Compositions, methods and systems for aerosol drug delivery

Abstract

1. A pharmaceutical composition deliverable from a metered dose inhaler, the pharmaceutical composition comprising: a propellant of pharmaceutical grade 1,1-difluoroethane (HFC-152a); a plurality of active agent particles; and a plurality of phospholipid particles comprising a perforated microstructure, the active agent particles comprising an active agent selected from a long-acting muscarinic antagonist (LAMA), a long-acting P2-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS) and a non-corticosteroid anti-inflammatory agent. A metered dose inhaler comprising a canister having an outlet valve comprising an actuator for dispensing a metered amount of the pharmaceutical composition, the canister containing the pharmaceutical composition. The composition for use in treating a pulmonary disease or disorder.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 291,538, filed December 20, 2021, which is incorporated by reference herein in its entirety for all purposes. [Background technology]

[0002] A method of targeted drug delivery that delivers active agents to the site of action is often desirable. For example, targeted delivery of active agents can reduce undesirable side effects, lower dosages, and reduce costs of treatment. With respect to respiratory delivery, inhalers are well-known devices for administering active agents to the airways of a subject, and several different inhaler systems are currently 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 may be used to deliver drugs in solubilized form or as a suspension. Typically, MDIs use propellants with relatively high vapor pressure to release aerosolized liquid particles containing the active agent into the airways when the MDI is actuated. Dry powder inhalers generally rely on the patient's inhalation effort to introduce the drug in dry powder form into the airways. Nebulizers impart energy to a liquid solution or suspension to form a drug aerosol that is inhaled.

[0004] MDIs are effective delivery devices that utilize the pressure generated by a propellant. The propellant must be safe and pharma- ceutically acceptable for patient use. The active agent to be delivered by an MDI is typically provided as a suspension of fine particulates dispersed within a propellant or combination of two or more propellants (i.e., a propellant "system"). However, the active agent fine particles suspended in the propellant or propellant system tend to rapidly aggregate or aggregate. Furthermore, the aggregation or aggregation of these fine particles can make delivery of the active agent difficult. Another problem associated with such suspension MDI formulations relates to crystal growth of the drug during storage, resulting in a decrease in the aerosol properties and delivery dose uniformity of such MDIs over time. Therefore, it is essential to properly formulate the active agent with excipients and propellants to form a stable suspension suitable for MDIs. The propellant properties play an important role in the performance of a suspension formulation for an MDI. 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, latent heat, etc. are also factors to be considered when formulating a suspension. Therefore, there remains a need to research and develop innovative suspension MDI formulations with desired characteristics. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides compositions, methods and systems for respiratory delivery of one or more active agents.

[0006] In some embodiments, the compositions described herein are formulated for pulmonary delivery of one or more active agents via an MDI. In other embodiments, the compositions described herein may be formulated for nasal delivery via an MDI. In some embodiments, the compositions include a pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant, a plurality of active agent particles, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the plurality of active agent particles include one, two, three, or four active agents 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.

[0007] In some embodiments, the composition comprises a pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant, a plurality of LAMA particles, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the composition comprises a pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant, a plurality of LABA particles, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the composition comprises a pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant, a plurality of SABA particles, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the composition comprises a pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant, a plurality of ICS particles, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the composition comprises a pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant, a plurality of non-corticosteroid anti-inflammatory agent particles, and a plurality of phospholipid particles comprising a perforated microstructure.

[0008] In some embodiments, the composition comprises a pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant, a plurality of active agent particles, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the composition comprises a pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant, a plurality of first species of active agent particles, a plurality of second species of active agent particles, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the first species of active agent particles comprise a first active agent, and the second species of active agent particles comprise a second active agent. In some embodiments, the composition described herein further comprises a plurality of third species of active agent particles, and the third species of active agent particles comprise a third active agent. In some embodiments, the composition described herein further comprises a plurality of fourth species of active agent particles, and the fourth species of active agent particles comprise a fourth active agent. In some embodiments, the 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 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 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.

[0009] The methods described herein include methods for treating a pulmonary disease or disorder in a patient by actuating a metered dose inhaler containing a composition described herein.

[0010] Also described herein is a system for pulmonary delivery of one or more active agents.In some embodiments, such a system comprises an MDI that comprises a canister having an outlet valve that comprises an actuator (e.g., a depressible valve stem) for dispensing a metered amount of the composition described herein. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows the aerodynamic particle size distribution of budesonide (BD), glycopyrrolate (GP) and formoterol fumarate (FF) by NGI of BGF-152a. [Diagram 2] FIG. 2 shows aerodynamic particle size distribution of BD by NGI stability data for 25° C. / 60% RH-valve-down-protected BGF-152a at initial, 1 month, 3 months, 6 months, and 12 months. [Diagram 3] FIG. 3 shows aerodynamic particle size distribution of GP from NGI stability data for 25° C. / 60% RH-valve-down-protected BGF-152a at initial, 1 month, 3 months, 6 months, and 12 months. [Figure 4] FIG. 4 shows aerodynamic particle size distribution of FF by NGI stability data for 25° C. / 60% RH-valve-down-protected BGF-152a at initial, 1 month, 3 months, 6 months, and 12 months. [Diagram 5] FIG. 5 shows aerodynamic particle size distribution of BD by NGI stability data for 40° C. / 75% RH-valve-down protected BGF-152a at initial, 1 month, 3 months, and 6 months. [Figure 6]FIG. 6 shows aerodynamic particle size distribution of GPs from NGI stability data for 40° C. / 75% RH-valve-down-protected BGF-152a at initial, 1 month, 3 months, and 6 months. [Figure 7] FIG. 7 shows aerodynamic particle size distribution of FF by NGI stability data for 40° C. / 75% RH-valve-down protected BGF-152a at initial, 1 month, 3 months, and 6 months. [Figure 8] FIG. 8 shows BD delivery uniformity stability data for 25° C. / 60% RH-valve protected BFF-152a. [Figure 9] FIG. 9 shows stability data of GP delivery uniformity for 25° C. / 60% RH-valve-protected BFF-152a. [Figure 10] FIG. 10 shows FF delivery uniformity stability data for 25° C. / 60% RH-valve down protected BFF-152a. [Figure 11] FIG. 11 shows BD delivery uniformity stability data for 40° C. / 75% RH-valve down protected BFF-152a. [Figure 12] FIG. 12 shows stability data of GP delivery uniformity for 40° C. / 75% RH-valve-protected BFF-152a. [Figure 13] FIG. 13 shows FF delivery uniformity stability data for 40° C. / 75% RH-valve down protected BFF-152a. [Figure 14] FIG. 14 shows the aerodynamic particle size distribution of GP and FF by NGI of GFF-152a. [Figure 15] FIG. 15 shows the uniformity of delivery of GP and FF of GFF-152a. [Figure 16] FIG. 16 shows aerodynamic particle size distribution of BD and AB (albuterol sulfate) by NGI of BDA-152a. [Figure 17]FIG. 17 shows the uniformity of delivery amount of BDA-152a between BD and AB. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] definition Unless otherwise specified, technical terms as used herein have their ordinary meanings as understood in the art. The following terms are defined in detail for the sake of clarity.

[0013] 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, pharmaceutical, medicinal, diagnostic, cosmetic, and prophylactic agents, as well as immunomodulatory agents. Active agent may be used interchangeably with terms such as drug, pharmaceutical, drug substance, or therapeutic agent. As used herein, active agent may also include natural or homeopathic products that are not generally considered therapeutic.

[0014] The terms "associated", "associated with" or "association" refer to an interaction or relationship between chemical components, compositions or structures that are in close proximity to a surface, such as the surface of another chemical component, composition or structure. Association includes, for example, adsorption, adhesion, covalent bonds, hydrogen bonds, ionic bonds and electrostatic attraction, Lifshitz-van der Waals interactions and polar interactions. The term "adhere" or "adhesion" refers to a form of association and is used as a generic term for all forces that tend to attract particles or aggregates to a surface. Adhesion also refers to keeping particles in contact with each other such that there is substantially no visible separation between the particles due to their different buoyancy in the propellant under normal conditions. In one embodiment, particles that adhere or bond to a surface are encompassed by the term adhesion. Normal conditions may include storage at room temperature or under accelerated forces due to gravity. As described herein, active particles may be associated with suspended particles to form a co-suspension, with substantially no visible separation or clumping between suspended particles and active particles due to differences in buoyancy in the propellant.

[0015] "Suspension particles" refers to a material or combination of materials 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 repeatable dosing, delivery or transport of the active agent to the target site of delivery, i.e., the respiratory tract. The suspension particles described herein can be dispersed in a suspension medium, including a propellant or propellant system, and configured according to any shape, size or surface characteristics that are convenient for achieving the desired suspension stability or active agent delivery performance. Exemplary suspension particles include particles that exhibit a particle size that facilitates respiratory delivery of the active agent and have a physical configuration that is convenient for the formulation and delivery of the stabilized suspensions described herein.

[0016] 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 associated with one or more of the other particle types. The association leads to an observable change in one or more characteristics of at least one of the individual particle types suspended in the suspension medium. The characteristics modified by the association may 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 sediment layer, adhesion to the container wall, adhesion to the valve member, and the rate and level of dispersion upon agitation. The term co-suspension includes partial co-suspensions, where the majority of the at least two particle types are associated with each other, but some separation (i.e., less than the majority) of the at least two particle types may be observed.

[0017] The term "metered dose" refers to the amount of active agent contained in the volume of formulation that exits the canister upon actuation of the MDI. The term "delivered dose" refers to the amount of active agent contained in the volume of formulation that exits the actuator nozzle and is available to be inhaled into the patient's lungs.

[0018] With respect to compositions that contain or provide respirable aggregates, particles, droplets, and the like, such as those described herein, the term "fine particle dose" or "FPD" refers to the dose within the respirable range in the total mass or fraction of a nominal or quantified amount. The respirable dose is the sum of the dose measured in vitro and delivered through the Micro Orifice Collector to Stage 3 in a Next Generation Impactor operated at a flow rate of 30 l / min.

[0019] With respect to compositions that contain or provide respirable aggregates, particles, droplets, and the like, such as those described herein, the term "fine particle fraction" or "FPF" refers to the percentage of delivered material compared to the delivered amount (i.e., the amount exiting the actuator of a delivery device such as an MDI) that is within the respirable range. The amount of delivered material that is within the respirable range is measured in vitro as the sum of material delivered through the Micro Orifice Collector to Stage 3 in a Next Generation Impactor operated at a flow rate of 30 l / min.

[0020] As used herein, the term "inhibit" refers to a significant reduction in the tendency for an event, symptom, or condition to occur or the extent to which that event, symptom, or condition occurs. The term "inhibit" or any form thereof is used in the broadest sense and includes minimize, prevent, reduce, inhibit, suppress, inhibit, inhibit, restrict, retard, and the like.

[0021] 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 according to United States Pharmacopeia ("USP") monograph 601.

[0022] As referred to herein, the term "light scattering diameter" refers to the size of a particle as measured by Fraunhofer diffraction mode using a laser diffraction particle size distribution analyzer equipped with a dry powder dispenser (e.g., Sympatec GmbH, Clasthal-Zellerfeld, Germany).

[0023] The term "solution-mediated phase transition" refers to the phenomenon in which a more soluble form of a solid material (i.e., particles or amorphous material with a small radius of curvature (the driving force for Ostwald ripening)) dissolves and recrystallizes into a more stable crystalline form that can coexist in equilibrium with the saturated jet solution.

[0024] "Patient" refers to an animal for which one or more of the active agents described herein have a therapeutic effect. In some embodiments, the patient is a human.

[0025] "Perforated microstructure" refers to a suspended particle that includes a structural matrix that defines or includes a shape that exhibits voids, pores, defects, hollows, spaces, cracks, openings, perforations, or holes that allow the surrounding suspension medium to penetrate, fill, or extend into the microstructure, such as the materials and preparations described in U.S. Pat. No. 6,309,623 to Weers, et al., the methods of which are incorporated herein by reference. The basic shape of the perforated microstructure is generally not essential, but any overall configuration that provides the desired formulation characteristics is contemplated herein. Thus, in some embodiments, the perforated microstructure may include a generally spherical shape, such as hollow porous spray-dried microspheres. However, crushed, corrugated, distorted, or collapsed granules of any basic shape or aspect ratio may also be suitable.

