CN117915892A

CN117915892A - Compositions, methods, and systems for aerosol drug delivery

Info

Publication number: CN117915892A
Application number: CN202280061042.9A
Authority: CN
Inventors: V·乔希; J·阿切贝尔; K·拉查兹; C·兰帕; L·梅洛; G·古铁雷斯; D·莱楚加-巴莱斯特罗斯; P·谭; M·里贝
Original assignee: AstraZeneca Pharmaceuticals LP
Current assignee: AstraZeneca Pharmaceuticals LP
Priority date: 2021-07-09
Filing date: 2022-07-08
Publication date: 2024-04-19
Also published as: CN117940115A; CN117915893A

Abstract

Compositions, methods, and systems for pulmonary delivery of active agents via a metered-dose inhaler are provided. In some embodiments, the composition comprises HFO-1234ze (E) suspension medium, active agent particles, and suspended particles. The active agent particles may comprise one, two, three or four active agents selected from the group consisting of: long Acting Muscarinic Antagonists (LAMA), long acting beta 2-agonists (LABA), short acting beta-agonists (SABA), inhaled Corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.

Description

Compositions, methods, and systems for aerosol drug delivery

Cross Reference to Related Applications

The present application claims the benefits of U.S. provisional application number 63/220,362 filed on day 7, month 9 of 2021 and U.S. provisional application number 63/282,356 filed on day 11, month 23 of 2021 in accordance with 35 U.S. C. ≡119 (e). Each of the above-listed applications is incorporated by reference herein in its entirety for all purposes.

Background

Targeted drug delivery methods that deliver active agents at the site of action are generally desirable. For example, targeted delivery of active agents may reduce undesirable side effects, reduce dosing requirements, and reduce treatment costs. In the context of respiratory tract delivery, inhalers are well known devices for administering active agents to the respiratory tract 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 (MDI), also known as pressurized metered dose inhalers (pmdis).

MDI may be used to deliver drugs in dissolved form or as suspensions. Generally, MDI uses a relatively high vapor pressure propellant to expel atomized droplets containing the active agent into the respiratory tract when the MDI is activated. Dry powder inhalers typically rely on the patient's inspiratory effort to introduce the medicament in dry powder form into the respiratory tract. The nebulizer forms a medicinal aerosol to be inhaled by imparting energy to the liquid solution or suspension. For over six decades MDI has provided a reliable, ready-to-use and easy-to-use medical aerosol delivery system. While dry powder inhalers and nebulizers play an important role in the management of both airways and organic diseases, there is currently no universal aerosol generation and delivery system to replace MDI.

MDI is an active delivery device that uses the pressure generated by a propellant. The propellant must be safe for use by the patient and pharmaceutically acceptable. The active agent to be delivered by the MDI is typically provided as a suspension of fine particles dispersed in one or a combination of two or more propellants (i.e., a propellant "system"). However, the fine particles of the active agent suspended in the propellant or propellant system tend to aggregate or flocculate rapidly. In turn, aggregation or flocculation of these fine particles can complicate delivery of the active agent. Another problem associated with such suspended MDI formulations relates to crystal growth of the drug during storage, which results in reduced aerosol properties and delivered dose uniformity of such MDI over time. It is therefore critical that the active agent is formulated appropriately with excipients and propellants to form a stable suspension suitable for MDI. The nature of the propellant plays an important role in the performance of the suspension formulation for MDI. For example, the liquid density, vapor pressure, and water solubility of propellants affect suspension stability, dose uniformity, aerosol performance, and moisture intrusion. 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 suspension formulations. Historically, the phase out of chlorofluorocarbon (CFC) propellants, which are ozone depleting agents, required reformulation of MDI with hydrofluoroalkane propellants. Although not ozone depleting, HFA propellants are greenhouse gases with high Global Warming Potential (GWP), and thus there remains a need for alternative MDI propellants with reduced environmental impact. However, the reformulation of MDI propellants is not a simple task-since taking into account the physicochemical properties of the various excipients and how the addition of these excipients may affect the overall MDI performance, substantial new techniques must be developed to enable conversion from CFCs to HFAs in MDI. For example, one of the major challenges is that conventional surfactants for CFC-based MDI are not suitable for HFA.

Because of the desire to develop new environmentally friendly MDI, there remains a need to research and develop innovative suspension MDI formulations.

Disclosure of Invention

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

In some embodiments, the compositions described herein are formulated for pulmonary delivery of one or more active agents via MDI. In other embodiments, the compositions described herein may be formulated for nasal delivery via MDI. In some embodiments, the composition comprises a pharmaceutical grade (1E) -1, 3-tetrafluoropropene (HFO-1234 ze (E)) 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 comprises one, two, three, or four active agents selected from the group consisting of: long Acting Muscarinic Antagonists (LAMA), long acting beta 2-agonists (LABA), short acting beta-agonists (SABA), inhaled Corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.

In some embodiments, the composition comprises a pharmaceutical grade (1E) -1, 3-tetrafluoropropene (HFO-1234 ze (E)) 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 (1E) -1, 3-tetrafluoropropene (HFO-1234 ze (E)) 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 (1E) -1, 3-tetrafluoropropene (HFO-1234 ze (E)) 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 (1E) -1, 3-tetrafluoropropene (HFO-1234 ze (E)) 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 (1E) -1, 3-tetrafluoropropene (HFO-1234 ze (E)) propellant, a plurality of non-corticosteroid anti-inflammatory agent particles, and a plurality of phospholipid particles comprising a perforated microstructure.

