Compositions, methods and systems for aerosol drug delivery

Abstract

Provided is a composition, method and system for pulmonary delivery of active agents by metered dose inhaler.In some embodiments, the composition comprises HFO-1234ze(E) suspension medium, active agent particles and suspended particles.Active agent particles can comprise one, two, three or four active agents selected from long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA), short-acting beta-agonists (SABA), inhaled corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 USC §119(e) of U.S. Provisional Application No. 63 / 220,362, filed July 9, 2021, and U.S. Provisional Application No. 63 / 282,356, filed November 23, 2021. Each of the above-cited applications is hereby incorporated by reference in its entirety for all purposes. [Background technology]

[0002] background Targeted drug delivery method is often desired to deliver active agent to the site of action.For example, targeted delivery of active agent can reduce undesirable side effects, reduce required dosage, and reduce treatment costs.In the context of respiratory delivery, inhalers are well-known devices for administering active agent to the airways of subjects, and several different inhaler systems are commercially available.Three common inhaler systems include dry powder inhalers, nebulizers, and metered dose inhalers (MDIs), also known as pressurized metered dose inhalers (pMDIs).

[0003] MDIs can be used to deliver medicines in solubilized form or as suspensions. Typically, MDIs use relatively high vapor pressure propellants to project active agent-containing aerosolized droplets into the respiratory tract when the MDI is activated. Dry powder inhalers utilize the patient's inspiratory effort to introduce medicine, generally in dry powder form, into the respiratory tract. Nebulizers impart energy to a liquid solution or suspension to form a medicinal aerosol to be inhaled. MDIs have provided a reliable, readily available, and easy-to-use medicinal aerosol delivery system for over 60 years. Although both dry powder inhalers and nebulizers have important roles in the management of airway and parenchymal diseases, there is still no universal aerosol production and delivery system to replace MDIs.

[0004] MIDs are active delivery devices that utilize pressure created by a propellant. The propellant must be safe and pharma- ceutically acceptable for use by patients. Active agents delivered by MDIs are typically provided as suspensions of fine particles dispersed within a propellant or combination of two or more propellants (i.e., a propellant "system"). However, the fine particles of active agent suspended in a propellant or propellant system tend to rapidly aggregate or flocculate. The aggregation or flocculation of these fine particles can then complicate the delivery of the active agent. Other challenges associated with such suspension MDI formulations relate to crystal growth of the drug during storage, which results in a decrease in the aerosol properties and delivered dose uniformity of such MDIs over time. It is therefore important to properly formulate the active agent with additives and propellants to form a stable suspension suitable for MDIs. The properties of the propellant play an important role in the manufacture of suspension formulations for MDIs. For example, the liquid density, vapor pressure and water solubility of the propellant affect suspension stability, dose uniformity, aerosol performance and moisture ingress. Other properties of the propellant such as dipole moment, surface tension, boiling point, liquid viscosity, and latent heat are also factors to consider when formulating a suspension formulation. Historically, the phase-out of chlorofluorocarbon (CFC) propellants, which are ozone-depleting agents, necessitated the reformulation of MDIs using hydrofluoroalkane (HFA) propellants. Although not ozone-depleting, HF propellants are greenhouse gases with high global warming potential (GWP), and therefore alternative MDI propellants with reduced environmental impact are still needed. However, reformulation of MDI propellants is not a straightforward task - due to consideration of the physicochemical properties of various additives and how the addition of these additives may affect overall MDI performance, substantial new technology had to be developed to allow the replacement of CFCs with HFAs in MDIs. For example, one of the major challenges was that the conventional surfactants used in CFC-based MDIs were not compatible with HFAs. Summary of the Invention [Problem to be solved by the invention]

[0005] As there is a desire to develop new environmentally friendly MDIs, there is still a need to research and develop innovative suspension MDI formulations. [Means for solving the problem]

[0006] overview The present invention provides compositions, methods and systems for respiratory delivery of one or more active agents.

[0007] In some embodiments, the compositions described herein are formulated for pulmonary delivery of one or more active agents via MDI. In other embodiments, the compositions described herein can be formulated for nasal delivery via MDI. In some embodiments, the compositions comprise a pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)) propellant, a plurality of active agent particles, and a plurality of particles of phospholipids comprising a porous microstructure. In some embodiments, the plurality of active agent particles comprise one, two, three or four active agents selected from long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA), short-acting beta-agonists (SABA), inhaled corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.

[0008] In some embodiments, the composition comprises a pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)) propellant, a plurality of LAMA particles, and a plurality of particles of phospholipids comprising a porous microstructure. In some embodiments, the composition comprises a pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)) propellant, a plurality of LABA particles, and a plurality of particles of phospholipids comprising a porous microstructure. In some embodiments, the composition comprises a pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)) propellant, a plurality of SABA particles, and a plurality of particles of phospholipids comprising a porous microstructure. In some embodiments, the composition comprises a pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)) propellant, a plurality of ICS particles, and a plurality of particles of phospholipids comprising a porous microstructure. In certain embodiments, the composition comprises a propellant of pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)), a plurality of non-corticosteroid anti-inflammatory agent particles, and a plurality of particles of phospholipid comprising a porous microstructure.

[0009] In some embodiments, the composition comprises a pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)) propellant, a plurality of particles of one or more active agents, and a plurality of particles of phospholipids comprising a porous microstructure. In some embodiments, the composition comprises a pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)) propellant, a plurality of particles of a first active agent, a plurality of particles of a second active agent, and a plurality of particles of phospholipids comprising a porous microstructure. In some embodiments, the particles of the first active agent comprise a first active agent, and the particles of the second active agent comprise a second active agent. In some embodiments, the compositions described herein further comprise a plurality of particles of a third active agent, wherein the particles of the third active agent comprise a third active agent. In some embodiments, the compositions described herein further comprise a plurality of particles of a fourth active agent, wherein the particles of the fourth active agent comprise a fourth active agent. In some embodiments, the active agent is selected from long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA), short-acting beta-agonists (SABA), inhaled corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.In some embodiments, the first and second active agents are selected from long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA), short-acting beta-agonists (SABA), inhaled corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.In further embodiments, the third active agent is selected from long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA), short-acting beta-agonists (SABA), inhaled corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents. In still further embodiments, the fourth active agent is selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS) and a non-corticosteroid anti-inflammatory agent.

[0010] The methods described herein include methods of treating a pulmonary disease or disorder in a patient by actuating a metered dose inhaler containing a composition described herein.

[0011] Also described herein is a system for pulmonary delivery of one or more active agents. In some embodiments, such a system includes an MDI that includes a canister equipped with an outlet valve that includes an actuator (e.g., a depressible valve stem) for dispensing a metered amount of the composition described herein. In some embodiments, the outlet valve is at least partially composed of bromobutyl material. For example, the internal neck gasket of the outlet valve can include or consist of bromobutyl material. Furthermore, one or more internal seat gaskets of the outlet valve can include or consist of bromobutyl material.

[0012] In certain embodiments, the present invention provides a pharmaceutical composition deliverable from a metered dose inhaler, comprising a propellant of pharmaceutical grade (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)) having a purity of at least about 99.90%; a plurality of particles of one or more active agents; and a plurality of particles of phospholipid comprising a porous microstructure, wherein the one or more active agents are selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent.

[0013] In some embodiments, the pharmaceutical composition comprises a plurality of particles of a first type of active agent, wherein the active agent is an ICS selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone, and triamcinolone, or a pharmaceutically acceptable salt or solvate thereof; and a plurality of particles of a second type of active agent, wherein the active agent is a SABA selected from bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, albuterol (salbutamol), terbutaline, tulobuterol, reproterol, and epinephrine, or a pharmaceutically acceptable salt or solvate thereof.

[0014] In certain embodiments of the pharmaceutical composition, the ICS is budesonide, or a pharma- ceutically acceptable salt or solvate thereof; and the SABA is albuterol, or a pharma- ceutically acceptable salt or solvate thereof.

[0015] In one embodiment, the pharmaceutical composition comprises a plurality of particles of a first type of active agent, wherein the active agent is an ICS selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone, and triamcinolone, or a pharmaceutically acceptable salt or solvate thereof; and a plurality of particles of a second type of active agent, wherein the active agent is a LABA selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, mirveterol, indacaterol, vilanterol, and saligenin or an indole-containing and adamantyl-derived beta-2 agonist, or a pharmaceutically acceptable salt or solvate thereof.

[0016] In certain embodiments of the pharmaceutical composition, the ICS is budesonide, or a pharma- ceutically acceptable salt or solvate thereof; and the LABA is formoterol, or a pharma- ceutically acceptable salt or solvate thereof.

[0017] In some embodiments of the pharmaceutical composition, the SABA is present in a concentration ranging from about 0.04 mg / mL to about 2.25 mg / mL.

[0018] In some embodiments of the pharmaceutical composition, the LABA is present in a concentration ranging from about 0.01 mg / mL to about 1 mg / mL.

[0019] In certain embodiments of the pharmaceutical composition, the ICS is present in a concentration ranging from about 0.1 mg / mL to about 20 mg / mL.

[0020] In some embodiments of the pharmaceutical composition, the porous microstructure comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). In other embodiments, the porous microstructure further comprises calcium chloride.

[0021] In certain embodiments of the pharmaceutical composition, the phospholipid particles are present in a concentration ranging from about 0.1 mg / mL to about 10 mg / mL.

[0022] In certain embodiments, the pharmaceutical composition comprises a propellant of pharmaceutical grade HFO-1234ze(E) having a purity of at least about 99.90%; a plurality of budesonide particles; a plurality of albuterol particles; and a plurality of particles of a phospholipid comprising a porous microstructure.

[0023] In some embodiments, the pharmaceutical composition comprises a propellant of pharmaceutical grade HFO-1234ze(E) having a purity of at least about 99.90%; a plurality of budesonide particles; a plurality of formoterol fumarate particles; and a plurality of particles of a phospholipid comprising a porous microstructure.

[0024] In certain embodiments of the pharmaceutical composition, the albuterol particles are in the propellant at a concentration sufficient to provide a delivered dose of glycopyrrolate per actuation of a metered dose inhaler selected from about 5 μg to about 50 μg per actuation, about 2 μg to about 25 μg per actuation, and about 6 μg to about 15 μg per actuation.

[0025] In certain embodiments of the pharmaceutical composition, the albuterol particles comprise micronized and crystalline albuterol sulfate.

[0026] In certain embodiments of the pharmaceutical composition, the formoterol particles are present in the composition at a concentration sufficient to provide a delivered dose of formoterol selected from about 1 μg to about 30 μg, about 0.5 μg to about 10 μg, about 2 μg to 5 μg, about 3 μg to about 10 μg, about 5 μg to about 10 μg, and 3 μg to about 30 μg per actuation of a metered dose inhaler.

[0027] In certain embodiments of the pharmaceutical composition, the formoterol particles comprise micronized and crystalline formoterol fumarate.

[0028] In certain embodiments of the pharmaceutical composition, the budesonide particles are included in the composition at a concentration sufficient to provide a delivered dose of budesonide selected from about 50 μg to about 400 μg, about 20 μg to about 600 μg, about 30 μg to 100 μg, about 50 μg to about 200 μg, and about 150 μg to about 350 μg per actuation of a metered dose inhaler.

[0029] In certain embodiments of the pharmaceutical composition, the budesonide particles comprise micronized budesonide.

[0030] In certain embodiments of the pharmaceutical composition, the phospholipid particles are present in the composition at a concentration sufficient to provide a delivered dose of the phospholipid particles selected from about 50 μg to about 400 μg.

[0031] In certain embodiments, the pharmaceutical composition has a C value of 100% of one or more active agents in a control pharmaceutical composition that contains a propellant of pharmaceutical grade HFA-134a. max , AUC inf or AUC last C of any one or more activators is about 80% to about 125% of max , AUC inf or AUC last Shows.

[0032] In one embodiment, the present invention provides a metered dose inhaler comprising a canister with an outlet valve comprising an actuator for dispensing a metered amount of the pharmaceutical composition of any of the above embodiments, wherein the canister contains the pharmaceutical composition.

[0033] In certain embodiments of the metered dose inhaler, the outlet valve comprises a neck gasket and at least one seat gasket, wherein the neck gasket or the at least one seat gasket is made of a bromobutyl material.

[0034] In some embodiments, the metered dose inhaler has a decrease in injected weight per actuation of less than about 10%, 9%, 8%, 7%, 6% or 5% over the course of the canister being emptied.

[0035] In some embodiments, the metered dose inhaler loses less than about 1.0%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% weight per year at 25° C. / 60% RH.

[0036] In certain embodiments, the metered dose inhaler has a delivered dose uniformity (DDU) for the pharmaceutical formulation selected from ±20% or better DDU, ±15% or better DDU, and ±10% or better DDU until the canister is empty.

[0037] In certain embodiments, the present invention provides a method of treating a pulmonary disease or disorder in a patient, comprising administering to the patient a pharmaceutical composition of any of the above embodiments by actuation of a metered dose inhaler of any of the above embodiments, wherein the metered dose inhaler contains the pharmaceutical composition.

[0038] In certain embodiments of the method, the pulmonary disease or disorder is asthma or COPD.

[0039] In certain embodiments, the invention provides a pharmaceutical composition of any of the above embodiments for use in the manufacture of a medicament for the treatment of a pulmonary disease or disorder.

[0040] In certain embodiments, the invention provides a pharmaceutical composition of any of the above embodiments for use in treating a pulmonary disease or disorder. [Brief description of the drawings]

[0041] [Figure 1] FIG. 1 is an isometric view of an aerosol delivery unit in the form of an MDI, according to an exemplary embodiment.

[0042] [Diagram 2] FIG. 2 is an exploded isometric view of the aerosol delivery unit of FIG. 1.

[0043] [Figure 3A] 2 is a side view and a portion thereof in cross section of the aerosol delivery unit of FIG. 1 showing the unit in a standby or storage configuration with the exhaust passage exposed to a desiccant.

[0044] [Figure 3B] 2 is a side view and a cross-sectional view of a portion of the aerosol delivery unit of FIG. 1 , showing the unit in an exhaust configuration in which the exhaust passage is temporarily separated by the aerosolized substance being exhausted from the canister into the inhalation passage for delivery to the user.

[0045] [Figure 4] FIG. 4 is a perspective view of an outlet valve of a canister suitable for use in conjunction with the aerosol delivery unit of FIGS. 1-3B.

[0046] [Diagram 5] FIG. 1 is a CT scan of the exit passage of an MDI according to an embodiment of the present invention, showing that the nozzle of the MDI is substantially free of deposits or buildup despite repeated use of the MDI to dispense formulations described herein.

[0047] [Figure 6]FIG. 1 is a chart illustrating the formulation weight loss over time for various MDI canisters containing outlet valves with internal gaskets of various materials when filled with a formulation containing an HFO propellant.

[0048] [Figure 7] 1 shows the individual deposition distribution of active agent particles dispensed from an MDI containing a triple co-suspension of glycopyrrolate, budesonide and formoterol active agent particles suspended in HFO-1234ze(E) propellant along with phospholipid suspension particles.

[0049] [Figure 8] 1 shows the deposition distribution of formoterol active agent particles dispensed from an MDI containing a triple co-suspension of glycopyrrolate, budesonide and formoterol active agent particles suspended in HFO-1234ze(E) propellant along with phospholipid suspension particles at several different relative humidity levels.

[0050] [Figure 9] 1 shows the deposition distribution of budesonide active agent particles dispensed from an MDI containing a triple co-suspension of glycopyrrolate, budesonide and formoterol active agent particles suspended in HFO-1234ze(E) propellant along with phospholipid suspension particles at several different relative humidity levels.

[0051] [Figure 10A] FIG. 1 shows the fine particle fraction (FPF) present in the delivered dose upon actuation of MDIs containing budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles, measured after storage of the MDIs at 25° C. and 60% relative humidity for the periods indicated.

[0052] [Figure 10B] FIG. 1 shows the fine particle fraction (FPF) present in the delivered dose upon actuation of MDIs containing budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles, measured after storage of the MDIs at 40° C. and 75% relative humidity for the periods indicated.

[0053] [Figure 10C] FIG. 1 shows the fine particle fraction (FPF) present in the delivered dose upon actuation of MDIs containing budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles, measured after storage of the MDIs at 30° C. and 65% relative humidity for the periods indicated.

[0054] [Figure 11A] 4 shows the fine particle mass (FPM) present in a delivered dose upon actuation of an MDI containing budesonide and phospholipid particles, measured after storage of the MDI at 25° C. and 60% relative humidity for the periods indicated.

[0055] [Figure 11B] 4 shows the fine particle mass (FPM) present in a delivered dose upon actuation of an MDI containing budesonide and phospholipid particles, measured after storage of the MDI at 40° C. and 75% relative humidity for the periods indicated.

[0056] [Figure 11C] 4 shows the fine particle mass (FPM) present in a delivered dose upon actuation of an MDI containing budesonide and phospholipid particles, measured after storage of the MDI at 30° C. and 65% relative humidity for the periods indicated.

[0057] [Figure 12A] 1 shows the degradation of budesonide active agent particles in MDI canisters containing active agent particles and phospholipid particles, measured after storage of the MDIs at 25° C. and 60% relative humidity for the periods indicated.

[0058] [Figure 12B] 1 shows the degradation of budesonide active agent particles in MDI canisters containing active agent particles and phospholipid particles, measured after storage of the MDIs at 40° C. and 75% relative humidity for the periods indicated.

[0059] [Figure 12C]1 shows the degradation of budesonide active agent particles in MDI canisters containing active agent particles and phospholipid particles, measured after storage of the MDIs at 30° C. and 65% relative humidity for the periods indicated.

[0060] [Figure 13A] FIG. 1 shows the degradation of glycopyrrolate active agent particles in MDI canisters containing active agent particles and phospholipid particles, measured after storage of the MDIs at 25° C. and 60% relative humidity for the periods indicated.

[0061] [Figure 13B] FIG. 1 shows the degradation of glycopyrrolate active agent particles in MDI canisters containing active agent particles and phospholipid particles, measured after storage of the MDIs at 40° C. and 75% relative humidity for the periods indicated.

[0062] [Figure 13C] FIG. 1 shows the degradation of glycopyrrolate active agent particles in MDI canisters containing active agent particles and phospholipid particles, measured after storage of the MDIs at 30° C. and 65% relative humidity for the periods indicated.

[0063] [Figure 14A] 1 shows the delivered dose uniformity (DDU) upon actuation of MDIs containing budesonide active agent particles and phospholipid particles following MDI storage at 25° C. and 60% relative humidity between the groups shown.

[0064] [Figure 14B] 1 shows the delivered dose uniformity (DDU) upon actuation of MDIs containing budesonide active agent particles and phospholipid particles following storage of the MDIs at 40° C. and 75% relative humidity between the groups shown.

[0065] [Figure 14C] 1 shows the delivered dose uniformity (DDU) upon actuation of MDIs containing budesonide active agent particles and phospholipid particles following storage of the MDIs at 30° C. and 65% relative humidity between the groups shown.

[0066] [Figure 15] BD, FF and DSPC aerodynamic particle size distributions by NGI for BFF-1234ze [22345-PT009-1234ze] are shown.

[0067] [Figure 16] Aerodynamic particle size distribution by BD's NGI comparing BFF-1234ze [red] and BFF-134a [blue] formulations.

[0068] [Figure 17] Aerodynamic particle size distribution by NGI of FF comparing BFF-1234ze [red] and BFF-134a [blue] formulations.

[0069] [Figure 18] BD aerodynamic particle size distribution from NGI stability data for BFF-1234ze, 25°C / 60%RH - valve closed, protected at initial (blue), 6 months (red) and 12 months (green).

[0070] [Figure 19] BFF-1234ze, FF aerodynamic particle size distribution from NGI stability data at 25°C / 60%RH - valve closed, protected at initial (blue), 6 months (red) and 12 months (green).

[0071] [Figure 20] DSPC aerodynamic particle size distribution from NGI stability data for BFF-1234ze, 25°C / 60%RH - valve closed, protected at initial (blue), 6 months (red) and 12 months (green).

[0072] [Figure 21] BFF-1234ze, 25°C / 60% RHBD and FF delivered dose uniformity stability data shown - valve closed, protected.

[0073] [Figure 22] BD, AB, and DSPC aerodynamic particle size distributions by NGI for BDA-1234ze.

[0074] [Figure 23] Aerodynamic particle size distribution by BD's NGI comparing BDA-1234ze [red] and BDA-134a [blue] formulations.

[0075] [Figure 24] Aerodynamic particle size distributions by NGI for AB comparing BDA-1234ze [red] and BDA-134a [blue] formulations.

[0076] [Diagram 25] BD aerodynamic particle size distribution from NGI stability data for BDA-1234ze, 25°C / 60%RH - valve closed, protected at initial (blue), 6 months (red) and 12 months (green).

[0077] [Figure 26] BDA-1234ze, showing AB aerodynamic particle size distribution from NGI stability data at 25°C / 60%RH - valve closed, protected at initial (blue), 6 months (red) and 12 months (green).

[0078] [Figure 27] BDA-1234ze, BD and AB delivered dose uniformity stability data at 25°C / 60%RH - valve closed, protected.

[0079] [Figure 28] GP and FF aerodynamic particle size distributions by NGI of GFF-1234ze are shown.

[0080] [Figure 29] BD, GP, FF and RF aerodynamic particle size distributions by NGI for BGFR-1234ze are shown.

[0081] [Diagram 30]1 shows the deposition distribution of budesonide, glycopyrrolate, formoterol and roflumilast active agent particles dispensed from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide, formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant with phospholipid suspension particles.