[0026] As is true for the suspended particles described herein, the perforated microstructure may be formed from any biocompatible material that does not substantially degrade or dissolve in the selected suspension medium. Although a wide variety of materials may be used to form the particles, in some embodiments the structural matrix is ​​associated with or includes a surfactant, such as a phospholipid or a fluorinated surfactant.

[0027] 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. As used herein, the term "propellant" refers to one or more pharmacologically inactive substances that use a vapor pressure high enough at normal room temperature to expel 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."

[0028] The term "respirable" generally refers to particles, agglomerates, droplets, etc. that are sized so that they can be inhaled and reach the trachea of ​​the lungs.

[0029] The terms "physical stability" and "physically stable" when used to refer to compositions described herein refer to a composition that is capable of resisting one or more of changes in particle size due to aggregation, flocculation, and solution-mediated phase transitions, and substantially maintaining the MMAD and fine particle content of suspended particles. In some embodiments, physical stability may be determined through subjecting the composition to accelerated degradation conditions, such as by temperature cycling.

[0030] The term "potent" when referring to an active agent refers to an active agent that is therapeutically effective at or below a dose in the range of about 0.01 mg / kg to about 1 mg / kg. Typical doses of potent active agents are generally in the range of about 100 μg to about 100 mg.

[0031] 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 are generally in the range of about 100 μg or less.

[0032] 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 may be measured through the delivery dose uniformity achieved by the compositions described herein.

[0033] The term "substantially insoluble" means that the composition is completely insoluble in a particular solvent or that the composition is not sufficiently soluble in that particular solvent. Substantially insoluble means that a particular solute has a solubility of less than 1 per 100 parts of solvent. The term substantially insoluble refers to the definitions "slightly soluble" (100-1000 parts of solvent per solute), "extremely soluble" (1000-10,000 parts of solvent per solute), and "practically insoluble" (greater than 10,000 parts of solvent per solute) as defined in Remington: The Science and Practice of Pharmacy, 21 st As shown in Table 16-1 in Ed. Lippincott, Williams & Wilkins, 2006, p. 212.

[0034] The term "surfactant" as used herein refers to any agent that selectively adsorbs to an 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 a hydrophilic portion and a lipophilic portion, and upon adsorption to microparticles, they tend to present a moiety to the continuous phase that does not attract similarly coated particles, thus reducing particle aggregation.

[0035] 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 may be an amount that relieves to some extent one or more symptoms of a disease or disorder in a patient; partially or completely restores to normal one or more physiological or biochemical parameters associated with or causing the disease or disorder; and / or reduces the likelihood of the onset of the disease or disorder.

[0036] The terms "chemically stable" and "chemically stable" refer to a formulation in which individual degradation products of the active agent remain below limits specified by 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 there is an acceptable mass balance between the active agent assay and the total degradation products (e.g., as defined in ICH guidance Q1E).

[0037] composition The compositions described herein include a suspension medium containing a propellant, active agent particles, and suspended particles. If desired, 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 species of active agent particles may be used, each different species of active agent particles including one or more different active agents. Alternatively, two or more species of suspended particles may be used in the composition for delivery of one or more active agents or active agent particles. In some embodiments, when two or more active agent particles are present, the compositions of the present invention are in the form of a fixed dose combination. By "fixed dose combination," it is meant two or more active agents in a single dosage form, such as a formulation in a single metered dose inhaler.

[0038] Generally, due to density differences between distinct species of particles and the medium in which they are suspended (e.g., the propellant or propellant system), buoyant forces cause creaming of particles having a lower density than the propellant and settling of particles having a higher density than the propellant. Thus, in a suspension consisting of a mixture of different types of particles having different densities or different tendencies to aggregate, the settling or creaming reactions are expected to be specific to each of the different particle types and to the particular suspension medium used, leading to separation of the different particle types within the suspension medium.

[0039] 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 coexist within the propellant (i.e., the active agent particles are associated with the suspended particles such that the suspended particles and the active agent particles do not exhibit substantial separation from one another, such as by specific settling or creaming, even after a period of time sufficient for a cream or sediment 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.

[0040] The propellant, active agent particles and suspended particle compositions according to the present invention provide desirable chemical stability, suspension stability and active agent delivery characteristics. For example, in certain 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 materials; differential settling or creaming of active agent particles and suspended particles; solution-mediated phase transition of active agent materials; and loss of active agent to the surfaces of the container closure system, particularly the metering valve member. Such qualities serve to achieve and maintain aerosol performance when the formulation is delivered from the MDI, and desirable characteristics such as fine particle percentage, fine particle dose and delivery dose uniformity are achieved and substantially maintained until the MDI canister in which the formulation is contained is emptied. In addition, the compositions according to the present invention can provide stable formulations that provide consistent dosing characteristics for even potent and very potent active agents while using relatively simple HFC suspension media that do not require modification, for example, by the addition of co-solvents, anti-solvents, solubilizers or adjuvants.

[0041] Providing a composition according to the description of the present invention may also simplify the formulation, delivery and dosing of a desired active agent.Without being bound by a particular theory, it is believed that by achieving a co-suspension of active agent particles and suspended particles, the delivery, physical stability and dosing of the active agent contained within such a dispersion system may be substantially controlled through the control of the size, composition, morphology and relative amount of the suspended particles, and is less dependent on the size and morphology of the active agent particles or on the properties of the propellant.Furthermore, in certain embodiments, the pharmaceutical compositions described herein may be formulated with HFC propellants or propellant systems that are substantially free of antisolvents, solubilizers, cosolvents or adjuvants.

[0042] In one embodiment, the composition described herein that includes a combination of two or more active agents may contain glycopyrronium bromide and formoterol fumarate as active agents. In one embodiment, the composition described herein that includes a combination of two or more active agents may contain budesonide, glycopyrronium bromide and formoterol fumarate as active agents. In one embodiment, the composition described herein that includes a combination of two or more active agents may contain albuterol sulfate and budesonide as active agents. In one embodiment, the composition described herein that includes a combination of two or more active agents may contain budesonide and formoterol fumarate as active agents. In one embodiment, the composition described herein that includes a combination of two or more active agents may contain budesonide, glycopyrronium bromide, formoterol fumarate and roflumilast as active agents.

[0043] In one embodiment, the compositions described herein that include a combination of two or more active agents may contain umeclidinium bromide, vilanterol triphenylacetate, and fluticasone furoate as active agents. In another embodiment, the compositions described herein that include a combination of two or more active agents may contain umeclidinium bromide and vilanterol triphenylacetate as active agents. In one embodiment, the compositions described herein that include a combination of two or more active agents may contain glycopyrronium bromide, indacaterol acetate, and mometasone furoate as active agents. In another embodiment, the compositions described herein that include a combination of two or more active agents may contain glycopyrronium bromide and indacaterol acetate as active agents. In one embodiment, the compositions described herein that include a combination of two or more active agents may contain glycopyrronium bromide, formoterol, and beclomethasone propionate as active agents. The compositions formulated according to the teachings of the present invention can inhibit the degradation of the active agents contained therein.

[0044] In some embodiments, compositions formulated according to the teachings of the present invention inhibit physical and / or chemical degradation of the active agent contained therein. For example, in certain embodiments, the compositions described herein may inhibit one or more of chemical degradation, aggregation, flocculation, and solution-mediated phase transition of the active agent contained therein. The chemical and suspension stability provided by the compositions described herein provides improved robustness in simulated use tests (SUTs) compared to conventional preparations. The simulated use tests include storage of MDI canisters for 5 weeks at 25° C. and 75% relative humidity (RH) without weekly cleaning of the device, and dispensing of the composition from the MDI at 25° C. and 50% RH. The improved robustness can be expressed in terms of consistency in shot weight (i.e., the weight of the composition dispensed upon actuation of the MDI), low levels of propellant leakage, and desirable delivered dose uniformity ("DDU") until the MDI canister is empty, even when the active agent to be delivered is very potent and delivered at a very low dose. For example, in some embodiments, the compositions described herein exhibit 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% shot weight loss when delivered by an MDI at SUT. In further embodiments, the compositions described herein exhibit 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% weight loss in an MDI per year at 20° C. and 60% RH. In further embodiments, the compositions described herein exhibit a DDU of ±20% or better, ±15% or better, or ±10% or better until the MDI canister is empty. Furthermore, compositions according to the present description exhibit improved robustness by substantially retaining FPF and FPD performance until the MDI canister is empty, even after being subjected to accelerated degradation conditions. For example, in some embodiments, the compositions described herein are dispensed from an MDI with an FPF that is maintained within about 85% or within about 95% of the initial FPF.The compositions described herein provide the additional benefit of achieving such performance while being formulated with an HFC propellant, e.g., HFC-152a. In certain embodiments, the compositions described herein achieve one or more of the targeted DDU, FPF, or FPD while being formulated with a suspension medium that includes only one or more HFC 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 modifying materials.

[0045] 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 toxically harmless upon inhalation or topical use. In addition, it is desirable that the propellant selected is relatively non-reactive 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, e.g., HFA-134a and HFA-227ea) or perfluorinated compounds (PFCs). 1,1-difluoroethane (HFC-152a) is considered more environmentally friendly, but given the significant differences between HFC-152a and other propellants, some barriers exist to the use of HFC-152a in MDI formulations. Furthermore, extensive experimentation will be required to identify a formulation that will deliver the desired dose of active agent particles with the desired DDU and consistent FPF values.

[0046] As shown in Table A below, the physiochemical properties vary widely among the various propellants.

[0047] [Table 1]

[0048] Surprisingly, for compositions containing active agent particles and suspended particles as described herein, it has been found that MDI formulations containing HFC-152a propellant are suitable as inhalants, despite the fact that HFC-152a and other propellants, such as HFAs, have significantly different structures and properties.

[0049] In some embodiments, the propellant is pharmaceutical grade HFC-152a. The term "pharmaceutical grade propellant" as used herein refers to a propellant that complies with GMP regulations for human use. For example, pharmaceutical grade propellants meet the guidelines of major health authorities, such as FDA or EMA guidelines for pharmaceutical quality of inhaled and nasal products, and their specifications as an excipient are established to ensure the quality and safety of the propellant, e.g., HFC-152a, for use in pharmaceutical products. Specifications testing includes propellant identity, appearance, assay, acidity, evaporation residue, water content, related impurities, and non-related impurities. Stability testing is also underway to demonstrate long-term physicochemical stability. In some embodiments, pharmaceutical grade HFC-152a has a purity of at least about 99.90%. In some embodiments, the propellant is pharmaceutical grade HFC-152a having a purity of about 99.90%, about 99.91%, about 99.92%, about 99.93%, about 99.94%, about 99.95% or higher. Pharmaceutical grade HFC-152a is suitable for use as a propellant due to both its overall purity and the absence or low levels of certain impurities. In some embodiments, pharmaceutical grade HFC-152a contains about 10 ppm, about 9 ppm, about 8 ppm, about 7 ppm, about 6 ppm, about 5 ppm or less of any one 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 some embodiments, pharmaceutical grade HFC-152a contains about 150 ppm, about 140 ppm, about 130 ppm, about 120 ppm, about 110 ppm, about 100 ppm or less of HCFC-124.

[0050] In some embodiments, the suspension medium may be formed from a single propellant. In certain embodiments, certain vapor pressure compounds are present at relatively low levels. Such compounds may be associated with the suspended particles.

[0051] In some embodiments, the suspension medium may be formed from a propellant or propellant system that is substantially free of additional materials including, for example, antisolvents, solubilizers, stabilizers, cosolvents, or adjuvants.

[0052] In some embodiments, the pharmaceutical composition of the present invention, which comprises a pharmaceutical grade HFC-152a propellant; a plurality of active agent particles; and a plurality of phospholipid particles, exhibits similar or comparable bioavailability of the active agent compared to a reference pharmaceutical composition, which comprises a pharmaceutical grade HFA-134a propellant; a plurality of active agent particles; and a plurality of phospholipid particles. As used herein, "reference pharmaceutical composition" refers to an alternative pharmaceutical composition that contains the same active agent particles and the same suspension particles as the pharmaceutical composition of the present invention, except for the propellant. For example, the pharmaceutical composition of the present invention and the reference pharmaceutical composition contain the same active agent particles and the same phospholipid particles, but the reference pharmaceutical composition contains pharmaceutical grade HFA-134a propellant, while the pharmaceutical composition of the present invention contains pharmaceutical grade HFC-152a propellant. HFA-134a is a hydrofluoroalkane (HFA) with the chemical name: 1,1,1,2-tetrafluoroethane. HFA-134a has been used as a propellant in metered dose inhalers. As used herein, "bioavailability" refers to the proportion of an active agent that enters the blood circulation when introduced into the body through the lungs. In one embodiment, similar or comparable bioavailability can be demonstrated, where the ratio of the geometric means of log-transformed Cmax, AUCinf, or AUClast for two products (e.g., a pharmaceutical composition of the present invention and a reference pharmaceutical composition) is about 0.80 to about 1.25 with or without a 90% confidence interval (CI) range.