In some embodiments, the composition comprises a pharmaceutical grade (1E) -1, 3-tetrafluoropropene (HFO-1234 ze (E)) propellant, a plurality of one or more types of active agent particles, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the composition comprises a pharmaceutical grade (1E) -1, 3-tetrafluoropropene (HFO-1234 ze (E)) propellant, a plurality of active agent particles of a first kind, a plurality of active agent particles of a second kind, and a plurality of phospholipid particles comprising a perforated microstructure. In some embodiments, the first type of active agent particles comprises a first active agent and the second type of active agent particles comprises a second active agent. In some embodiments, the compositions described herein further comprise a plurality of active agent particles of a third species, wherein the active agent particles of the third species comprise a third active agent. In some embodiments, the compositions described herein further comprise a plurality of active agent particles of a fourth species, wherein the active agent particles of the fourth species comprise a fourth active agent. In some embodiments, the active agent is selected from the group consisting of a Long Acting Muscarinic Antagonist (LAMA), a long acting beta 2-agonist (LABA), a short acting beta-agonist (SABA), an Inhaled Corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent. In some embodiments, the first and second active agents are selected from the group consisting of Long Acting Muscarinic Antagonists (LAMA), long acting beta 2-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 the group consisting of a Long Acting Muscarinic Antagonist (LAMA), a long acting beta 2-agonist (LABA), a short acting beta-agonist (SABA), an Inhaled Corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent. In still further embodiments, the fourth active agent is selected from the group consisting of a Long Acting Muscarinic Antagonist (LAMA), a long acting beta 2-agonist (LABA), a short acting beta-agonist (SABA), an Inhaled Corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent.

Methods described herein include methods of treating a pulmonary disease or disorder in a patient by actuating a metered dose inhaler containing a composition as described herein.

Also described herein are systems for pulmonary delivery of one or more active agents. In some embodiments, such systems comprise an MDI comprising a canister having an outlet valve comprising an actuator (e.g., a depressible valve stem) for dispensing a metered amount of a composition as described herein. In some embodiments, the outlet valve is at least partially constructed of bromobutyl material. For example, the internal neck gasket of the outlet valve may comprise or consist of bromobutyl material. Further, the one or more internal seat washers of the outlet valve may comprise or consist of bromobutyl material.

In one embodiment, the present disclosure provides a pharmaceutical composition deliverable from a metered dose inhaler, the pharmaceutical composition comprising: a pharmaceutical grade (1E) -1, 3-tetrafluoro-1-propene (HFO-1234 ze (E)) propellant having a purity of at least about 99.90%; a plurality of one or more types of active agent particles; and a plurality of phospholipid particles comprising a perforated microstructure; wherein the one or more active agents are selected from the group consisting of Long Acting Muscarinic Antagonists (LAMA), long acting beta 2-agonists (LABA), short acting beta-agonists (SABA), inhaled Corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.

In one embodiment, the pharmaceutical composition comprises a plurality of active agent particles of a first species; wherein the active agent is LAMA selected from the group consisting of: glycopyrrolate (glycopyrrolate), dexpirronium, tiotropium, trospium, aclidinium (aclidinium), turnidium (umeclidinium) and daptomium (darotropium), or pharmaceutically acceptable salts or solvates thereof; and a plurality of active agent particles of a second species; wherein the active agent is a LABA selected from the group consisting of: bambuterol (bambuterol), clenbuterol (clenbuterol), formoterol (formoterol), salmeterol (salmeterol), carmoterol (carmoterol), miveterol (milveterol), indacaterol (indacaterol), vilantro (vilanterol), and beta ₂ agonists derived from salidroside or indole and adamantyl; or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment of the pharmaceutical composition, LAMA is glycopyrrolate or a pharmaceutically acceptable salt or solvate thereof; and the LABA is formoterol or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the pharmaceutical composition comprises a plurality of active agent particles of a first species; wherein the active agent is LAMA selected from the group consisting of: glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, turnidiammonium, and daptomide; or a pharmaceutically acceptable salt or solvate thereof; a plurality of active agent particles of a second species; wherein the active agent is a LABA selected from the group consisting of: bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, miveraterol, indacaterol, vilantro and β ₂ agonists derived from salicin or indole and adamantyl; or a pharmaceutically acceptable salt or solvate thereof; and a plurality of third species of active agent particles; wherein the active agent is an ICS selected from the group consisting of: beclomethasone (beclomethasone), budesonide (ciclesonide), flunisolide (flunisolide), fluticasone (fluticasone), methylprednisolone (methylprednisolone), mometasone (mometasone), prednisone (prednisone) and triamcinolone, or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment of the pharmaceutical composition, LAMA is glycopyrrolate or a pharmaceutically acceptable salt or solvate thereof; LABA is formoterol or a pharmaceutically acceptable salt or solvate thereof; and the ICS is budesonide or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment of the pharmaceutical composition, LAMA is present at a concentration in the range of about 0.04mg/mL to about 2.25 mg/mL.

In one embodiment of the pharmaceutical composition, the LABA is present at a concentration in the range of about 0.01mg/mL to about 1 mg/mL.

In one embodiment of the pharmaceutical composition, ICS is present at a concentration in the range of about 0.1mg/mL to about 20 mg/mL.

In one embodiment of the pharmaceutical composition, the perforated microstructure comprises 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC). In another embodiment, the perforated microstructure further comprises calcium chloride.

In one embodiment of the pharmaceutical composition, the phospholipid particles are present at a concentration in the range of about 0.1mg/mL to about 10 mg/mL.

In one embodiment, a pharmaceutical composition comprises: a pharmaceutical grade HFO-1234ze (E) propellant having a purity of at least about 99.90%; a plurality of glycopyrronium particles; a plurality of formoterol particles; and a plurality of phospholipid particles comprising a perforated microstructure.

In one embodiment, a pharmaceutical composition comprises: a pharmaceutical grade HFO-1234ze (E) propellant having a purity of at least about 99.90%; a plurality of glycopyrronium particles; a plurality of formoterol particles; a plurality of budesonide particles; and a plurality of phospholipid particles comprising a perforated microstructure.

In one embodiment of the pharmaceutical composition, the concentration of glycopyrrolate particles in the propellant is sufficient to provide a delivered dose of glycopyrrolate per actuation of a metered dose inhaler selected from the group consisting of: 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.

In one embodiment of the pharmaceutical composition, the glycopyrrolate particles comprise micronized and crystalline glycopyrrolate.

