl)ethane, 1,6-bis(trialkoxysilyl)hexane, 1,8-bis(trialkoxysilyl)octane, 1,4-bis(trialkoxysilylethyl)benzene, bis(trialkoxysilyl)itaconate, and 4,4'-bis(trialkoxysilyl)-1,1'-diphenyl, where any trialkoxy group can independently be trimethoxy or triethoxy.

[0077] The coating solvent generally includes an alcohol or a hydrofluoroether.

[0078] When the coating solvent is an alcohol, the preferred alcohol is a C1-C4 alcohol, particularly an alcohol selected from ethanol, n-propanol, isopropanol, or a mixture of two or more of these alcohols.

[0079] When the coating solvent is a hydrofluoroether, it is preferred that the coating solvent contains a C4-C 10 hydrofluoroether. Generally, the hydrofluoroether has the following formula, C g F 2g+1 OC<� h H 2h+1 where g is 2, 3, 4, 5, or 6 and h is 1, 2, 3, or 4. Examples of suitable hydrofluoroethers include those selected from the group consisting of methyl heptafluoropropyl ether, ethyl heptafluoropropyl ether, methyl nonafluorobutyl ether, ethyl nonafluorobutyl ether, and mixtures thereof.

[0080] The polyfluoropolyethersilane may have the following formula, R f Q 1 v [Q 2 w [-C(R4 )2-Si(X) 3-x (R 5 ) x ] y ] z Here: R f This is the polyfluoropolyether moiety; Q 1 It is a trivalent linking group; Each Q 2 is an independently selected divalent or trivalent organic linking group; Each R 4 These are independently hydrogen or C 1-4 It is an alkyl group; Each X is independently a hydrolyzable group or a hydroxyl group; R 5 is C 1-8 It is an alkyl or phenyl group; v and w are independently 0 or 1, x is 0, 1 or 2; y is 1 or 2; and z is 2, 3 or 4.

[0081] Polyfluoropolyether moiety R f is, -(C n F 2n O)-, -(CF(Z)O)-, -(CF(Z)C n F 2n O)-,-(C n F 2nThe repeating units may include perfluoro repeating units selected from the group consisting of CF(Z)O)-, -(CF2CF(Z)O)-, and combinations thereof; where n is an integer from 1 to 6, and Z is a perfluoroalkyl group, an oxygen-containing perfluoroalkyl group, a perfluoroalkoxy group, or an oxygen-substituted perfluoroalkoxy group, which may be linear, branched, or cyclic, and in the case of oxygen-containing or oxygen-substituted groups, have 1 to 5 carbon atoms and up to 4 oxygen atoms, and in the case of repeating units containing Z, the number of consecutive carbon atoms is up to 6. In particular, n may be an integer from 1 to 4, more specifically an integer from 1 to 3. In the case of repeating units containing Z, the number of consecutive carbon atoms may be up to 4, more specifically up to 3. Generally, n is 1 or 2, Z is a -CF3 group, and further, z is 2, R f is -CF2O(CF2O) m (C2F4O) p CF2-, -CF(CF3)O(CF(CF3)CF2O) p CF(CF3)-, -CF2O(C2F4O) p CF2-, -(CF2)3O(C4F8O) p (CF2)3-, -CF(CF3)-(OCF2CF(CF3)) p OC t F 2t -O(CF(CF3)CF2O) p Selected from the group consisting of CF(CF3)-, where t is 2, 3, or 4, where m is from 1 to 50, and p is from 3 to 40.