[0053] In some embodiments, the pharmaceutical compositions of the invention exhibit a Cmax, AUCinf, or AUClast of any one or more active agents that is 80%-125% of the Cmax, AUCinf, or AUClast of the one or more active agents of the reference pharmaceutical composition, as determined by a geometric mean ratio (GMR). In some embodiments, the pharmaceutical compositions of the invention comprise a pharmaceutical grade HFC-152a propellant; a plurality of active agent particles; and a plurality of phospholipid particles comprising a perforated microstructure, while the reference pharmaceutical composition comprises a pharmaceutical grade HFA-134a propellant; a plurality of active agent particles; and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, both the pharmaceutical compositions of the invention and the reference pharmaceutical composition are administered by actuating a metered dose inhaler, with each actuation of the pharmaceutical composition of the invention providing the same delivered amount of active agent as each actuation of the reference 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.

[0054] As used herein, Cmax, AUCinf and AUClast are pharmacokinetic indices used to determine the dosing of active agents. As used herein, Cmax means the maximum concentration of active agent in blood after a dose is administered, for example, via inhalation. As used herein, area under the curve (AUC) is the definite integral of the curve that describes the variation of active agent concentration in plasma as a function of time. As used herein, AUCinf means the area under the curve extrapolated to infinity from the time of dosing to the last measurable concentration. As used herein, AUClast means the area under the curve from the time of dosing to the last measurable concentration.

[0055] In some embodiments, the pharmaceutical compositions of the present invention exhibit a Cmax of budesonide that is 80%-125% of the Cmax of budesonide in the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit a Cmax of glycopyrrolate that is 80%-125% of the Cmax of glycopyrrolate in the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit a Cmax of formoterol that is 80%-125% of the Cmax of formoterol in the reference pharmaceutical composition. In some embodiments, the Cmax of budesonide is the geometric mean of the logarithmically transformed values. In some embodiments, the pharmaceutical compositions of the present invention exhibit a Cmax of budesonide and formoterol that is 80%-125% of the Cmax of budesonide and formoterol in the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit a Cmax of budesonide and albuterol that is 80%-125% of the Cmax of budesonide and albuterol in the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit a Cmax for glycopyrrolate and formoterol that is 80%-125% of the Cmax for glycopyrrolate and formoterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit a Cmax for budesonide, glycopyrrolate and formoterol that is 80%-125% of the Cmax for budesonide, glycopyrrolate and formoterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit a Cmax for budesonide, glycopyrrolate, formoterol and roflumilast that is 80%-125% of the Cmax for budesonide, glycopyrrolate, formoterol and roflumilast of the reference pharmaceutical composition.

[0056] In some embodiments, the pharmaceutical composition of the present invention exhibits an AUCinf for budesonide that is 80%-125% of the AUCinf for budesonide of the reference pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention exhibits an AUCinf for glycopyrrolate that is 80%-125% of the AUCinf for glycopyrrolate of the reference pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention exhibits an AUCinf for formoterol that is 80%-125% of the AUCinf for formoterol of the reference pharmaceutical composition. In some embodiments, the AUCinf for budesonide is the geometric mean of the logarithmically transformed values. In some embodiments, the pharmaceutical composition of the present invention exhibits an AUCinf for budesonide and formoterol that is 80%-125% of the AUCinf for budesonide and formoterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit AUCinf for budesonide and albuterol that is 80%-125% of the AUCinf for budesonide and albuterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit AUCinf for glycopyrrolate and formoterol that is 80%-125% of the AUCinf for glycopyrrolate and formoterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit AUCinf for budesonide, glycopyrrolate and formoterol that is 80%-125% of the AUCinf for budesonide, glycopyrrolate and formoterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit AUCinf for budesonide, glycopyrrolate, formoterol and roflumilast that is 80%-125% of the AUCinf for budesonide, glycopyrrolate, formoterol and roflumilast of the reference pharmaceutical composition.

[0057] In some embodiments, the pharmaceutical composition of the present invention exhibits an AUClast of budesonide that is 80%-125% of the AUClast of budesonide in the reference pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention exhibits an AUClast of glycopyrrolate that is 80%-125% of the AUClast of glycopyrrolate in the reference pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention exhibits an AUClast of formoterol that is 80%-125% of the AUClast of formoterol in the reference pharmaceutical composition. In some embodiments, the AUClast of budesonide is the geometric mean of the logarithmically transformed values. In some embodiments, the pharmaceutical composition of the present invention exhibits an AUClast of budesonide and formoterol that is 80%-125% of the AUClast of budesonide and formoterol in the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit AUClast for budesonide and albuterol that are 80%-125% of the AUClast for budesonide and albuterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit AUClast for glycopyrrolate and formoterol that are 80%-125% of the AUClast for glycopyrrolate and formoterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit AUClast for budesonide, glycopyrrolate and formoterol that are 80%-125% of the AUClast for budesonide, glycopyrrolate and formoterol of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention exhibit AUClast for budesonide, glycopyrrolate, formoterol and roflumilast that are 80% to 125% of the AUClast for budesonide, glycopyrrolate, formoterol and roflumilast of the reference pharmaceutical composition.

[0058] Surfactant particles The active agent particles contained in the compositions described herein are formed from a material capable of dispersing and suspending in a suspension medium and sized to facilitate delivery of respirable particles from the composition. In one embodiment, the active agent particles are thus provided as micronized particles, and at least 90% of the active agent particles by volume exhibit a light scattering diameter of about 7 μm or less. In some embodiments, at least 90% of the active agent particles by volume exhibit a light scattering diameter of about 5 μm or less. In other embodiments, at least 90% of the active agent particles by volume exhibit a light scattering 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 a light scattering diameter selected from 6 μm or less, 5 μm or less, 4 μm or less, or 3 μm or less. In another embodiment, the active agent particles are provided as micronized particles, and at least 50% of the active agent particles by volume exhibit a light scattering diameter of about 4 μm or less. In further embodiments, the active agent particles are provided as micronized particles, and at least 50% of the active agent particles by volume exhibit a light scattering diameter selected from about 3 μm or less, about 2 μm or less, or about 1.5 μm or less, and about 1 μm or less. In further embodiments, the active agent particles are provided as micronized particles, and at least 50% of the active agent particles by volume exhibit a light scattering 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.

[0059] In certain embodiments, the active agent particles comprise glycopyrrolate, and at least 90% of the active agent particles by volume exhibit a light scattering diameter of about 7 μm or less. In certain embodiments, the active agent particles comprise budesonide, and at least 90% of the active agent particles by volume exhibit a light scattering diameter of about 7 μm or less. In certain embodiments, the active agent particles comprise formoterol, and at least 90% of the active agent particles by volume exhibit a light scattering diameter of about 5 μm or less. In certain embodiments, the active agent particles comprise albuterol, and at least 90% of the active agent particles by volume exhibit a light scattering diameter of about 5 μm or less.

[0060] The active agent particles may be formed exclusively of the active agent or the active agent particles may be formulated to include one or more active agents in combination with one or more excipients or adjuvants. In certain embodiments, the active agent present in the active agent particles may be exclusively or substantially crystalline. In another embodiment, the active agent particles may include an active agent that exists in both a crystalline and an amorphous state. In yet another embodiment, the active agent particles may include an active agent that exists in both a crystalline and an amorphous state. In a further embodiment, two or more active agents are present in the active agent particles, and at least one such active agent may be present in a crystalline or substantially crystalline form and at least one other active agent may be present in an amorphous state. In yet another embodiment, where two or more active agents are present in the active agent particles, each such active agent may be present in a crystalline or substantially crystalline form. When the active agent particles described herein include one or more active agents in combination with one or more excipients or adjuvants, the excipients and adjuvants may be selected based on the chemical and physical properties of the active agents used. Excipients suitable for formulating active agent particles include, for example, lipids, phospholipids, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, synthetic or natural polymers, or surfactant materials.

[0061] Any suitable process may be used to achieve micronized active agent particles for inclusion in the compositions described herein.Various processes may be used to create active agent particles suitable for use in the formulations described herein, including, but not limited to, micronization by milling or grinding process, crystallization or recrystallization process, process using precipitation from supercritical or near-supercritical solvent, spray drying, spray freeze drying or freeze drying.Patent documents that teach suitable methods for obtaining micronized active agent particles include, for example, U.S. Patent No. 6,063,138, U.S. Patent No. 5,858,410, U.S. Patent No. 5,851,453, U.S. Patent No. 5,833,891, U.S. Patent No. 5,707,634 and WO 2007 / 009164. When the active agent particles comprise an active agent material that is formulated with one or more excipients or adjuvants, the micronized active agent particles can be formed using one or more of the processes described above, and such processes can be used to achieve active agent particles having a desired size distribution and particle configuration.

[0062] The active agent particles may be provided in any suitable concentration in the suspension medium. The active agent contained in the active agent particles is substantially insoluble in the suspension medium. In some embodiments, the active agent exhibits significant solubility in the suspension medium despite being substantially insoluble. However, even when the active agent exhibits significant solubility in the suspension medium, the compositions described herein serve to preserve the physical stability of such active agents. In particular, in certain embodiments, the active agent contained in the compositions described herein may exhibit sufficient solubility in the suspension medium such that as much as 5% of the total active agent mass is dissolved in the suspension medium. Alternatively, the solubility of the active agent may result in the dissolution of as little as 1% of the total active agent mass in the suspension medium. In another embodiment, the solubility of the active agent may result in the dissolution of as little as 0.5% of the total active agent mass in the suspension medium. In yet another embodiment, the solubility of the active agent may result in the dissolution of as little as 0.05% of the total active agent mass in the suspension medium. In yet another embodiment, the solubility of the active agent may result in the dissolution of as little as 0.025% of the total active agent mass in the suspension medium.

[0063] A variety of therapeutic or prophylactic agents can be incorporated into the co-suspension compositions disclosed herein. Exemplary active agents include those that may be administered in the form of an aerosolized agent, and active agents suitable for use in the compositions described herein include those that may be presented or formulated in a form that is dispersible in the selected suspension medium (e.g., substantially insoluble or soluble in the suspension medium that substantially maintains the co-suspension formulation), can form a co-suspension with the suspended particles, and are susceptible to respirable uptake in physiologically effective amounts. Active agents that may be utilized in forming the active agent particles described herein can have a variety of biological activities.

[0064] Examples of specific active agents that may be included in compositions according to the present description 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 epinephrine. long-acting beta2 adrenergic receptor agonists ("LABA"), such as bambuterol, clenbuterol, formoterol, and salmeterol; ultra-long-acting beta2 adrenergic receptor agonists, such as carmoterol, milveterol, indacaterol, and saligenin or indole-containing adamantyl-derived beta2 agonists; corticosteroids, such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone , methylprednisolone, mometasone, prednisone and triamcinolone; anti-inflammatory drugs such as fluticasone propionate, beclomethasone dipropionate, flunisolide, budesonide, tripedane, cortisone, prednisone, prednisolone, dexamethasone, betamethasone or triamcinolone acetonide; antitussives such as noscapine; bronchodilators such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterene. ol, salbutamol, albuterol, salmeterol, terbutaline; as well as muscarinic antagonists, including long-acting muscarinic antagonists ("LAMA"), such as glycopyrrolate, dexpirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipratropium, atropine, benztropine, or oxitropium.

[0065] If necessary, the active agent provided in the composition, including but not limited to those described in detail herein, may be used in the form of a salt (e.g., as an alkali metal salt or amine salt or an acid addition salt) or as its ester, solvate (hydrate), derivative or free base. In addition, the active agent may be in any crystalline form or isomeric form or mixture of isomeric forms, for example as a pure enantiomer, a mixture of enantiomers, as a racemate or as 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.