In one embodiment of the pharmaceutical composition, the formoterol particles are included in the composition in a concentration sufficient to provide a formoterol delivery dose selected from the group consisting of: the metered dose inhaler is between about 1 μg and about 30 μg, between about 0.5 μg and about 10 μg, between about 2 μg and 5 μg, between about 3 μg and about 10 μg, between about 5 μg and about 10 μg, and between 3 μg and about 30 μg per actuation.

In one embodiment of the pharmaceutical composition, the formoterol particles comprise micronized and crystalline formoterol fumarate.

In one embodiment of the pharmaceutical composition, the budesonide particles are included in the composition in a concentration sufficient to provide a budesonide delivery dose selected from the group consisting of: the metered-dose inhaler is 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.

In one embodiment of the pharmaceutical composition, the budesonide particles comprise micronized budesonide.

In one embodiment of the pharmaceutical composition, the phospholipid particles are included in the composition in a concentration sufficient to provide a delivered dose of phospholipid particles selected from between about 50 μg to about 400 μg.

In one embodiment, the pharmaceutical composition exhibits a Cmax, AUCinf or AUClast of any one or more of the active agents that is about 80% to about 125% of the Cmax, AUCinf or AUClast of the active agent of the reference pharmaceutical composition comprising a pharmaceutical grade HFA-134a propellant.

In one embodiment, the present disclosure provides a metered dose inhaler comprising a canister having an outlet valve comprising an actuator for dispensing a metered dose of a pharmaceutical composition according to any one of the preceding embodiments, wherein the canister contains the pharmaceutical composition.

In one embodiment of the metered dose inhaler, the outlet valve comprises a neck gasket and at least one seat gasket; and the neck gasket or at least one seat gasket is constructed of bromobutyl material.

In one embodiment, the metered dose inhaler exhibits less than about a 10%, 9%, 8%, 7%, 6% or 5% reduction in the weight of the injection per actuation throughout the process of emptying the canister.

In one embodiment, the metered dose inhaler exhibits a weight loss of less than about 1.0%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% per year at 25 ℃/60% RH.

In one embodiment, the metered dose inhaler exhibits a drug formulation Delivery Dose Uniformity (DDU) throughout the process of emptying the canister selected from the group consisting of: 20% or better DDU, ±15% or better DDU, and 10% or better DDU.

In one embodiment, the present disclosure provides a method of treating a pulmonary disease or disorder in a patient comprising administering a pharmaceutical composition according to any one of the preceding embodiments to the patient by actuating a metered dose inhaler according to any one of the preceding embodiments; wherein the metered dose inhaler comprises the pharmaceutical composition.

In one embodiment of the method, the pulmonary disease or disorder is asthma or COPD.

In one embodiment, the present disclosure provides a pharmaceutical composition according to any one of the preceding embodiments for use in the manufacture of a medicament for the treatment of a pulmonary disease or disorder.

In one embodiment, the present disclosure provides a pharmaceutical composition according to any one of the preceding embodiments for use in treating a pulmonary disease or disorder.

Drawings

Fig. 1 is an isometric view of an aerosol delivery unit in the form of an MDI according to an example embodiment.

Fig. 2 is an exploded isometric view of the aerosol delivery unit of fig. 1.

Fig. 3A is a side view of the aerosol delivery unit of fig. 1, a portion of which is shown in cross-section, showing the unit in a stand-by or storage configuration, with the exhaust channel exposed to the desiccant material.

Fig. 3B is a side view of the aerosol delivery unit of fig. 1, a portion of which is shown in cross-section, showing the unit in a discharge configuration, wherein the discharge channel is temporarily isolated from the desiccant material as the aerosolized substance is discharged from the canister into the inhalation channel for delivery to a user.

Fig. 4 is a perspective view of an outlet valve of a canister suitable for use in conjunction with the aerosol delivery unit of fig. 1-3B.

Fig. 5 is a CT scan of the discharge channel of MDI according to certain aspects of the present disclosure, showing that the discharge orifice of MDI is substantially free of deposited or accumulated material despite repeated use of MDI to dispense the formulation described herein.

Fig. 6 is a graph showing the loss of formulation weight over time for various MDI canisters including outlet valves having internal gaskets of different materials when filled with formulations containing HFO propellants.

Figure 7 shows the individual deposition profile of active agent particles dispensed from an MDI comprising a triple co-suspension of glycopyrronium, budesonide and formoterol active agent particles suspended in HFO-1234ze (E) propellant together with phospholipid suspension particles.

Figure 8 shows the deposition profile of formoterol active particles dispensed from an MDI comprising a triple co-suspension of glycopyrrolate, budesonide and formoterol active particles suspended in HFO-1234ze (E) propellant together with phospholipid suspension particles at several different relative humidity levels.

Figure 9 shows the deposition profile of budesonide active particles dispensed from an MDI comprising a triple co-suspension of glycopyrrolate, budesonide and formoterol active particles suspended in HFO-1234ze (E) propellant together with phospholipid suspension particles at several different relative humidity levels.

Figure 10A shows the Fine Particle Fraction (FPF) present in the delivered dose upon actuation of MDI containing budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles as measured after storage of MDI at 25 ℃ and 60% relative humidity for a specified period of time.

Figure 10B shows the Fine Particle Fraction (FPF) present in the delivered dose upon actuation of MDI containing budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles as measured after storage of the MDI for a specified period of time at 40 ℃ and 75% relative humidity.

Figure 10C shows the Fine Particle Fraction (FPF) present in the delivered dose upon actuation of MDI containing budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles as measured after storage of MDI at 30 ℃ and 65% relative humidity for a specified period of time.

Figure 11A shows the mass of Fine Particles (FPM) present in the delivered dose upon actuation of MDI containing budesonide and phospholipid particles, as measured after storage of MDI at 25 ℃ and 60% relative humidity for a specified period of time.

Figure 11B shows the mass of Fine Particles (FPM) present in the delivered dose upon actuation of MDI containing budesonide and phospholipid particles, as measured after storage of MDI at 40 ℃ and 75% relative humidity for a specified period of time.