[0082] Crosslinking agents may be included. Exemplary crosslinking agents include tetramethoxysilane; tetraethoxysilane; tetrapropoxysilane; tetrabutoxysilane; methyltriethoxysilane; dimethyldiethoxysilane; octadecyltriethoxysilane; 3-glycidoxypropyltrimethoxysilane; 3-glycidoxypropyltriethoxysilane; 3-aminopropyltrimethoxysilane; 3-aminopropyltriethoxysilane; bis(3-trimethoxysilylpropyl)amine; 3-aminopropyltri(methoxyethoxyethoxy)silane; N(2-aminoethyl)3-amine This includes nopropyltrimethoxysilane; bis(3-trimethoxysilylpropyl)ethylenediamine; 3-mercaptopropyltrimethoxysilane; 3-mercaptopropyltriethoxysilane; 3-trimethoxysilylpropyl methacrylate; 3-triethoxysilylpropyl methacrylate; bis(trimethoxysilyl)itaconate; allyltriethoxysilane; allyltrimethoxysilane; 3-(N-allylamino)propyltrimethoxysilane; vinyltrimethoxysilane; vinyltriethoxysilane; and mixtures thereof.

[0083] The components to be coated may be pre-treated by washing or other means before coating. Washing may be carried out using a solvent such as hydrofluoroether, for example HFE72DE, or an azeotropic mixture of about 70% w / w transdichloroethylene and 30% w / w methyl and ethyl nonafluorobutyl and nonafluoroisobutyl ethers.

[0084] The aforementioned first acceptable coating is particularly useful for coating valve components, including one or more of the valve stem, bottle emptier, spring, and tank. This coating system may be used with any type of inhaler and formulation described herein. In embodiments, the pharmaceutical performance of the MDI of the present invention is controlled to be similar to that of a reference inhaler. For example, in embodiments, the pharmaceutical performance of the MDI of the present invention is similar to that of Relvar® Ellipta® 100 / 25, a dry powder inhaler product in which individual doses contain 100 micrograms of fluticasone furoate and 25 micrograms of vilanterol triphenylacetate. The vilanterol dose of Relvar® Ellipta® 100 / 25 is given as a base equivalent, i.e., the dose is 25 micrograms of vilanterol base present in the form of vilanterol triphenylacetate. This is also true for each vilanterol dose of other Relvar and Breo products described below. In embodiments, the pharmaceutical performance of the MDI of this disclosure is the same as that of Relvar® Ellipta® 200 / 25, a dry powder inhaler product containing individual doses of 200 micrograms of fluticasone furoate and 25 micrograms of vilanterol triphenylacetate. In embodiments, the pharmaceutical performance of the MDI of this disclosure is the same as that of Breo® Ellipta® 100 / 25, a dry powder inhaler product containing individual doses of 100 micrograms of fluticasone furoate and 25 micrograms of vilanterol triphenylacetate. In embodiments, the pharmaceutical performance of the MDI of this disclosure is the same as that of Breo® Ellipta® 200 / 25, a dry powder inhaler product containing individual doses of 200 micrograms of fluticasone furoate and 25 micrograms of vilanterol triphenylacetate.In embodiments, the pharmaceutical performance of the MDI of this disclosure is the same as that of Relvar® Ellipta® 92 / 22, a dry powder inhaler product that delivers a nominal dose of 92 micrograms of fluticasone furoate and 22 micrograms of vilanterol triphenylacetate per inhalation. In embodiments, the pharmaceutical performance of the MDI of this disclosure is the same as that of Relvar® Ellipta® 184 / 22, a dry powder inhaler product that delivers a nominal dose of 184 micrograms of fluticasone furoate and 22 micrograms of vilanterol triphenylacetate per inhalation. In embodiments, the pharmaceutical performance of the MDI of this disclosure is the same as that of Breo® Ellipta® 92 / 22, a dry powder inhaler product that delivers a nominal dose of 92 micrograms of fluticasone furoate and 22 micrograms of vilanterol triphenylacetate per inhalation. In embodiments, the pharmaceutical performance of the MDI of this disclosure is similar to that of Breo® Ellipta® 184 / 22, a dry powder inhaler product that delivers a nominal dose of 184 micrograms of fluticasone furoate and 22 micrograms of vilanterol triphenylacetate per inhalation.

[0085] Similar pharmaceutical performance can be evaluated by either in vitro or in vivo testing methods.