[0082] [Figure 31A] FIG. 1 shows the deposition distribution of roflumilast active agent particles dispensed from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant along with actuated phospholipid suspension particles after 3 months under stability storage conditions representative of accelerated stability (40° C. / 75% RH - valve closed, protected) and after 3 months under stability storage conditions representative of real-time stability (25° C. / 60% RH - valve closed, protected).

[0083] [Figure 31B] FIG. 1 shows the deposition distribution of budesonide active agent particles dispensed from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant along with phospholipid suspension particles upon actuation after 3 months under stability storage conditions representative of accelerated stability (40° C. / 75% RH - valve closed, protected) and after 3 months under stability storage conditions representative of real-time stability (25° C. / 60% RH - valve closed, protected).

[0084] [Figure 31C] FIG. 1 shows the deposition distribution of glycopyrrolate active agent particles dispensed from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant along with phospholipid suspension particles upon actuation, after 3 months under stability storage conditions representative of accelerated stability (40° C. / 75% RH - valve closed, protected) and after 3 months under stability storage conditions representative of real-time stability (25° C. / 60% RH - valve closed, protected).

[0085] [Figure 31D] FIG. 1 shows the deposition distribution of formoterol active agent particles dispensed from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant along with phospholipid suspension particles upon actuation, after 3 months under stability storage conditions representative of accelerated stability (40° C. / 75% RH - valve closed, protected) and after 3 months under stability storage conditions representative of real-time stability (25° C. / 60% RH - valve closed, protected).

[0086] [Diagram 32] 1 shows the delivered dose uniformity (DDU) of roflumilast, formoterol, budesonide and glycopyrrolate active agent particles dispensed early and late in life from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant with phospholipid suspension particles.

[0087] [Figure 33A] 4 shows the delivered dose uniformity (DDU) of roflumilast active agent particles dispensed early and late in life from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant with phospholipid suspended particles after 3 months under stability storage conditions representative of accelerated stability (40° C. / 75% RH - valve closed, protected) and after 3 months under stability storage conditions representative of real-time stability (25° C. / 60% RH - valve closed, protected).

[0088] [Figure 33B]4 shows the delivered dose uniformity (DDU) of early and late life dispensed formoterol active agent particles from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant with phospholipid suspended particles after 3 months under stability storage conditions representative of accelerated stability (40° C. / 75% RH - valve closed, protected) and after 3 months under stability storage conditions representative of real time stability (25° C. / 60% RH - valve closed, protected).

[0089] [Figure 33C] 4 shows the delivered dose uniformity (DDU) of budesonide active agent particles dispensed early and late in life from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant with phospholipid suspended particles after 3 months under stability storage conditions representative of accelerated stability (40° C. / 75% RH - valve closed, protected) and after 3 months under stability storage conditions representative of real time stability (25° C. / 60% RH - valve closed, protected).

[0090] [Figure 33D] 4 shows the delivered dose uniformity (DDU) of glycopyrrolate active agent particles dispensed early and late in life from an MDI containing a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze(E) propellant with phospholipid suspended particles after 3 months under stability storage conditions representative of accelerated stability (40° C. / 75% RH - valve closed, protected) and after 3 months under stability storage conditions representative of real time stability (25° C. / 60% RH - valve closed, protected).

[0091] [Diagram 34] 1 shows aerodynamic particle size distributions of budesonide and formoterol fumarate by the HFA-134a (BFF-134a) and HFO-1234ze (BFF-1234ze) next generation impactors (NGI).

[0092] [Diagram 35] Aerodynamic particle size distributions of budesonide and formoterol fumarate measured by next generation impactor (NGI) for HFA-134a (BFF Crystal-134a) and HFO-1234ze (BFF Crystal-1234ze)

[0093] [Diagram 36] 1 shows aerodynamic particle size distributions of budesonide, glycopyrronium, and formoterol fumarate by next generation impactors (NGI) for HFA-134a (BGF-134a) and HFO-1234ze (BGF-1234ze).

[0094] [Figure 37] 1 shows aerodynamic particle size distributions of budesonide, glycopyrronium, and formoterol fumarate by next generation impactor (NGI) for HFA-134a (BGF crystal-134a) and HFO-1234ze (BGF-1234ze). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0095] Detailed Description definition Unless specifically defined otherwise, technical terms used herein have their ordinary meanings as understood in the art. The following terms are specifically defined for purposes of clarity.

[0096] The term "active agent" is used herein to include any agent, drug, compound, composition or other substance that may be used or administered to a human or animal for any purpose, including therapeutic agents, drugs, pharmacological agents, diagnostic agents, cosmetic agents, and prophylactic agents, as well as immunomodulatory agents. Active agent may be used interchangeably with the terms drug, medicine, medicament, drug substance, or treatment. As used herein, active agent may also include natural or homeopathic products that are not generally considered to be therapeutic agents.

[0097] The terms "bond", "bonded with" or "bonding" refer to an interaction or relationship between chemicals, compositions or structures in the vicinity of a surface, such as the surface of another chemical, composition or structure. Bonding includes, for example, adsorption, adhesion, covalent bonds, hydrogen bonds, ionic bonds and electrostatic attraction, Lifshitz-van der Waals interactions and polar interactions. The term "adhesion" or "adhesion" refers to a form of bonding and is used as a general term for all forces that cause particles or masses to be attracted to a surface. Adhesion also refers to bringing or maintaining particles in contact with each other such that under normal conditions, separation due to differences in buoyancy in the propellant is substantially invisible. In some embodiments, particles placed or bonded to a surface are encompassed by the term adhesion. Normal conditions can include storage at room temperature or under gravitational acceleration forces. The active particles described herein can be combined with suspended particles to form a co-suspension, where there is substantially no visible separation or aggregation between the suspended particles and the active particles due to differences in buoyancy in the propellant.

[0098] "Suspension particles" refers to a substance or combination of substances that is acceptable for respiratory delivery and acts as a vehicle for active agent particles. The suspension particles interact with the active agent particles to facilitate repeated dosing, delivery, or transport of the active agent to the delivery target site, i.e., the respiratory tract. The suspension particles described herein are dispersed in a suspension medium, including a propellant or propellant system, and can be configured with any shape, size, or surface characteristics to achieve the desired suspension stability or active agent delivery performance. Examples of suspension particles include particles that exhibit a particle size that facilitates respiratory delivery of the active agent and have a physical configuration suitable for formulation and delivery of the stabilized suspensions described herein.

[0099] The term "co-suspension" refers to a suspension of two or more types of particles with different compositions in a suspension medium, where one type of particle is at least partially bound to one or more of the other particle types. The binding results in one or more observable changes in at least one characteristic of the individual particle types suspended in the suspension medium. The characteristics modified by binding can include, for example, one or more of the rate of aggregation or flocculation, the rate and nature of separation, i.e., settling or creaming, the density of the cream or sedimented layer, the rate and level of adhesion to container walls, adhesion to valve parts, and dispersion by agitation. The term co-suspension includes co-suspensions in which the majority of at least two particle types are bound to each other, but some separation (i.e., less than the majority) of the at least two particle types can be observed.

[0100] The term "metered dose" or "actuated dose" refers to the amount of active agent contained in the formulation volume expelled from the canister upon actuation of the MDI. The term "delivered dose" refers to the amount of active agent contained in the formulation volume that is expelled from the actuator nozzle and available to be inhaled into the patient's lungs. In some embodiments, the delivered dose is about 85% to about 95% of the metered dose.

[0101] In the context of compositions that include or provide inhalable aggregates, particles, droplets, etc., such as those described herein, the term "fine particle dose" or "FPD" refers to a dose, in terms of total mass or fraction of a nominal or metered dose, within the inhalable range. Dose within the inhalable range is measured in vitro as the sum of the dose delivered at stage 3 through the micro-orifice collector in a next generation impactor operating at a flow rate of 30 l / min.

[0102] In the context of compositions that include or provide inhalable aggregates, particles, droplets, etc., such as those described herein, the term "fine particle fraction" or "FPF" refers to the proportion of delivered substance relative to the delivered dose (i.e., the amount that leaves the actuator of a delivery device such as an MDI) that is within the inhalable range. The amount of delivered substance within the inhalable range is measured in vitro as the sum of the substance delivered at stage 3 through the micro-orifice collector in a next generation impactor operating at a flow rate of 30 l / min.

[0103] As used herein, the term "inhibition" refers to a measurable reduction in the tendency of an event, symptom or condition to occur or the extent to which an event, symptom or condition occurs. The term "inhibition" or any of its forms is used in its broadest sense and includes minimizing, preventing, reducing, suppressing, repressing, inhibiting, restricting, limiting, slowing the progression, and the like.

[0104] As used herein, "mass median aerodynamic diameter" or "MMAD" refers to the aerodynamic diameter of an aerosol where 50% of the aerosol's mass is composed of particles having an aerodynamic diameter smaller than the MMAD, where the MMAD is calculated in accordance with United States Pharmacopeia ("USP") monograph 601.

[0105] As used herein, the term "optical diameter" refers to the size of a particle measured in Fraunhofer diffraction mode using a laser diffraction particle size analyzer equipped with a dry powder dispenser (e.g., Sympatec GmbH, Clasthal-Zellerfeld, Germany).

[0106] The term "solution-mediated transformation" refers to the phenomenon in which a more soluble form of solid material (i.e., particles with a small radius of curvature (the driving force for Ostwald ripening) or amorphous material) dissolves and recrystallizes into a more stable crystalline form that can coexist in equilibrium with the saturated propellant solution.

[0107] "Patient" refers to an animal for which one or more of the active agents described herein can have a therapeutic effect. In certain embodiments, the patient is a human.

[0108] "Porous microstructure" refers to a suspended particle that includes a structural matrix that shows, defines, or includes gaps, pores, defects, cavities, spaces, interstitial spaces, openings, perforations, or holes that allow the surrounding suspension medium to penetrate, fill, or permeate the microstructure, such as the materials and preparations described in U.S. Patent 6,309,623 to Weers, et al. (the method of which is incorporated herein by reference) and U.S. Patent 8,815,258, U.S. Patent 9,463,161, and U.S. Patent Application Publication 2011 / 0135737. The basic shape of the porous microstructure is generally not essential, and any overall configuration that provides the desired formulation characteristics is contemplated herein. Thus, in some embodiments, the porous microstructure can include hollow, porous, approximately spherical shapes such as spray-dried microspheres. However, collapsed, corrugated, deformed, or crushed particles of any basic shape or aspect ratio can also be suitable.

[0109] As is true for the suspended particles described herein, the porous microstructures may be in the form of any biocompatible material that does not substantially degrade or dissolve in the selected suspension medium. While a wide variety of materials can be used to form the particles, in certain embodiments, the structural matrix is ​​combined with or includes a surfactant, such as a phospholipid or a fluorinated surfactant.

[0110] The term "suspension medium" as used herein refers to a substance that provides a continuous phase in which active agent particles and suspended particles can be dispersed to provide a co-suspension formulation. The suspension medium used in the formulations described herein includes a propellant. The term "propellant" as used herein refers to one or more pharmacologically inert substances that exert a vapor pressure high enough at normal room temperature to propel the medicament from the canister of the MDI to the patient upon actuation of the metering valve of the MDI. Thus, the term "propellant" refers to both a single propellant and a combination of two or more different propellants that form a "propellant system."

[0111] The term "respirable" generally refers to particles, agglomerates, droplets, etc., that are of a size such that they can be inhaled and reach the airways of the lungs.

[0112] The terms "physical stability" and "physically stable" as used herein in reference to compositions refer to compositions that are resistant to one or more of aggregation, flocculation and particle size changes due to solution-mediated transformation, and can substantially maintain the MMAD and fine particle dose of suspended particles. In some embodiments, physical stability can be evaluated by subjecting the composition to accelerated degradation conditions, such as by temperature cycling.

[0113] The term "potent," when referring to an active agent, refers to an active agent that is therapeutically effective at a dose of about 0.01 mg / kg to about 1 mg / kg or less. Typical doses of potent active agents generally range from about 100 μg to about 100 mg.

[0114] The term "highly potent," when referring to an active agent, refers to an active agent that is therapeutically effective at a dose of about 10 μg / kg or less. Typical doses of highly potent active agents generally range up to about 100 μg.

[0115] The terms "suspension stability" and "stable suspension" refer to a suspension formulation that can maintain the properties of a co-suspension of active agent particles and suspended particles over a period of time. In some embodiments, suspension stability can be measured via the delivered dose uniformity achieved by the compositions described herein.

[0116] The term "substantially insoluble" means that the composition is completely insoluble or sparingly soluble in a particular solvent. Substantially insoluble means that a particular solute has a solubility of less than 1 part per 100 parts of solvent. The term substantially insoluble is defined in Remington: The Science and Practice of Pharmacy, 21 st Includes definitions of "slightly soluble" (100-1000 parts solvent per part solute), "extremely soluble" (1000-10,000 parts solvent per part solute), and "practically soluble" (>10,000 parts solvent per part solute) as given in Table 16-1 in ed. Lippincott, Williams & Wilkins, 2006, p. 212.

[0117] As used herein, the term "surfactant" refers to any agent that preferentially adsorbs to the interface between two immiscible phases, such as the interface between water and an organic polymer solution, the water / air interface, or the organic solvent / air interface. Surfactants generally have hydrophilic and lipophilic portions such that adsorption to microparticles tends to present portions of the continuous phase that do not attract similarly coated particles, thus reducing particle aggregation.

[0118] A "therapeutically effective amount" is an amount of a compound that achieves a therapeutic effect by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the onset of a disease or disorder. A therapeutically effective amount can be an amount that relieves to some extent one or more symptoms of a disease or disorder in a patient; partially or completely restores one or more physiological or biochemical parameters associated with or causing the disease or disorder to normal; and / or reduces the likelihood of the onset of a disease or disorder.

[0119] The terms "chemically stable" and "chemical stability" refer to a formulation in which the individual degradation products of the active agent remain below the limits specified in regulatory requirements during the shelf life of the product for human use (e.g., 1% of the total chromatographic peak area according to ICH guidance Q3B(R2)) and the mass balance between the active agent assay and the total degradation products is acceptable (e.g., as defined by ICH guidance Q1E).

[0120] composition The compositions described herein include a propellant, a suspension medium that includes active agent particles and suspended particles. Optionally, the compositions described herein may include one or more additional components. In addition, variations and combinations of the components of the compositions described herein may be used. For example, the active agent particles included in the composition may include two or more active agents; or two or more different types of active agent particles may be used, with each active agent particle including a different type of active agent. In some embodiments, two or more types of suspended particles may be used in the composition for delivery of two or more active agents or active agent particles. In some embodiments, when two or more active agent particles are present, the composition is in the form of a fixed dose combination. By "fixed dose combination" is meant that two or more active agents are in a single dose form, such as a formulation in a fixed dose inhaler.

[0121] In general, due to density differences between another type of particle and the medium in which it is suspended (e.g., the propellant or propellant system), buoyant forces result in creaming of particles less dense than the propellant and settling of particles more dense than the propellant. Thus, in a suspension consisting of a mixture of different types of particles with different densities or different flocculation tendencies, it is expected that the settling or creaming behavior will be specific to each of the different particle types and the particular suspension medium used, leading to separation of the different particle types within the suspension medium.

[0122] However, the combination of propellant, active agent particles, and suspended particles described herein provides a co-suspension in which the active agent particles and suspended particles are juxtaposed within the propellant (i.e., the active agent particles are associated with the suspended particles such that the suspended particles and active agent particles do not exhibit substantial separation from one another, such as by differential settling or creaming, even after a period of time sufficient for a cream or sedimented layer to form.) In particular, the active agent particles are associated with the suspended particles such that there is no substantial separation of the active agent particles and suspended particles within the continuous phase formed by the suspension medium under typical patient use conditions.

[0123] The propellant, active agent particle and suspended particle compositions of the present invention provide desirable chemical stability, suspension stability and active agent delivery characteristics. For example, in some embodiments, when present in an MDI canister, the compositions described herein can inhibit or reduce one or more of the following: aggregation of active agent material; differential settling or creaming of active agent particles and suspended particles; solution-mediated transformation of active agent material; and loss of active agent to the surfaces of the container closure system, particularly the metering valve components. Such qualities act to achieve and maintain aerosol performance as the formulation is delivered from the MDI, such that desirable fine particle fraction, fine particle dose and delivered dose uniformity characteristics are achieved and substantially maintained throughout the entire time the MDI canister in which the formulation is contained is emptied. Furthermore, the compositions of the present invention can provide stable formulations that provide consistent dosing characteristics, even for potent and very potent active agents, while using relatively simple HFO suspension media that do not need to be modified, for example, by the addition of co-solvents, anti-solvents, solubilizers or adjuvants. Additionally, in specific embodiments, the pharmaceutical compositions described herein are substantially free of anti-solvents, solubilizers, co-solvents, or adjuvants and can be formulated using an HFO propellant or propellant system.

[0124] In some embodiments, compositions formulated according to the present teachings inhibit physical and / or chemical degradation of the active agent contained therein. For example, in specific embodiments, the compositions described herein may inhibit one or more of chemical degradation, aggregation, coagulation, and solution-mediated transformation of the active agent contained in the composition. The chemical stability and suspension stability provided by the compositions described herein provide enhanced robustness in simulated use tests (SUTs) compared to conventional formulations. The simulated use test includes storage of MDI canisters at 25° C. and 75% relative humidity (RH) for 5 weeks without weekly cleaning of the device, and dispensing of the composition from the MDI at 25° C. and 50% RH. The enhanced robustness can take the form of consistency in shot weight (i.e., the weight of the composition dispensed upon activation of the MDI), low levels of propellant leakage, and desirable delivered dose uniformity ("DDU") over the course of emptying the MDI canister, even when the active agent to be delivered is highly potent and delivered at very low doses. For example, in some embodiments, the compositions described herein, when delivered by an MDI at SUT, lose less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5% of shot weight. In further embodiments, the compositions described herein lose less than about 1.0%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of weight per year in an MDI at 20° C. and 60% RH. In still further embodiments, the compositions described herein exhibit a DDU of ±20% or better, ±15% or better, or ±10% or better during the emptying of an MDI canister. Furthermore, the compositions of the present invention exhibit enhanced robustness by substantially retaining FPF and FPD performance during the emptying of an MDI canister even after being subjected to accelerated degradation conditions. For example, in certain embodiments, the compositions described herein are dispensed from an MDI with an FPF maintained within about 85% or within about 95% of the initial FPF. The compositions described herein offer the added benefit of achieving such performance while being formulated using an HFO propellant.In specific embodiments, the compositions described herein achieve one or more of the targeted DDU, FPF, or FPD while being formulated in a suspension medium containing only one or more HFO propellants, without the need to modify the propellant characteristics, e.g., by the addition of one or more co-solvents, anti-solvents, solubilizers, adjuvants, or other propellant modifiers.

[0125] Suspension Media The suspension medium contained in the compositions described herein includes one or more propellants. In general, propellants suitable for use as suspension mediums are propellant gases that can be liquefied under pressure at room temperature and are safe and toxicologically harmless when inhaled or used topically. In addition, it is desirable that the selected propellant be relatively unreactive with the suspended particles or active agent particles. In the past, compositions for delivery by MDI were typically formulated using chlorofluorocarbon (CFC) propellants, hydrofluoroalkanes (HFAs) or perfluorinated compounds (PFCs). Propellants containing hydrofluoroolefins (HFOs) are considered more environmentally friendly, but there have been some barriers to the use of HFOs in MDI formulations, given the significant differences between HFOs and other propellants. For example, 1,1,1,2-tetrafluoroethane (norflurane, also known as HFA-134a or HFC-134a) is widely used in industrial, consumer and pharmaceutical products as a refrigerant or propellant, but the thermodynamic differences between HFOs and HFA-134a indicate that HFOs cannot be used as a drop-in replacement for HFA-134a. Also, HFOs for industrial or consumer use do not comply with Good Manufacturing Practice (GMP) regulations and are not considered safe for patient use. Furthermore, the performance of pMDIs is highly dependent on the propellant, as propellant properties affect suspension stability, suspension atomization, aerosol droplet size, etc. For example, bacterial testing has shown that the same suspended particles have lower suspension stability in HFO-1234ze compared to HFA-134a and HFA-227ea (Wang, H., et al., Respiratory Drug Delivery, Lisbon, Portugal, 2019). Therefore, considerable experimentation is required to identify a formulation that will deliver a desired dose of active agent particles at the desired DDU and total FPF values. As shown in Table A below, the physicochemical properties vary widely with different propellants.

[0126] [Table 1]

[0127] Surprisingly, it has been found that for compositions comprising active agent particles and suspended particles as described herein, MDI formulations comprising HFO propellants are suitable for use as inhalants, despite the significantly different structures and properties of HFOs and other propellants, e.g., HFAs.