Figure 11C shows the mass of Fine Particles (FPM) present in the delivered dose upon actuation of MDI containing budesonide and phospholipid particles, as measured after storage of MDI at 30 ℃ and 65% relative humidity for a specified period of time.

Fig. 12A shows the measurement of the degradation of budesonide active particles in MDI canisters containing active particles and phospholipid particles after storage of the MDI at 25 ℃ and 60% relative humidity for a specified period of time.

Fig. 12B shows the measurement of the degradation of budesonide active particles in MDI canisters containing active particles and phospholipid particles after storage of the MDI at 40 ℃ and 75% relative humidity for a specified period of time.

Fig. 12C shows the measurement of the degradation of budesonide active particles in MDI canisters containing active particles and phospholipid particles after storage of the MDI at 30 ℃ and 65% relative humidity for a specified period of time.

Fig. 13A shows the results of measurements of glycopyrronium active agent particle degradation in MDI canisters containing active agent particles and phospholipid particles after storage of MDI at 25 ℃ and 60% relative humidity for a specified period of time.

Fig. 13B shows the results of measurements of glycopyrronium active agent particle degradation in MDI canisters containing active agent particles and phospholipid particles after storage of MDI at 40 ℃ and 75% relative humidity for a specified period of time.

Fig. 13C shows the results of measurements of glycopyrronium active agent particle degradation in MDI canisters containing active agent particles and phospholipid particles after storage of MDI at 30 ℃ and 65% relative humidity for a specified period of time.

Figure 14A shows the Delivered Dose Uniformity (DDU) when MDI containing budesonide active particles and phospholipid particles is actuated after storage of the MDI at 25 ℃ and 60% relative humidity for a specified period of time.

Figure 14B shows the Delivered Dose Uniformity (DDU) when MDI containing budesonide active particles and phospholipid particles is actuated after storage of the MDI at 40 ℃ and 75% relative humidity for a specified period of time.

Figure 14C shows the Delivered Dose Uniformity (DDU) when MDI containing budesonide active particles and phospholipid particles is actuated after storage of the MDI at 30 ℃ and 65% relative humidity for a specified period of time.

Figure 15 shows the aerodynamic particle size distribution of BD, FF and DSPC of BFF-1234ze through the NGI.

Figure 16 shows the aerodynamic particle size distribution of BD through NGI comparing BFF-1234ze and BFF-134a formulations.

Figure 17 shows the aerodynamic particle size distribution of FF through NGI comparing BFF-1234ze and BFF-134a formulations.

Figure 18 shows the aerodynamic particle size distribution stability data for BD passing NGI at 25 ℃/60% RH-valve closure, protected BFF-1234ze at initial, 6 months and 12 months.

Figure 19 shows aerodynamic particle size distribution stability data for FF passing NGI at 25 ℃/60% rh-valve closed, protected BFF-1234ze at initial, 6 months and 12 months.

Figure 20 shows aerodynamic particle size distribution stability data for the passing NGI of DSPCs at 25 ℃/60% rh-valve closure, protected BFF-1234ze at initial, 6 months and 12 months.

Figure 21 shows delivered dose uniformity stability data for BD and FF of 25 ℃/60% RH-valve closed, protected BFF-1234 ze.

Figure 22 shows the aerodynamic particle size distribution through the NGI for BD, AB and DSPC of BDA-1234 ze.

Figure 23 shows the aerodynamic particle size distribution of BD through NGI comparing BDA-1234ze and BDA-134a formulations.

Figure 24 shows the aerodynamic particle size distribution of AB passing through the NGI for a comparison of BDA-1234ze and BDA-134a formulations.

Figure 25 shows aerodynamic particle size distribution stability data for BD passing NGI at 25 ℃/60% rh-valve closed, protected BDA-1234ze at initial, 6 months and 12 months.

Figure 26 shows aerodynamic particle size distribution stability data for AB passing NGI at 25 ℃/60% rh-valve closed, protected BDA-1234ze at initial, 6 months and 12 months.

Figure 27 shows delivered dose uniformity stability data for BD and AB of protected BDA-1234ze at 25 ℃/60% rh-valve closed.

Figure 28 shows the aerodynamic particle size distribution of GP and FF of GFF-1234ze through NGI.

Figure 29 shows the aerodynamic particle size distribution of BD, GP, FF and RF passing through NGI for BGFR-1234 ze.

Figure 30 shows the deposition profile of budesonide, glycopyrrolate, formoterol and roflumilast (roflumilast) active agent particles dispensed from an MDI comprising a quadruple co-suspension of glycopyrrolate, budesonide, formoterol and roflumilast active agent particles suspended in HFO-1234ze (E) propellant together with phospholipid suspension particles.

Figure 31A shows the deposition profile of roflumilast active agent particles dispensed upon actuation from an MDI comprising a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in a HFO-1234ze (E) propellant together with phospholipid suspension particles, after 3 months at stability storage conditions representing accelerated stability (40 ℃/75% rh-valve closed, protected) and 3 months at stability storage conditions representing real-time stability (25 ℃/60% rh-valve closed, protected).

Figure 31B shows the deposition profile of budesonide active particles dispensed upon actuation from an MDI comprising a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active particles suspended in an HFO-1234ze (E) propellant together with phospholipid suspension particles, after 3 months at stability storage conditions representing accelerated stability (40 ℃/75% rh-valve closed, protected) and 3 months at stability storage conditions representing real-time stability (25 ℃/60% rh-valve closed, protected).

Figure 31C shows the deposition profile of glycopyrrolate active agent particles dispensed upon actuation from MDI comprising a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze (E) propellant together with phospholipid suspension particles after 3 months at stability storage conditions representing accelerated stability (40 ℃/75% rh-valve closed, protected) and 3 months at stability storage conditions representing real time stability (25 ℃/60% rh-valve closed, protected).