[0086] Suitable in vitro test methods, though not limited to those listed, include single-acting content and aerodynamic particle size distribution. Single-acting content may be measured at the beginning, middle, and / or end of the MDI's lifespan using a flow rate of 28.3 L / min. United States Pharmacopeia <601> Apparatus A or other suitable apparatus may be used. The aerodynamic particle size distribution may be measured at the beginning, middle, and / or end of the life cycle using a flow rate of 28.3 L / min. United States Pharmacopeia <601> Apparatus 1, Apparatus 6, or other suitable apparatus may be used. Single working content may be further analyzed to determine particulate mass (FPM) and / or impactor stage mass (ISM). Aerodynamic particle size distribution may be further analyzed to determine aerodynamic median mass (MMAD).

[0087] Suitable in vivo testing methods include, but are not limited to, pharmacokinetic (PK) bioequivalence testing and clinical pharmacodynamic bioequivalence testing. Those skilled in the art will understand the suitable variables and ranges required to establish bioequivalence. In an exemplary PK bioequivalence test, bioequivalence is considered established if the geometric mean ratio of the test sample to the reference sample, where the area under the curve (AUC) and Cmax (maximum concentration) of the activity and / or active metabolite in plasma falls within the range of 80–125%, has a 90% confidence interval. In an exemplary clinical pharmacodynamic bioequivalence test, bioequivalence is established if the geometric mean ratio of one or more clinical measurements of lung function, such as FEV1, falls within the range of 80–125%, has a 90% confidence interval.

[0088] List of exemplary embodiments The following embodiments are illustrative and not intended to limit the scope unless otherwise specified. 1. Fluticasone particles or pharmaceutically acceptable salts or solvates thereof; Vilanterol triphenylacetate particles; and 1,1-Difluoroethane (HFA-152a); A composition containing the following: 2. A composition according to Embodiment 1, wherein the fluticasone or a pharmaceutically acceptable salt or solvate thereof is fluticasone furoate. 3. A composition according to any of the embodiments described above, wherein the vilanterol or a pharmaceutically acceptable salt or solvate thereof is vilanterol triphenylacetate. 4. A composition according to any of the embodiments described above, wherein the propellant is substantially composed of 1,1-difluoroethane (HFA-152a). 5. A composition according to any of the embodiments, wherein the canister size of the fluticasone is between about 2 micrometers and 4 micrometers. 6. A composition according to any of the embodiments, wherein the canister size of the vilanterol triphenylacetate is between about 1 micrometer and 2 micrometers. 7. A composition according to any of the embodiments described above, wherein the concentration of fluticasone is between approximately 1.0 mg / g and 2.5 mg / g. 8. A composition according to any of the embodiments, wherein the concentration of fluticasone is between approximately 2.0 mg / g and 4.5 mg / g. 9. A composition according to any of the embodiments, wherein the concentration of vilanterol triphenylacetate is between about 0.2 mg / g and 1.0 mg / g. 10. Fluticasone particles or pharmaceutically acceptable salts or solvates thereof; Vilanterol particles or pharmaceutically acceptable salts or solvates thereof; and A composition comprising 1,1-difluoroethane (HFA-152a), wherein fluticasone and vilanterol or pharmaceutically acceptable salts or solvates thereof are the sole active ingredients in the composition. 11. A composition of Embodiment 10, wherein the fluticasone or a pharmaceutically acceptable salt or solvate thereof is fluticasone furoate. 12. A composition according to any one of Embodiments 10 to 11, wherein the vilanterol or a pharmaceutically acceptable salt or solvate thereof is vilanterol triphenylacetate. 13. A composition according to any one of Embodiments 10 to 12, wherein the propellant is substantially composed of 1,1-difluoroethane (HFA-152a). 14. A composition according to any one of Embodiments 10 to 13, wherein the canister size of the fluticasone is between about 2 micrometers and 4 micrometers. 15. A composition according to any of Embodiments 10 to 14, wherein the canister size of the vilanterol triphenylacetate is between about 1 micrometer and 2 micrometers. 16. A composition according to any one of Embodiments 10 to 15, wherein the concentration of fluticasone is between approximately 1.0 mg / g and 2.5 mg / g. 17. A composition according to any one of Embodiments 10 to 16, wherein the concentration of fluticasone is between approximately 2.0 mg / g and 4.5 mg / g. 18. A composition according to any one of Embodiments 10 to 17, wherein the concentration of vilanterol triphenylacetate is between about 0.2 mg / g and 1.0 mg / g. 19. An aerosol canister comprising the composition described in any of the above embodiments. 20. An aerosol canister of Embodiment 19, comprising at least one surface having a primer composition comprising a silane having two or more reactive silane groups separated by an organic linking group, wherein the primer composition comprises at least a partially fluorinated compound. 21. An aerosol canister according to Embodiment 20, wherein the at least partially fluorinated compound is a polyfluoropolyethersilane. 22. An aerosol canister according to Embodiment 20 or Embodiment 21, wherein the at least one surface is at least a part of the valve surface. 23. An inhaler comprising a composition according to any of Embodiments 1 to 18, or an aerosol canister according to any of Embodiments 19 to 23. [Examples]