[0066] Since the disclosed compositions allow for reproducible delivery of very low doses of active agents, in certain embodiments, the active agents included in the compositions described herein may be selected from one or more potent or highly potent active agents. For example, in certain embodiments, the compositions described herein may include one or more potent active agents to be delivered at a dose selected from between about 100 μg to about 100 mg, 100 μg to about 10 mg, and about 100 μg to about 1 mg per actuation of the MDI. In other embodiments, the compositions described herein may include one or more potent or highly potent active agents to be delivered at a dose selected from about 80 μg or less, about 40 μg or less, about 20 μg or less, between about 10 μg to about 100 μg, between about 5 μg to about 50 μg, and between 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 between 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.

[0067] The compositions described herein may contain a combination of two or more active agents, if desired. For example, a combination of two or more species of active agent particles may be co-suspended with a single species of suspended particles. Alternatively, the composition may contain two or more species of active agent particles co-suspended with two or more different species of suspended particles. Furthermore, the compositions described herein may contain two or more active agents combined within a single species of active agent particles. For example, when active agent particles are formulated using one or more excipients or adjuvants in addition to the active agent material, such active agent particles may contain individual particles that contain two or more different active agents.

[0068] In certain embodiments, the active agent included in the compositions described herein is a LAMA active agent. When the composition includes a LAMA active agent, in certain embodiments, the LAMA active agent may be selected from, for example, glycopyrrolate, dexpyrronium, tiotropium, trospium, aclidinium, umeclidinium, and darotropium, including any pharma- ceutically acceptable salts, esters, isomers, or solvates thereof. In some embodiments, the LAMA active agent is present in a concentration ranging from about 0.04 mg / mL to about 2.25 mg / mL.

[0069] Glycopyrrolate can be used to treat inflammatory or obstructive pulmonary diseases and disorders, such as those described herein. Like an anticholinergic agent, glycopyrrolate acts as a bronchodilator and provides an antisecretory effect that is beneficial for use in the therapy of pulmonary diseases and disorders characterized by increased mucus secretion. Glycopyrrolate is a quaternary ammonium salt. If desired, glycopyrrolate may be used in the form of a salt (e.g., as an alkali metal salt or an amine salt or an acid addition salt) or as an ester or as a solvate (hydrate). In addition, glycopyrrolate may be in any crystalline form or in an 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 glycopyrrolate in the suspension medium. 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, diphenylacetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylic acid, 3-hydroxynaphthalene-2-carboxylic acid, methanesulfonate and benzenesulfonate. In certain embodiments of the compositions described herein, the bromide salt of glycopyrrolate, i.e., 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide, also referred to as (RS)-[3-(SR)-hydroxy-1,1-dimethylpyrrolidinium bromide] α-cyclopentylmandelic acid, is used and can be prepared according to the procedure described in U.S. Pat. No. 2,956,062.

[0070] When the compositions described herein include glycopyrrolate, in certain embodiments, the compositions may include sufficient glycopyrrolate to provide a target delivery amount selected from about 1 μg to about 200 μg per actuation of the MDI, about 5 μg to about 150 μg per actuation of the MDI, about 10 μg to 100 μg per actuation of the MDI, between about 5 μg to about 50 μg per actuation of the MDI, between about 2 μg to about 25 μg per actuation of the MDI, and between about 6 μg to about 15 μg per actuation of the MDI. In other such embodiments, the formulation includes sufficient glycopyrrolate to provide a dose selected from about 200 μg or less, about 150 μg or less, about 75 μg or less, about 40 μg or less, about 20 μg or less, or about 10 μg or less per actuation. In 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. In order to achieve the targeted delivery amounts described herein, when the compositions described herein comprise glycopyrrolate as an active agent, in certain embodiments, the amount of glycopyrrolate included in the composition may be selected, for example, from between about 0.04 mg / mL and about 2.25 mg / mL.

[0071] In other embodiments, tiotropium, including any pharmaceutically acceptable salt, ester, isomer or solvate thereof, may be selected as the LAMA active agent for inclusion 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, such as those described herein.Tiotropium, including crystalline and pharmaceutically acceptable salt forms of tiotropium, are described, for example, in U.S. Patent No. 5,610,163, U.S. Patent No. RE39,820, U.S. Patent No. 6,777,423 and U.S. Patent No. 6,908,928. When the compositions described herein include tiotropium, in certain embodiments, the compositions may include sufficient tiotropium to provide a delivery amount selected from between about 2.5 μg to about 50 μg, about 4 μg to about 25 μg, and between 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 the MDI. In other such embodiments, the formulation includes sufficient tiotropium to provide a delivery amount selected from about 50 μg or less, about 20 μg or less, about 10 μg or less, about 5 μg or less, or about 2.5 μg or less per actuation of the MDI. In further embodiments, the formulation includes sufficient tiotropium to provide a delivery amount selected from about 3 μg, 6 μg, 9 μg, 18 μg, and 36 μg per actuation of the MDI. To achieve the delivery amounts described herein, when the compositions described herein include tiotropium as an active agent, in certain embodiments, the amount of tiotropium included in the composition may be selected, for example, from between about 0.01 mg / mL and about 0.5 mg / mL.

[0072] In certain 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 adamantyl-derived β2 agonists, and any pharma-ceutically acceptable salt, ester, isomer, or solvate 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.

[0073] In certain such embodiments, formoterol is selected as the LABA active agent. Formoterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders, such as those 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 fumarate dihydrate. If necessary, formoterol can be used in the form of a salt (e.g., as an alkali metal salt or amine salt or an acid addition salt) or as an ester or as a solvate (hydrate). In addition, 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 may be selected to optimize the activity and / or stability of formoterol and / or minimize the solubility of formoterol in the suspension medium. 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, methanesulfuric acid, p-toluenesulfonic acid and 3-hydroxy-2-naphthalenecarboxylic acid. Hydrates of formoterol are described, for example, in U.S. Pat. No. 3,994,974 and U.S. Pat. No. 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.

[0074] In certain embodiments, the formoterol material utilized to form the formoterol particles is formoterol fumarate, and in one such embodiment, the formoterol fumarate is present in a dihydrate form. Formoterol fumarate may also be referred to by the chemical name N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (E)-2-butenedioate anhydrate. When the compositions described herein include formoterol, in certain embodiments, the compositions described herein may include formoterol in a concentration to achieve a target delivery amount selected from between 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 to 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 delivery amount selected from about 30 μg or less, about 10 μg or less, about 5 μg or less, about 2.5 μg or less, about 2 μg or less, or about 1.5 μg or less per actuation. In 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. To achieve the targeted delivery amounts described herein, when the compositions described herein comprise formoterol as an active agent, in certain embodiments, the amount of formoterol included in the composition may be selected from, for example, between about 0.01 mg / mL and about 1 mg / mL, between about 0.01 mg / mL and about 0.5 mg / mL, and between about 0.03 mg / mL and about 0.4 mg / mL.

[0075] When the pharmaceutical composition described herein comprises a LABA active agent, in certain embodiments, the active agent may 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, such as those described herein.Salmeterol, pharmaceutically acceptable salts of salmeterol and the method of producing it are described, for example, in US Patent No. 4,992,474, US Patent No. 5,126,375 and US Patent No. 5,225,445.

[0076] 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 delivery amount selected from between 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 the MDI. In other embodiments, the compositions described herein may include salmeterol in an amount sufficient to provide a delivery amount selected from about 120 μg or less, about 40 μg or less, about 20 μg or less, about 10 μg or less, about 8 μg or less, or about 6 μg or less per actuation of the MDI. To achieve the target delivery levels described herein, when the compositions described herein include salmeterol as an active agent, in certain embodiments, the amount of salmeterol included in the composition may be selected from, for example, between about 0.04 mg / mL and about 4 mg / mL, between about 0.04 mg / mL and about 2.0 mg / mL, and between about 0.12 mg / mL and about 0.8 mg / mL.

[0077] When the pharmaceutical compositions described herein comprise a SABA active agent, in certain embodiments, the active agent may 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 certain 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, such as those described herein. Albuterol, pharma- ceutically acceptable salts of albuterol (such as albuterol sulfate) and methods for producing same are described, for example, in U.S. Patent No. 3,705,233.

[0078] 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 delivery amount selected from between 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 the MDI. In other embodiments, the compositions described herein may include albuterol in an amount sufficient to provide a delivery amount selected from about 300 μg or less, about 200 μg or less, about 150 μg or less, about 100 μg or less, about 50 μg or less, about 30 μg or less, about 20 μg or less, or about 10 μg or less per actuation of the MDI. In 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. To achieve the targeted delivery amounts described herein, when the compositions described herein comprise albuterol as an active agent, in certain embodiments, the amount of albuterol included in the composition may be selected from, for example, between about 0.1 mg / mL and about 10 mg / mL, between about 0.1 mg / mL and about 5 mg / mL, and between about 0.3 mg / mL and about 4 mg / mL.

[0079] In yet other embodiments, the compositions described herein include a corticosteroid, such as an inhaled corticosteroid (ICS). Such active agents may 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.

[0080] When the composition comprises an ICS active agent, in certain embodiments, mometasone may be selected. Mometasone, its pharma- ceutically acceptable salts, such as mometasone furoate, and the preparation of such materials are known and described, for example, in U.S. Pat. Nos. 4,472,393, 5,886,200, and 6,177,560. Mometasone is suitable for use in treating diseases or disorders associated with pulmonary inflammation or obstruction, such as those described herein (see, for example, U.S. Pat. Nos. 5,889,015, 6,057,307, 6,057,581, 6,677,322, 6,677,323, and 6,365,581).

[0081] When the compositions described herein comprise mometasone, in certain 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 amount selected from between 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 amount selected from between about 400 μg or less, about 200 μg or less, or about 100 μg or less per actuation of an MDI.

[0082] In other embodiments, the compositions described herein comprise a corticosteroid selected from fluticasone and budesonide. Both fluticasone and budesonide are suitable for use in the treatment of conditions associated with pulmonary inflammation or obstruction, such as those described herein. Fluticasone, fluticasone pharma- ceutically acceptable salts, such as fluticasone propionate, and the preparation of such materials are known and are described, for example, in U.S. Patent No. 4,335,121 and U.S. Patent No. 4,187,301 and U.S. Patent Publication No. 2008125407. Budesonide, which has the chemical name (RS)-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal, butyraldehyde, is also well known and is described, for example, in U.S. Patent No. 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 delivery amount selected from between about 20 μg and about 200 μg, between 50 μg and about 175 μg, and between about 80 μg and 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 delivery amount selected from about 175 μg or less, about 160 μg or less, about 100 μg or less, or about 80 μg or less 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 delivery amount selected from about 30 μg to about 240 μg, between about 30 μg to about 120 μg, between about 30 μg to about 100 μg, between about 50 μg to about 400 μg, between about 20 μg to about 600 μg, between about 50 μg to about 200 μg, between about 150 μg to about 350 μg, and between about 30 μg to about 50 μg per actuation of the MDI.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 amount selected from about 240 μg or less, about 160 μg or less, about 120 μg or less, about 80 μg or less, or about 50 μg or less per actuation of the MDI. In 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. To achieve the target delivery amounts described herein, when the compositions described herein include budesonide as an active agent, in certain embodiments, the amount of budesonide included in the composition may be selected from, for example, between about 0.1 mg / mL and about 20 mg / mL, between about 0.1 mg / mL and about 5 mg / mL, and between about 0.3 mg / mL and about 6 mg / mL.

[0083] In a further embodiment, the compositions described herein comprise 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 may 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 materials are known and are described, for example, in U.S. Patent No. 8,604,064 and U.S. Patent No. 9,145,365 and U.S. Patent No. 9,321,726. Roflumilast is suitable for use in treating diseases or disorders associated with pulmonary inflammation or obstruction, such as those described herein. Roflumilast is sometimes used to treat COPD, especially severe COPD, and is available as an oral medication. Gastrointestinal side effects are common with oral administration of roflumilast.