Figure 31D shows the deposition profile of formoterol active particles dispensed upon actuation from an MDI comprising a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active particles suspended in HFO-1234ze (E) propellant together with phospholipid suspension particles, after 3 months at stability storage conditions representing accelerated stability (40 ℃/75% rh-valve closed, protected) and 3 months at stability storage conditions representing real time stability (25 ℃/60% rh-valve closed, protected).

Figure 32 shows the Delivered Dose Uniformity (DDU) of roflumilast, formoterol, budesonide and glycopyrrolate active agent particles dispensed at the beginning of life and at the end of life from an MDI comprising a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze (E) propellant with phospholipid suspension particles.

Figure 33A shows the Delivered Dose Uniformity (DDU) of roflumilast active particles dispensed from MDI comprising a quadruple co-suspension of glycopyrronium, budesonide and formoterol and roflumilast active particles suspended in HFO-1234ze (E) propellant with phospholipid suspension particles at the beginning and end of life after 3 months at stability storage conditions representing accelerated stability (40 ℃/75% rh-valve closed, protected) and 3 months at stability storage conditions representing real-time stability (25 ℃/60% rh-valve closed, protected).

Figure 33B shows the Delivered Dose Uniformity (DDU) of formoterol active particles dispensed from MDI comprising a quadruple co-suspension of glycopyrronium, budesonide and formoterol and roflumilast active particles suspended in HFO-1234ze (E) propellant with phospholipid suspension particles at the beginning and end of life after 3 months at stability storage conditions representing accelerated stability (40 ℃/75% rh-valve closed, protected) and 3 months at stability storage conditions representing real-time stability (25 ℃/60% rh-valve closed, protected).

Figure 33C shows the Delivered Dose Uniformity (DDU) of budesonide active particles dispensed from MDI comprising a quadruple co-suspension of glycopyrronium, budesonide and formoterol and roflumilast active particles suspended in HFO-1234ze (E) propellant with phospholipid suspension particles at the beginning and end of life after 3 months at stability storage conditions representing accelerated stability (40 ℃/75% rh-valve closed, protected) and 3 months at stability storage conditions representing real-time stability (25 ℃/60% rh-valve closed, protected).

Figure 33D shows the Delivered Dose Uniformity (DDU) of glycopyrrolate active agent particles dispensed from MDI comprising a quadruple co-suspension of glycopyrrolate, budesonide and formoterol and roflumilast active agent particles suspended in HFO-1234ze (E) propellant with phospholipid suspension particles at the beginning and end of life after 3 months at stability storage conditions representing accelerated stability (40 ℃/75% rh-valve closed, protected) and 3 months at stability storage conditions representing real-time stability (25 ℃/60% rh-valve closed, protected).

Figure 34 shows the aerodynamic particle size distribution of budesonide and formoterol fumarate through a New Generation Impactor (NGI) for HFA-134a (BFF-134 a) and HFO-1234ze (BFF-1234 ze).

Figure 35 shows the aerodynamic particle size distribution of budesonide and formoterol fumarate through a New Generation Impactor (NGI) for HFA-134a (BFF crystal-134 a) and HFO-1234ze (BFF crystal-1234 ze).

Figure 36 shows the aerodynamic particle size distribution of budesonide, glycopyrrolate and formoterol fumarate of HFA-134a (BGF-134 a) and HFO-1234ze (BGF-1234 ze) through a New Generation Impactor (NGI).

Figure 37 shows the aerodynamic particle size distribution of budesonide, glycopyrrolate and formoterol fumarate of HFA-134a (BGF crystal-134 a) and HFO-1234ze (BGF-1234 ze) through a New Generation Impactor (NGI).

Detailed Description

Definition of the definition

Unless specifically defined otherwise, technical terms as used herein have the usual meaning as understood in the art. For clarity, the following terms are specifically defined.

The term "active agent" is used herein to include any pharmaceutical agent, drug, compound, composition or other substance that can be used or administered to a human or animal for any purpose, including therapeutic agents, pharmaceuticals, pharmacological agents, diagnostic agents, cosmetic and prophylactic agents, and immunomodulators. The active agent may be used interchangeably with the terms drug, pharmaceutical, drug medicament, drug substance or therapeutic agent. As used herein, an active agent may also encompass natural or homeopathic products that are not generally considered therapeutic.

The term "associate" or "associate with … …" refers to an interaction or relationship between chemical entities, compositions, or structures under conditions that are proximate to a surface (such as the surface of another chemical entity, composition, or structure). Association includes, for example, adsorption, adhesion, covalent bonding, hydrogen bonding, ionic bonding, and electrostatic attraction, lifshitz-VAN DER WAALS interactions, and polar interactions. The term "adhesion" refers to a form of association and is used as a generic term for all forces tending to cause a particle or substance to be attracted to a surface. Adhesion also refers to bringing the particles into contact with each other and maintaining them in contact such that under normal conditions there is substantially no visible separation between the particles due to differences in their buoyancy in the propellant. In one embodiment, particles that are attached to or bound to a surface are encompassed within the term adhesion. Normal conditions may include storage at room temperature or under acceleration forces due to gravity. As described herein, the active particles may associate with the suspended particles to form a co-suspension in which there is substantially no visible separation between the suspended particles and the active agent particles or flocs thereof due to the difference in buoyancy in the propellant.

"Suspended particles" refers to a material or combination of materials that are acceptable for respiratory delivery and serve as vehicles for active agent particles. The suspended 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 suspended particles described herein are dispersed in a suspension medium comprising a propellant or propellant system and may be configured according to any shape, size or surface characteristics suitable to achieve the desired suspension stability or active agent delivery performance. Exemplary suspended particles include particles that exhibit particle sizes that facilitate respiratory delivery of an active agent and have physical configurations suitable for formulation and delivery of a stable suspension as described herein.

The term "co-suspension" refers to a suspension of two or more types of particles having different compositions in a suspension medium, wherein one type of particle is at least partially associated with one or more other particle types. This association results in an observable change in one or more characteristics of at least one of the individual particle types suspended in the suspending medium. Characteristics modified by association may include, for example, one or more of the rate of aggregation or flocculation, the rate and nature of separation (i.e., sedimentation or creaming), the density of the creaming or sedimentation 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 in which a majority of at least two particle types are associated with each other, however, some separation (i.e., less than a majority) of at least two particle types may be observed.