[0128] In some embodiments, the HFO propellant is 1,3,3,3-tetrafluoropropene, also referred to as HFO-1234ze. HFO-1234ze has a trans form (also referred to as (1E)-1,3,3,3-tetrafluoropropene, HFO-1234ze(E)) and a cis form (also referred to as (1Z)-1,3,3,3-tetrafluoropropene, HFO-1234ze(Z)). In some embodiments, the HFO propellant is HFO-1234ze(E), also known as trans-1,3,3,3-tetrafluoroprop-1-ene. In some embodiments, the propellant is a pharmaceutical grade HFO, such as pharmaceutical grade HFO-1234ze(E). As used herein, the term "pharmaceutical grade propellant" refers to a propellant that is compliant with GMP regulations for use in humans. For example, pharmaceutical grade propellants comply with the guidelines of major health organizations, such as the FDA or EMA Pharmaceutical Quality Guideline for Inhaled / Intranasal Drugs, and have established specifications as excipients to ensure the quality and safety of propellants for pharmaceutical use, such as HFO-1234ze(E). Specifications tests include propellant identity, apparent, assay, acidity, total residue, moisture content, related impurities and non-related impurities. Stability tests are also performed to demonstrate long-term physicochemical stability. In some embodiments, pharmaceutical grade HFO-1234ze(E) has a purity of at least about 99.90%. In some embodiments, the propellant is pharmaceutical grade HFO-1234ze(E) with a purity of at least about 99.90%, at least about 99.91%, at least about 99.92%, at least about 99.93%, at least about 99.94%, at least about 99.95%. Pharmaceutical grade HFO-1234ze(E) is suitable for use as a propellant due to its overall purity and the absence or low levels of certain impurities.In certain embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of any of the following impurities: HFO-1234yf, HFO-1234ze(Z), HFC-125, CFC-11, HFC-245cb, HFO-1225ye(Z) or HFO-1225ye(E), CFC-113, and CFC-114. In certain embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of HFO-1234yf. In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of HFO-1234ze(Z). In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of HFC-125. In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of CFC-11. In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of HFC-245cb. In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of HFO-1225ye(Z). In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of HFO-1225ye(E). In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of CFC-113.In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 10 ppm or less, about 9 ppm or less, about 8 ppm or less, about 7 ppm or less, about 6 ppm or less, or about 5 ppm or less of CFC-114. In some embodiments, pharmaceutical grade HFO-1243ze(E) contains about 150 ppm or less, about 140 ppm or less, about 130 ppm or less, about 120 ppm or less, about 110 ppm or less, or about 100 ppm or less of HCFC-124. In some embodiments, pharmaceutical grade HFO-1234ze(E) contains about 400 ppm or less, about 375 ppm or less, about 350 ppm or less, about 325 ppm or less, or about 300 ppm or less of HFC-152a.

[0129] In some embodiments, the suspension medium may be in the form of a propellant, such as pharmaceutical grade HFO-1234ze(E). In some embodiments, certain vapor pressure compounds are present at relatively low levels. Such compounds may bind to the suspended particles.

[0130] In certain embodiments, the suspension medium can be in the form of a propellant or propellant system that is substantially free of additional substances including, for example, anti-solvents, solubilizers, stabilizers, co-solvents, or adjuvants.

[0131] In some embodiments, the pharmaceutical composition comprising pharmaceutical grade HFO-1234ze(E) propellant; a plurality of active agent particles; and a plurality of phospholipid particles exhibits similar or equivalent bioavailability of the active agent compared to a control pharmaceutical composition comprising pharmaceutical grade HFA-134a propellant; a plurality of active agent particles; and a plurality of phospholipid particles. As used herein, "control pharmaceutical composition" refers to another pharmaceutical composition that comprises the same active agent particles and the same suspension particles as the pharmaceutical composition, except for the propellant. For example, the pharmaceutical composition and the control pharmaceutical composition comprise the same active agent particles and the same phospholipid particles, but the control pharmaceutical composition comprises pharmaceutical grade HFA-134a propellant, while the pharmaceutical composition comprises pharmaceutical grade HFO-1234ze(E) propellant. HFA-134a is a hydrofluorocarbon with the chemical name 1,1,1,2-tetrafluoroethane. HFA-134a is used as a propellant in metered dose inhalers. As used herein, "bioavailability" refers to the proportion of active agent that enters the circulation when introduced into the body via the lungs. In certain embodiments, similar or equivalent bioavailability is measured by comparing the log-transformed C max , AUC inf or AUC last It can be shown that the ratio of the geometric means of is about 0.80 to about 1.25, with or without 90% confidence interval (CI) limits.

[0132] In certain embodiments, the pharmaceutical composition has a geometric mean C of one or more of the active agents of a control pharmaceutical composition. max , AUC inf or AUC last C of any one or more active agents, which is about 80% to about 125% of max , AUC inf or AUC lastIn some embodiments, the pharmaceutical composition comprises a propellant of pharmaceutical grade HFO-1234ze(E); a plurality of active agent particles; and a plurality of particles of phospholipids comprising a porous microstructure, while the control pharmaceutical composition comprises a propellant of pharmaceutical grade HFA-134a; a plurality of active agent particles; and a plurality of particles of phospholipids comprising a porous microstructure. In some embodiments, the pharmaceutical composition and the control pharmaceutical composition are both administered by actuation of a metered dose inhaler, wherein each actuation of the pharmaceutical composition provides the same delivered dose of active agent as each actuation of the control pharmaceutical composition. In some embodiments, the active agent particles comprise an active agent selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent, as described herein.

[0133] The C used here max , AUC inf and AUC last is the pharmacokinetic parameter used to determine active agent dosing. max means the maximum concentration of an active agent in the blood after administration of a fixed dose, for example by inhalation. As used herein, area under the curve (AUC) is the definite integral of the curve showing the variation of the concentration of an active agent in the plasma as a function of time. As used herein, AUC inf means the area under the curve from the time of dosing to the last measurable concentration and extrapolated to infinity. As used herein, AUC last means the area under the curve from the time of dosing to the last measurable concentration.

[0134] In certain embodiments, the pharmaceutical composition has a C of budesonide of the control pharmaceutical composition. max C of budesonide, which is about 80% to about 125% of max In one embodiment, the pharmaceutical composition has a C of glycopyrrolate of the control pharmaceutical composition. max C of glycopyrrolate, which is about 80% to about 125% of max In one embodiment, the pharmaceutical composition has a C of formoterol of the control pharmaceutical composition. maxC of formoterol, which is about 80% to about 125% of max In one embodiment, the C of budesonide is max is the geometric mean of the logarithmically transformed values. In some embodiments, the pharmaceutical composition comprises a combination of budesonide and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide and albuterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate, and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate, formoterol and roflumilast active agent particles.

[0135] In one embodiment, the pharmaceutical composition has a lower AUC inf The AUC of budesonide is about 80% to about 125% of the inf In one embodiment, the pharmaceutical composition has a lower AUC inf The AUC of formoterol is about 80% to about 125% of the inf In one embodiment, the AUC inf is the geometric mean of the logarithmically transformed values. In some embodiments, the pharmaceutical composition comprises a combination of budesonide and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide and albuterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate, and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate, formoterol and roflumilast active agent particles.

[0136] In one embodiment, the pharmaceutical composition has a lower AUC last The AUC of budesonide is about 80% to about 125% of the last In one embodiment, the pharmaceutical composition has a lower AUC last AUC of glycopyrrolate is about 80% to about 125% of the AUC of last In one embodiment, the pharmaceutical composition has a lower AUC last The AUC of formoterol is about 80% to about 125% of the last In one embodiment, the pharmaceutical composition has a lower AUC last The AUC of budesonide and formoterol is about 80% to about 125% of the last In one embodiment, the AUC last is the geometric mean of the logarithmically transformed values. In some embodiments, the pharmaceutical composition comprises a combination of budesonide and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide and albuterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate, and formoterol active agent particles. In some embodiments, the pharmaceutical composition comprises a combination of budesonide, glycopyrrolate, formoterol and roflumilast active agent particles.

[0137] Surfactant particles The active agent particles contained in the compositions described herein are formed from a material that can be dispersed and suspended in a suspension medium and are sized to facilitate delivery of inhalable particles from the composition. In some embodiments, the active agent particles are therefore provided as microparticles, with at least 90% of the active agent particles by volume exhibiting an optical diameter of about 7 μm or less. In some embodiments, at least 90% exhibit an optical diameter of about 5 μm or less. In other embodiments, at least 90% of the active agent particles by volume exhibit an optical diameter selected from the ranges of about 7 μm to about 1 μm, about 5 μm to about 2 μm, and about 3 μm to about 2 μm. In further embodiments, at least 90% of the active agent particles by volume exhibit an optical diameter selected from 6 μm or less, 5 μm or less, 4 μm or less, or 3 μm or less. In other embodiments, the active agent particles are provided as microparticles, with at least 50% of the active agent particles by volume exhibiting an optical diameter of about 4 μm or less. In further embodiments, the active agent particles are provided as microparticles, wherein at least 50% by volume of the active agent particles exhibit an optical diameter selected from about 3 μm or less, about 2 μm or less, about 1.5 μm or less, and about 1 μm or less. In still further embodiments, the active agent particles are provided as microparticles, wherein at least 50% by volume of the active agent particles exhibit an optical diameter selected from the ranges of about 4 μm to about 1 μm, about 3 μm to about 1 μm, about 2 μm to about 1 μm, about 1.3 μm, and about 1.9 μm.

[0138] In some embodiments, the active agent particles comprise glycopyrrolate, and at least 90% of the active agent particles by volume have an optical diameter of about 7 μm or less. In some embodiments, the active agent particles comprise budesonide, and at least 90% of the active agent particles by volume have an optical diameter of about 7 μm or less. In some embodiments, the active agent particles comprise formoterol, and at least 90% of the active agent particles by volume have an optical diameter of about 5 μm or less. In some embodiments, the active agent particles comprise albuterol, and at least 90% of the active agent particles by volume have an optical diameter of about 5 μm or less.

[0139] The active agent particles may be formed entirely of the active agent or may be formulated to include a combination of one or more active agents and one or more additives or adjuvants. In a specific embodiment, the active agent present in the active agent particles may be completely or substantially crystalline. In other embodiments, the active agent particles may include active agents that exist in both crystalline and amorphous states. In yet other embodiments, the active agent particles may include active agents that exist in both crystalline and amorphous states. In still further embodiments, when two or more active agents are present in the active agent particles, at least one such active agent may be present in crystalline or substantially crystalline form, and at least one other active agent may be present in amorphous state. In still other embodiments, when two or more active agents are present in the active agent particles, each such active agent may be present in crystalline or substantially crystalline form. When the active agent particles described herein include a combination of one or more active agents and one or more additives or adjuvants, the additives and adjuvants may be selected based on the chemical and physical properties of the active agents used. Excipients suitable for formulation of active agent particles include, for example, lipids, phospholipids, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, synthetic or natural polymers, or surfactant materials.

[0140] Any suitable method can be used to incorporate micronized active agent particles into the compositions described herein. A variety of processes can be used to make active agent particles suitable for use in the formulations described herein, including, but not limited to, pulverization by milling or grinding process, crystallization or recrystallization process, process using precipitation from supercritical or near-critical solvent, spray drying, spray freeze drying or freeze drying. Patent references that teach suitable methods for obtaining micronized active agent particles include, for example, U.S. Patent 6,063,138, U.S. Patent 5,858,410, U.S. Patent 5,851,453, U.S. Patent 5,833,891, U.S. Patent 5,707,634 and International Patent Publication WO2007 / 009164. When the active agent particles include an active agent substance formulated with one or more additives or adjuvants, the micronized active agent particles can be formed using one or more of the above processes, and such processes can be used to achieve active agent particles with desired size distribution and particle shape.

[0141] The active agent particles may be provided in the suspension medium at any suitable concentration. The active agent contained in the active agent particles is substantially insoluble in the suspension medium. In some embodiments, the active agent exhibits measurable solubility in the suspension medium despite being substantially insoluble. However, even when the active agent exhibits measurable solubility in the suspension medium, the compositions described herein serve to preserve the physical stability of such active agents. In particular, in specific embodiments, the active agent contained in the compositions described herein may exhibit sufficient solubility in the suspension medium such that up to 5% of the total active agent mass is dissolved in the suspension medium. Alternatively, the solubility of the active agent allows up to 1% of the total active agent mass to be dissolved in the suspension medium. In other embodiments, the solubility of the active agent allows up to 0.5% of the total active agent mass to be dissolved in the suspension medium. In yet other embodiments, the solubility of the active agent allows up to 0.05% of the total active agent mass to be dissolved in the suspension medium. In yet other embodiments, the solubility of the active agent allows up to 0.025% of the total active agent mass to be dissolved in the suspension medium.

[0142] A variety of therapeutic or prophylactic agents may be incorporated into the co-suspension compositions disclosed herein. Examples of active agents include those that may be administered in the form of an aerosolized pharmaceutical, and active agents suitable for use in the compositions described herein include those that are present in a form or can be formulated in such a way that they are dispersible in the selected suspension medium (e.g., are substantially insoluble or exhibit a solubility that substantially maintains the co-suspension formulation in the suspension medium), can form a co-suspension with the suspended particles, and are subject to uptake by inhalation in a physiologically effective amount. Active agents that may be utilized to form the active agent particles described herein may have a variety of biological activities.

[0143] Examples of specific active agents that may be included in the compositions of the present invention include, for example, short-acting beta agonists (SABAs), such as bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, salbutamol (albuterol), terbutaline, tulobuterol, reproterol, ipratropium, and estrogen. pinephrine; long-acting beta2 adrenergic receptor agonists ("LABA"), such as bambuterol, clenbuterol, formoterol, and salmeterol; ultra-long-acting beta2 adrenergic receptor agonists, such as carmoterol, mirveterol, indacaterol, and saligenin or indole-containing and adamantyl-derived beta2 agonists; corticosteroids, such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, quasone, methyl-prednisolone, mometasone, prednisone and triamcinolone; anti-inflammatory drugs, such as fluticasone propionate, beclomethasone dipropionate, flunisolide, budesonide, tripedan, cortisone, prednisone, prednisolone, dexamethasone, betamethasone or triamcinolone acetonide; antitussives, such as noscapine; bronchodilators, such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline. , metaproterenol, salbutamol, albuterol, salmeterol, terbutaline; and long-acting muscarinic antagonists ("LAMA"), such as glycopyrrolate, dexspironium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipratropium, atropine, benzatropine, or oxitropium.

[0144] The active agent provided in the composition, including but not limited to those specifically described herein, may be used in the form of a salt (e.g., an alkali metal or amine salt or an acid addition salt) or an ester, solvate (e.g., a hydrate), derivative or free base, if appropriate. Furthermore, the active agent may be in any crystalline form or isomeric form or mixture of isomeric forms, such as a pure enantiomer, a racemic mixture of enantiomers or a mixture thereof. In this regard, the form of the active agent may be selected to optimize the activity and / or stability of the active agent and / or to minimize the solubility of the active agent in the suspension medium.

[0145] To allow the compositions disclosed herein to reproducibly deliver very low doses of active agents, in some embodiments, the active agents included in the compositions described herein can be selected from one or more potent or highly potent active agents. For example, in some embodiments, the compositions described herein can include one or more potent active agents to be delivered at a dose selected from about 100 μg to about 100 mg, about 100 μg to about 10 mg, and about 100 μg to 1 mg per actuation of the MDI. In other embodiments, the compositions described herein can include one or more potent or highly potent active agents to be delivered at a dose selected from up to about 80 μg, up to about 40 μg, up to about 20 μg, about 10 μg to about 100 μg, about 5 μg to about 50 μg, and about 1 μg to about 10 μg per actuation of the MDI. Additionally, in certain embodiments, the compositions described herein may include one or more highly potent active agents to be delivered at a dose selected from about 0.1 to about 2 μg, about 0.1 to about 1 μg, and about 0.1 to about 0.5 μg per actuation of the MDI.

[0146] The compositions described herein may optionally include a combination of two or more active agents. For example, a combination of two or more types of active agent particles may be co-suspended with one type of suspended particle. Alternatively, the compositions may include two or more types of active agent particles co-suspended with two or more different types of suspended particle. Still further, the compositions described herein may include two or more active agents combined within one type of active agent particle. For example, when active agent particles are formulated using one or more additives or adjuvants in addition to the active agent substance, such active agent particles may include individual particles that include two or more different active agents.

[0147] In some embodiments, the active agent contained in the composition described herein is a LAMA active agent.When the composition contains a LAMA active agent, in a specific embodiment, the LAMA active agent can be selected from, for example, glycopyrrolate, dexpironium, tiotropium, trospium, aclidinium, umeclidinium and darotropium, including any pharmaceutically acceptable salt, ester, isomer or solvate thereof.In some embodiments, the LAMA active agent is present in a concentration ranging from about 0.04mg / mL to about 2.25mg / mL.

[0148] Glycopyrrolate may be used to treat inflammatory or obstructive pulmonary diseases and disorders, for example, as described herein. As an anticholinergic agent, glycopyrrolate acts as a bronchodilator and provides an antisecretory effect, which is beneficial for use in treating pulmonary diseases and disorders characterized by increased mucus secretion. Glycopyrrolate is a quaternary ammonium salt. Glycopyrrolate may be used in the form of a salt (e.g., an alkali metal or amine salt or an acid addition salt) or an ester or a solvate (hydrate), if appropriate. Furthermore, glycopyrrolate may be in any crystalline form or isomeric form or mixture of isomeric forms, such as a pure enantiomer, a mixture of enantiomers, a racemate, or a mixture thereof. In this regard, the form of glycopyrrolate may be selected to optimize the activity and / or stability of glycopyrrolate and / or to minimize the solubility of the active agent in the suspension medium of glycopyrrolate. Suitable counterions are pharma- ceutically acceptable counterions, including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate. In a specific embodiment of the compositions described herein, the bromide salt of glycopyrrolate, i.e., 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide, also known as (RS)-[3-(SR)-hydroxy-1,1-dimethylpyrrolidinium bromide] α-cyclopentyl mandelate, is used and can be prepared by the method set forth in U.S. Pat. No. 2,956,062.

[0149] When the compositions described herein include glycopyrrolate, in certain embodiments, the compositions may include sufficient glycopyrrolate to provide a targeted delivery dose selected from about 1 μg to about 200 μg per actuation of an MDI, about 5 μg to about 150 μg per actuation of an MDI, about 10 μg to about 100 μg per actuation of an MDI, about 5 μg to about 50 μg per actuation of an MDI, about 2 μg to about 25 μg per actuation of an MDI, and about 6 μg to about 15 μg per actuation of an MDI. In other such embodiments, the formulation includes sufficient glycopyrrolate to provide a dose selected from up to about 200 μg, up to about 150 μg, up to about 75 μg, up to about 40 μg, up to about 20 μg, or up to about 10 μg per actuation. In still further embodiments, the formulation comprises sufficient glycopyrrolate to provide a dose selected from about 2 μg per actuation, about 5 μg per actuation, about 7 μg per actuation, about 9 μg per actuation, about 18 μg per actuation, 36 μg per actuation, or about 72 μg per actuation. When the compositions described herein comprise glycopyrrolate as an active agent, in order to achieve the targeted delivery doses described herein, in specific embodiments, the amount of glycopyrrolate included in the composition can be selected from, for example, about 0.04 mg / mL to about 2.25 mg / mL.

[0150] In other embodiments, tiotropium (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) may be selected as the LAMA active agent to be included in the compositions described herein.Tiotropium is a known long-acting anticholinergic drug suitable for use in treating diseases or disorders associated with pulmonary inflammation or obstruction as described herein.Tiotropium includes the crystalline and pharmaceutically acceptable salt forms of tiotropium, for example, as described in US Patent 5,610,163, US Patent RE39,820, US Patent 6,777,423 and US Patent 6,908,928. When the compositions described herein include tiotropium, in certain embodiments, the compositions may include sufficient tiotropium to provide a delivered dose selected from about 2.5 μg to about 50 μg, about 4 μg to about 25 μg per actuation, and about 2.5 μg to about 20 μg, about 10 μg to about 20 μg, and about 2.5 μg to about 10 μg per actuation of an MDI. In other such embodiments, the formulation includes sufficient tiotropium to provide a delivered dose selected from up to about 50 μg, up to about 20 μg, up to about 10 μg, up to about 5 μg, or up to about 2.5 μg per actuation of an MDI. In still further embodiments, the formulation includes sufficient tiotropium to provide a delivered dose selected from about 3 μg, 6 μg, 9 μg, 18 μg, and 36 μg per actuation of an MDI. When the compositions described herein include tiotropium as an active agent, in order to achieve the delivered doses described herein, in specific embodiments, the amount of tiotropium included in the composition can be selected, for example, from about 0.01 mg / mL to about 0.5 mg / mL.

[0151] In some embodiments, the compositions described herein include a LABA active agent.In such embodiments, the LABA active agent can be selected from, for example, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, mirveterol, indacaterol, vilanterol, and saligenin or indole-containing and adamantyl-derived β2 agonists and any pharma-ceutically acceptable salts, esters, isomers, or solvates thereof.In some embodiments, the LABA active agent is present in a concentration ranging from about 0.01 mg / mL to about 1 mg / mL.

[0152] In some such embodiments, formoterol is selected as the LABA active agent. Formoterol can be used, for example, for the treatment of inflammatory or obstructive pulmonary diseases and disorders, as described herein. Formoterol has the chemical name (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide, and is generally used in pharmaceutical compositions as racemic fumaric acid dihydrate salt. Where appropriate, formoterol can be used in the form of a salt (e.g., alkali metal or amine salt or acid addition salt) or as an ester or solvate (hydrate). Furthermore, formoterol can be in any crystalline form or isomeric form or mixture of isomeric forms, such as pure enantiomers, mixtures of enantiomers, racemates, or mixtures thereof. In this regard, the form of formoterol can be selected to optimize the activity and / or stability of formoterol and / or minimize the solubility of the active agent in the suspension medium of formoterol.Pharmaceutically acceptable salts of formoterol include, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as fumaric acid, maleic acid, acetic acid, lactic acid, citric acid, tartaric acid, ascorbic acid, succinic acid, glutaric acid, gluconic acid, tricarballylic acid, oleic acid, benzoic acid, p-methoxybenzoic acid, salicylic acid, o- and p-hydroxybenzoic acid, p-chlorobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid and 3-hydroxy-2-naphthalenecarboxylic acid.Hydrates of formoterol are described, for example, in U.S. Patent 3,994,974 and U.S. Patent 5,684,199. Certain crystalline forms of formoterol and other β2 adrenergic receptor agonists are described, for example, in WO 95 / 05805, and certain isomers of formoterol are described in US Pat. No. 6,040,344.