[0089] 1,1-Difluoroethane (HFA-152a) was obtained from Mexichem (Runcorn, UK). Vilanterol triphenylacetate was obtained from Hovione (Portugal). Fluticasone furoate was obtained from Hovione (Portugal).

[0090] Example 1 A metered-dose inhaler (MDI) was prepared using a 16 mL aluminum canister coated with FEP (IntraPac International, Mooresville, North Carolina, USA), a 63 microliter 3M retention-type valve with a PBT (polybutylene terephthalate) stem and an EPDM (ethylene-propylene dienterpolymer elastomer) diaphragm seal (3M), and a 0.25 mm outlet orifice diameter 3M Mk6 actuator (Oechsler, Ansbach, Germany) fitted with an integrated dose counter. The valve was coated with a fluoropolymer coating according to the general process described in Example 2 of Jinks et al., U.S. Patent Application Publication No. 2017 / 0152396. Vilanterol triphenylacetate was micronized to provide a median mass diameter (MMD) of approximately 1.5 microns. Fluticasone furoate was homogenized under high pressure to provide a median mass diameter (MMD) in the range of approximately 3.5 microns. The canisters were cold-filled with a suspension formulation containing 0.1744% fluticasone furoate, 0.0698% vilanterol triphenylacetate, and 99.7558% HFA-152a. The bulk formulation for cold-filling individual canisters was prepared by mixing fluticasone furoate and vilanterol triphenylacetate with the HFA-152a propellant in a container cooled to below -40°C. The suspension was mixed under high shear for 10 minutes using a Silverson mixer (Silverson, Chesham, UK).

[0091] Delivery dose trial The delivery dose at the start of a unit lifetime was determined using a standard unit spray collector (USCA) fitted with a filter. For each determination, the MDI was attached to the USCA using a coupler and operated once. Immediately before attachment, the MDI was shaken vigorously. Before collecting the test sample, the MDI was prepared by operating it four times. Before each preparation operation, the MDI was shaken vigorously. The flow rate through the instrument was adjusted to 28.3 L / min ± 0.5 L / min. The test sample deposited in the USCA was collected by rinsing with a known volume of collection solution. The collected sample was then analyzed for sample content using HPLC analysis referencing a known standard. An HPLC instrument equipped with a UV detector (220 nm at 0 min, 240 nm at 5 min) and a symmetry shield RP18, 150 mm × 4.6 mm (3.5 μm) column (temperature 25 °C) was used. The mobile phase consisted of 10 mM SDS (sodium dodecyl sulfate), 60:40 (v / v) acetonitrile, and 50 mM NH4OAc (ammonium sulfate), at pH 5.50. The injection volume was 50 μl, and the flow rate was 1.0 mL / min.

[0092] The uniformity of the dose at the start of life was 90.0 mcg / action for fluticasone furoate and 23.1 mcg / action for vilanterol.