The term "metered dose" or "actuation 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 exiting the actuator nozzle and which can be inhaled into the patient's lungs. In some embodiments, the delivered dose is about 85% to about 95% of the metered dose.

In the context of compositions containing or providing inhalable aggregates, particles, drops, etc. (such as the compositions described herein), the term "fine particle dose" or "FPD" refers to a dose expressed as a fraction of the total mass or nominal or metered dose within the inhalable range. The dose in the inhalable range is the sum of the doses delivered in the micropore collector in the new generation of impactors operating at stage 3 through a flow rate of 30l/min, measured in vitro.

In the context of compositions containing or providing inhalable aggregates, particles, drops, etc. (such as the compositions described herein), the term "fine particle fraction" or "FPF" refers to the proportion of material delivered relative to the delivered dose (i.e., the amount exiting from the actuator of the delivery device (such as MDI)) in the inhalable range. The amount of material delivered in the respirable range is the sum of the materials delivered in the microporous collector in the new generation of impactors measured in vitro as operating at stage 3 through a flow rate of 30 l/min.

As used herein, the term "inhibit" refers to a trend in occurrence of a phenomenon, symptom, or condition or a measurable decrease in the extent of occurrence of the phenomenon, symptom, condition. The term "inhibit" or any form thereof is used in the broadest sense and includes minimizing, preventing, reducing, suppressing (repress), suppressing (suppress), suppressing, restricting, limiting, slowing the progression thereof, and the like.

As used herein, "mass median aerodynamic diameter" or "MMAD" refers to the aerodynamic diameter of an aerosol below which 50% of the mass of the aerosol consists of particles having an aerodynamic diameter less than MMAD calculated according to the United States Pharmacopeia (USP) monograph 601.

As referred to herein, the term "optical diameter" means the particle size measured by Fraunhofer diffraction pattern using a laser diffraction particle size analyzer (e.g., sympatec GmbH, clasthal-Zellerfeld, germany) equipped with a dry powder dispenser.

The term "solution mediated transformation" refers to a phenomenon in which a more soluble form of a solid material (i.e., particles or amorphous material having a smaller radius of curvature (driving force for ostwald ripening)) dissolves and recrystallizes to a more stable crystalline form (which may coexist in equilibrium with its saturated propellant solution).

By "patient" is meant an animal in which one or more of the active agents described herein will have a therapeutic effect. In some embodiments, the patient is a human.

By "perforated microstructure" is meant a suspended particle comprising a structural matrix that exhibits, defines, or contains voids, pores, defects, depressions, spaces, interstitial spaces, apertures, perforations, or holes that allow surrounding suspension media to penetrate, fill, or diffuse into the microstructure, such as those materials and formulations described in U.S. patent No. 6,309,623 to Weers et al (which is incorporated herein by reference) and U.S. patent No. 8,815,258, U.S. patent No. 9,463,161, and U.S. patent application publication 2011/0135737. In general, the primary form of the perforated microstructure is not critical, and any overall configuration that provides the desired formulation characteristics is contemplated herein. Thus, in some embodiments, the perforated microstructures may include approximately spherical shapes, such as hollow, porous, spray-dried microspheres. However, any predominant form or aspect ratio of collapsed, corrugated, deformed or crushed particulate matter may also be compatible.

As with the suspended particles described herein, the perforated microstructures can be formed of any biocompatible material that does not substantially degrade or dissolve in the selected suspending medium. While various 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 fluorinated surfactant).

The term "suspension medium" as used herein refers to a material that provides a continuous phase in which active agent particles and suspended particles can be dispersed to provide a co-suspension formulation. Suspension media used in the formulations described herein include propellants. As used herein, the term "propellant" refers to one or more pharmacologically inert substances that exert a vapor pressure at normal room temperature that is high enough to propel a medicament from the canister of an MDI to a 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".

The term "inhalable" generally refers to particles, aggregates, droplets, etc., that are sized such that they may be inhaled and reach the airways of the lungs.

The terms "physical stability" and "physically stable," when used in reference to the compositions described herein, refer to compositions that are resistant to one or more of aggregation, flocculation, and particle size change due to solution-mediated transformation, and are capable of substantially maintaining MMAD and fine particle dosing of suspended particles. In some embodiments, physical stability may be assessed by subjecting the composition to accelerated degradation conditions (such as by temperature cycling).

When referring to an active agent, the term "effective" means an active agent that is therapeutically effective at or below a dose ranging from about 0.01mg/kg to about 1 mg/kg. Typical dosages of effective active agents are generally in the range of about 100 μg to about 100 mg.

When referring to an active agent, the term "highly effective" means an active agent that is therapeutically effective at or below a dose of about 10 μg/kg. Typical dosages of highly potent active agents are generally in the range of up to about 100 μg.

The terms "suspension stability" and "stable suspension" refer to a suspension formulation capable of maintaining the co-suspension properties of the active agent particles and the suspended particles over a period of time. In some embodiments, suspension stability may be measured by the delivered dose uniformity achieved by the compositions described herein.

The term "substantially insoluble" means that the composition is completely insoluble in the particular solvent or that it is poorly soluble in the particular solvent. By substantially insoluble is meant that the solubility of a particular solute is less than one part per 100 parts of solvent. The term substantially insoluble includes the definitions of "sparingly soluble" (100 to 1000 parts of solvent per part of solute), "very sparingly soluble" (1000 to 10,000 parts of solvent per part of solute) and "practically insoluble" (more than 10,000 parts of solvent per part of solute) as given in Table 16-1 of Remington: THE SCIENCE AND PRACTICE of Pharmacy, 21 st edition Lippincott, williams & Wilkins,2006, page 212.