[0153] In a specific embodiment, the formoterol material utilized to form formoterol particles is formoterol fumarate, and in some such embodiments, formoterol fumarate exists in dihydrate form.Formoterol fumarate can be represented by the chemical name N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]phenyl]formamide (E)-2-dioate dihydrate. When the compositions described herein include formoterol, in some embodiments, the compositions described herein may include formoterol in a concentration to achieve a target delivered dose selected from about 1 μg to about 30 μg, about 0.5 μg to about 10 μg, about 1 μg to about 10 μg, about 2 μg and 5 μg, about 2 μg to about 10 μg, about 3 μg to about 10 μg, about 5 μg to about 10 μg and 3 μg to about 30 μg per actuation of the MDI. In other embodiments, the compositions described herein may include formoterol in an amount sufficient to provide a target delivered dose selected from up to about 30 μg, up to about 10 μg, up to about 5 μg, up to about 2.5 μg, up to about 2 μg or up to about 1.5 μg per actuation. In still further embodiments, the formulation comprises sufficient formoterol to provide a dose selected from about 2 μg per actuation, about 4.5 μg per actuation, about 4.8 μg per actuation, about 5 μg per actuation, about 10 μg per actuation, about 20 μg per actuation, or about 30 μg per actuation. When the compositions described herein comprise formoterol as an active agent, in order to achieve the targeted delivery doses described herein, in specific embodiments, the amount of formoterol included in the composition can be selected from, for example, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, and about 0.03 mg / mL to about 0.4 mg / mL.

[0154] When the pharmaceutical composition described herein comprises a LABA active agent, in some embodiments, the active agent can be salmeterol, including any pharmaceutically acceptable salt, ester, isomer or solvate thereof.Salmeterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders, for example, as described herein.Salmeterol, pharmaceutically acceptable salts of salmeterol and the preparation method thereof are described, for example, in US Patent 4,992,474, US Patent 5,126,375 and US Patent 5,225,445.

[0155] When salmeterol is included as a LABA active agent, in certain embodiments, the compositions described herein may include salmeterol in a concentration to achieve a delivered dose selected from about 2 μg to about 120 μg, about 4 μg to about 40 μg, about 8 μg to 20 μg, about 8 μg to about 40 μg, about 20 μg to about 40 μg, and about 12 μg to about 120 μg per actuation of an MDI. In other embodiments, the compositions described herein may include salmeterol in an amount sufficient to provide a delivered dose selected from up to about 120 μg, up to about 40 μg, up to about 20 μg, up to about 10 μg, up to about 8 μg, or up to about 6 μg per actuation of an MDI. When the compositions described herein include salmeterol as an active agent, in order to achieve the targeted delivery doses described herein, in specific embodiments, the amount of salmeterol included in the composition can be selected from, for example, about 0.04 mg / mL to about 4 mg / mL, about 0.04 mg / mL to about 2.0 mg / mL, and about 0.12 mg / mL to about 0.8 mg / mL.

[0156] When the pharmaceutical compositions described herein include a SABA active agent, in some embodiments, the active agent can be bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, albuterol (salbutamol), terbutaline, tulobuterol, reproterol, and epinephrine (including any pharma- ceutically acceptable salts, esters, isomers, or solvates thereof). In some such embodiments, albuterol is selected as the SABA active agent. Albuterol has the chemical name alpha 1 -[(tert-butylamino)methyl]4-hydroxy-m-xylene-α,α'-diol, C 13 H 21 Albuterol has the empirical formula of NO3. Albuterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders, for example, as described herein. Albuterol, pharma- ceutically acceptable salts of albuterol (e.g., albuterol sulfate), and methods for their preparation are described, for example, in U.S. Patent 3,705,233.

[0157] When albuterol is included as a SABA active agent, in certain embodiments, the compositions described herein may include albuterol in a concentration to achieve a delivered dose selected from about 10 μg to about 200 μg, about 20 μg to about 300 μg, about 30 μg to about 150 μg, about 50 μg to about 200 μg, about 30 μg to about 100 μg, and about 1 μg to about 300 μg per actuation of an MDI. In other embodiments, the compositions described herein may include albuterol in an amount sufficient to provide a delivered dose selected from up to about 300 μg, up to about 200 μg, up to about 150 μg, up to about 100 μg, up to about 50 μg, up to about 30 μg, up to about 20 μg, or up to about 10 μg per actuation of an MDI. In still further embodiments, the formulation comprises sufficient albuterol to provide a dose selected from about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, or about 150 μg per actuation. When the compositions described herein comprise albuterol as an active agent, in order to achieve the targeted delivery doses described herein, in specific embodiments, the amount of albuterol included in the composition can be selected from, for example, about 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 5 mg / mL, and about 0.3 mg / mL to about 4 mg / mL.

[0158] In yet other embodiments, the compositions described herein include a corticosteroid, such as an inhaled corticosteroid (ICS). Such active agents can be selected from, for example, beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone, and triamcinolone, and any pharma- ceutically acceptable salts, esters, isomers, or solvates thereof. In some embodiments, the ICS active agent is present in a concentration ranging from about 0.1 mg / mL to about 10 mg / mL.

[0159] When the composition comprises ICS active agent, in a specific embodiment, mometasone can be selected.Pharmacologically acceptable salts of mometasone, such as mometasone furoate, and the preparation of such substances are known, and are described, for example, in US Patent 4,472,393, US Patent 5,886,200 and US Patent 6,177,560.Mometasone is suitable for use in the treatment of diseases or disorders associated with pulmonary inflammation or obstruction, as described herein (see, for example, US Patent 5,889,015, US Patent 6,057,307, US Patent 6,057,581, US Patent 6,677,322, US Patent 6,677,323 and US Patent 6,365,581).

[0160] When the compositions described herein comprise mometasone, in specific embodiments, the compositions comprise mometasone (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) in an amount sufficient to provide a target delivery dose selected from about 20 μg to about 400 μg, about 20 μg to about 200 μg, about 50 μg to about 200 μg, about 100 μg to about 200 μg, about 20 μg to about 100 μg, and about 50 μg to about 100 μg per actuation of an MDI. In yet other embodiments, the compositions described herein may comprise mometasone (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) in an amount sufficient to provide a target delivery dose selected from up to about 400 μg, up to about 200 μg, or up to about 100 μg per actuation of an MDI.

[0161] In other embodiments, the compositions described herein comprise a corticosteroid selected from fluticasone and budesonide. Both fluticasone and budesonide are suitable for use in treating pulmonary inflammation or obstruction-related conditions as described herein. Fluticasone, fluticasone pharma- ceutically acceptable salts such as fluticasone propionate and the preparation of such substances are known and are described, for example, in U.S. Patent 4,335,121, U.S. Patent 4,187,301 and U.S. Patent Publication US2008125407. Budesonide, which has the chemical name (RS)-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde, is also known and is described, for example, in U.S. Patent 3,929,768. In certain embodiments, the compositions described herein may comprise fluticasone (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) in an amount sufficient to provide a target delivered dose selected from about 20 μg to about 200 μg, about 50 μg to about 175 μg, and about 80 μg to about 160 μg per actuation of an MDI. In other embodiments, the compositions described herein may comprise fluticasone (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) in an amount sufficient to provide a target delivered dose selected from up to about 175 μg, up to about 160 μg, up to about 100 μg, or up to about 80 μg per actuation of an MDI. When the compositions described herein comprise budesonide, in certain embodiments, the compositions described herein may comprise budesonide (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration to achieve a target delivered dose selected from about 30 μg to about 240 μg, about 30 μg to about 120 μg, about 30 μg to about 100 μg, about 50 μg to about 400 μg, about 20 μg to about 600 μg, about 50 μg to about 200 μg, about 150 μg to about 350 μg, and about 30 μg to about 50 μg per MDI actuation.In other embodiments, the compositions described herein may contain budesonide (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) in an amount sufficient to provide a targeted delivery dose selected from about 240 μg, about 160 μg, about 120 μg, about 80 μg, or about 50 μg per actuation of an MDI. In yet further embodiments, the formulation contains sufficient budesonide to provide a dose selected from about 20 μg per actuation, about 40 μg per actuation, about 80 μg per actuation, about 100 μg per actuation, about 160 μg per actuation, about 200 μg per actuation, or about 300 μg per actuation. When the compositions described herein include budesonide as an active agent, in order to achieve the targeted delivery doses described herein, in specific embodiments, the amount of budesonide included in the composition can be selected from, for example, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 5 mg / mL, and about 0.3 mg / mL to about 6 mg / mL.

[0162] In yet another embodiment, the composition described herein comprises a non-corticosteroid anti-inflammatory agent, such as a phosphodiesterase-4 (PDE-4) inhibitor and a Janus kinase (JAK) inhibitor. Such an anti-inflammatory agent can be selected from, for example, roflumilast, apremilast, crisaborole, ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib and upadacitinib; or any pharmaceutically acceptable salt, ester, isomer or solvate thereof. Roflumilast, pharmaceutically acceptable salts of roflumilast and the preparation of such substances are known and are described, for example, in US Patent 8,604,064, US Patent 9,145,365 and US Patent 9,321,726. Roflumilast is suitable for use in the treatment of pulmonary inflammation or obstruction associated with pulmonary inflammation or obstruction as described herein. Roflumilast may be used to treat COPD, especially severe COPD, and is available as an oral medication. Gastrointestinal side effects are common with oral administration of roflumilast.

[0163] When the compositions described herein comprise roflumilast, in certain embodiments, the compositions described herein may comprise roflumilast (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration to achieve a target delivery dose selected from about 1 μg to about 100 μg, about 5 μg to about 80 μg, about 5 μg to about 50 μg, about 5 μg to about 25 μg, about 10 μg to 25 μg, about 30 μg to about 240 μg, about 30 μg to about 120 μg, about 30 μg to about 100 μg, about 50 μg to about 400 μg, about 20 μg to about 600 μg, about 50 μg to about 200 μg, about 150 μg to about 350 μg, and about 30 μg to about 50 μg per MDI actuation. In other embodiments, the compositions described herein may contain roflumilast (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) in an amount sufficient to provide a target delivery dose selected from about 240 μg, about 160 μg, about 120 μg, about 80 μg, or about 50 μg per actuation of an MDI. In yet further embodiments, the formulation contains sufficient roflumilast to provide a dose selected from about 20 μg per actuation, about 40 μg per actuation, about 80 μg per actuation, about 100 μg per actuation, about 160 μg per actuation, about 200 μg per actuation, or about 300 μg per actuation. When the compositions described herein include roflumilast as an active agent, in order to achieve the targeted delivery doses described herein, in specific embodiments, the amount of roflumilast included in the composition can be selected from, for example, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 5 mg / mL, and about 0.3 mg / mL to about 6 mg / mL.

[0164] The compositions described herein may be formulated to include (and deliver) a single active agent. Alternatively, the compositions described herein may include two or more active agents. In specific embodiments that include two or more active agents, the compositions described herein may include a combination of active agents selected from a combination of LAMA and LABA active agents, a combination of LAMA and corticosteroid active agents, a combination of LAMA and SABA active agents, a combination of LAMA and non-corticosteroid anti-inflammatory active agents, a combination of LABA and SABA active agents, a combination of LABA and non-corticosteroid anti-inflammatory active agents, a combination of SABA and corticosteroid active agents, a combination of SABA and non-corticosteroid anti-inflammatory active agents, and a combination of LABA and corticosteroid active agents. In other embodiments, the compositions described herein may include three or more active agents. In some such embodiments, the compositions include a combination of active agents selected from a combination of LAMA, LABA, corticosteroid, and non-corticosteroid anti-inflammatory active agents. For example, the compositions described herein may include a combination of active agents selected from a combination of glycopyrrolate and formoterol, a combination of formoterol and budesonide, a combination of budesonide and albuterol, a combination of glycopyrrolate, formoterol and budesonide, and a combination of glycopyrrolate, formoterol, budesonide and roflumilast.

[0165] It will be apparent to one of ordinary skill in the art that, with the aid of the present invention, a wide variety of active agents may be incorporated into the suspensions disclosed herein. The above list of active agents is illustrative and not limiting.

[0166] Suspended particles The suspended particles contained in the compositions described herein serve to stabilize and facilitate delivery of the active agent contained in the compositions. Although various forms of suspended particles may be used, suspended particles are typically formed from pharmacologically inactive substances that are acceptable for inhalation and are substantially insoluble in the selected propellant. Generally, the majority of suspended particles are in the respirable range in size. In a specific embodiment, therefore, the MMAD of the suspended particles is not greater than about 10 μm, but not lower than about 500 nm. In another embodiment, the MMAD of the suspended particles is about 5 μm to about 750 nm. In yet another embodiment, the MMAD of the suspended particles is about 1 μm to about 3 μm. When used in the embodiment of nasal delivery from an MDI, the MMAD of the suspended particles is 10 μm to 50 μm.

[0167] To achieve respirable suspended particles within the recited MMAD ranges, the suspended particles typically exhibit a volume median optical diameter of about 0.2 μm to about 50 μm. In some embodiments, the suspended particles exhibit a volume median optical diameter not exceeding about 25 μm. In other embodiments, the suspended particles exhibit a volume median optical diameter selected from about 0.5 μm to about 15 μm, about 1.5 μm to about 10 μm, and about 2 μm to about 5 μm.

[0168] The concentration of the suspended particles contained in the composition of the present invention can be adjusted, for example, depending on the amount of active agent particles and suspension medium used.In some embodiments, the suspended particles are contained in the suspension medium at a concentration selected from about 0.1 mg / mL to about 15 mg / mL, about 0.1 mg / mL to about 10 mg / mL, 1 mg / mL to about 15 mg / mL, about 3 mg / mL to about 10 mg / mL, 5 mg / mL to about 8 mg / mL and about 6 mg / mL.In other embodiments, the suspended particles are contained in the suspension medium at a concentration of up to about 30 mg / mL.In still other embodiments, the suspended particles are contained in the suspension medium at a concentration of up to about 25 mg / mL.

[0169] The relative amount of suspended particles to active agent particles is selected to achieve the co-suspension contemplated herein. Co-suspension compositions can be achieved when the amount of suspended particles exceeds the amount of active agent particles, measured by mass. For example, in specific embodiments, the ratio of the total mass of suspended particles to the total mass of active agent particles can be about 3:1 to about 15:1, or about 2:1 and 8:1. Alternatively, the ratio of the total mass of suspended particles to the total mass of active agent particles can be greater than about 1, for example, up to about 1.5, up to about 5, up to about 10, up to about 15, up to about 17, up to about 20, up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150 and up to about 200, depending on the nature of the suspended particles and active agent particles used. In further embodiments, the ratio of the total mass of suspended particles to the total mass of active agent particles can be selected from about 10 to about 200, about 60 to about 200, about 15 to about 60, about 15 to about 170, about 15 to about 60, about 16, about 60, and about 170.

[0170] In other embodiments, the amount of suspended particles is less than the amount of active agent particles, measured by mass.For example, in a specific embodiment, the mass of suspended particles can be about 20% of the total mass of active agent particles.However, in some embodiments, the total mass of suspended particles can be close to or equal to the total mass of active agent particles.

[0171] The suspension particles suitable for use in the compositions described herein can be formed from one or more pharma- ceutically acceptable substances or additives that are suitable for inhalation delivery and do not substantially decompose or dissolve in the suspension medium.In some embodiments, the perforated microstructures defined herein can be used as suspension particles.Suspension particles and perforated microstructures for use as suspension particles and their manufacturing methods are described in US Patent 8,815,258 and US Patent 9,463,161 and US Patent Publication 2011 / 0135737.

[0172] Phospholipids from both natural and synthetic sources can be used to produce suspension particles that contain porous microstructures suitable for use in the compositions described herein.In a specific embodiment, the selected phospholipid has a gel to liquid crystalline phase transition above about 400°C.Examples of phospholipids are relatively long-chain (i.e., C16-C22) saturated lipids, and can include saturated phospholipids such as saturated phosphatidylcholine with acyl chain length of 16C or 18C (palmitoyl and stearoyl).Examples of phospholipids include phosphoglycerides such as dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol, short-chain phosphatidylcholine, long-chain saturated phosphatidylethanolamine, long-chain saturated phosphatidylserine, long-chain saturated phosphatidylglycerol and long-chain saturated phosphatidylinositol. Further additives are disclosed in International Patent Publication WO 96 / 32149 and US Patents 6,358,530, 6,372,258 and 6,518,239.In certain embodiments, the suspension particles are phospholipid particles comprising 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

[0173] In other embodiments, the suspended particles used in the compositions described herein can be selected to increase the storage stability of selected active agents, similar to those disclosed in International Patent Publication WO2005 / 000267.For example, in some embodiments, the suspended particles can include a pharma- ceutically acceptable glass stabilizing additive having a Tg of at least 55°C, at least 75°C, or at least 100°C.Glass-forming agents suitable for use in the compositions described herein include, but are not limited to, one or more of trileucine, sodium citrate, sodium phosphate, ascorbic acid, inulin, cyclodextrin, polyvinylpyrrolidone, mannitol, sucrose, trehalose, lactose, and proline.Further examples of glass-forming additives are disclosed in U.S. Patents RE37,872, 5,928,469, 6,258,341, and 6,309,671. In a specific embodiment, the suspended particles may include a calcium salt, such as calcium chloride, as described, for example, in US Pat. No. 7,442,388.

[0174] In some embodiments, the suspended particle is a porous microstructure that comprises DSPC and calcium chloride.In some embodiments, the porous microstructure comprises about 93% or more DSPC and about 7% or less calcium chloride.In some embodiments, the porous microstructure comprises about 94% DSPC and about 6% calcium chloride.In some embodiments, the porous microstructure comprises about 95% DSPC and about 5% calcium chloride.

[0175] The suspended particles can be designed, sized and shaped as desired to provide desired stability and active agent delivery characteristics. In some exemplary embodiments, the suspended particles comprise the porous microstructures described herein. When the porous microstructures are used as suspended particles in the compositions described herein, they can comprise at least one of the following: lipids, phospholipids, non-ionic surfactants, non-ionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof, especially those approved for pulmonary use. Specific surfactants that can be used to manufacture the porous microstructures include poloxamer 188, poloxamer 407 and poloxamer 338. Other specific surfactants include oleic acid or its alkali salts. In some embodiments, the porous microstructures comprise more than about 10% w / w surfactant.

[0176] In addition, the suspended particles described herein may include fillers such as polymer particles. The polymers may be formed from biocompatible and / or biodegradable polymers, copolymers or blends. In some embodiments, polymers capable of forming aerodynamically light particles may be used, such as functionalized polyester graft copolymers and biodegradable polyanhydrides. For example, bulk eroding polymers based on polyesters containing poly(hydroxy acids) may be used. Polyglycolic acid (PGA), polylactic acid (PLA) or copolymers thereof may be used to form suspended particles. The polyesters may include charged or functional groups such as amino acids. For example, the suspended particles may be in the form of poly(D,L-lactic acid) and / or poly(D,L-lactic-co-glycolic acid) (PLGA) incorporating surfactants such as DPPC.

[0177] Other potential polymer candidates for use in the suspension particles may include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), polyvinyl compounds such as polyvinyl alcohol, polyvinyl ethers and polyvinyl esters, polymers of acrylic and methacrylic acid, cellulose and other polysaccharides and peptides or proteins or copolymers or blends thereof. Polymers may be selected or modified to have appropriate stability and degradation rates in vivo for different controlled drug delivery applications.

[0178] In embodiments of the compositions described herein that include one or more of glycopyrrolate, formoterol, budesonide, and albuterol as active agents, the ratio of the total mass of suspended particles to the total mass of active agent particles can be selected from about 1 to about 20, about 1 to about 15, about 1.5 to about 10, about 2.5 to about 15, about 2.5 to about 10, about 2.5 to about 8, about 10 to about 30, about 15 to about 25, about 10 to about 200, about 50 to about 125, and about 5 to about 50.

[0179] In some embodiments, the suspended particles can be produced by forming an oil-in-water emulsion using a fluorocarbon oil (e.g., perfluorooctyl bromide, perfluorodecalin), which can be emulsified using a surfactant such as a long-chain saturated phospholipid. The resulting perfluorocarbon in water emulsion can then be treated to reduce the oil droplet size using a high-pressure homogenizer. The perfluorocarbon emulsion can be fed to a spray dryer. As is well known, spray drying is a one-step process that converts a fed liquid into a dry particle size. Spray drying has been used to provide powdered pharmaceutical substances for various routes of administration, including inhalation. During spray drying, fluorocarbon oils, such as those described above, can function as foaming agents. The operating conditions of the spray dryer (e.g., inlet and outlet temperatures, feed rate, atomization pressure, drying air flow rate, and nozzle configuration) can be adjusted to produce the desired particle size resulting in a yield of the resulting dry microstructure. Exemplary such methods of producing porous microstructures are disclosed in US Pat. No. 8,815,258, US Pat. No. 9,463,161 and US Patent Publication 2011 / 0135737.

[0180] The compositions described herein may contain two or more kinds of suspended particles.For example, the compositions described herein may contain one kind of active agent particles and two or more kinds of suspended particles.Alternatively, in other embodiments, the compositions described herein may contain two or more kinds of active agent particles combined with two or more kinds of suspended particles.