[0084] 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 amount selected from about 30 μg to about 240 μg, between about 30 μg to about 120 μg, between about 30 μg to about 100 μg, between about 50 μg to about 400 μg, between about 20 μg to about 600 μg, between about 50 μg to about 200 μg, between about 150 μg to about 350 μg, and between about 30 μg to about 50 μg per actuation of the MDI. 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 targeted delivery amount selected from about 240 μg or less, about 160 μg or less, about 120 μg or less, about 80 μg or less, or about 50 μg or less per actuation of the MDI. In 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. To achieve the target delivery amounts described herein, when the compositions described herein include roflumilast as an active agent, in certain embodiments, the amount of roflumilast included in the composition may be selected from, for example, between about 0.1 mg / mL and about 20 mg / mL, between about 0.1 mg / mL and about 5 mg / mL, and between about 0.3 mg / mL and about 6 mg / mL.

[0085] The compositions described herein can be formulated to contain (and deliver) a single active agent. Alternatively, the compositions described herein may contain two or more active agents. In certain embodiments, when two or more active agents are included, the compositions described herein may contain 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 contain three or more active agents. In certain such embodiments, the compositions contain 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.

[0086] It will be understood by those skilled in the art, with the aid of this disclosure, that a wide variety of active agents may be incorporated into the suspensions disclosed herein. The above list of active agents is by way of example and not limitation.

[0087] Suspended particles The suspended particles contained in the compositions described herein serve to facilitate the stabilization and delivery of the active agent contained therein. Although various forms of suspended particles may be used, suspended particles are typically formed from pharmacologically inert materials that are acceptable for inhalation and substantially insoluble in the selected propellant. In general, the majority of suspended particles are sized within the respirable range. In certain embodiments, the MMAD of the suspended particles is therefore not greater than about 10 μm, but is greater than or equal to about 500 nm. In alternative embodiments, the MMAD of the suspended particles is between about 5 μm and about 750 nm. In yet other embodiments, the MMAD of the suspended particles is between about 1 μm and about 3 μm. When used in embodiments for nasal delivery from an MDI, the MMAD of the suspended particles is between 10 μm and 50 μm.

[0088] To achieve respirable suspended particles within the recited MMAD ranges, the suspended particles typically exhibit a volume median light scattering diameter of between about 0.2 μm and about 50 μm. In one embodiment, the suspended particles exhibit a volume median light scattering diameter not exceeding about 25 μm. In another embodiment, the suspended particles exhibit a volume median light scattering diameter selected from between about 0.5 μm and about 15 μm, between about 1.5 μm and about 10 μm, and between about 2 μm and about 5 μm.

[0089] The concentration of the suspended particles contained in the composition according to the present invention can be adjusted, for example, by the amount of active agent particles and suspension medium used. In one embodiment, 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 another embodiment, the suspended particles are contained in the suspension medium at a concentration of about 30 mg / mL or less. In yet another embodiment, the suspended particles are contained in the suspension medium at a concentration of about 25 mg / mL or less.

[0090] The relative amount of suspended particles to active agent particles is selected to achieve the co-suspension contemplated herein. Co-suspension compositions may be achieved in which the amount of suspended particles, measured by mass, exceeds the amount of active agent particles. For example, in certain embodiments, the ratio of the total mass of suspended particles to the total mass of active agent particles may be between about 3:1 and about 15:1, or alternatively about 2:1 and 8:1. Alternatively, the ratio of the total mass of suspended particles to the total mass of active agent particles may be greater than about 1, such as about 1.5 or less, about 5 or less, about 10 or less, about 15 or less, about 17 or less, about 20 or less, about 30 or less, about 40 or less, about 50 or less, about 60 or less, about 75 or less, about 100 or less, about 150 or less, and about 200 or less, 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 may be selected from between about 10 and about 200, between about 60 and about 200, between about 15 and about 60, between about 15 and about 170, between about 15 and about 60, about 16, about 60, and about 170.

[0091] In other embodiments, the amount of suspended particles measured by mass is less than the active agent particles.For example, in certain embodiments, the mass of suspended particles may be as low as 20% of the total mass of active agent particles.However, in some embodiments, the total mass of suspended particles may also be close to or equal to the total mass of active agent particles.

[0092] The suspension particles suitable for use in the compositions described herein may be formed from one or more pharma- ceutically acceptable materials or excipients suitable for inhalation delivery and do not substantially decompose or dissolve in the suspension medium.In one embodiment, the perforated microstructures defined herein may be used as suspension particles.Suspension particles and perforated microstructures for use as suspension particles and the method of preparation thereof are described in U.S. Patent No. 8,815,258 and U.S. Patent No. 9,463,161 and in U.S. Patent Application Publication No. 2011 / 0135737.

[0093] Phospholipids from both natural and synthetic sources may be used to prepare suspension particles containing perforated microstructures suitable for use in the compositions described herein. In certain embodiments, the phospholipids selected have a gel-liquid crystal phase transition above about 400° C. Exemplary phospholipids are relatively long chain (i.e., C16-C22) saturated lipids and may include saturated phospholipids such as saturated phosphatidylcholines (palmitoyl and stearoyl) having acyl chain lengths of 16C or 18C. Exemplary 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. Additional excipients are disclosed in WO 96 / 32149 and U.S. Patent Nos. 6,358,530, 6,372,258 and 6,518,239. In certain embodiments, the suspended particles are phospholipid particles comprising 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

[0094] In another aspect, the suspended particles utilized in the compositions described herein may be selected to increase the storage stability of the selected active agent, similar to those disclosed in International Patent Application Publication No. WO 2005 / 000267. For example, in one embodiment, the suspended particles may include a pharma- ceutically acceptable glass-stable excipient 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 thleucine, sodium citrate, sodium phosphate, ascorbic acid, inulin, cyclodextrin, polyvinylpyrrolidone, mannitol, sucrose, trehalose, lactose, and proline. Examples of additional glass-forming excipients are disclosed in U.S. Patents RE37,872, RE5,928,469, RE6,258,341, and RE6,309,671. In certain embodiments, the suspended particles may include a calcium salt, such as calcium chloride, as described, for example, in US Pat. No. 7,442,388.

[0095] In certain embodiments, the suspension particles are porous microstructures comprising DSPC and calcium chloride.

[0096] The suspended particles may be designed, sized and shaped as desired to provide the desired stability and active agent delivery characteristics. In an exemplary embodiment, the suspended particles include the perforated microstructures described herein. When perforated microstructures are used as suspended particles in the compositions described herein, they may include at least one of the following: lipids, phospholipids, non-ionic detergents, non-ionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof, particularly those approved for pulmonary use. Particular surfactants that may be used in the preparation of perforated microstructures include poloxamer 188, poloxamer 407 and poloxamer 338. Other particular surfactants include oleic acid or its alkali salts. In one embodiment, the perforated microstructures include more than about 10% w / w surfactant.

[0097] Additionally, the suspended particles described herein may include bulking agents such as polymeric particles. The polymeric polymer may be formed from biocompatible and / or biodegradable polymers, copolymers or blends. In one embodiment, polymers capable of forming aerodynamically light particles such as functional polyester graft copolymers and biodegradable polyanhydrides may be used. For example, polyester-based bulk eroding polymers including poly(hydroxy acids) may be used. Polyglycolic acid (PGA), polylactic acid (PLA) or copolymers thereof may be used to form the suspended particles. The polyester may include charged or functionalizable groups such as amino acids. For example, the suspended particles may be formed from poly(D,iota-lactic acid) and / or poly(D,iota-lactic acid-glycolic acid copolymer) (PLGA), which may incorporate a surfactant such as DPPC.

[0098] Other possible polymer candidates for use in the suspended particles may include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(polyethylene 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 with or modified to have appropriate stability and degradation rates in vivo for a variety of controlled drug delivery applications.

[0099] 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 may be selected from between about 1 and about 20, between about 1 and about 15, between about 1.5 and about 10, between about 2.5 and about 15, between about 2.5 and about 10, between about 2.5 and about 8, between about 10 and about 30, between about 15 and about 25, between about 10 and about 200, between about 50 and about 125, and between about 5 and about 50.

[0100] In some embodiments, the suspended particles may be prepared by forming an oil-in-water emulsion using a fluorocarbon oil (e.g., perfluorooctyl bromide, perfluorodecalin), which may be emulsified using a surfactant such as a long-chain saturated phospholipid. The resulting perfluorocarbon in water emulsion may then be processed using a high-pressure homogenizer to reduce the oil droplet size. The perfluorocarbon emulsion may be sent to a spray dryer. As is well known, spray drying is a one-step process that converts a sent liquid into a dry granular form. Spray drying has been used to provide powdered pharmaceutical materials for various administrative routes, including inhalation. With respect to spray drying, fluorocarbon oils, as described above, may function as foaming agents. The operating conditions of the spray dryer (such as inlet and outlet temperatures, feed rate, atomization pressure, drying air flow rate, and nozzle configuration) can be adjusted to produce the desired particle size and a certain yield of the resulting dried microstructure. Exemplary such methods for producing perforated microstructures are disclosed in U.S. Pat. No. 8,815,258, U.S. Pat. No. 9,463,161 and U.S. Patent Application Publication No. 2011 / 0135737.

[0101] The compositions described herein may contain two or more kinds of suspended particles.For example, the compositions described herein may contain a single 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.

[0102] Compositions formulated according to the teachings of the present invention can inhibit the degradation of active agents contained therein. For example, in certain embodiments, the compositions described herein inhibit one or more of aggregation, clumping, and solution-mediated phase transition of active agent materials contained therein. The pharmaceutical compositions described herein are advantageous for respiratory delivery via MDIs, such that combinations including potent and highly potent active agents achieve a desirable delivery dose uniformity ("DDU") of each active agent contained in a combination of two or more active agents. As shown in detail in the examples included 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 until the MDI canister is empty. In one such embodiment, the compositions described herein achieve a DDU of ±25% or better for each active agent until the MDI canister is empty. In another such embodiment, the compositions described herein achieve a DDU of ±20% or better for each active agent until the MDI canister is empty. In further embodiments, the compositions described herein achieve a DDU of ±15% or better for each active agent until the MDI canister is empty. In further embodiments, the compositions described herein achieve a DDU of ±10% or better for each active agent until the MDI canister is empty.

[0103] The pharmaceutical compositions described herein also serve to substantially retain FPF and FPD performance until the MDI canister is empty, even after exposure to accelerated degradation conditions. For example, compositions according to the present description maintain 80%, 85%, 90%, 95% or even more of the original FPF and FPD performance until the MDI canister is empty, even after exposure to accelerated degradation conditions. The compositions described herein provide the additional benefit of achieving such performance while eliminating or substantially avoiding the combination effects often experienced with compositions formulated using non-CFC and non-HFA propellants and incorporating multiple active agents. In certain embodiments, the compositions described herein are formulated with a suspension medium that includes only one or more HFC propellants, yet achieve one or all of the targeted DDU, FPF and FPD without the need to modify the propellant characteristics, such as by the addition of one or more co-solvents, anti-solvents, solubilizers, adjuvants or other propellant modifying materials.

[0104] method The compositions formulated according to the teachings of the present invention can inhibit the degradation of the active agent contained therein. For example, in certain embodiments, the compositions described herein inhibit one or more of aggregation, clumping, and Ostwald ripening of the active agent contained therein. The stability provided by the compositions described herein allows the compositions to be dispensed to achieve a desired delivery dose uniformity ("DDU") until the MDI canister is empty, even when the active agent delivered is highly potent and the delivery amount of the active agent is selected from, for example, less than one 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 low doses of highly potent active agents, the compositions described herein can achieve ±30% or better DDU for each active agent contained in the composition. In alternative embodiments, the compositions described herein achieve a DDU of ±25% or better for each active agent contained in the composition. In further embodiments, the compositions described herein achieve a DDU of ±20% or better, ±15% or better, or ±10% or better for each active agent contained in the composition.

[0105] Furthermore, compositions according to the present description serve to substantially retain FPF and FPD performance until the MDI canister is empty, even after exposure to accelerated degradation conditions. For example, compositions according to the present description maintain 80%, 85%, 90%, 95% or even more of the original FPF and FPD performance, even when they incorporate multiple active agents. The compositions described herein provide the additional benefit of achieving such performance while being formulated using non-CFC and non-HFA propellants. In certain embodiments, the compositions described herein are formulated with a suspension medium that includes only one or more HFC propellants, yet achieve the desired one or all of the targeted DDU, FPF and FPD without the need to modify the characteristics of the HFC propellant, such as by the addition of one or more co-solvents, anti-solvents, solubilizers, adjuvants or other propellant modifying materials.