[0093] Next-generation impactor (NGI) testing The aerodynamic particle size distribution emitted from each MDI was evaluated using a next-generation impactor (MSP, Shoreview, Minnesota). For each test, the MDI was mounted in the throat section of an NGI apparatus (Emmace anatomical throat, Emmace Consulting, Lund, Sweden) and operated six times within the apparatus. The MDI was vigorously shaken before each operation. The MDI was prepared by operating four times immediately before mounting. The MDI was vigorously shaken before each preparation spray. The flow rate through the apparatus during the test was adjusted to 30 L / min. Test samples (fluticasone furoate and vilanterol triphenylacetate) deposited on the valve stem, actuator, throat assembly (Emmace anatomical throat), independent uncoated collection cups 1-7, microorifice collector (MOC), and final filter components were collected by rinsing each independent component with a known volume of collection solution. The recovered samples were then analyzed for sample content using HPLC analysis referencing known standards. An HPLC instrument equipped with a UV detector (220 nm at 0 min, 240 nm at 5 min) and a symmetry shield RP-18, 4.6-150 mm column (column temperature 25°C) was used. The mobile phase was 10 mM SDS, 60:40 (v / v) acrylonitrile:50 mM NH4OAc, pH 5.5. The injection volume was 50 microliters, and the flow rate was 1.0 mL / min.

[0094] Table 1 shows the particulate mass (FPM), impactor size mass (ISM), aerodynamic median mass diameter (MMAD), and throat retention data for fluticasone furoate (FF) and vilanterol (V). Three independent MDIs were tested at each time point, and the results are expressed as averages.

[0095] The throat retention volume was determined as the ratio of the sample content from the throat assembly to the total content outside the valve.

[0096] [Table 1]

[0097] Particulate mass (FPM) was calculated using CITDAS (Copley Inhaler Testing Data Analysis Software, Copley Scientific, Nottingham, UK) as the total sample content of particles smaller than 5 micrometers (um), and reported as micrograms per run (mcg / run).

[0098] The aerodynamic median mass diameter (MMAD) was calculated using CITDAS (Copley Inhaler Testing Data Analysis Software).

[0099] The impactor size mass (ISM) was determined as the sum of the sample contents determined for cups 2–7, MOC, and filter, and reported as micrograms per run (mcg / run).

[0100] Example 2 A metered-dose inhaler (MDI) was prepared using a 16 mL aluminum canister coated with FEP (IntraPac International, Mooresville, North Carolina, USA), a 25 microliter 3M retention-type valve with a PBT stem and EPDM diaphragm seal (3M), and a 3M Mk6 actuator with a 0.25 mm outlet orifice diameter and a spray length of 0.8 mm. The actuator was equipped with an integrated dose counter. The valve was coated with a fluoropolymer coating according to the general process described in Example 2 of Jinks et al., U.S. Patent Application Publication No. 2017 / 0152396. Vilanterol triphenylacetate was pulverized to provide a median mass diameter (MMD) of approximately 1.5 microns. Fluticasone furoate was homogenized under high pressure to provide a median mass diameter (MMD) in the range of approximately 3.5 microns. The canisters were cold-filled with a suspension formulation containing 0.8791% by mass of fluticasone furoate, 0.1758% by mass of vilanterol triphenylacetate, and 98.9451% by mass of HFA-152a. In the filling procedure, fluticasone furoate and vilanterol triphenylacetate were injected into each canister, followed by the injection of cooled (approximately -55°C to -60°C) HFA-152a. Each canister was crimped with a valve and then sonicated for 10 minutes to disperse the suspension. The assembled MDIs were tested according to the NGI test procedure described above. For fluticasone furoate, the calculated FPM was 104.9 micrograms / acting and the calculated MMAD was 3.5 micrometers. For vilanterol, the calculated FPM was 13.6 micrograms / acting and the calculated MMAD was 2.6 micrometers.

[0101] Example 3 MDI was prepared using a 50-microliter valve, except that the formulation contained 0.4396% by mass of fluticasone furoate, 0.0879% by mass of vilanterol triphenylacetate, and 99.4725% by mass of HFA-152a, except that the formulation contained 0.4396% by mass of fluticasone furoate, 0.0879% by mass of vilanterol triphenylacetate, and 99.4725% by mass of HFA-152a. The assembled MDI was tested according to the NGI test procedure described above. For fluticasone furoate, the calculated FPM was 69.3 micrograms / acting and the calculated MMAD was 3.4 micrometers. For vilanterol, the calculated FPM was 8.8 micrograms / acting and the calculated MMAD was 2.7 micrometers.