[0181] Composition embodiments In some embodiments, compositions comprising a combination of two or more active agents described herein may include budesonide, glycopyrrolate, and formoterol as active agents. In embodiments of compositions described herein comprising budesonide, glycopyrrolate, and formoterol as active agents, the ratio of the total mass of suspended particles to the total mass of active agent particles may be selected from about 1 to about 20, about 1 to about 15, about 1.5 to about 10, about 2.5 to about 15, about 2.5 to about 10, about 2.5 to about 8, about 10 to about 30, about 15 to about 25, about 10 to about 200, about 50 to about 125, and about 5 to about 50. In all embodiments, the active agent to suspended particle ratio is based on the free form (e.g., free acid or free base form) of the active agent. In some embodiments, the compositions are administered by oral inhalation. In some embodiments, compositions described herein comprising budesonide, glycopyrrolate, and formoterol as active agents may be included in the reservoir of a metered dose inhaler (MDI) device. In some embodiments, the compositions described herein may include budesonide (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivery dose selected from about 70 μg to about 170 μg, about 75 μg to about 165 μg, and about 80 μg to about 160 μg of budesonide per inhalation. In some embodiments, the compositions described herein may include glycopyrrolate (including any pharma-ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivery dose selected from about 5 μg to about 10 μg and about 5 μg to about 15 μg of glycopyrrolate per inhalation. In some embodiments, the compositions described herein may include formoterol (including any pharma-ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivery dose selected from about 1 μg to about 5 μg and about 2 μg to about 4 μg of formoterol per inhalation. In certain embodiments, the composition may be administered as two inhalations twice daily.In some embodiments, the compositions described herein comprise about 0.240% to about 0.360% (w / w) budesonide, about 0.010% to about 0.016% (w / w) glycopyrronium bromide, about 0.007% to about 0.011% (w / w) formoterol fumarate, about 0.410% to about 0.615% (w / w) DSPC porous particles, and HFO-1234ze(E). In some embodiments, the compositions described herein comprise about 0.268% to about 0.328% by weight (w / w) budesonide, about 0.012% to about 0.015% by weight (w / w) glycopyrronium bromide, about 0.008% to about 0.010% by weight (w / w) formoterol fumarate, about 0.461% to about 0.564% by weight (w / w) DSPC porous particles, and HFO-1234ze(E). In some embodiments, the compositions described herein include about 0.283% to about 0.314% by weight (w / w) budesonide, about 0.013% to about 0.014% by weight (w / w) glycopyrronium bromide, about 0.008% to about 0.010% by weight (w / w) formoterol fumarate, about 0.487% to about 0.538% by weight (w / w) DSPC porous particles, and HFO-1234ze(E). Table 1 shows exemplary embodiments of compositions that include combinations of two or more active agents, including glycopyrrolate, formoterol, and budesonide as active agents. In some embodiments, the exemplary compositions of Table 1 can provide a delivered dose of about 160 μg budesonide, about 9 μg glycopyrronium bromide, and about 4.8 μg formoterol fumarate per actuation of a metered dose inhaler.

[0182] [Table 2]

[0183] In some embodiments, compositions comprising a combination of two or more active agents described herein may include glycopyrrolate and formoterol as active agents. In some embodiments of compositions described herein comprising glycopyrrolate and formoterol as active agents, the ratio of the total mass of suspended particles to the total mass of active agent particles may be selected from about 1 to about 25, about 1 to about 20, about 1.5 to about 10, about 2.5 to about 15, about 2.5 to about 10, about 2.5 to about 8, about 10 to about 30, about 15 to about 25, about 10 to about 200, about 50 to about 125, and about 5 to about 50. In all embodiments, the active agent to suspended particle ratio is based on the free base form of the active agent. In some embodiments, the compositions are administered by oral inhalation. In some embodiments, compositions described herein comprising glycopyrrolate and formoterol as active agents may be included in the reservoir of a metered dose inhaler (MDI) device. In some embodiments, the compositions described herein may contain glycopyrrolate (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivery dose selected from about 5 μg to about 10 μg and about 5 μg to about 15 μg of glycopyrrolate per inhalation. In some embodiments, the compositions described herein may contain formoterol (including any pharma-ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivery dose selected from about 1 μg to about 5 μg of formoterol per inhalation. In some embodiments, the compositions may be administered twice daily, 2 inhalations per inhalation. In some embodiments, the compositions described herein include about 0.011% to about 0.016% (w / w) glycopyrronium bromide, about 0.007% to about 0.011% (w / w) formoterol fumarate, about 0.411% to about 0.617% (w / w) DSPC porous particles, and HFO-1234ze(E). In some embodiments, the compositions described herein include about 0.012% to about 0.015% (w / w) glycopyrronium bromide, about 0.008% to about 0.010% (w / w) formoterol fumarate, about 0.411% to about 0.617% (w / w) DSPC porous particles, and HFO-1234ze(E).In some embodiments, the compositions described herein include about 0.013% to about 0.014% by weight (w / w) glycopyrronium bromide, about 0.008% to about 0.010% by weight (w / w) formoterol fumarate, about 0.488% to about 0.540% by weight (w / w) DSPC porous particles, and HFO-1234ze(E). Table 2 shows exemplary embodiments of compositions including glycopyrrolate and formoterol as active agents. In some embodiments, the exemplary compositions of Table 2 can provide the delivered doses of Table 2 per actuation of a metered dose inhaler.

[0184] [Table 3]

[0185] In some embodiments, compositions comprising a combination of two or more active agents described herein may comprise budesonide and albuterol sulfate as active agents. In some embodiments of compositions described herein comprising budesonide and albuterol sulfate as active agents, the ratio of the total mass of suspended particles to the total mass of active agent particles may be selected from about 1 to about 25, about 1 to about 20, about 1.5 to about 10, about 2.5 to about 15, about 2.5 to about 10, about 2.5 to about 8, about 10 to about 30, about 15 to about 25, about 10 to about 200, about 50 to about 125, and about 5 to about 50. In all embodiments, the active agent to suspended particle ratio is based on the free base form of the active agent. In some embodiments, the compositions are administered by oral inhalation. In some embodiments, compositions described herein comprising budesonide and albuterol sulfate as active agents may be contained in a reservoir of a metered dose inhaler (MDI) device. In some embodiments, the compositions described herein may include budesonide (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration to achieve a target delivered dose selected from about 35 μg to about 90 μg, and about 40 μg to about 85 μg, and about 45 μg to about 80 μg of budesonide per inhalation. In some embodiments, the compositions described herein may include albuterol sulfate (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration to achieve a target delivered dose selected from about 75 μg to about 95 μg, and about 80 μg to about 90 μg of albuterol sulfate per inhalation. In some embodiments, the compositions may be administered twice daily, two inhalations per inhalation. In some embodiments, the compositions described herein comprise about 0.058% to about 0.088% by weight (w / w) budesonide, about 0.131% to about 0.197% by weight (w / w) albuterol sulfate, about 0.267% to about 0.401% by weight (w / w) DSPC porous particles, and HFO-1234ze(E).In some embodiments, the compositions described herein comprise about 0.065% to about 0.080% by weight (w / w) budesonide, about 0.147% to about 0.180% by weight (w / w) albuterol sulfate, about 0.301% to about 0.367% by weight (w / w) DSPC porous particles, and HFO-1234ze(E).In some embodiments, the compositions described herein comprise about 0.069% to about 0.077% by weight (w / w) budesonide, about 0.156% to about 0.172% by weight (w / w) albuterol sulfate, about 0.317% to about 0.351% by weight (w / w) DSPC porous particles, and HFO-1234ze(E).In some embodiments, the compositions described herein comprise about 0.116% to about 0.175% by weight (w / w) budesonide, about 0.131% to about 0.197% by weight (w / w) albuterol sulfate, about 0.266% to about 0.400% by weight (w / w) DSPC porous particles, and HFO-1234ze(E). In some embodiments, the compositions described herein include about 0.131% to about 0.161% by weight (w / w) budesonide, about 0.147% to about 0.180% by weight (w / w) albuterol sulfate, about 0.300% to about 0.366% by weight (w / w) DSPC porous particles, and HFO-1234ze(E). In some embodiments, the compositions described herein include about 0.138% to about 0.153% by weight (w / w) budesonide, about 0.156% to about 0.172% by weight (w / w) albuterol sulfate, about 0.316% to about 0.350% by weight (w / w) DSPC porous particles, and HFO-1234ze(E). Tables 3A and 3B show two exemplary embodiments of compositions including budesonide and albuterol sulfate as active agents. In some embodiments, the exemplary compositions of Table 3A can provide a delivered dose of about 40 μg budesonide and about 90 μg albuterol sulfate per actuation of a metered dose inhaler. In some embodiments, the exemplary compositions of Table 3B can provide a delivered dose of about 80 μg budesonide and about 90 μg albuterol sulfate per actuation of a metered dose inhaler.

[0186] [Table 4]

[0187] [Table 5]

[0188] In some embodiments, compositions comprising a combination of two or more active agents described herein may include budesonide and formoterol as active agents. In some embodiments of compositions described herein comprising budesonide and formoterol as active agents, the ratio of the total mass of suspended particles to the total mass of active agent particles may be selected from about 1 to about 25, about 1 to about 20, about 1.5 to about 10, about 2.5 to about 15, about 2.5 to about 10, about 2.5 to about 8, about 10 to about 30, about 15 to about 25, about 10 to about 200, about 50 to about 125, and about 5 to about 50. In all embodiments, the active agent to suspended particle ratio is based on the free base form of the active agent. In some embodiments, the compositions are administered by oral inhalation. In some embodiments, compositions described herein comprising budesonide and formoterol as active agents may be included in the reservoir of a metered dose inhaler (MDI) device. In some embodiments, the composition may include budesonide (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivery dose selected from about 70 μg to about 170 μg, about 75 μg to about 165 μg, and about 80 μg to about 160 μg of budesonide per inhalation. In some embodiments, the composition may include formoterol (including any pharma-ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivery dose selected from about 1 μg to about 5 μg and about 2 μg to about 4 μg of formoterol per inhalation. In some embodiments, the composition may be administered twice daily, 2 inhalations per inhalation. In some embodiments, the compositions described herein comprise about 0.238% to about 0.358% by weight (w / w) budesonide, about 0.007% to about 0.011% by weight (w / w) formoterol fumarate, about 0.410% to about 0.615% by weight (w / w) DSPC porous particles, and HFO-1234ze(E).In some embodiments, the compositions described herein comprise about 0.268% to about 0.329% by weight (w / w) budesonide, about 0.008% to about 0.010% by weight (w / w) formoterol fumarate, about 0.461% to about 0.564% by weight (w / w) DSPC porous particles, and HFO-1234ze(E).In some embodiments, the compositions described herein comprise about 0.283% to about 0.314% by weight (w / w) budesonide, about 0.008% to about 0.010% by weight (w / w) formoterol fumarate, about 0.487% to about 0.538% by weight (w / w) DSPC porous particles, and HFO-1234ze(E).In some embodiments, the compositions described herein comprise about 0.119% to about 0.180% by weight (w / w) budesonide, about 0.007% to about 0.011% by weight (w / w) formoterol fumarate, about 0.410% to about 0.616% by weight (w / w) DSPC porous particles, and HFO-1234ze(E). In some embodiments, the compositions described herein include about 0.134% to about 0.165% (w / w) budesonide, about 0.008% to about 0.010% (w / w) formoterol fumarate, about 0.462% to about 0.565% (w / w) DSPC porous particles, and HFO-1234ze(E). In some embodiments, the compositions described herein include about 0.142% to about 0.157% (w / w) budesonide, about 0.008% to about 0.010% (w / w) formoterol fumarate, about 0.487% to about 0.539% (w / w) DSPC porous particles, and HFO-1234ze(E). Tables 4A and 4B show two exemplary embodiments of compositions including budesonide and formoterol as active agents. In certain embodiments, the exemplary compositions of Table 4A are capable of providing a delivered dose of Table 4A per actuation of a metered dose inhaler. In certain embodiments, the exemplary compositions of Table 4B are capable of providing a delivered dose of Table 4B per actuation of a metered dose inhaler.

[0189] [Table 6]

[0190] [Table 7]

[0191] In some embodiments, compositions comprising a combination of two or more active agents described herein may include budesonide, glycopyrrolate, formoterol, and roflumilast as active agents. In some embodiments of compositions described herein comprising budesonide, glycopyrrolate, formoterol, and roflumilast as active agents, the ratio of the total mass of suspended particles to the total mass of active agent particles may be selected from about 1 to about 20, about 1 to about 15, about 1.5 to about 10, about 2.5 to about 15, about 2.5 to about 10, about 2.5 to about 8, about 10 to about 30, about 15 to about 25, about 10 to about 200, about 50 to about 125, and about 5 to about 50. In all embodiments, the active agent to suspended particle ratio is based on the free base form of the active agent. In some embodiments, the composition is administered by oral inhalation. In some embodiments, the compositions described herein, including budesonide, glycopyrrolate, formoterol, and roflumilast as active agents, may be contained in a reservoir of a metered dose inhaler (MDI) device. In some embodiments, the compositions may include budesonide (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivered dose selected from about 70 μg to about 170 μg, about 75 μg to about 165 μg, and about 80 μg to about 160 μg of budesonide per inhalation. In some embodiments, the compositions described herein may include glycopyrrolate (including any pharma-ceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivered dose selected from about 5 μg to about 10 μg, and about 5 μg to about 15 μg of glycopyrrolate per inhalation. In some embodiments, the compositions described herein may include formoterol (including any pharma- ceutically acceptable salt, ester, isomer, or solvate thereof) in a concentration that achieves a target delivered dose selected from about 1 μg to about 5 μg and about 2 μg to about 4 μg of formoterol per inhalation. In some embodiments, the compositions described herein may include roflumilast (including any pharma-ceutically acceptable salt, ester, isomer, or solvate thereof) in a concentration that achieves a target delivered dose selected from about 1 μg to about 25 μg, about 5 μg to about 20 μg, and about 10 μg to about 15 μg of roflumilast per inhalation.In some embodiments, the compositions may be administered twice daily, two inhalations per dose. In some embodiments, the compositions described herein include about 0.024% to about 0.036% by weight (w / w) roflumilast, about 0.238% to about 0.358% by weight (w / w) budesonide, about 0.010% to about 0.016% by weight (w / w) glycopyrronium bromide, about 0.007% to about 0.011% by weight (w / w) formoterol fumarate, about 0.410% to about 0.615% by weight (w / w) DSPC porous particles, and HFO-1234ze(E). In some embodiments, the compositions described herein comprise about 0.026% to about 0.033% (w / w) roflumilast, about 0.268% to about 0.329% (w / w) budesonide, about 0.012% to about 0.015% (w / w) glycopyrronium bromide, about 0.008% to about 0.010% (w / w) formoterol fumarate, about 0.461% to about 0.564% (w / w) DSPC porous particles, and HFO-1234ze(E). In certain embodiments, the compositions described herein comprise about 0.028% to about 0.031% (w / w) roflumilast, about 0.283% to about 0.314% (w / w) budesonide, about 0.013% to about 0.014% (w / w) glycopyrronium bromide, about 0.008% to about 0.010% (w / w) formoterol fumarate, about 0.486% to about 0.538% (w / w) DSPC porous particles, and HFO-1234ze(E). Table 5 shows exemplary embodiments of compositions comprising budesonide, glycopyrrolate, formoterol, and roflumilast as active agents.

[0192] [Table 8]

[0193] In some embodiments, compositions comprising combinations of two or more active agents described herein may include umeclidinium bromide, vilanterol triphenylacetate, and fluticasone furoate as active agents. In other embodiments, compositions comprising combinations of two or more active agents described herein may include umeclidinium bromide and vilanterol triphenylacetate as active agents. In some embodiments, compositions comprising combinations of two or more active agents described herein may include glycopyrronium bromide, indacaterol acetate, and mometasone furoate as active agents. In other embodiments, compositions comprising combinations of two or more active agents described herein may include glycopyrronium bromide and indacaterol acetate as active agents. In some embodiments, compositions comprising combinations of two or more active agents described herein may include glycopyrronium bromide, formoterol, and beclomethasone propionate as active agents. Compositions formulated according to the present teachings can inhibit the degradation of the active agents contained therein. For example, in specific embodiments, the compositions described herein inhibit one or more of aggregation, clumping, and solution-mediated transformation of active agent substances contained in the compositions. The pharmaceutical compositions described herein are suitable for respiratory delivery via an MDI in a manner that achieves a desired delivered dose uniformity ("DDU") of each active agent contained in a combination of two or more active agents, even in combinations that include potent and highly potent actives. As detailed in the examples contained herein, even when delivering very low doses of two or more active agents, the compositions described herein can achieve a DDU of ±30% or better for each active agent over the course of the MDI canister being emptied. In some such embodiments, the compositions described herein achieve a DDU of ±25% or better for each active agent over the course of the MDI canister being emptied. In other such embodiments, the compositions described herein achieve a DDU of ±20% or better for each active agent over the course of the MDI canister being emptied.In further embodiments, the compositions described herein achieve a DDU of ±15% or better for each active agent over the life of the MDI canister. In yet further embodiments, the compositions described herein achieve a DDU of ±10% or better for each active agent over the life of the MDI canister.

[0194] The pharmaceutical compositions described herein also aid in the substantial retention of FPF and FPD performance during the emptying of an MDI canister, even after being subjected to accelerated degradation conditions. For example, the compositions of the present invention maintain 80%, 85%, 90%, 95% or more of the original FPF and FPD performance during the emptying of an MDI canister, even after being subjected to accelerated degradation conditions. The compositions described herein provide the added benefit of being formulated using non-CFC and non-HF propellants, achieving such performance while eliminating or substantially avoiding the combination effects often experienced with compositions incorporating multiple active agents. In a specific embodiment, the compositions described herein achieve one or all of the targeted DDU, FPF and FPD performance while being formulated in a suspension medium that includes only HFO propellants, without the need to modify the characteristics of the HFO propellant, such as by the addition of one or more co-solvents, anti-solvents, solubilizers, adjuvants or other propellant modifiers.

[0195] method Compositions formulated according to the present teachings can inhibit the degradation of active agents contained therein. For example, in specific embodiments, the compositions described herein inhibit one or more of aggregation, clumping, and Ostwald ripening of active agents contained in the compositions. The stability provided by the compositions described herein allows the compositions to be dispensed in a manner that achieves a desirable delivered dose uniformity ("DDU") over the course of an empty MDI canister, even when the active agents delivered are highly potent and the delivered dose of active agent is, for example, less than any of 100 μg, 80 μg, 40 μg, 20 μg, 10 μg, 9 μg, 8 μg, 7 μg, 6 μg, 5 μg, 4 μg, 3 μg, 2 μg, 1 μg, 0.5 μg, and 0.1 μg per MDI actuation. As detailed in the examples included herein, even with very low doses of highly potent active agents, the compositions described herein can achieve a DDU of ±30% or better for each active agent contained in the composition. In another embodiment, the compositions described herein achieve a DDU of ±25% or better for each active agent included in the composition. In yet further embodiments, the compositions described herein achieve a DDU of ±20% or better, ±15% or better, or ±10% or better for each active agent included in the composition.

[0196] Furthermore, the compositions of the present invention help to substantially retain FPF and FPD performance throughout the life of the MDI canister, even after being subjected to accelerated degradation conditions. For example, the compositions of the present invention maintain 80%, 85%, 90%, 95% or more of the original FPF and FPD performance, even when multiple active agents are incorporated. The compositions described herein provide the additional benefit of achieving such performance while being formulated using non-CFC and non-HF propellants. In a specific embodiment, the compositions described herein achieve one or all of the desired targeted DDU, FPF and FPD performance while being formulated in a suspension medium that includes only one or more HFO propellants, without the need to modify the characteristics of the HFO propellant, such as by the addition of one or more co-solvents, anti-solvents, solubilizers, adjuvants or other propellant modifiers.

[0197] The stability and physical characteristics of the compositions described herein support some methods. For example, in some embodiments, a method of formulating a pharmaceutical composition for respiratory delivery of an active agent is provided herein. The method includes providing a suspension medium comprising an HFO propellant as described herein, one or more types of active agent particles and one or more types of suspension particles, and combining such components to form a composition in which the active agent particles are combined with the suspension particles to form a co-suspension as described herein. In some such embodiments, the combination of the active agent particles and the suspension particles is such that they do not separate due to different buoyancy in the propellant. As will be appreciated, the method of formulating a pharmaceutical composition described herein includes providing two or more types of active agent particles combined with one or more types of suspension particles. Alternatively, the method may include providing two or more types of suspension particles combined with one or more types of active agent particles.

[0198] In further embodiments, the compositions described herein support, for example, methods of forming a stabilized formulation of an active agent for pulmonary delivery, methods of maintaining the FPF and / or FPD for the duration of an MDI canister's emptying, methods of pulmonary delivery of potent or highly potent active agents, and methods of achieving a DDU selected from ±30% or better, ±25% or better, ±20% or better, ±15% or better, and ±10% or better for potent and highly potent drugs administered via pulmonary delivery.

[0199] In methods involving pulmonary delivery of active agents using compositions described herein, the compositions can be delivered by an MDI. Thus, in specific embodiments of such methods, an MDI loaded with a composition described herein is obtained, and the desired active agent is administered to a patient via pulmonary delivery through actuation of the MDI. For example, in one embodiment, after shaking the MDI device, the mouthpiece is placed in the patient's mouth between the lips and teeth. The patient typically exhales deeply to empty the lungs, and then takes a slow, deep breath while actuating the cartridge of the MDI. Upon actuation, a certain volume of the formulation travels from the expansion chamber out of the actuator nozzle into a highly viscous spray that is inhaled into the patient's lungs. In one embodiment, the dose of active agent delivered during the emptying of the MDI canister is not more than 20% of the average delivered dose or not less than 20% of the average delivered dose. In one embodiment, the dose of active agent delivered during the emptying of the MDI canister is not more than 15% of the average delivered dose or not less than 15% of the average delivered dose. In some embodiments, the dose of active agent delivered during the entire MDI canister emptying period is not more or less than 10% of the average delivered dose.