[0106] The stability and physical characteristics of the compositions described herein aid in some methods. For example, in one embodiment, a method is provided herein for formulating a pharmaceutical composition for respiratory delivery of an active agent. The method includes providing a suspension medium comprising an HFC propellant as described herein, one or more species of active agent particles and one or more species of suspended particles, and combining such components to form a composition, where the active agent particles are associated with the suspended particles such that a co-suspension as described herein is formed. In one such embodiment, the association of the active agent particles and the suspended particles is such that they do not separate due to their different buoyancies in the propellant. As will be appreciated, the method for formulating a pharmaceutical composition as described herein can include providing two or more species of active agent particles in combination with one or more species of suspended particles. Alternatively, the method may include providing two or more suspended particles in combination with one or more species of active agent particles.

[0107] In further embodiments, the compositions described herein support, for example, methods for forming stabilized formulations of active agents for pulmonary delivery, methods for maintaining the FPF and / or FPD until the MDI canister is emptied, methods for pulmonary delivery of potent or highly potent active agents, and methods for 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.

[0108] In a method involving pulmonary delivery of an active agent using the compositions described herein, the composition may be delivered by an MDI. Thus, in certain embodiments of such a method, an MDI loaded with the compositions described herein is obtained, and the desired active agent is administered to a patient through pulmonary delivery through actuation of the MDI. For example, in one embodiment, after shaking the MDI device, the mouthpiece is inserted into the patient's mouth between the lips and teeth. The patient typically exhales deeply to empty the lungs, and then inhales slowly and deeply while actuating the cartridge of the MDI. Upon actuation, a certain volume of the formulation moves into the expansion chamber and exits the actuator nozzle, becoming a high velocity aerosol that is inhaled into the patient's lungs. In some embodiments, the dose of active agent delivered until the MDI canister is empty is not more than 20% more than the average delivery amount, and not more than 20% less than the average delivery amount. In some embodiments, the dose of active agent delivered until the MDI canister is empty is not more than 15% more than or less than the average delivery amount. In some embodiments, the dose of active agent delivered until the MDI canister is empty is not more than 10% more or less than the average delivered amount.

[0109] In a particular embodiment of the method for providing a stabilized formulation of an active agent for pulmonary delivery, the present disclosure provides a method for suppressing solution-mediated phase transition of an active agent in a pharmaceutical formulation for pulmonary delivery. In one embodiment, a suspension medium as described herein, such as a suspension medium formed by an HFC propellant, is obtained. Suspension particles are also obtained or prepared as described herein. One or more species 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, and the active agent particles are associated with the suspension particles in a continuous phase formed by the suspension medium. Compared to the active agent contained in the same suspension medium in the absence of the suspension particles, the co-suspension according to the description of the present invention is found to exhibit higher resistance to solution-mediated phase transition and irreversible crystal aggregation, thus leading to improved stability and uniformity of dosage, and enabling the formulation of an active agent that is somewhat physically unstable in the suspension medium alone.

[0110] In certain embodiments, methods are provided for preserving the FPF and / or FPD provided by pharmaceutical formulations for pulmonary delivery of respirable co-suspensions described herein that can maintain the FPD and / or FPF within ±20%, ±15%, ±10% or even ±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 exposed to accelerated degradation conditions. In one embodiment, a suspension medium as described herein is obtained, such as a suspension medium formed by an HFC propellant. Suspension particles are also obtained or prepared as described herein. One or more species of active agent particles as described herein are also obtained, where the suspension medium, the suspended particles and the active agent particles are combined to form a co-suspension, where the active agent particles are associated with the suspended particles in the suspension medium. Even after exposure of such compositions to one or more temperature cycling events, the co-suspension maintains the FPD or FPF within ±20%, ±15%, ±10% or even ±5% of the respective values ​​measured before exposure of the composition to one or more temperature cycling events.

[0111] Methods for treating patients suffering from inflammatory or obstructive pulmonary diseases or conditions are provided herein. In certain embodiments, such methods include pulmonary delivery of a therapeutically effective amount of a pharmaceutical composition described herein, and in certain such embodiments, pulmonary administration of the pharmaceutical composition is achieved by delivering the composition using an MDI. In certain embodiments, the compositions, methods and systems described herein can be used to treat patients suffering from a disease or disorder selected from asthma, chronic obstructive pulmonary disease (COPD), exacerbations of airway hyperresponsiveness resulting from other drug therapies, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, and any other respiratory disease, condition, trait, genotype or phenotype that may respond to administration of, for example, LAMA, LABA, SABA, ICS, non-corticosteroid anti-inflammatory agents or other active agents described herein, whether alone or in combination with other therapies. In certain embodiments, the compositions, systems and methods described herein can be used to treat pulmonary inflammation and obstruction associated with cystic fibrosis. In certain embodiments of methods for treating a patient suffering from an inflammatory or obstructive pulmonary disease or condition, the pulmonary disease condition is selected from those detailed herein, and the method comprises pulmonary delivery of a composition according to the present description to the patient via an MDI, where the pulmonary delivery of such composition comprises administering one or more active agents at a dose or dose range described in connection with the compositions disclosed herein.

[0112] Metered Dose Inhaler System As described with respect to 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 the drug in aerosol form. In one embodiment, the MDI system includes a pressurized liquid phase formulation filled canister disposed in an actuator formed with a mouthpiece. The MDI system may include the formulation described herein, including a suspension medium including an HFC propellant (e.g., HFC-152a), 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 one exemplary embodiment, the canister may have a volume ranging from about 5 ml to about 25 ml, such as a canister having a volume of 19 ml. After shaking the device, the mouthpiece is inserted into the patient's mouth between the lips and teeth. The patient typically exhales deeply to empty the lungs, and then inhales slowly and deeply while firing the cartridge.

[0113] Within an exemplary cartridge is a metering valve that includes a metering chamber capable of holding a defined volume of formulation (e.g., 63 μl or any other suitable volume available in commercially available metering valves), which upon actuation is released into an expansion chamber at the distal end of the valve stem. The actuator holds the canister and may further include a port with an actuator nozzle for receiving the valve stem of the metering valve. Upon actuation, a specific volume of the formulation travels into the expansion chamber and exits the actuator nozzle, becoming a high velocity aerosol that is inhaled into the patient's lungs.

[0114] The following abbreviations are used throughout this disclosure, including the figures and examples: ·AB: Albuterol · AS: Albuterol sulfate BD: Budesonide ·FF: Formoterol fumarate ·GP: Glycopyrrolate RF: Roflumilast BGF: Budesonide / Glycopyrrolate / Formoterol (combination) GFF: Glycopyrrolate / formoterol fumarate (combination) BDA-152a: Budesonide / albuterol (combination) in HFC-152a BFF-152a: Budesonide / formoterol fumarate (combination) in HFC-152a BGF-152a: Budesonide / glycopyrrolate / formoterol (combination) in HFC-152a GFF-152a: Glycopyrrolate / formoterol fumarate (combination) in HFC-152a BGFR: Budesonide / Glycopyrrolate / Formoterol fumarate / Roflumilast (combination) 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

[0115] The specific examples contained herein are for illustrative purposes only and should not be construed as limiting the present disclosure.In addition, the compositions, systems and methods disclosed herein have been described with respect to their specific embodiments, and many details have been described for illustrative purposes, and it will be apparent to those skilled in the art that the present disclosure can accommodate additional embodiments and that some of the details described herein may be modified without departing from the basic principles of the present disclosure.Any active agents and reagents used in the following examples are commercially available or can be prepared according to standard literature procedures by those skilled in the art with the aid of the teachings provided herein.The entire contents of all publications, patents and patent applications referenced herein are hereby incorporated herein by reference. EXAMPLES

[0116] Example 1 Suspended particles were prepared by spray drying an emulsion of PFOB (perfluorooctyl bromide) and water stabilized by DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine). The detailed preparation procedure has been documented previously. 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.

[0117] Active agent particles formed from glycopyrrolate (pyrrolidinium, 3-((cyclopentylhydroxyphenylacetyl)oxy)-1,1-dimethyl-bromide) were formed by micronizing glycopyrrolate using a jet mill. The particle size distribution of the micronized glycopyrrolate (GP) was determined by laser diffraction. 50% by volume of the micronized particles exhibited a light scattering diameter smaller than 2.1 μm and 90% by volume were smaller than 5 μm.

[0118] 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 purchased 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. Fifty percent by volume of the micronized particles exhibited a light scattering diameter smaller than 1.6 μm, and 90% by volume exhibited a light scattering diameter smaller than 3.9 μm.

[0119] 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 micronizing budesonide using a jet mill. The particle size distribution of budesonide (BD) was determined by laser diffraction. 50% by volume of the micronized particles exhibited a light scattering diameter smaller than 1.9 μm and 90% by volume exhibited a light scattering diameter smaller than 4.3 μm.

[0120] Active agent particles formed from albuterol sulfate, α1[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate, were formed by micronizing albuterol sulfate using a jet mill. The particle size distribution of albuterol sulfate (AS) was determined by laser diffraction. 50% by volume of the micronized particles exhibited a light scattering diameter smaller than 1.5 μm, and 90% by volume exhibited a light scattering diameter smaller than 3.3 μm.

[0121] Metered dose inhalers were prepared by first dispensing the appropriate amount of suspended particles and active agent particles through an additive vessel (AV) and adding the appropriate amount of HFC-152a (1,1-difluoroethane) propellant. The mixture is stirred to facilitate powder wetting and then transferred to a pressure vessel where the suspension is mixed. A valve (BK357, Bespak, King's Lynn, UK) consisting of a 50 uL metering chamber is crimped onto a fluorinated ethylene polymer (FEP) coated aluminium canister (Presspart, Blackburn, UK) and the suspension is then pressure filled through the valve. The canister was fitted with a polypropylene actuator (#10024269, Bespak, King's Lynn, UK) with a 0.32 mm or 0.39 mm orifice.

[0122] Example 2 A metered dose inhaler was prepared containing a triple co-suspension composition containing glycopyrrolate, budesonide and formoterol active agent particles, with each type of active agent particles being provided as micronized crystalline API material. The active agent particles were suspended in HFC-152a propellant with phospholipid particles. As shown in Figure 1 and Table 1, the three types of active agent particles containing phospholipid particles showed uniform aerodynamic particle size deposition profiles.

[0123] [Table 2]

[0124] Example 3 The fraction of fine particles (FPF) present in the delivered dose upon start-up of MDIs containing budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles was measured after storage of the MDIs under various temperature and relative humidity conditions for various periods of time (see Tables 2 and 3 below).

[0125] The fine particle mass (FPM) present in the delivered dose upon start-up of MDIs containing budesonide and phospholipid particles was measured after storage of the MDIs under various temperature and relative humidity conditions for various periods of time (see Tables 2 and 3 below).

[0126] [Table 3]

[0127] [Table 4]

[0128] Example 4 The delivery uniformity upon start-up of MDIs containing budesonide, glycopyrrolate and formoterol active agent particles and phospholipid particles was measured after storage of the MDIs under various temperature and relative humidity conditions for various periods of time (see Figures 8-13).

[0129] Example 5 The degradation of budesonide, glycopyrrolate, and formoterol active agent particles in MDI canisters containing active agent particles and phospholipid particles was measured after storage of the MDIs under various temperature and relative humidity conditions for various periods of time (see Tables 4 and 5 below).

[0130] [Table 5]

[0131] [Table 6]

[0132] Example 6 A randomized, single-blind, three-period, three-drug, single-dose crossover study was conducted to evaluate the relative bioavailability of BGF MDI HFC-152a and BGF MDI HFO-1234ze compared with BGF MDI HFA-134a in healthy subjects.

[0133] The investigational products include (1) a budesonide / glycopyrronium / formoterol (BGF) metered-dose inhaler (MDI) test drug formulated with HFC-152a propellant and (2) a budesonide / glycopyrronium / formoterol (BGF) metered-dose inhaler (MDI) reference drug formulated with HFA-134a propellant. The indication being studied is chronic obstructive pulmonary disease (COPD), and the development phase is Phase 1.

[0134] Purpose of the test: Main purpose: To determine the relative bioavailability between test and reference formulations of budesonide, glycopyrronium and formoterol (BGF) fixed dose combinations (FDCs) when administered as BGF metered dose inhalers (MDIs) with three different propellants.