The term "surfactant" as used herein refers to any agent that preferentially adsorbs to the interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water/air interface, or an organic solvent/air interface. Surfactants typically have hydrophilic and lipophilic portions such that when adsorbed onto the microparticles they tend to present portions that do not attract like coated particles to the continuous phase, thereby reducing particle agglomeration.

A "therapeutically effective amount" is an amount of a compound that achieves a therapeutic effect by inhibiting a disease or condition in a patient or by prophylactically inhibiting or preventing the onset of a disease or condition. A therapeutically effective amount may be one or more symptoms that alleviate the disease or disorder in the patient to some extent; partially or completely restoring to normal one or more physiological or biochemical parameters associated with the disease or disorder or with the cause of the disease or disorder; and/or an amount that reduces the likelihood of onset of the disease or disorder.

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

Composition and method for producing the same

The compositions described herein comprise a suspending medium comprising a propellant, active agent particles, and suspending particles. The compositions described herein may comprise one or more additional ingredients, if desired. Furthermore, 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; alternatively, two or more different types of active agent particles may be used, wherein each different type of active agent particle comprises a different active agent. In some embodiments, two or more types of suspended particles may be used in the composition to deliver two 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" is meant a single dosage form of two or more active agents, such as a formulation in a single metered dose inhaler.

Generally, buoyancy causes particle milk out, which is less dense than the propellant, and particle deposition, which is more dense than the propellant, due to the density differences between the different kinds of particles and the medium in which they are suspended (e.g. the propellant or the propellant system). Thus, in suspensions composed of a mixture of different types of particles having different densities or different flocculation tendencies, the sedimentation or creaming behaviour is expected to be specific for each different particle type and the specific suspension medium used, and would be expected to result in separation of the different particle types in the suspension medium.

However, the combination of propellant, active agent particles, and suspending particles described herein provides a co-suspension in which the active agent particles and suspending particles are co-located within the propellant (i.e., the active agent particles are associated with the suspending particles such that the suspending particles and active agent particles do not exhibit substantial separation from one another (such as by differential deposition or milk deposition) even after a time sufficient to form a milk-out layer or deposit). In particular, the active agent particles are associated with the suspended particles such that under typical patient use conditions, the active agent particles and suspended particles are not substantially separated in the continuous phase formed by the suspending medium.

The combination of propellant, active agent particles and suspended particles according to the present description provides the desired chemical stability, suspension stability and active agent delivery characteristics. For example, in certain embodiments, a composition as described herein may inhibit or reduce one or more of the following when present in an MDI canister: flocculation of the active agent material; differential deposition or emulsion of active agent particles and suspended particles; solution-mediated conversion of the active agent material; and loss of active agent to the surface of the container closure system, particularly the metering valve components. These characteristics act to achieve and maintain aerosol performance when the formulation is delivered from the MDI, such that the desired fine particle fraction, fine particle dose, and delivered dose uniformity characteristics are achieved and substantially maintained throughout the process of emptying the MDI canister containing the formulation. Furthermore, compositions according to the present description can provide stable formulations that provide consistent dosing characteristics, even for potent and highly potent active agents, while using relatively simple HFO suspension media that do not require modification by addition of, for example, a latent solvent, an anti-solvent, a solubilizing agent, or an adjuvant. Furthermore, in certain embodiments, the pharmaceutical compositions described herein may be formulated with HFO propellants or propellant systems that are substantially free of anti-solvents, solubilizing agents, cosolvents, or adjuvants.

In some embodiments, compositions formulated according to the present teachings inhibit physical and/or chemical degradation of the active agent contained therein. For example, in certain embodiments, the compositions described herein may inhibit one or more of chemical degradation, flocculation, aggregation, and solution-mediated transformation of an active agent contained in the composition. The chemical stability and suspension stability provided by the compositions described herein provide enhanced robustness in the Simulated Use Test (SUT) as compared to conventional formulations. The simulated use test involves storing MDI canisters for five weeks at 25 ℃ and 75% Relative Humidity (RH), without weekly cleaning devices, and dispensing the composition from the MDI at 25 ℃ and 50% RH. The enhanced robustness may take the form of: consistency in injection weight (i.e., weight of composition dispensed upon activation of the MDI), low level of propellant leakage, and desired Delivery Dose Uniformity (DDU) throughout the process of emptying the MDI canister, even where the active agent to be delivered is highly effective and delivered at very low doses. For example, in some embodiments, the compositions described herein exhibit an injection weight reduction of 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% when delivered by MDI in a SUT. In further embodiments, the compositions described herein exhibit a weight loss in MDI per year of 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% at 20 ℃ and 60% RH. In yet further embodiments, the compositions described herein exhibit a DDU of ±20% or better, ±15% or better or ±10% or better throughout the process of emptying the MDI canister. Furthermore, the compositions according to the present description exhibit enhanced robustness by substantially maintaining FPF and FPD performance throughout the process of evacuating an MDI canister, even after experiencing accelerated degradation conditions. For example, in some embodiments, the compositions described herein are dispensed from MDI at an FPF maintained within about 85% or about 95% of the original FPF. The compositions described herein provide the additional benefit of achieving this property when formulated with HFO propellants. In particular embodiments, the compositions described herein achieve one or more of the target DDU, FPF, or FPD when formulated with a suspension medium comprising only one or more HFO propellants, and do not require modification of the propellant characteristics, such as by addition of, for example, one or more latent solvents, anti-solvents, solubilizing agents, adjuvants, or other propellant modifying materials.