[0200] In a specific embodiment of the method for providing a stabilized formulation of an active agent for pulmonary delivery, the present invention provides a method for inhibiting solution-mediated transformation of an active agent in a pharmaceutical composition for pulmonary delivery. In an embodiment, a suspension medium as described herein is obtained, such as a suspension medium formed by an HFO propellant. Suspension particles are also obtained or produced as described herein. One or more types of active agent particles as described herein are also obtained, and the suspension medium, suspension particles and active agent particles are combined to form a co-suspension in which the active agent particles are combined within the continuous phase formed by the suspension particles and the suspension medium. It has been found that the co-suspension of the present invention shows high tolerance to solution-mediated transformation and irreversible crystal aggregation when compared to the active agent contained in the same suspension medium in the absence of suspension particles, and therefore can lead to improved stability and dosage uniformity, allowing the formulation of active agents that are somewhat physically unstable in the suspension medium alone.

[0201] In a specific embodiment of the method of maintaining the FPF and / or FPD provided by a pharmaceutical formulation for pulmonary delivery of an inhalable co-suspension as described herein, a formulation is provided that is capable of maintaining the FPD and / or FPF within ±20%, ±15%, ±10% or ±5% of the initial FPD and / or FPF, respectively, until the MDI canister is emptied. Such performance can be achieved even after the co-suspension is subjected to accelerated degradation conditions. In an embodiment, a suspension medium as described herein is obtained, such as a suspension medium formed by an HFO propellant. Suspended particles are also obtained or produced as described herein. One or more species of active agent particles as described herein are also obtained, and the suspension medium, suspended particles and active agent particles are combined to form a co-suspension in which the active agent particles are associated with the suspended particles in the suspension medium. Even after such a composition is exposed to one or more temperature cycling events, the co-suspension maintains an FPD or FPF within ±20%, ±15%, ±10% or ±5% of the respective values ​​measured before the composition is exposed to one or more temperature cycling events.

[0202] Provided herein is a method for treating patients with inflammatory or obstructive pulmonary diseases or conditions.In a specific embodiment, such method comprises pulmonary delivery of a therapeutically effective amount of the pharmaceutical composition described herein, and in some such embodiments, pulmonary administration of the pharmaceutical composition is achieved by delivery of the composition using an MDI.In some embodiments, the compositions, methods and systems described herein can be used to treat patients with diseases or disorders selected from asthma, chronic obstructive pulmonary disease (COPD), airway hyperresponsiveness as a result of other drug therapies, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergy, respiratory disorder, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, and any other respiratory disease, condition, trait, genotype or phenotype that can respond to administration of, for example, LAMA, LABA, SABA, ICS, non-corticosteroid anti-inflammatory agents, or other active agents described herein, alone or in combination with other therapies.In some embodiments, the compositions, systems and methods described herein can be used to treat pulmonary inflammation and obstruction associated with cystic fibrosis. In specific embodiments of the methods of treating a patient having an inflammatory or obstructive pulmonary disease or condition, the pulmonary disease or condition is selected from those specifically described herein, and the method comprises pulmonary delivery of a composition of the invention to the patient via an MDI, wherein such pulmonary delivery of a composition comprises administration of one or more active agents in association with a composition described herein, at a dose or dose range described herein.

[0203] Metered dose inhaler system As described in connection with the methods provided herein, the compositions disclosed herein may be used in an MDI system. The MDI is configured to deliver a specific amount of medicament in aerosol form. In some embodiments, the MDI system includes a pressurized, liquid-phase formulation-filled canister configured in an actuator formed with a mouthpiece. The MDI system may include a formulation described herein that includes an HFO propellant, a suspension medium that includes at least one species of active agent particles, and at least one species of suspended particles. The canister used in the MDI may be of any suitable configuration, and in some exemplary embodiments, the canister may have a volume ranging from about 5 ml to about 25 ml, for example, a canister having a volume of 19 ml. After shaking the device, the mouthpiece is placed in the patient's mouth between the lips and teeth. The patient typically exhales deeply to empty the lungs, and then takes a slow, deep breath while actuating the cartridge.

[0204] Inside the exemplary cartridge is a metering valve that includes a metering chamber capable of holding a defined amount of formulation (e.g., 63 μl or any other suitable volume available in commercially available metering valves) that is released into an expansion chamber at the distal end of the valve stem upon actuation. The actuator holds a canister and may also include a port with an actuator nozzle that receives the valve stem of the metering valve. Upon actuation, a specific volume of formulation travels from the expansion chamber out the actuator nozzle into a highly viscous spray that is inhaled into the patient's lungs.

[0205] Examples of suitable MDIs are shown and described in International Application Publication No. WO2019 / 074799, which is incorporated herein by reference in its entirety. A suitable MDI may include, for example, an aerosol delivery unit 100 for selectively delivering a dose of an aerosolized substance, as shown in Figures 1-3B, which includes structure and associated functionality for exposing the exhaust passageway of the inhaler to a desiccant, at least during storage of the inhaler.

[0206] 1-3B, the aerosol delivery unit 100 includes a base housing 104 and a canister 110 housed in the base housing 104, which can be moved from an initial position I shown in FIG. 3A to an ejection position D shown in FIG. 3B to selectively eject a dose of an aerosolized substance to be inhaled by a user. The canister 110 includes a canister body 116 containing the substance to be ejected and an outlet valve 112 including a valve stem 114 extending from the canister body 116. The valve stem 114 defines a portion of an ejection passage 120 extending from the canister body 116 to a nozzle 122 mounted on the aerosol delivery unit 100, which then leads to an inhalation passage 126 through which the aerosolized substance passes before being ejected through a mouthpiece opening 128 for inhalation by a user during an inhalation event. The ejection passage 120 and the inhalation passage 126 may be collectively referred to as a drug delivery conduit. As will be appreciated by those skilled in the relevant art, when the valve stem 114 is moved relative to the canister body 116, as shown in FIG. 3B, a measured amount of the substance contained in the canister body 116 is expelled from the discharge orifice 122 via the inhalation passage 126 for inhalation by the user.

[0207] 1 , the aerosol delivery unit 100 may further include a fuel gauge component 107 secured to a lower top of the canister 110 to provide a fuel gauge function and to provide a user interface for depressing the canister 110. The aerosol delivery unit 100 may also include a cap 105 for covering a mouthpiece opening 128 of the aerosol delivery unit 100 when the unit 100 is stored. The cap 105 may be completely separate from the base housing 104 or may be connected to the base housing 104 by a tether 106 that allows the cover 105 to be removed from the mouthpiece opening 128 while still connected to the base housing 104.

[0208] 3A and 3B, the aerosol delivery unit 100 further includes a desiccant chamber 150 containing a desiccant 152 in fluid communication with the exhaust passage 120, at least when the aerosol delivery unit 100 is in the storage configuration and not actively exhausting an aerosolized substance. For example, according to the exemplary embodiment shown in FIGS. 3A and 3B, the desiccant chamber 150 is provided at the end of the canister 110 between the lower end of the canister body 116 and a separate desiccant housing 154 and stem seal 156 coupled to the end of the canister 110. The desiccant 152 may be provided in a semi-annular form (as shown in FIG. 2) and may include a central passage 153 through which the valve stem 114 of the canister 110 extends. The stem seal 156 may be an annular seal integrally formed with the desiccant housing 154, such as by a multi-shot injection molding process, or may otherwise be provided as a separate sealing element coupled to the desiccant housing 154. In some examples, the stem seal 156 may be provided as a bellows-type seal fixed between the valve stem 114 and the desiccant housing 154, providing a desiccant chamber 150 that changes volume as the canister 110 moves during an inhalation event due to deformation of the stem seal 156. In other examples, such as the exemplary embodiment shown in Figures 3A and 3B, the desiccant chamber 150 may have a fixed volume.

[0209] 3A, the desiccant 152 in the desiccant chamber 150 is in fluid communication with the exhaust passageway 120 through an opening 124 in the side of the valve stem 114 which is used to pass material contained in the canister body 116 towards the exhaust orifice 122 as the valve stem 114 moves during an inhalation event. In this manner, the exhaust passageway 120 remains exposed to the desiccant 152 when the canister 110 is in an initial position I, such as during storage of the unit 100. In some instances, the desiccant may be sufficient to keep the exhaust passageway dry during use (e.g., <25% RH) for substantially the entire product life of the canister of material to be exhausted.

[0210] Advantageously, the desiccant housing 154 may be coupled to an end or collar of the canister 110 to form a cartridge 160 (FIG. 2) that is easily removable from the base housing 104. In this manner, the desiccant housing 154 and canister 110 may be easily removed from the base housing 104 in order to move the canister 110 when the desiccant 152 is depleted and / or replaced, if desired. The desiccant housing 154 may be coupled to an end or collar of the canister 110 by elastic bands, clips, detents, or other devices or techniques including friction or interference fit configurations. 3A and 3B, the desiccant chamber 150 is shown as being coupled to the bottom end or collar of the canister 110, it will be appreciated that in other embodiments the desiccant chamber may be provided in a separate desiccant housing coupled to the base housing 104 separate from the canister 110, the desiccant chamber may be formed entirely within the base housing itself, or the desiccant chamber may be provided in a separate element attached to the base housing 104. Additionally, the desiccant may be provided in a variety of different forms, such as a gel form, a powder form, a granular form, or a compact, and may consist of or include different materials, such as silica, activated charcoal, calcium sulfate, or calcium chloride.

[0211] 1-3B, the desiccant housing 154 may be coupled to an end or collar of the canister 110 to form a cartridge 160 mountable to the base housing 104 for fitting the stem seat / nozzle block 132 therein. Further details of the cartridge 160 and the stem seat / nozzle block 132 elements may be seen in the exploded view of FIG. 2. As shown in FIG. 2, the desiccant housing 154 may form a cup-like structure having a generally cylindrical sidewall that is sized and shaped to receive the lower end of the canister 110. The desiccant 152 may be provided in a molded body. The desiccant 152 may be configured to be located at the lower end of the desiccant housing 154. The desiccant housing 154 may include one or more positioning or coupling features that aid in coupling or otherwise configuring the desiccant 152 within the desiccant housing 154. The desiccant 152 is shaped so as not to obstruct the valve stem opening of the stem seal 156 provided in the desiccant housing 154 for receiving the valve stem 114 of the canister 110. For example, the desiccant 152 may have a semi-annular shape with a central passage 153 or other clearance for the valve stem 114. In certain examples, such as in the exemplary embodiment shown in FIGS. 1-3B, the desiccant 152 may partially surround the valve stem 114 and may extend beyond the ends of the valve stem 114. The desiccant housing 154 and the desiccant 152 may also be correspondingly shaped and each may extend beyond the ends of the valve stem 114. In this manner, the desiccant 152 may substantially fill the desiccant chamber 150 to provide a relatively large amount of desiccant suitable for continuously removing moisture from the passage of the valve stem 114 at least over the usable life of the substance (e.g., drug formulation) contained in the canister 110.

[0212] 3A and 3B, the canister seal 117 may be configured around the periphery of the canister body 116, such as around the lower neck portion, to provide a resilient member between the canister body 116 and the desiccant housing 154 that may be compressed when the canister 110 and the desiccant housing 154 are coupled together. The canister seal 117 may provide a sealing location that separates the desiccant chamber 150 when the aerosol delivery unit 100 is fully assembled and helps prevent moisture from entering the desiccant chamber 150 from anywhere other than the exhaust passage 120. In a similar manner, the stem seal 156 may provide a sealing location that separates the desiccant chamber 150 when the aerosol delivery unit 100 is fully assembled and helps prevent moisture from entering the desiccant chamber 150. In this manner, the desiccant chamber 150 is effectively isolated from the external environment apart from the exhaust passage 120, which may be exposed to the external environment via the inhalation passage 126 when the mouthpiece cap 105 is moved from the base housing 104.

[0213] 3A and 3B, when the valve stem 114 is in the extended position, a portion of the exhaust passageway 120 defined by the valve stem 114 is in fluid communication with the desiccant chamber 152 through an opening 124 in the side of the valve stem 114. Conversely, when the valve stem 114 of the canister 110 is fully depressed, the desiccant chamber 152 is temporarily isolated from the exhaust passageway 120 defined by the valve stem 114.

[0214] Similarly, when the canister 100 is loaded into the desiccant housing 154, the valve stem 114 projects from its lower end and is then received in a stem seat / nozzle block 132 provided in the base housing 104. According to the exemplary embodiment of FIG. 2, the stem seat / nozzle block 132 may be provided in a mouthpiece unit 131 that is connectable with the base housing 104 and includes an inhalation passageway 126 and a mouthpiece opening 128 for delivery of an aerosolized substance to a user. As shown, when the cartridge 160 is installed, the desiccant 152 may extend from a position above the discharge orifice 122 of the stem seat / nozzle block 132 to a position below the discharge orifice 122, substantially filling the desiccant chamber 150 within the desiccant housing 154 and providing a relatively large amount of desiccant suitable for continuously removing moisture from the passageway of the valve stem 114 at least over the usable life of the substance (e.g., a drug formulation) contained in the canister 110. In this manner, the embodiment may be particularly well suited to eliminating, reducing or minimizing the presence of moisture in the exhaust passage 120 and any associated fouling, even when the exhaust passage 120 is not completely isolated from the external environment after the substance has been exhausted during an inhalation event.

[0215] Some embodiments provide an MDI, such as the aerosol delivery unit 100 shown in Figures 1-3B, in which one or more internal components of the outlet valve 112 are comprised at least in part of a bromobutyl material (eg, bromobutyl rubber).

[0216] For example, Figure 4 illustrates an outlet valve 200 of a canister 201 of an MDI containing a formulation to be expelled, where the outlet valve 200 comprises one or more internal components comprising or consisting of a bromobutyl material (e.g. bromobutyl rubber). For example, the outlet valve 200 includes an inner core 202 and a valve stem 204 that are movably movable relative to a metering chamber 208 for dispensing a metered amount of the formulation through a valve body 206 and an outlet passageway 205 of the outlet valve 200 during operation of the MDI device. The inner core 202 and valve stem 204 are biased by a spring element 207 towards an extended position and are selectively depressible to dispense a metered amount of the formulation.

[0217] To help ensure consistent, metered delivery of formulation, the outlet valve 200 further includes a plurality of gaskets for sealing and isolating the interior cavity of the metering chamber 208 relative to the valve body 206 and the canister 201, as well as for sealing and isolating the interior formulation cavity of the canister 201 from the external environment. More specifically, upper and lower seat gaskets 212a,b are provided that slidably engage the inner core 202 and the valve stem 204 to seal and isolate the interior cavity of the metering chamber 208 relative to the valve body 206 and the canister 201. As shown in FIG. 4, the upper seat gasket 212a is provided between the metering chamber 208 and the valve body 206 to surround and seal a portion of the movable inner core 202. The lower seat gasket 212b is provided between the metering chamber 208 and the canister 201 to surround and seal a portion of the movable valve stem 204 that protrudes from the canister 201. Advantageously, one or more of the sheet gaskets 212a,b may comprise or consist of a bromobutyl material (e.g., bromobutyl rubber). Additionally, as further shown in Figure 4, a neck gasket 214 is provided between the valve body 206 and the canister 201 to further help seal and isolate the internal formulation cavity from the external environment. Advantageously, the neck gasket 214 may comprise or consist of a bromobutyl material (e.g., bromobutyl rubber).

[0218] By forming one or more of the internal gaskets of the outlet valve 200, i.e., one or more of the seat gaskets 212a,b and / or the neck gasket 214, to comprise or consist of a bromobutyl material (e.g., bromobutyl rubber), the outlet valve 200 has been shown to be particularly effective in dispensing and maintaining a consistent metered amount of formulation over time and through operation, as well as avoiding fouling or clogging of the nozzle of the MDI device. Furthermore, the outlet valve 200 is particularly effective in avoiding weight loss of the formulation over time, as compared to other suitable gasket materials. Thus, MDIs of such construction are particularly well suited for delivery of formulations to users.

[0219] As an example, Figure 5 shows a CT scan image of the discharge passageway of an MDI having a formulation canister equipped with an outlet valve including an internal sheet and neck gasket made of a bromobutyl material (e.g., bromobutyl rubber), where the MDI was used to repeatedly dispense the formulation under controlled environmental conditions (25°C / 60% RH). Notably, Figure 5 shows that there is substantially no material deposited or accumulated on the nozzle of the MDI, even though the MDI was used repeatedly to dispense the formulations described herein.

[0220] FIG. 6 provides a comparison of formulation weight loss over time for different valve seat gasket and valve neck gasket formulations. As can be seen from FIG. 6, configurations in which the valve neck gasket is made of a bromobutyl material (e.g., bromobutyl rubber) consistently showed a significant reduction in weight loss over time compared to the control configuration (left-most column of the chart). Furthermore, when the valve seat gasket is also made of a bromobutyl material, e.g., bromobutyl rubber (right-most column of the chart), the weight loss over time approached 0%. That is, providing an internal gasket made of a bromobutyl material (e.g., bromobutyl rubber) showed unexpected performance.

[0221] The following abbreviations are used throughout this specification, including the figures and examples: ·AB: Albuterol · AS: Albuterol sulfate BD: Budesonide FF: Formoterol fumarate ·GP: Glycopyrrolate RF: Roflumilast BDA: Budesonide / Albuterol (combination) BGF: Budesonide / Glycopyrrolate / Formoterol (combination) GFF: Glycopyrrolate / formoterol fumarate (combination) BFF: Budesonide / formoterol fumarate (combination) BGFR: Budesonide / Glycopyrrolate / Formoterol fumarate / Roflumilast (combination) BDA-1234ze: Budesonide / albuterol (combination) in HFO-1234ze(E) formulation BDA-134a: Budesonide / albuterol (combination) in HFA-134a formulation BFF-1234ze: Budesonide / formoterol fumarate (combination) in HFO-1234ze(E) formulation BFF-134a: Budesonide / formoterol fumarate (combination) in HFA-134a formulation CFC-11: Trichlorofluoromethane CFC-113: 1,1,2-trichloro-1,2,2-trifluoroethane CFC-114: 1,2-dichlorotetrafluoroethane HCFC-124: 1-chloro-1,2,2,2-tetrafluoroethane HFA-227ea: 1,1,1,2,3,3,3-heptafluoropropane HFC-125: Pentafluoroethane, also known as 1,1,1,2,2-pentafluoroethane HFC-152a: 1,1-difluoroethane HFC-245cb: 1,1,1,2,2-Pentafluoropropane HFO-1225ye(Z): cis-1,2,3,3,3-pentafluoropropene HFO-1225ye(E): trans-1,2,3,3,3-pentafluoropropene ·HFO-1234yf: 2,3,3,3-tetrafluoropropene HFO-1234ze(Z): cis-1,3,3,3-tetrafluoroprop-1-ene PP: Porous particles of phospholipids

[0222] Specific embodiments In certain aspects, the present invention provides the following specific embodiments: Embodiment 1. A pharmaceutical composition deliverable from a metered dose inhaler, comprising: Pharmaceutical grade (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)) propellant; a plurality of active agent particles; and Multiple particles of phospholipids containing porous microstructures wherein the active agent particles comprise an active agent selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS) and a non-corticosteroid anti-inflammatory agent.

[0223] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the plurality of active agent particles comprises two or more species of active agent particles, wherein each type of active agent particle comprises a different active agent selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent.

[0224] Embodiment 3. A pharmaceutical composition deliverable from a metered dose inhaler, comprising: Pharmaceutical grade (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)) propellant; A plurality of particles of a first type of active agent; a plurality of particles of a second type of active agent; and Multiple particles of phospholipids containing porous microstructures wherein the particles of a first type of active agent comprise a first active agent and the particles of a second type of active agent comprise a second active agent, wherein the first and second active agents are selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS) and a non-corticosteroid anti-inflammatory agent.

[0225] Embodiment 4. The pharmaceutical composition of embodiment 3, further comprising a plurality of particles of a third active agent, wherein the third active agent particles comprise a third active agent selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent.

[0226] Embodiment 5. The pharmaceutical composition of embodiment 4, further comprising a plurality of fourth active agent particles, wherein the fourth active agent particles comprise a fourth active agent selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent.

[0227] Embodiment 6. The pharmaceutical composition of any of embodiments 1 to 5, wherein the LAMA is present in a concentration ranging from about 0.04 mg / mL to about 2.25 mg / mL.

[0228] Embodiment 7. The pharmaceutical composition of any of embodiments 1 to 5, wherein the LABA is present at a concentration in the range of about 0.01 mg / mL to about 1 mg / mL.

[0229] Embodiment 8. The pharmaceutical composition of any of embodiments 1 to 5, wherein the ICS is present in a concentration ranging from about 0.1 mg / mL to about 20 mg / mL.

[0230] Embodiment 9. The pharmaceutical composition of any of embodiments 1-5, wherein the non-corticosteroid anti-inflammatory agent is present in a concentration ranging from about 0.1 mg / mL to about 20 mg / mL.

[0231] Embodiment 10. The pharmaceutical composition of any of embodiments 1 to 9, wherein the phospholipid particles are present in a concentration ranging from about 0.1 mg / mL to about 10 mg / mL.

[0232] Embodiment 11. The pharmaceutical composition of any of embodiments 1 to 10, wherein the porous microstructure comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride.

[0233] Embodiment 12. The pharmaceutical composition of any of embodiments 1 to 11, wherein the phospholipid particles exhibit a volume median optical diameter selected from about 0.2 μm to about 50 μm, about 0.5 μm to about 15 μm, about 1.5 μm to about 10 μm, and about 2 μm to about 5 μm.

[0234] 13. The total mass of the phospholipid particles is: i) a plurality of active agent particles of embodiment 1; ii) any of the first, second, third and fourth types of active agent particles; or iii) A combination of any two of the first, second, third and fourth types of activator particles. 13. The pharmaceutical composition of any of embodiments 1 to 12, wherein the total mass of the pharmaceutical composition exceeds

[0235] Embodiment 14. The pharmaceutical composition of any of embodiments 3 to 13, wherein the first active agent is a LAMA; and the second active agent is a LABA.