[0135] Secondary Objectives: To determine the pharmacokinetic (PK) parameters of BGF when administered in three different spray formulations.To evaluate the safety and tolerability of the combination of BGF when administered as a single dose in three different spray formulations in healthy subjects.

[0136] Study design: This study was a randomized, single-blind, three-period, three-drug, single-dose, single-center, crossover study that included evaluation of the PK characteristics of BGF MDIs formulated with three different propellants: hydrofluoroolefin (HFO-1234ze)-treatment A (study), hydrofluorocarbon (HFC-152a)-treatment B (study), and hydrofluoroalkane (HFA-134a)-treatment C (reference).

[0137] The studies included: Screening period: ≤28 days prior to first dose. Three treatment periods of up to 3 days each: subjects stayed from the morning before the first dose of BGF MDI (Day -1) in Treatment Period 1, throughout all treatment and washout periods, 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 washout period of 3-7 days between each dose. Each subject received 3 single-dose treatments of BGF MDI after an overnight fast of at least 8 hours (1 dose HFO-1234ze [Treatment A]; 1 dose HFC-152a [Treatment B] and 1 dose HFA-134a [Treatment C]).

[0138] Main selection criteria: Healthy, non-smoking, male subjects aged 18-60 years with a vein suitable for repeated cannulation or venipuncture. Subjects must have a body mass index (BMI) between 18 and 30 kg / m2, inclusive, and a weight of at least 50 kg and no more than 100 kg, inclusive. Subjects must have a forced expiratory volume in one second (FEV1) ≥ 80% predicted for age, height, and race at the screening visit.

[0139] Investigational Products: Treatment A (Test): BGF MDI HFO-1234ze(E) with strengths / concentrations of 160 / 7.2 / 4.8 μg per start-up.

[0140] Treatment B (Test): BGF MDI HFC-152a with strengths / concentrations of 160 / 7.2 / 4.8 μg per start-up.

[0141] Treatment C (reference): BGF MDI HFA-134a with strengths / concentrations of 160 / 7.2 / 4.8 μg per actuation.

[0142] Exam length: Each subject was to participate in the study for no more than 53 days.

[0143] Treatment compliance: Dosing was performed at the Parexel Early Phase Clinical Unit in Los Angeles. All investigational medicinal products (IMPs) administration was recorded in Parexel's electronic source data collection information management system (CLINBASE™). Compliance was ensured by direct observation and witnessing of IMP administration.

[0144] Criteria: Pharmacokinetic parameters: Primary PK parameters: Cmax, AUCinf and AUClast for test and reference treatments. Secondary PK parameters: tmax, t1 / 2λz, MRT, λz, CL / F, Vz / F, TRCmax, TRAUCinf and TRAUClast.

[0145] Safety endpoints: Adverse events (AEs) / serious adverse events (SAEs). 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.

[0146] Statistical methods: Determining case numbers: This was a pilot PK study to determine the relative bioavailability between the two test formulations of BGF MDI compared to the conventional formulation, therefore, no sample size calculation was performed.

[0147] Forty-eight healthy subjects (the number of subjects was increased from 24 to 48 per protocol amendment 2 to allow for replacement subjects due to dosing deviations involving the original 23 subjects) were expected to be randomized into a 3-period, 3-drug, 6-sequence Williams design: ABC, BCA, CAB, ACB, BAC, and CBA to ensure at least 20 evaluable subjects at the end of the last treatment period.

[0148] Subjects were considered evaluable if they had an evaluable PK profile, i.e., (1) received active treatment, (2) did not significantly violate protocol inclusion or exclusion criteria or significantly deviate from the protocol, and (3) had unavailable or incomplete data that could have influenced the PK analysis. Pharmacokinetic Data Presentation and Analysis:

[0149] All PK concentrations, summary parameters, and statistical analyses were presented for the PK analysis population unless otherwise stated. PK concentration and parameter tables were presented for the safety analysis population and included all reportable individual PK results. Individual PK concentration and parameter data for any subjects not included in the PK analysis population or excluded from the narrative summary tables, figures, and / or inferential statistical analyses were included in the tables and flagged with an appropriate footnote.

[0150] The test treatments, Treatments A and B (BGF MDI HFO and BGF MDI HFC, respectively), were compared with the reference treatment, Treatment C (BGF MDI HFA) separately for each analyte. Statistical analysis was performed using a linear mixed-effects analysis of variance model with the natural logarithms of Cmax, AUCinf, and AUClast as response variables, with sequence and period, treatment as fixed effects, and subject nested within sequence as a random effect. Back-transformed from the logarithmic scale, geometric means for Cmax, AUCinf, and AUClast were estimated and presented along with within-patient coefficient of variation confidence intervals (CI) (two-sided 95%). Additionally, ratios of geometric means were estimated and presented along with CIs (two-sided 90%).

[0151] In addition, the median difference in untransformed tmax between test and reference treatments for each analyte and the corresponding 90% CI for the median difference for each analyte were calculated using the non-parametric Hodges Lehmann method.

[0152] Presentation and analysis of safety and eligibility data: Safety data (scheduled and unscheduled) were presented in data listing tables. Continuous variables were summarized by treatment using descriptive statistics (n, mean, standard deviation [SD], minimum, median, maximum). Categorical variables were summarized in frequency tables (frequencies and percentages) by treatment, where appropriate. Analysis of safety variables was based on the safety analysis set.

[0153] Adverse events were summarized by preferred term (PT) and system organ class (SOC) using MedDRA terminology. In addition, SAEs and AEs leading to discontinuation were tabulated and the number of subjects with any AE, SAE, AE leading to discontinuation, and severe AE were summarized. Adverse events occurring before dosing were reported separately.

[0154] Data were presented in tabulations and listings for vital signs, clinical laboratory tests, digital and 12-lead safety ECGs (lists only), telemetry (lists only), and spirometry. Results of taste assessments were presented separately in the listings only. Any new or worsening clinically significant abnormal medical physical examination findings compared to baseline assessments were reported as AEs. Data were summarized for observations at each scheduled evaluation time point with the corresponding change from baseline, if one was established. Clinical laboratory data were reported in units provided by the clinical laboratory at Safety Review Committee (SRC) meetings and in International System of Units (SI) units in the Clinical Study Report (CSR).

[0155] Outlying values ​​for safety laboratory assessments were flagged in individual tables and summarized narratively using agreed-upon standard reference ranges and / or extended reference ranges (e.g. AstraZeneca, program or laboratory ranges).

[0156] Protocol Deviations: Overall, serious protocol deviations were reported for 26 subjects (55.3%) during the study: For Treatment A (HFO propellant): 23 subjects (48.9%) reported other significant protocol deviations (subject did not self-administer via inhaler as outlined in the protocol; a nurse administered the dose). For Treatment B (HFC propellant): 23 subjects (48.9%) reported other significant protocol deviations (subject did not self-administer via inhaler as outlined in the protocol; a nurse administered the dose), and 2 (4.3%) subjects did not receive the full expected dose due to problems during inhalation. For Treatment C (HFA propellant): 23 subjects (48.9%) reported other significant protocol deviations (subject did not self-administer via inhaler as outlined in the protocol; a nurse administered the dose), and 1 (2.1%) subject did not receive the full expected dose due to problems during inhalation.

[0157] The number of subjects was increased from 24 to 48 per protocol amendment 2 to allow for replacement subjects due to dosing deviations involving the original 23 subjects.

[0158] There were 23 subjects who were excluded from the PK analysis population due to reported protocol deviations. No significant protocol deviations related to COVID-19 were reported during the study.

[0159] Pharmacokinetic Results: Systemic exposure to budesonide from BGF MDI HFC was comparable to BGF MDI HFA with GMR and 90%CI of 98.78% (78.67%, 124.0%), 98.03% (83.33%, 115.3%) and 98.80% (84.59%, 115.4%) for Cmax, AUCinf and AUClast, respectively. Systemic exposure to glycopyrronium from BGF MDI HFC was comparable to BGF MDI HFA with GMR and 90%CI of 94.88% (74.69%, 120.5%) and 99.71% (80.84%, 123.0%) for Cmax and AUClast, respectively. Systemic exposure to formoterol from BGF MDI HFC was comparable to BGF MDI HFA with GMR and 90%CI of 100.1% (83.78%, 119.5%), 116.7% (86.31%, 157.8%) and 107.0% (88.82%, 128.9%) for Cmax, AUCinf and AUClast, respectively.

[0160] Safety Results: There were no deaths, SAEs, or AEs leading to discontinuation of IMP reported during the study. No new safety signals were observed, no clinically relevant trends were observed for vital signs, physical examination, clinical laboratory results, spirometry, or taste assessment, and no abnormal clinically significant 12-lead safety and digital ECG or ECG 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 populations studied.

[0161] Given this clinical trial, systemic exposure to budesonide, glycopyrronium and formoterol was similar for BGF MDI HFC-152a compared to the reference drug (BGF MDI HFA-134a). There was no indication of meaningful differences between the products in this taste evaluation. The combination of budesonide, glycopyrronium and formoterol, when administered as a single dose in the HFC-152a and HFA-134a formulations, demonstrated an acceptable safety profile and was well tolerated in the population studied.

[0162] Example 7 A metered dose inhaler containing a dual co-suspension composition containing glycopyrrolate and formoterol fumarate active agent particles was prepared, with each type of active agent particle being provided as a micronized crystalline API material. The active agent particles were suspended in HFC-152a propellant along with phospholipid particles. As shown in Figure 14 and Table 6, the two types of active agent particles containing phospholipid particles exhibited uniform aerodynamic particle size deposition profiles. (See Table 6 below)

[0163] [Table 7]

[0164] Example 8 A metered dose inhaler containing a dual co-suspension composition comprising budesonide and albuterol sulfate 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 HFC-152a propellant along with phospholipid particles. As shown in Figure 16 and Table 7, the two types of active agent particles containing phospholipid particles exhibited uniform aerodynamic particle size deposition profiles. (See Table 7 below)

[0165] [Table 8]

[0166] Example 9 Delivery uniformity upon start-up of MDIs containing glycopyrrolate and formoterol fumarate active agent particles and phospholipid particles was measured after preparation of the inhaler. The data demonstrates similar delivery of glycopyrrolate and formoterol fumarate both near the beginning and near the end of the inhaler's shelf life (see Figure 15).

[0167] Example 10 The delivery uniformity upon start-up of MDIs containing budesonide and albuterol sulfate active agent particles and phospholipid particles was measured after preparation of the inhalers. The data demonstrates similar delivery of budesonide and albuterol sulfate both near the beginning and near the end of the inhaler's shelf life (see FIG. 17).

[0168] The various embodiments described above 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 publications mentioned in this specification and / or listed in the application data sheet are incorporated herein by reference in their entirety, unless otherwise stated herein. Aspects of the embodiments can be modified if necessary to use the concepts of various patents, applications, and publications to provide further embodiments.

[0169] 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 should not be construed to limit 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 range of equivalents to which such claims are entitled. Thus, the claims are not limited by this disclosure.

Claims

1. 1. A pharmaceutical composition deliverable from a metered dose inhaler, said pharmaceutical composition comprising: Pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant; a plurality of active agent particles; and comprising a plurality of phospholipid particles comprising a perforated microstructure; 1. A pharmaceutical composition, wherein the active agent particles comprise an active agent selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent.

2. 10. The pharmaceutical composition of claim 1, wherein the plurality of active agent particles comprises two or more species of active agent particles, each species of active agent particles comprising a different active agent selected from long-acting muscarinic antagonists (LAMAs), long-acting beta-agonists (LABAs), short-acting beta-agonists (SABAs), inhaled corticosteroids (ICS), and non-corticosteroid anti-inflammatory agents.

3. 1. A pharmaceutical composition deliverable from a metered dose inhaler, said pharmaceutical composition comprising: Pharmaceutical grade 1,1-difluoroethane (HFC-152a) propellant; a plurality of first species of active agent particles; a plurality of second species of active agent particles; and comprising a plurality of phospholipid particles comprising a perforated microstructure; 1. A pharmaceutical composition, wherein the first species of active agent particles comprise a first active agent, the second species of active agent particles comprise a second active agent, and the first and second active agents are selected from long-acting muscarinic antagonists (LAMAs), long-acting beta-agonists (LABAs), short-acting beta-agonists (SABAs), inhaled corticosteroids (ICS), and non-corticosteroid anti-inflammatory agents.