[0102] Example 4 MDI was prepared using a 63-microliter valve, except that the formulation contained 0.3489% by mass of fluticasone furoate, 0.0698% by mass of vilanterol triphenylacetate, and 99.5813% by mass of HFA-152a, except that the formulation contained 0.3489% by mass of fluticasone furoate, 0.0698% by mass of vilanterol triphenylacetate, and 99.5813% by mass of HFA-152a. The MDI was tested according to the NGI test procedure described above. For fluticasone furoate, the calculated FPM was 55.9 micrograms / acting and the calculated MMAD was 3.3 micrometers. For vilanterol, the calculated FPM was 6.7 micrograms / acting and the calculated MMAD was 2.3 micrometers.

[0103] Example 5 MDI was prepared using a 100 microliter valve, except that the formulation contained 0.2198% by mass of fluticasone furoate, 0.0440% by mass of vilanterol triphenylacetate, and 99.7362% by mass of HFA-152a, except that the formulation contained 0.2198% by mass of fluticasone furoate, 0.0440% by mass of vilanterol triphenylacetate, and 99.7362% by mass of HFA-152a. The assembled MDI was tested according to the NGI test procedure described above. For fluticasone furoate, the calculated FPM was 45.2 micrograms / acting and the calculated MMAD was 3.3 micrometers. For vilanterol, the calculated FPM was 5.5 micrograms / acting and the calculated MMAD was 2.5 micrometers.

[0104] Example 6 MDI was prepared according to the procedure described in Example 2, except that the formulation contained 0.4396% by mass of fluticasone furoate, 0.1758% by mass of vilanterol triphenylacetate, and 99.3846% by mass of HFA-152a. The assembled MDI was tested according to the NGI test procedure described above. For fluticasone furoate, the calculated FPM was 41.0 micrograms / acting and the calculated MMAD was 3.1 micrometers. For vilanterol, the calculated FPM was 11.4 micrograms / acting and the calculated MMAD was 2.1 micrometers.

[0105] Example 7 An MDI was prepared using a 50-microliter valve, except that the formulation contained 0.2198% by mass of fluticasone furoate, 0.0879% by mass of vilanterol triphenylacetate, and 99.6923% by mass of HFA-152a, except that the formulation contained 0.2198% by mass of fluticasone furoate, 0.0879% by mass of vilanterol triphenylacetate, and 99.6923% by mass of HFA-152a. The assembled MDI was tested according to the NGI test procedure described above. For fluticasone furoate, the calculated FPM was 26.3 micrograms / acting and the calculated MMAD was 2.9 micrometers. For vilanterol, the calculated FPM was 7.7 micrograms / acting and the calculated MMAD was 2.2 micrometers.

[0106] Example 8 An MDI was prepared using a 63-microliter valve, except that the formulation contained 0.1744% by mass of fluticasone furoate, 0.0698% by mass of vilanterol triphenylacetate, and 99.7558% by mass of HFA-152a, except that the formulation contained 0.1744% by mass of fluticasone furoate, 0.0698% by mass of vilanterol triphenylacetate, and 99.7558% by mass of HFA-152a. The assembled MDI was tested according to the NGI test procedure described above. For fluticasone furoate, the calculated FPM was 23.8 micrograms / acting and the calculated MMAD was 3.0 micrometers. For vilanterol, the calculated FPM was 5.9 micrograms / acting and the calculated MMAD was 2.3 micrometers.

[0107] Example 9 An MDI was prepared using a 100 microliter valve, except that the formulation contained 0.1099% by mass of fluticasone furoate, 0.0440% by mass of vilanterol triphenylacetate, and 99.8461% by mass of HFA-152a, except that the formulation contained 0.1099% by mass of fluticasone furoate, 0.0440% by mass of vilanterol triphenylacetate, and 99.8461% by mass of HFA-152a. The assembled MDI was tested according to the NGI test procedure described above. For fluticasone furoate, the calculated FPM was 19.3 micrograms / acting and the calculated MMAD was 3.2 micrometers. For vilanterol, the calculated FPM was 4.2 micrograms / acting and the calculated MMAD was 2.6 micrometers.