[0236] Embodiment 15. The pharmaceutical composition of any of embodiments 4 to 13, wherein the first active agent is a LAMA; the second active agent is a LABA; and the third active agent is an ICS.

[0237] Embodiment 16. The pharmaceutical composition of any of embodiments 5-13, wherein the first active agent is a LAMA; the second active agent is a LABA; the third active agent is an ICS; and the fourth active agent is a non-corticosteroid anti-inflammatory agent.

[0238] Embodiment 17. The pharmaceutical composition of any of embodiments 3-13, wherein the first active agent is a SABA; and the second active agent is an ICS.

[0239] Embodiment 18. The pharmaceutical composition of any of embodiments 3 to 13, wherein the first active agent is a LABA; and the second active agent is an ICS.

[0240] Embodiment 19. The pharmaceutical composition of any of the previous embodiments, wherein the LAMA is selected from glycopyrrolate, dexpironium, tiotropium, trospium, aclidinium, umeclidinium, and darotropium, or a pharma- ceutically acceptable salt or solvate thereof.

[0241] Embodiment 20. The pharmaceutical composition of any of the previous embodiments, wherein the LABA is selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, mirveterol, indacaterol, vilanterol and saligenin or indole-containing and adamantyl-derived beta-2 agonists or a pharma-ceutically acceptable salt or solvate thereof.

[0242] Embodiment 21. The pharmaceutical composition of any of the previous embodiments, wherein the SABA is selected from bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, albuterol (salbutamol), terbutaline, tulobuterol, reproterol, and epinephrine, or a pharma- ceutically acceptable salt or solvate thereof.

[0243] Embodiment 22. The pharmaceutical composition of any of the previous embodiments, wherein the ICS is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone and triamcinolone, or a pharma- ceutically acceptable salt or solvate thereof.

[0244] Embodiment 23. The pharmaceutical composition of any of the previous embodiments, wherein the non-corticosteroid anti-inflammatory agent is roflumilast or a pharma- ceutically acceptable salt or solvate thereof.

[0245] Embodiment 24. The pharmaceutical composition of any of the preceding embodiments, which exhibits enhanced robustness in a simulated use test (SUT).

[0246] Embodiment 25. The pharmaceutical composition of any of the preceding embodiments, which exhibits less than about 1.0%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% weight loss in a metered dose inhaler at 25° C. / 60% RH per year.

[0247] 26. Pharmaceutical grade HFO-1234ze(E) propellant; Multiple glycopyrrolate particles; Multiple formoterol particles; and Multiple particles of phospholipids containing porous microstructures The pharmaceutical composition of any of the previous embodiments, comprising:

[0248] 27. Pharmaceutical grade HFO-1234ze(E) propellant; Multiple glycopyrrolate particles; Multiple formoterol particles; A plurality of budesonide particles; and Multiple particles of phospholipids containing porous microstructures The pharmaceutical composition of any of the previous embodiments, comprising:

[0249] 28. Pharmaceutical grade HFO-1234ze(E) propellant; Multiple albuterol particles; A plurality of budesonide particles; and Multiple particles of phospholipids containing porous microstructures The pharmaceutical composition of any of the previous embodiments, comprising:

[0250] 29. Pharmaceutical grade HFO-1234ze(E) propellant; Multiple formoterol particles; A plurality of budesonide particles; and Multiple particles of phospholipids containing porous microstructures The pharmaceutical composition of any of the previous embodiments, comprising:

[0251] EMBODIMENT 30. Pharmaceutical grade HFO-1234ze(E) propellant; Multiple glycopyrrolate particles; Multiple formoterol particles; Multiple budesonide particles; A plurality of roflumilast particles; and Multiple particles of phospholipids containing porous microstructures The pharmaceutical composition of any of the previous embodiments, comprising:

[0252] Embodiment 31. The pharmaceutical composition of any of the preceding embodiments, wherein the glycopyrrolate active agent particles are in the propellant at a concentration sufficient to provide a delivered dose of glycopyrrolate per actuation of a metered dose inhaler selected from about 5 μg to about 50 μg per actuation, about 2 μg to about 25 μg per actuation, and about 6 μg to about 15 μg per actuation.

[0253] Embodiment 32. The pharmaceutical composition of any of the preceding embodiments, wherein the concentration of glycopyrrolate in the propellant is from about 0.04 mg / ml to about 2.25 mg / ml.

[0254] Embodiment 33. The pharmaceutical composition of any of the preceding embodiments, wherein at least 90% of the glycopyrrolate active agent particles by volume exhibit an optical diameter of 7 μm or less.

[0255] Embodiment 34. The pharmaceutical composition of any of the preceding embodiments, wherein the formoterol active agent particles are present in the composition at a concentration sufficient to provide a delivered dose of formoterol selected from about 1 μg to about 30 μg, about 0.5 μg to about 10 μg, about 2 μg to 5 μg, about 3 μg to about 10 μg, about 5 μg to about 10 μg, and 3 μg to about 30 μg per actuation of a metered dose inhaler.

[0256] Embodiment 35. The pharmaceutical composition of any of the preceding embodiments, wherein the concentration of formoterol in the propellant is selected from about 0.01 mg / ml to about 1 mg / ml, about 0.01 mg / ml to about 0.5 mg / ml, and about 0.03 mg / ml to about 0.4 mg / ml.

[0257] Embodiment 36. The pharmaceutical composition of any of the preceding embodiments, wherein at least 90% of the formoterol active agent particles by volume exhibit an optical diameter of 5 μm or less.

[0258] Embodiment 37. The pharmaceutical composition of any of the preceding embodiments, wherein the budesonide active agent particles are present in the composition at a concentration sufficient to provide a delivered dose of budesonide selected from about 50 μg to about 400 μg, about 20 μg to about 600 μg, about 30 μg to 100 μg, about 50 μg to about 200 μg, and about 150 μg to about 350 μg per actuation of a metered dose inhaler.

[0259] Embodiment 38. The pharmaceutical composition of any of the preceding embodiments, wherein the concentration of budesonide in the propellant is selected from about 0.1 mg / ml to about 20 mg / ml, about 0.1 mg / ml to about 5 mg / ml, and about 0.3 mg / ml to about 6 mg / ml.

[0260] Embodiment 39. The pharmaceutical composition of any of the preceding embodiments, wherein at least 90% of the budesonide active agent particles by volume exhibit an optical diameter of 7 μm or less.

[0261] Embodiment 40. The pharmaceutical composition of any of the preceding embodiments, wherein the albuterol active agent particles are present in the composition at a concentration sufficient to provide a delivered dose of albuterol selected from about 10 μg to about 200 μg, about 20 μg to about 300 μg, about 30 μg to 150 μg, and about 50 μg to about 200 μg per actuation of a metered dose inhaler.

[0262] Embodiment 41. The pharmaceutical composition of any of the preceding embodiments, wherein the concentration of albuterol in the propellant is selected from about 0.1 mg / ml to about 10 mg / ml, about 0.1 mg / ml to about 5 mg / ml, and about 0.3 mg / ml to about 4 mg / ml.

[0263] Embodiment 42. The pharmaceutical composition of any of the preceding embodiments, wherein at least 90% of the albuterol active agent particles by volume exhibit an optical diameter of 5 μm or less.

[0264] Embodiment 43. The pharmaceutical composition of any of the preceding embodiments, wherein the roflumilast active agent particles are present in the composition at a concentration sufficient to provide a delivered dose of roflumilast selected from about 50 μg to about 400 μg, about 20 μg to about 600 μg, about 30 μg to 100 μg, about 50 μg to about 200 μg, and about 150 μg to about 350 μg per actuation of a metered dose inhaler.

[0265] Embodiment 44. The pharmaceutical composition of any of the preceding embodiments, wherein the concentration of roflumilast in the propellant is selected from about 0.1 mg / ml to about 20 mg / ml, about 0.1 mg / ml to about 5 mg / ml, and about 0.3 mg / ml to about 6 mg / ml.

[0266] Embodiment 45. The pharmaceutical composition of any of the preceding embodiments, wherein at least 90% of the roflumilast active agent particles by volume exhibit an optical diameter of 5 μm or less.

[0267] Embodiment 46. The pharmaceutical composition of any of the previous embodiments, wherein the glycopyrrolate particles comprise glycopyrrolate or a pharma- ceutically acceptable salt thereof.

[0268] Embodiment 47. The pharmaceutical composition of embodiment 46, wherein glycopyrrolate or a pharma- ceutically acceptable salt thereof is in crystalline and / or micronized form.

[0269] Embodiment 48. The pharmaceutical composition of any of the previous embodiments, wherein the formoterol particles comprise formoterol or a pharma- ceutically acceptable salt thereof.

[0270] Embodiment 49. The pharmaceutical composition of embodiment 48, wherein the formoterol or a pharma- ceutically acceptable salt thereof is in crystalline and / or micronized form.

[0271] Embodiment 50. The pharmaceutical composition of any of the previous embodiments, wherein the albuterol particles comprise albuterol or a pharma- ceutically acceptable salt thereof.

[0272] Embodiment 51. The pharmaceutical composition of embodiment 50, wherein the albuterol or a pharma- ceutically acceptable salt thereof is in crystalline and / or micronized form.

[0273] Embodiment 52. The pharmaceutical composition of any of the previous embodiments, wherein the budesonide particles comprise budesonide in crystalline and / or micronized form.

[0274] Embodiment 53. The pharmaceutical composition of any of the previous embodiments, wherein the roflumilast particles comprise roflumilast or a pharma- ceutically acceptable salt thereof.

[0275] Embodiment 54. The pharmaceutical composition of embodiment 53, wherein the roflumilast or a pharma- ceutically acceptable salt thereof is in crystalline and / or micronized form.

[0276] Embodiment 55. A metered dose inhaler comprising a canister with an outlet valve comprising an actuator for dispensing a metered amount of the pharmaceutical composition of any of embodiments 1 to 54, wherein the canister contains the pharmaceutical composition.

[0277] Embodiment 56. A metered dose inhaler of embodiment 55, exhibiting enhanced robustness in a simulated use test (SUT).

[0278] Embodiment 57. The metered dose inhaler of embodiment 55 or 56, which exhibits less than about 10%, 9%, 8%, 7%, 6% or 5% reduction in dose weight per actuation over the course of the canister being emptied.

[0279] Embodiment 58. A metered dose inhaler of any of embodiments 55 to 57, which exhibits less than about 1.0%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% weight loss at 25°C / 60% RH per year.

[0280] Embodiment 59. A metered dose inhaler of any of embodiments 55 to 58, wherein at least one internal gasket of the outlet valve is made at least in part of a bromobutyl material.

[0281] Embodiment 60. A metered dose inhaler of any of embodiments 55 to 59, wherein the outlet valve comprises a neck gasket and at least one seat gasket, and the neck gasket and / or at least one seat gasket is made of bromobutyl material.

[0282] Embodiment 61. The metered dose inhaler of any of embodiments 55 to 60, wherein the delivered dose uniformity (DDU) for the pharmaceutical formulation is selected from ±20% or better DDU, ±15% or better DDU, and ±10% or better DDU over the course of the canister being emptied.

[0283] Embodiment 62. A metered dose inhaler of any of embodiments 55 to 61, wherein the pharmaceutical composition is dispensed at an initial fine particle fraction, and the initial fine particle fraction dispensed from the metered dose inhaler is substantially maintained such that the fine particle fraction delivery from the metered dose inhaler is maintained within 85% of the initial fine particle fraction until the canister is emptied.

[0284] Embodiment 63. The metered dose inhaler of embodiment 62, wherein the fine particle fraction delivery from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.

[0285] Embodiment 64. A method of treating a pulmonary disease or disorder in a patient, comprising administering to the patient a pharmaceutical composition of any of Embodiments 1 to 54 by actuation of a metered dose inhaler, wherein the metered dose inhaler contains the pharmaceutical composition.

[0286] Embodiment 65. The method of embodiment 64, wherein the pulmonary disease or disorder is selected from at least one of asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, respiratory disorders, respiratory distress syndrome, pulmonary hypertension, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis.

[0287] Embodiment 66. The method of embodiment 64 or 65, wherein the pulmonary disease or disorder is asthma or COPD.

[0288] Embodiment 67. The method of any of embodiments 64 to 66, wherein the metered dose inhaler is described in any of embodiments 54 to 63.

[0289] Embodiment 68. The pharmaceutical composition of any of Embodiments 1 to 54 for use in the manufacture of a medicament for the treatment of a pulmonary disease or disorder.

[0290] Embodiment 69. The pharmaceutical composition of any of embodiments 1 to 54 for use in treating a pulmonary disease or disorder.

[0291] Embodiment 70. One or more C of the active agent of the control pharmaceutical composition max , AUC inf or AUC last C of the activator, which is about 80% to about 125% of max , AUC inf or AUC last 55. The pharmaceutical composition of any of the embodiments 1 to 54, wherein the pharmaceutical composition has any one or more of the following:

[0292] Embodiment 71. The pharmaceutical composition comprises one or more C of the active agent of the control pharmaceutical composition. max , AUC inf or AUC last C of the activator, which is about 80% to about 125% ofmax , AUC inf or AUC last 64. A metered dose inhaler according to any one of embodiments 55 to 63, comprising any one or more of the following:

[0293] Embodiment 72. The pharmaceutical composition comprises one or more C of the active agent of the control pharmaceutical composition. max , AUC inf or AUC last C of the activator, which is about 80% to about 125% of max , AUC inf or AUC last The method of any one of embodiments 64 to 67, comprising any one or more of the following steps:

[0294] The specific examples contained herein are for illustrative purposes only and should not be construed as limiting the present invention. Additionally, the compositions, systems and methods disclosed herein have been described in connection with certain embodiments thereof, and although numerous details have been set forth for illustrative purposes, those skilled in the art will recognize that the present invention is capable of further embodiments, and that the specific details described herein may be varied without departing from the principles of the present invention. All active agents and reagents used in the following examples are either commercially available or can be prepared by those skilled in the art using standard literature methods utilizing the teachings provided herein. The entire contents of all publications, patents and patent applications cited herein are incorporated herein by reference. EXAMPLES

[0295] Example 1 The suspended particles were prepared by spray drying an emulsion of PFOB (perfluorooctyl bromide) stabilized by DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and water. Details of the preparation method can be found in WO2010 / 138862, WO2010 / 138868 and WO2010 / 138884, the contents of which are incorporated herein by reference in their entirety. The particle size distribution of the suspended particles was determined by laser diffraction. 50% by volume of the suspended particles were smaller than 2.9 μm, and the geometric standard deviation of the distribution was 1.8.

[0296] Active agent particles formed from glycopyrrolate (pyrrolidinium, 3-((cyclopentylhydroxyphenylacetyl)oxy)-1,1-dimethyl-, bromide) were formed by micronization using a jet mill. The particle size distribution of the micronized glycopyrrolate (GP) was determined by laser diffraction. 50% by volume of the microparticles exhibited an optical diameter smaller than 2.1 μm, and 90% by volume were smaller than 5 μm.

[0297] Formoterol fumarate, (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate, also known as (±)-2'-hydroxy-5-[(RS)-1-hydroxy-2-[[RS)-p-methoxy-α-methylphenethyl]-amine]ethyl]formanilide fumarate dihydrate, was received micronized by the manufacturer (Inke) and used as the active agent particles. The particle size distribution of the micronized formoterol fumarate (FF) was determined by laser diffraction. 50% by volume of the microparticles exhibited an optical diameter smaller than 1.6 μm and 90% by volume exhibited an optical diameter smaller than 3.9 μm.

[0298] Active agent particles formed from budesonide, 16,17-(butylidenebis(oxy))-11,21-dihydroxy-(11-β,16-α)-pregna-1,4-diene-3,20-dione, were formed by micronization of budesonide using a jet mill. The particle size distribution of budesonide (BD) was determined by laser diffraction. 50% by volume of the microparticles exhibited an optical diameter smaller than 1.9 μm and 90% by volume exhibited an optical diameter smaller than 4.3 μm.

[0299] Active agent particles formed from albuterol were formed by micronization of albuterol sulfate using a jet mill. The particle size distribution of albuterol sulfate (AS) was determined by laser diffraction. 50% by volume of the microparticles exhibited an optical diameter less than 1.5 μm and 90% by volume exhibited an optical diameter less than 3.3 μm.

[0300] Active agent particles formed from roflumilast were formed by micronization of roflumilast using a jet mill. Particle size distribution of roflumilast (RF) was determined by laser diffraction. 50% by volume of the microparticles exhibited an optical diameter smaller than 1.0 μm and 90% by volume exhibited an optical diameter smaller than 2.4 μm.

[0301] Metered dose inhalers were prepared by first dispensing the appropriate amount of suspended particles and active agent particles into an additive container (AV) and adding the appropriate amount of HFO-1234ze(E) (1,3,3,3-tetrafluoropropene) propellant. The mixture was stirred to facilitate wetting of the powder and then transferred to a pressurizer where the suspension was mixed. A valve consisting of a 50 μL metering chamber (BK357, Bespak, King's Lynn, UK) was crimped onto a fluorinated ethylene polymer (FEP) coated aluminum can (Presspart, Blackburn, UK) and then pressure filled through the valve. The canister was fitted with a polypropylene actuator with a 0.32 mm orifice (# 10024269, Bespak, King's Lynn, UK).

[0302] Example 2 Metered dose inhalers were prepared containing a triple co-suspension composition containing glycopyrrolate, budesonide and formoterol active agent particles, with each type of active agent particle provided as a micronized, crystalline API material. The active agent particles were suspended in HFO-1234ze(E) propellant in the presence or absence of phospholipid particles. In the formulations containing phospholipid particles, the three types of active agent particles exhibited uniform deposition distributions, as shown in Figure 7. In the formulations without phospholipid particles, the three types of active agent particles exhibited individual deposition distributions.

[0303] Example 3 Metered dose inhalers were prepared containing a triple co-suspension composition containing glycopyrrolate, budesonide and formoterol active agent particles, with each type of active agent particle provided as a micronized, crystalline API material. The active agent particles were suspended in HFA-134 propellant or HFO-1234ze(E) propellant in the absence of phospholipid particles. The deposition distribution of budesonide in each formulation was tested at 0% and 50% relative humidity. The HFA-134 propellant formulation showed a greater effect of relative humidity on deposition distribution than the HFO-1234ze(E) propellant.

[0304] Example 4 A metered dose inhaler was prepared containing a dual co-suspension composition containing budesonide and formoterol active agent particles, with each type of active agent particle provided as a micronized, crystalline API material. The active agent particles were suspended in HFO-1234ze(E) propellant with or without phospholipid particles. As shown in Figure 15, the two types of active agent particles and suspended particles showed uniform deposition distribution. Table 6 provides the FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition characterized by NGI (next generation impactor). As shown in Figures 16 and 17, budesonide and formoterol fumarate, respectively, produced similar aPSD (aerodynamic particle size distribution) by NGI with HFO-1234ze(E) as in HFA-134a. Table 7 provides the FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition characterized by NGI (next generation impactor). As shown in Figures 18, 19 and 20, the aPSD of budesonide, formoterol fumarate and suspended particles expressed as DSPC, respectively, were stable for 12 months when stored with the valve closed and protected at 25°C / 60%RH. Table 8 provides the FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition characterized by NGI (next generation impactor). As shown in Figure 21, budesonide and formoterol fumarate are stable for 12 months when stored with the valve closed and protected at 25°C / 60%RH, showing the delivered dose per volume.

[0305] [Table 9]

[0306] [Table 10]

[0307] [Table 11]

[0308] In the formulation without phospholipid particles, the two types of active agent particles showed individual deposition distributions, whereas in the formulation with phospholipid particles, the two types of active agent particles showed uniform deposition distributions.

[0309] Example 5 A metered dose inhaler was prepared containing a dual co-suspension composition containing budesonide and albuterol active agent particles, with each type of active agent particle provided as a micronized, crystalline API material. The active agent particles were suspended in HFO-1234ze(E) propellant with or without phospholipid particles. As shown in Figure 22, the two types of active agent particles and suspended particles showed uniform deposition distribution. Table 9 provides the FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition characterized by NGI (next generation impactor). As shown in Figures 23 and 24, budesonide and albuterol, respectively, produced similar aPSD (aerodynamic particle size distribution) by NGI with HFO-1234ze(E) as in HFA-134a. Table 10 provides the FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition characterized by NGI (next generation impactor). As shown in Figures 25 and 26, the aPSD of budesonide and albuterol were stable for 12 months when stored with the valve closed and protected at 25°C / 60%RH. Table 11 provides the FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition characterized by NGI (next generation impactor). As shown in Figure 27, budesonide and albuterol were stable for 12 months when stored with the valve closed and protected at 25°C / 60%RH, showing the delivered dose per volume expressed as %LC (percent of label claim).

[0310] [Table 12]

[0311] [Table 13]

[0312] [Table 14]

[0313] In the formulation without phospholipid particles, the two types of active agent particles showed individual deposition distributions, whereas in the formulation with phospholipid particles, the two types of active agent particles showed uniform deposition distributions.

[0314] Example 6 A metered dose inhaler was prepared containing a dual co-suspension composition containing glycopyrrolate and formoterol active agent particles, with each type of active agent particle provided as a micronized, crystalline API material. The active agent particles were suspended in HFO-1234ze(E) propellant in the presence or absence of phospholipid particles. As shown in Figure 28, the two types of active agent particles and suspended particles showed uniform deposition distribution in the phospholipid particle-containing formulation.