4. 4. The pharmaceutical composition of claim 3, further comprising a plurality of third species of active agent particles; said third species of active agent particles comprising a third active agent selected from long-acting muscarinic antagonists (LAMAs), long-acting beta-agonists (LABAs), short-acting beta-agonists (SABAs), inhaled corticosteroids (ICS), and non-corticosteroid anti-inflammatory agents.

5. 5. The pharmaceutical composition of claim 4, further comprising a plurality of fourth species of active agent particles; said fourth species of active agent particles comprising a fourth active agent selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), a short-acting beta-agonist (SABA), an inhaled corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent.

6. 4. The pharmaceutical composition of claim 1, wherein the LAMA is present at a concentration ranging from about 0.04 mg / mL to about 2.25 mg / mL.

7. 4. The pharmaceutical composition of claim 1, wherein the LABA is present at a concentration ranging from about 0.01 mg / mL to about 1 mg / mL.

8. 4. The pharmaceutical composition of claim 1, wherein the ICS is present at a concentration ranging from about 0.1 mg / mL to about 20 mg / mL.

9. 4. The pharmaceutical composition of claim 1 or 3, wherein the non-corticosteroid anti-inflammatory agent is present in a concentration ranging from about 0.1 mg / mL to about 20 mg / mL.

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

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

12. 4. The pharmaceutical composition of claim 1, wherein the phospholipid particles exhibit a volume median light scattering diameter selected from between about 0.2 μm and about 50 μm, between about 0.5 μm and about 15 μm, between about 1.5 μm and about 10 μm, and between about 2 μm and about 5 μm.

13. The total mass of the phospholipid particles is: i) a plurality of active agent particles according to claim 1; ii) any one of the first, second, third, or fourth species of active agent particles; or iii) a combination of any two of said first, second, third and fourth species of active agent particles; 4. The pharmaceutical composition of claim 1 or 3, wherein the total mass of the pharmaceutical composition exceeds

14. 4. The pharmaceutical composition of claim 3, wherein the first active agent is a LAMA; and the second active agent is a LABA.

15. 5. The pharmaceutical composition of claim 4, wherein the first active agent is a LAMA; the second active agent is a LABA; and the third active agent is an ICS.

16. 6. The pharmaceutical composition of claim 5, 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.

17. 4. The pharmaceutical composition of claim 3, wherein the first active agent is SABA; and the second active agent is ICS.

18. 4. The pharmaceutical composition of claim 3, wherein the first active agent is a LABA; and the second active agent is an ICS.

19. 4. The pharmaceutical composition of claim 1 or 3, wherein the LAMA is selected from glycopyrrolate, dexpyrronium, tiotropium, trospium, aclidinium, umeclidinium, and darotropium; or a pharmaceutically acceptable salt or solvate thereof.

20. The LABAs include bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, mirveterol, indacaterol, vilanterol, and saligenin or indole-containing β-amantyl derivatives derived from adamantyl. ２ 4. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of a benzodiazepine, ...

21. 4. The pharmaceutical composition of claim 1 or 3, wherein said SABA is selected from bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, albuterol (salbutamol), terbutaline, tulobuterol, reproterol and epinephrine; or its pharmaceutically acceptable salt or solvate.

22. 4. The pharmaceutical composition of claim 1 or 3, wherein the ICS is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone, and triamcinolone; or a pharmaceutically acceptable salt or solvate thereof.

23. 4. The pharmaceutical composition of claim 1 or 3, wherein the non-corticosteroid anti-inflammatory agent is roflumilast or a pharmaceutically acceptable salt or solvate thereof.

24. 10. The pharmaceutical composition of claim 1 or 3, which exhibits improved robustness in a simulated use test (SUT).

25. 10. The pharmaceutical composition of claim 1 or 3, 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.

26. Pharmaceutical grade HFC-152a propellant; a plurality of glycopyrrolate particles; a plurality of formoterol particles; and Multiple phospholipid particles containing perforated microstructures 4. The pharmaceutical composition of claim 1 or 3, comprising:

27. Pharmaceutical grade HFC-152a propellant; a plurality of glycopyrrolate particles; a plurality of formoterol particles; a plurality of budesonide particles; and Multiple phospholipid particles containing perforated microstructures 4. The pharmaceutical composition of claim 1 or 3, comprising:

28. Pharmaceutical grade HFC-152a propellant; a plurality of albuterol particles; a plurality of budesonide particles; and Multiple phospholipid particles containing perforated microstructures 4. The pharmaceutical composition of claim 1 or 3, comprising:

29. Pharmaceutical grade HFC-152a propellant; a plurality of formoterol particles; a plurality of budesonide particles; and Multiple phospholipid particles containing perforated microstructures 4. The pharmaceutical composition of claim 1 or 3, comprising:

30. Pharmaceutical grade HFC-152a propellant; a plurality of glycopyrrolate particles; a plurality of formoterol particles; a plurality of budesonide particles; a plurality of roflumilast particles; and Multiple phospholipid particles containing perforated microstructures 4. The pharmaceutical composition of claim 1 or 3, comprising:

31. 4. The pharmaceutical composition of claim 1 or 3, wherein the glycopyrrolate active agent particles are in a concentration in the propellant sufficient to provide a delivered dose of glycopyrrolate per actuation of the metered dose inhaler selected from between about 5 μg and about 50 μg per actuation, between about 2 μg and about 25 μg per actuation, and between about 6 μg and about 15 μg per actuation.

32. 4. The pharmaceutical composition of claim 1, wherein the concentration of glycopyrrolate in the propellant is between about 0.04 mg / ml and about 2.25 mg / ml.

33. 4. The pharmaceutical composition of claim 1 or 3, wherein at least 90% of the glycopyrrolate active agent particles by volume exhibit a light scattering diameter of 7 μm or less.

34. 4. The pharmaceutical composition of claim 1 or 3, wherein the formoterol active agent particles are included in the composition at a concentration sufficient to provide a delivered amount of formoterol selected from between about 1 μg to about 30 μg, between about 0.5 μg to about 10 μg, between about 2 μg to 5 μg, between about 3 μg to about 10 μg, between about 5 μg to about 10 μg, and between 3 μg to about 30 μg per actuation of the metered dose inhaler.

35. 4. The pharmaceutical composition of claim 1, wherein the concentration of formoterol in the propellant is selected from between about 0.01 mg / ml and about 1 mg / ml, between about 0.01 mg / ml and about 0.5 mg / ml, and between about 0.03 mg / ml and about 0.4 mg / ml.

36. 4. The pharmaceutical composition of claim 1 or 3, wherein at least 90% of the formoterol active agent particles by volume exhibit a light scattering diameter of 5 μm or less.

37. 4. The pharmaceutical composition of claim 1 or 3, wherein the budesonide active agent particles are present in the composition at a concentration sufficient to provide a delivered amount of budesonide selected from between about 50 μg and about 400 μg, between about 20 μg and about 600 μg, between about 30 μg and 100 μg, between about 50 μg and about 200 μg, and between about 150 μg and about 350 μg per actuation of the metered dose inhaler.

38. 4. The pharmaceutical composition of claim 1, wherein the concentration of budesonide in the propellant is selected from between about 0.1 mg / ml and about 20 mg / ml, between about 0.1 mg / ml and about 5 mg / ml, and between about 0.3 mg / ml and about 6 mg / ml.

39. 4. The pharmaceutical composition of claim 1 or 3, wherein at least 90% of the budesonide active agent particles by volume exhibit a light scattering diameter of 7 μm or less.

40. 4. The pharmaceutical composition of claim 1, wherein the albuterol active agent particles are present in the composition at a concentration sufficient to provide a delivered dose of albuterol selected from between about 10 μg and about 200 μg, between about 20 μg and about 300 μg, between about 30 μg and 150 μg, and between about 50 μg and about 200 μg per actuation of a metered dose inhaler.

41. 4. The pharmaceutical composition of claim 1, wherein the concentration of albuterol in the propellant is selected from between about 0.1 mg / ml and about 10 mg / ml, between about 0.1 mg / ml and about 5 mg / ml, and between about 0.3 mg / ml and about 4 mg / ml.

42. 10. The pharmaceutical composition of claim 1 or 3, wherein at least 90% of the albuterol active agent particles by volume exhibit a light scattering diameter of 5 μm or less.

43. 4. The pharmaceutical composition of claim 1, wherein the roflumilast active agent particles are present in the composition at a concentration sufficient to provide a delivered amount of roflumilast selected from between about 50 μg and about 400 μg, between about 20 μg and about 600 μg, between about 30 μg and 100 μg, between about 50 μg and about 200 μg, and between about 150 μg and about 350 μg per actuation of the metered dose inhaler.

44. 4. The pharmaceutical composition of claim 1, wherein the concentration of roflumilast in the propellant is selected from between about 0.1 mg / ml and about 20 mg / ml, between about 0.1 mg / ml and about 5 mg / ml, and between about 0.3 mg / ml and about 6 mg / ml.

45. 4. The pharmaceutical composition of claim 1 or 3, wherein at least 90% of the roflumilast active agent particles by volume exhibit a light scattering diameter of 5 μm or less.

46. 4. The pharmaceutical composition of claim 1 or 3, wherein the glycopyrrolate particles comprise glycopyrrolate or a pharmaceutically acceptable salt thereof.

47. 47. The pharmaceutical composition of claim 46, wherein the glycopyrrolate or pharmaceutically acceptable salt thereof is in crystalline and / or micronized form.

48. 4. The pharmaceutical composition of claim 1 or 3, wherein the formoterol particles comprise formoterol or a pharmaceutically acceptable salt thereof.

49. 49. The pharmaceutical composition of claim 48, wherein the formoterol or pharmaceutically acceptable salt thereof is in crystalline and / or micronized form.

50. 4. The pharmaceutical composition of claim 1 or 3, wherein the albuterol particles comprise albuterol or a pharmaceutically acceptable salt thereof.

51. 51. The pharmaceutical composition of claim 50, wherein the albuterol or pharmaceutically acceptable salt thereof is in crystalline and / or micronized form.

52. 4. The pharmaceutical composition of claim 1 or 3, wherein the budesonide particles comprise budesonide in crystalline and / or micronized form.

53. The pharmaceutical composition of claim 1 or 3, wherein the roflumilast particles comprise roflumilast or a pharmaceutically acceptable salt thereof.

54. 54. The pharmaceutical composition of claim 53, wherein the roflumilast or a pharmaceutically acceptable salt thereof is in crystalline and / or micronized form.

55. 10. A metered dose inhaler comprising a canister having an outlet valve including an actuator for dispensing a metered amount of the pharmaceutical composition of claim 1 or 3, said canister containing said pharmaceutical composition.

56. 56. The metered dose inhaler of claim 55, which exhibits a delivered dose uniformity (DDU) for the pharmaceutical composition selected from ±20% or better DDU, ±15% or better DDU, and ±10% or better DDU until the canister is empty.

57. 56. The metered dose inhaler of claim 55, wherein the pharmaceutical composition is dispensed at an initial fine particle ratio, the initial fine particle ratio dispensed from the metered dose inhaler is substantially maintained, and the fine particle ratio delivered from the metered dose inhaler is maintained within 85% of the initial fine particle ratio until the canister is emptied.

58. 56. A metered dose inhaler according to claim 55, wherein the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.

59. 10. The pharmaceutical composition of claim 1 or 3 for the treatment of a pulmonary disease or disorder.

60. The pharmaceutical composition of claim 59, 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, allergy, respiratory disorder, respiratory distress syndrome, pulmonary hypertension, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis.

61. The pharmaceutical composition described in claim 60, wherein the pulmonary disease or disorder is asthma or COPD.

62. The pharmaceutical composition of claim 59, administered using a metered dose inhaler of claim 55.

63. 4. The pharmaceutical composition of claim 1 or 3, which exhibits a Cmax, AUCinf or AUClast for any one or more of said active agents that is 80% to 125% of the Cmax, AUCinf or AUClast for one or more of said active agents in a reference pharmaceutical composition.

64. 56. A metered dose inhaler according to claim 55, wherein the pharmaceutical composition exhibits a Cmax, AUCinf or AUClast for any one or more of the active agents that is 80% to 125% of the Cmax, AUCinf or AUClast for that one or more of the active agents of a reference pharmaceutical composition.

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