[0108] All references and publications cited herein are expressly incorporated in their entirety by reference.

[0109] Various features and aspects of this disclosure are described in the following claims.

Claims

1. Fluticasone particles or pharmaceutically acceptable salts or solvates thereof; Vilanterol particles or pharmaceutically acceptable salts or solvates thereof; and 1,1-Difluoroethane (HFA-152a); A composition containing the following:

2. A composition according to claim 1, wherein the fluticasone or a pharmaceutically acceptable salt or solvate thereof is fluticasone furoate.

3. A composition according to claim 1 or claim 2, wherein the vilanterol or a pharmaceutically acceptable salt or solvate thereof is vilanterol triphenylacetate.

4. A composition according to any one of claims 1 to 3, wherein the propellant comprises substantially 1,1-difluoroethane (HFA-152a).

5. A composition according to any one of claims 1 to 4, contained in a canister, wherein the size of the fluticasone particles in the canister is between about 2 micrometers and 4 micrometers.

6. A composition according to any one of claims 1 to 5, contained in a canister, wherein the size of the vilanteroltriphenylacetate particles in the canister is between about 1 micrometer and 2 micrometers.

7. A composition according to any one of claims 1 to 6, wherein the concentration of fluticasone is between about 1.0 mg / g and 2.5 mg / g.

8. A composition according to any one of claims 1 to 7, wherein the concentration of fluticasone is between about 2.0 mg / g and 4.5 mg / g.

9. A composition according to any one of claims 1 to 8, wherein the concentration of vilanterol triphenylacetate is between about 0.2 mg / g and 1.0 mg / g.

10. Fluticasone particles or pharmaceutically acceptable salts or solvates thereof; Vilanterol particles or pharmaceutically acceptable salts or solvates thereof; and A composition comprising 1,1-difluoroethane (HFA-152a), wherein fluticasone and vilanterol or pharmaceutically acceptable salts or solvates thereof are the sole active ingredients in the composition.

11. A composition according to claim 10, wherein the fluticasone or a pharmaceutically acceptable salt or solvate thereof is fluticasone furoate.

12. A composition according to any one of claims 10 to 11, wherein the propellant further comprises 1,1,1,2,3,3,3-heptafluoropropane or 1,1,1,2-tetrafluoroethane.

13. A composition according to any one of claims 10 to 12, wherein the propellant comprises substantially 1,1-difluoroethane (HFA-152a).

14. A composition according to any one of claims 10 to 13, contained in a canister, wherein the size of the fluticasone particles in the canister is between about 2 micrometers and 4 micrometers.

15. A composition according to any one of claims 10 to 14, contained in a canister, wherein the size of the vilanterol triphenylacetate particles in the canister is between about 1 micrometer and 2 micrometers.

16. A composition according to any one of claims 10 to 15, wherein the concentration of fluticasone is between about 1.0 mg / g and 2.5 mg / g.

17. A composition according to any one of claims 10 to 16, wherein the concentration of fluticasone is between about 2.0 mg / g and 4.5 mg / g.

18. A composition according to any one of claims 10 to 17, wherein the concentration of vilanterol triphenylacetate is between about 0.2 mg / g and 1.0 mg / g.

19. An aerosol canister comprising the composition according to any one of claims 1 to 18.

20. An aerosol canister according to claim 19, comprising at least one surface having a primer composition comprising a silane having two or more reactive silane groups separated by an organic linking group, wherein the primer composition comprises a coating composition comprising at least a partially fluorinated compound.

21. An aerosol canister according to claim 20, wherein the at least partially fluorinated compound is a polyfluoropolyethersilane.

22. An aerosol canister according to claim 20 or claim 21, wherein the at least one surface is at least a part of the valve surface.

23. An inhaler comprising the composition according to any one of claims 1 to 18, or the aerosol canister according to any one of claims 19 to 22.

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