[0315] Example 7 Metered dose inhalers were prepared containing a triple co-suspension composition containing glycopyrrolate, budesonide and formoterol active agent particles, with each type of active agent particle provided as a micronized, crystalline API material. The active agent particles were suspended in either HFA-134a or HFO-1234ze(E) propellants and formulated with or without phospholipid particles.

[0316] The deposition distribution of formoterol active agent particles was tested at several different environmental humidity (RH) levels ranging from 0% to 100%. Formulations without phospholipid particles showed increased throat and stage 3 deposition with HFO-1234ze(E) compared to HFA-134a. However, this difference was not observed with formulations containing phospholipid particles, which showed similar formoterol deposition distribution with HFO-1234ze(E) (Figure 8, lower panel) and HFA-134a (Figure 8, upper panel).

[0317] The deposition distribution of budesonide active agent particles was tested at several different environmental humidity (RH) levels ranging from 0% to 100%. The budesonide deposition distribution in the HFA-134a formulation without phospholipid particles was more sensitive to RH level than the HFO-1234ze(E) formulation without phospholipid particles. In the presence of phospholipid particles, both the HFA-134a and HFO-1234ze(E) formulations were more sensitive to RH compared to the formulation without phospholipid particles, and both formulations showed similar changes in deposition distribution based on RH level (Figure 9).

[0318] The deposition distribution of glycopyrrolate active agent particles was tested at several different environmental humidity (RH) levels ranging from 0% to 100%. In the presence of phospholipid particles, both HFA-134a and HFO-1234ze(E) formulations were more sensitive to RH compared to the formulation without phospholipid particles, and both formulations showed similar changes in deposition distribution based on RH level.

[0319] Example 8 The fine particle fraction (FPF) present in the actuated delivered dose of MDIs containing budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles was measured after storage of the MDIs for various periods of time under various temperature and relative humidity conditions (Figures 10A, 10B, 10C).

[0320] The fine particle fraction (FPM) present in the actuation delivered dose of MDIs containing budesonide and phospholipid particles was measured after storage of the MDIs for varying periods of time and under various temperature and relative humidity conditions (Figures 11A, 11B, 11C).

[0321] Example 9 The degradation of budesonide (FIGS. 12A, 12B, 12C) and glycopyrrolate (FIGS. 13A, 13B, 13C) active agent particles in MDI canisters containing active agent particles and phospholipid particles was measured after storage of the MDIs for varying periods of time and under various temperature and relative humidity conditions.

[0322] Example 10 The delivered dose uniformity upon actuation of MDIs containing budesonide active agent particles and phospholipid particles was measured following storage of the MDIs for varying periods of time under various temperature and relative humidity conditions (FIGS. 14A, 14B, 14C).

[0323] Example 11 A metered dose inhaler containing a quadruple co-suspension composition containing glycopyrrolate, budesonide, formoterol and roflumilast active agent particles was prepared, with each type of active agent particle provided as a micronized, crystalline API material. The active agent particles were suspended in HFO-1234ze(E) propellant and formulated with phospholipid particles. The deposition distribution of each type of active agent particle was tested in freshly prepared MDIs after three months of storage at 25°C and 75% relative humidity and after three months of storage at 40°C and 75% relative humidity. The quadruple formulation demonstrated consistent aerosol distribution for each of the four types of active agent particles, which remained consistent after three months of storage at the temperatures and relative humidity levels tested.

[0324] Example 12 A randomized, single-blind, three-period, three-treatment, single-dose, crossover study was conducted to evaluate the relative bioavailability of BGF MDI HFO-1234ze(E) and BGF MDI HFC-152a compared with BGF MDI HFA-134a in healthy subjects.

[0325] The investigational medicinal products include (1) a test budesonide / glycopyrronium / formoterol (BGF) metered-dose inhaler (MDI) formulated with HFO-1234ze(E) propellant and (2) a control budesonide / glycopyrronium / formoterol (BGF) metered-dose inhaler (MDI) formulated with HFA-134 propellant. The indication being studied is chronic obstructive pulmonary disease (COPD) and the development phase is Phase 1.

[0326] Test Objectives: Primary goal: To assess the relative bioavailability between test and reference formulations of a fixed dose combination (FDC) of budesonide, glycopyrronium and formoterol (BGF) when administered as a budesonide, glycopyrronium and formoterol metered dose inhaler (MDI) using three different propellants.

[0327] Secondary goal: To determine the pharmacokinetic (PK) parameters of BGF when administered in three different propellant formulations.To evaluate the safety and tolerability of the combination of BGF when administered as a single dose in three different propellant formulations in healthy subjects.

[0328] Test Design: This study was a randomized, single-blind, three-period, three-treatment, single-dose, single-center, crossover study.The study involved evaluation of the PK properties of BGF MDI formulated with three different propellants: hydrofluoroolefin (HFO-1234ze(E)) - treatment A (study), hydrofluorocarbon (HFC-152a) - treatment B (study), and hydrofluoroalkane (HFA-134a) - treatment C (control).

[0329] The test consists of: Screening Period: Up to 28 days prior to first dose. · 3 treatment periods of up to 3 days each: Subjects were admitted from the morning before the first dose of BGF MDI (day -1) in treatment period 1, throughout the entire treatment and washout period, until discharge on day 2 in treatment period 3. Follow-up: Within 3–7 days after the last dose of BGF MDI. There was a 3–7 day washout period between each dose. Each subject received 3 single doses of BGF MDI (single dose HFO-1234ze(E) [Treatment A]; single dose HFC-152a [Treatment B] and single dose HFA-134a [Treatment C]) after an overnight fast of at least 8 hours.

[0330] Main admission criteria: Healthy, non-smoking male subjects aged 18-60 years with a vein suitable for intubation or venipuncture. Subjects were required to have a body mass index (BMI) of 18-30 kg / m 2 (inclusive) and weight must be at least 50 kg and not exceed 100 kg (inclusive). Subjects must have a forced expiratory volume in 1 second (FEV1) ≥ 80% predicted for their age, height, and ethnicity at the time of the screening visit.

[0331] Investigational Products: Treatment A (Test): BGF MDI HFO-1234ze(E) at strengths / concentrations of 160 / 7.2 / 4.8 μg per actuation. Treatment B (Test): BGF MDI HFC-152a at strengths / concentrations of 160 / 7.2 / 4.8 μg per actuation. Treatment C (control): BGF MDI HFA-134a at strengths / concentrations of 160 / 7.2 / 4.8 μg per actuation.

[0332] Test period: Each subject was to participate in the study for a maximum of 53 days.

[0333] Treatment Compliance: Medication was administered at the Parexel Early Phase Clinical Unit in Los Angeles. All investigational medicinal products (IMPs) were administered using Parexel's electronic source data collection and information management system (CLINBASE TM ) Compliance was verified by direct supervision and witnessing administration of IMP.

[0334] Evaluation criteria: Pharmacokinetic parameters: Primary PK parameters: C of test and control treatments max , AUC inf and AUC last . Secondary PK parameters: t max , t1 / 2λz, MRT, λz, CL / F, Vz / F, TRC max ,TRAUC inf and TRAUC last .

[0335] Safety variables: Adverse Events (AE) / Serious Adverse Events (SAE). · Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, oxygen saturation and respiratory rate). 12-Lead Safety and Digital Electrocardiogram (ECG) and ECG Telemetry Physical examination. · Clinical laboratory evaluation (hematology, clinical chemistry and urinalysis) Spirometry. Taste evaluation.

[0336] Statistical methods: Sample size determination: This was a pilot PK study to determine the relative bioavailability of two test formulations of BGF MDI compared to the conventional formulation, therefore, no sample size calculation was performed.

[0337] Forty-eight healthy subjects (the number of subjects increased from 24 to 48 following protocol amendment 2 for subject replacement due to dosing deviations involving the original 23 subjects) were projected to be randomized into a 6-sequence Williams design with 3 periods and 3 treatments: ABC, BCA, CAB, ACB, BAC, and CBA, to ensure that at least 20 subjects would be evaluable at the end of the treatment period.

[0338] Subjects were considered evaluable if their PK profile was evaluable, i.e., (1) they received active agent treatment, (2) there were no significant violations of protocol entry or exclusion criteria or significant deviations from the protocol, and (3) there were no unavailable or incomplete data that could affect the PK analysis, presentation, and pharmacokinetic data analysis: For the PK analysis set, full PK concentrations, parameter summaries, and statistical analyses were provided unless otherwise noted. For the safety analysis set, PK concentration and parameter listings were provided and included all reportable individual PK results. Individual PK concentration and parameter data for any subject not included in the PK analysis set or excluded from the descriptive summary tables, figures, and / or inferential statistical analyses were included in the listing and flagged with an appropriate footnote.

[0339] The test treatments, treatments A and B (BGF MDI HFO and BGF MDI HFC, respectively), were compared separately to the control treatment, treatment C (BGF MDI HFA), for each specimen. Statistical analysis was performed with C as the response variable. max , AUC inf and AUC last , was conducted using a linear mixed-effects ANOVA model with treatment sequence and period as fixed effects, and subjects nested within sequence as a random effect. max , AUC inf and AUC last Geometric means were estimated and presented along with their within-subject coefficients of variation (CIs) (2-sided 95%). Additionally, ratios of geometric means were estimated and presented along with their CIs (2-sided 90%).

[0340] In addition, for each sample, the untransformed t max The median deviation and the corresponding 90% CI of the median deviation for each sample were calculated using the nonparametric Hodges-Lehman method.

[0341] Presentation and analysis of safety and eligibility data: Safety data (scheduled and unscheduled) were presented in the Data Listings. Continuous variables were summarized using descriptive statistics (n, mean, standard deviation [SD], minimum, median, maximum) by treatment. Categorical variables were summarized in frequency tables (frequencies and percentages) by treatment, when applicable. Analysis of safety variables was based on the safety analysis set.

[0342] Adverse events were summarized by preferred term (PT) and system organ class (SOC) using the Medical Dictionary for Regulatory Relevant Terms (MedDRA) lexicon. In addition, SAEs and AEs leading to discontinuation were listed and the number of subjects with any AE, SAE, or AE leading to discontinuation and AEs were summarized with severity intensity. Adverse events occurring before dosing were reported separately.

[0343] Vital signs, clinical laboratory tests, digital and 12-lead safety ECGs (list only), telemetry (list only) and spirometry data were tabulated and listed. Taste assessment results were tabulated separately only. Any new or worsening clinically relevant abnormal physical examination findings compared to baseline assessment were reported as AEs. Data were summarized as observations at each scheduled evaluation with corresponding changes from baseline when a baseline was defined. Laboratory data were reported in units provided by the clinical laboratory for Safety Review Committee (SRC) meetings and in the International System of Units (SI) in the Clinical Study Report (CSR).

[0344] Out-of-range values ​​for safety laboratory assessments were flagged in the individual listings and summarized narratively using agreed standard control ranges and / or extended control ranges (e.g., AstraZeneca, programmatic or laboratory ranges).

[0345] Protocol Deviations: Major protocol deviations were reported in a total of 26 (55.3%) subjects during the study: For Treatment A (HFO propellant): 23 (48.9%) subjects were reported with other significant protocol deviations (subject did not self-administer with inhaler as outlined in protocol; nurse administered). For Treatment B (HFC propellant): 23 (48.9%) subjects were reported with other significant protocol deviations (subject did not self-administer with inhaler as outlined in protocol; nurse administered), and 2 (4.3%) subjects did not receive the full expected dose due to problems during inhalation. For Treatment C (HF propellant): 23 (48.9%) subjects were reported with other significant protocol deviations (subject did not self-administer with inhaler as outlined in protocol; nurse administered), and 1 (2.1%) subject did not receive the full expected dose due to problems during inhalation.

[0346] The number of subjects was increased from 24 to 48 following protocol amendment 2 to replace subjects due to dosing deviations involving the original 23 subjects.

[0347] Twenty-three subjects were excluded from the PK analysis set due to reported protocol deviations. No significant COVID-19-related protocol deviations were reported during the study.

[0348] Pharmacokinetic Results: The systemic exposure of budesonide from BGF MDI HFO was comparable to that from BGF MDI HFA, with max , AUC inf and AUC last The GMRs and 90% CIs for were 111.7% (91.01%, 137.1%), 104.7% (91.95%, 119.2%) and 107.2% (94.53%, 121.9%) for ESRD, ESRD, and ESRD, respectively. The systemic exposure of glycopyrronium from BGF MDI HFO was comparable to that from BGF MDI HFA, with C max and AUC last The GMRs and 90% CIs for 108.3% (85.50%, 137.3%) and 106.1% (86.18%, 130.6%) were respectively for The systemic exposure of formoterol from BGF MDI HFO was comparable to that from BGF MDI HFA, with max , AUC inf and AUC last The GMRs and 90% CIs for were 109.1% (97.02%, 122.7%), 96.00% (70.33%, 131.0%), and 98.13% (86.44%, 111.4%) for 1H-CC-CC-NC-NC-NC-PRO, 1H-CC-NC-PRO, and 1H-CC-NC-PRO.

[0349] Safety results: No deaths, SAEs or AEs leading to discontinuation of IMP were reported during this study. No new safety signals were observed, no clinically relevant trends were observed in vital signs, physical examination, clinical laboratory results, spirometry and taste assessments, and no abnormal clinically significant 12-lead safety and digital ECG and electrocardiogram telemetry findings were reported. The combination of budesonide, glycopyrronium and formoterol, when administered as a single dose in three different propellant formulations, demonstrated an acceptable safety profile and was well tolerated in the study population.

[0350] In view of this clinical trial, systemic exposure of budesonide, glycopyrronium and formoterol was comparable in BGF MDI HFO-1234ze(E) compared to the reference product, BGF MDI HFA-134a. No significant differences between the products were noted in this taste evaluation. The combination of budesonide, glycopyrronium and formoterol, when administered as a single dose in the HFO-1234ze(E) and HFA-134a formulations, was well tolerated with an acceptable safety profile in the study population.

[0351] Example 13 Figure 34 depicts the aerosol particle size distribution (aPSD) measured by Next Generation Impactor (NGI), expressed as a percent of total recovered mass, of budesonide (BD) and formoterol fumarate (FF) active agent particles actuated from an MDI containing a dual fixed dose combination co-suspension of budesonide and formoterol fumarate active agent particles suspended in HFA-134a (formulation designated BFF-134a) or HFO-1234ze(E) (formulation designated BFF-1234ze) propellants with phospholipid suspension particles. The profiles showed similar aerosol distributions between HFA-134a and HFO-1234ze(E) for both active agent particles.

[0352] Figure 35 depicts the aPSD, as measured by NGI, expressed as a percent of the total recovered mass of budesonide (BD) and formoterol fumarate (FF) active agent particles actuated from an MDI containing a triple fixed dose combination co-suspension of budesonide and formoterol fumarate active agent particles suspended in HFA-134a without phospholipid suspension particles (formulation designated BFF crystal-134a) or HFO-1234ze(E)BFF crystal-1234ze) propellant. The profiles showed unique aerosol distributions between HFA-134a and HFO-1234ze(E) for both active agent particles.

[0353] Table 12 provides a summary of the fine particle fraction, <6.4 μm (FPF), fine particle dose, <6.4 μm (FPD), mass median aerodynamic diameter (MMAD) and throat deposition for budesonide and formoterol fumarate calculated from the NGI datasets for BFF-134a, BFF-1234ze, BFF-Crystal-134a and BFF-Crystal-1234ze.

[0354] [Table 15]

[0355] Example 14 Figure 36 depicts the aerosol particle size distribution (aPSD) measured by next generation impactor (NGI), expressed as a percent of total recovered mass, of budesonide (BD), glycopyrronium (GP) and formoterol fumarate (FF) active agent particles actuated from an MDI containing a triple fixed dose combination co-suspension of budesonide, glycopyrronium and formoterol fumarate active agent particles suspended in phospholipid suspension particles containing HFA-134a (formulation designated BGF-134a) or HFO-1234ze(E) (formulation designated BGF-1234ze) propellant. The profiles show similar aerosol distributions between HFA-134a and HFO-1234ze(E) for total active agent particles.

[0356] Figure 37 depicts the aPSD, as measured by NGI, expressed as a percent of total recovered mass, of budesonide (BD), glycopyrronium (GP) and formoterol fumarate (FF) active agent particles actuated from an MDI containing a triple fixed dose combination co-suspension of budesonide, glycopyrronium and formoterol fumarate active agent particles suspended in HFA-134a (formulation designated BGF crystal-134a) or HFO-1234ze(E) (formulation designated BGF crystal-1234ze) propellants without phospholipid suspension particles. The profiles show a unique aerosol distribution between FA-134a and HFO-1234ze(E) for all active agent particles.

[0357] Table 13 provides a summary of the fine particle fraction, <6.4 μm (FPF), fine particle dose, <6.4 μm (FPD), mass median aerodynamic diameter (MMAD) and throat deposition for budesonide, glycopyrronium and formoterol fumarate calculated from the NGI data sets for BGF-134a, BGF-1234ze, BGFcrystal-134a and BGFcrystal-1234ze.

[0358] [Table 16]

[0359] The above various embodiments can be combined to provide further embodiments.All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent literature described herein and / or listed in application data sheets are incorporated herein by reference in their entirety, unless otherwise specified herein.The features of the embodiments can be modified, if necessary, to use the concepts used in various patents, applications and publications to provide further embodiments.

[0360] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used herein should not be construed to limit the scope of the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure.

Claims

1. A pharmaceutical composition deliverable from a metered-dose inhaler, comprising: a propellant of pharmaceutical grade (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)) having a purity of at least 99.90%; a plurality of particles of one or more active agents; and a plurality of particles of a phospholipid containing a porous microstructure wherein the one or more active agents are selected from long-acting muscarinic antagonists (LAMA), long-acting β2-agonists (LABA), short-acting beta-agonists (SABA), inhaled corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents, (i) a plurality of budesonide particles and a plurality of albuterol particles; (ii) a plurality of glycopyrrolate particles and a plurality of formoterol particles; or (iii) a plurality of budesonide particles and a plurality of formoterol particles The pharmaceutical composition.

2. The pharmaceutical composition of claim 1, wherein (i) the SABA is present at a concentration in the range of 0.04 mg / mL to 2.25 mg / mL, (ii) the LABA is present at a concentration in the range of about 0.01 mg / mL to about 1 mg / mL, (iii) the ICS is present at a concentration in the range of 0.1 mg / mL to 20 mg / mL, and (iv) the LAMA is present at a concentration in the range of 0.04 mg / mL to 2.25 mg / mL.

3. The pharmaceutical composition of claim 1, wherein the porous microstructure comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride.

4. The pharmaceutical composition of claim 1, wherein the phospholipid particles are present at a concentration in the range of 0.1 mg / mL to 10 mg / mL.

5. The pharmaceutical composition of claim 1, wherein the albuterol particles are in the propellant at a concentration sufficient to provide a delivery dose of glycopyrrolate per actuation of the metered-dose inhaler selected from 5 μg to 50 μg per actuation, 2 μg to 25 μg per actuation, and 6 μg to 15 μg per actuation.

6. The pharmaceutical composition of claim 1, wherein the albuterol particles comprise albuterol sulfate.

7. The pharmaceutical composition of claim 6, wherein the albuterol particles comprise micronized and crystalline albuterol sulfate.

8. The pharmaceutical composition of claim 1, wherein the formoterol particles are included in the composition at a concentration sufficient to provide a delivery dose of formoterol selected from 1 μg to 30 μg, 0.5 μg to 10 μg, 2 μg to 5 μg, 3 μg to 10 μg, 5 μg to 10 μg, and 3 μg to 30 μg per actuation of the metered-dose inhaler.

9. The pharmaceutical composition of claim 1, wherein the formoterol particles comprise formoterol fumarate.

10. The pharmaceutical composition of claim 9, wherein the formoterol particles comprise micronized and crystalline formoterol fumarate.

11. The pharmaceutical composition of claim 1, wherein the budesonide particles are included in the composition at a concentration sufficient to provide a delivery dose of budesonide selected from 50 μg to 400 μg, 20 μg to 600 μg, 30 μg to 100 μg, 50 μg to 200 μg, and 150 μg to 350 μg per actuation of the metered-dose inhaler.

12. The pharmaceutical composition of claim 1, wherein the budesonide particles comprise micronized budesonide.

13. The pharmaceutical composition of claim 1, wherein the phospholipid particles are included in the composition at a concentration sufficient to provide a delivery dose of phospholipid particles selected from 50 μg to 400 μg.

14. A metered-dose inhaler comprising a canister with an outlet valve including an actuator for dispensing a measured amount of the pharmaceutical composition of claim 1, wherein the canister contains the pharmaceutical composition.

15. The metered-dose inhaler of claim 14, wherein the outlet valve includes a neck gasket and at least one sheet gasket, and the neck gasket or at least one sheet gasket is made of bromobutyl material.

16. The metered-dose inhaler of claim 14, which shows a decrease of less than 10%, 9%, 8%, 7%, 6%, or 5% of the injection weight per actuation until the canister is empty.

17. The metered-dose inhaler of claim 14, which shows a weight loss of less than 1.0%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% per year at 25°C / 60% RH.

18. The metered-dose inhaler of claim 14, wherein the delivery dose uniformity (DDU) for the pharmaceutical formulation is selected from ±20% or better DDU, ±15% or better DDU, and ±10% or better DDU until the canister is empty.

19. The pharmaceutical composition of claim 1 for use in the treatment of lung diseases or disorders.

20. A pharmaceutical composition for use according to claim 19, wherein the treatment is a method of treating a lung disease or disorder in a patient, and comprises administering the pharmaceutical composition to the patient by actuation of a metered dose inhaler, wherein the metered dose inhaler contains the pharmaceutical composition.

21. The pharmaceutical composition according to claim 19, wherein the lung disease or disorder is asthma or COPD.

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