Suspension medium

The suspending medium included in the compositions described herein includes one or more propellants. In general, suitable propellants for use as suspending media are those propellant gases which can liquefy under pressure at room temperature and which are safe and toxicologically non-toxic upon inhalation or topical use. Furthermore, it is desirable that the selected propellant is relatively unreactive with the suspended particles or active agent particles. In the past, compositions for delivery by MDI have typically been formulated using chlorofluorocarbon (CFC) propellants, hydrofluoroalkanes (HFAs) or perfluorinated compounds (PFCs). Propellants comprising Hydrofluoroolefins (HFOs) are considered more environmentally friendly, but there are several obstacles to using HFOs in MDI formulations given the significant differences between HFOs and other propellants. For example, 1, 2-tetrafluoroethane (also known as norhalothane, HFA-134a or HFC-134 a) is widely used as a refrigerant or propellant in industrial, consumer and pharmaceutical products, however, HFO has proven to be unusable as a substitute for HFA-134a due to the thermodynamic differences between HFO and HFA-134 a. Furthermore, HFOs for industrial or consumer use do not comply with Good Manufacturing Practice (GMP) regulations and are considered unsafe for patient use. Furthermore, the performance of pMDI is highly dependent on the propellant because the propellant characteristics affect suspension stability, suspension atomization, aerosol droplet diameter, etc. For example, a recent study has shown that the same suspended particles have lower suspension stability in HFO-1234ze than HFA-134a and HFA-227ea (Wang, H. Et al, respiratory Drug Delivery, lisbon, portugal, 2019). Thus, extensive experimentation will be required to identify formulations that will deliver the desired dose of active agent particles at the desired DDU and consistent FPF values. As shown in table a below, the physicochemical properties in the different propellants vary widely.

Propellant characteristics:

unexpectedly, it has been found that MDI formulations containing HFO propellants are suitable for use as inhalation drugs for compositions comprising active agent particles and suspended particles as described herein, despite the fact that HFO and other propellants (e.g., HFA) have significantly different structures and characteristics.

In some embodiments, the HFO propellant is 1, 3-tetrafluoropropene, also known as HFO-1234ze. HFO-1234ze has a trans form ((1E) -1, 3-tetrafluoropropene, also known as HFO-1234ze (E)) and a cis form ((1Z) -1, 3-tetrafluoropropene, also known as HFO-1234ze (Z)). In some embodiments, the HFO propellant is HFO-1234ze (E), also known as trans-1, 3-tetrafluoroprop-1-ene. In some embodiments, the propellant is a pharmaceutical grade HFO, such as pharmaceutical grade HFO-1234ze (E). The term "pharmaceutical grade propellant" as used herein means a propellant for use in humans that complies with GMP regulations. For example, pharmaceutical grade propellants conform to guidelines of major health authorities such as the inhalation of the FDA or EMA and Nasal product pharmaceutical quality guidelines (Guideline on The Pharmaceutical Quality of Inhalation to Nasal Products), and their specifications as excipients have been established to ensure the quality and safety of propellants, for example HFO-1234ze (E) for pharmaceutical product use. Specification testing included propellant identity, appearance, assay, acidity, total residue, moisture content, related impurities, and unrelated impurities. Stability studies are also underway to demonstrate long-term physicochemical stability. In some embodiments, pharmaceutical grade HFO-1234ze (E) has a purity of at least about 99.90%. In some embodiments, the propellant is pharmaceutical grade HFO-1234ze (E) having a purity of at least about 99.90%, at least about 99.91%, at least about 99.92%, at least about 99.93%, at least about 99.94%, at least about 99.95%. Pharmaceutical grade HFO-1234ze (E) is suitable for use as a propellant due to its overall purity and the absence or low concentration of specific impurities. In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less of any of the following impurities: HFO-1234yf, HFO-1234ze (Z), HFC-125, CFC-11, HFC-245cb, HFO-1225ye (Z) or HFO-1225ye (E), CFC-113 and CFC-114. In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less HFO-1234yf. In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less HFO-1234ze (Z). In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less HFC-125. In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, about 5ppm or less of CFC-11. In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less HFC-245cb. In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less HFO-1225ye (Z). In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less HFO-1225ye (E). In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less of CFC-113. In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 10ppm or less, about 9ppm or less, about 8ppm or less, about 7ppm or less, about 6ppm or less, or about 5ppm or less of CFC-114. In some embodiments, pharmaceutical grade HFO-1243ze (E) contains about 150ppm or less, about 140ppm or less, about 130ppm or less, about 120ppm or less, about 110ppm or less, or about 100ppm or less HCFC-124. In some embodiments, pharmaceutical grade HFO-1234ze (E) contains about 400ppm or less, about 375ppm or less, about 350ppm or less, about 325ppm or less or about 300ppm or less HFC-152a.

In some embodiments, the suspension medium may be formed from a single propellant (e.g., pharmaceutical grade HFO-1234ze (E)). In certain embodiments, certain vapor pressure compounds are present at relatively low levels. Such compounds may be associated with suspended particles.

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, anti-solvents, solubilizers, stabilizers, latent solvents, or adjuvants.

In some embodiments, a pharmaceutical grade HFO-1234ze (E) propellant is included; a plurality of active agent particles; and a plurality of phospholipid particles, with a pharmaceutical composition of the invention comprising a pharmaceutical grade HFA-134a propellant; a plurality of active agent particles; exhibit similar or comparable bioavailability of the active agent as compared to a reference pharmaceutical composition of a plurality of phospholipid particles. As used herein, "reference to a pharmaceutical composition" means an alternative pharmaceutical composition that contains the same active agent particles and the same suspended particles as the pharmaceutical composition of the present invention except for the propellant. For example, the pharmaceutical composition of the invention and the reference pharmaceutical composition comprise the same active agent particles and the same phospholipid particles, but the reference pharmaceutical composition comprises a pharmaceutical grade HFA-134a propellant, and the pharmaceutical composition of the invention comprises a pharmaceutical grade HFO-1234ze (E) propellant. HFA-134a is a hydrofluorocarbon, chemical name: 1, 2-tetrafluoroethane. HFA-134a has been used as a propellant for metered-dose inhalers. As used herein, "bioavailability" means the proportion of an active agent that enters the circulation when introduced into the body through the lungs. In one embodiment, similar or comparable bioavailability may be exhibited, wherein the ratio of the geometric mean of the log-transformed Cmax, AUCinf or AUClast of the two products (e.g., the pharmaceutical composition of the invention and the reference pharmaceutical composition) is from about 0.80 to about 1.25, with or without the 90% Confidence Interval (CI) limit.

In some embodiments, the pharmaceutical compositions of the invention exhibit a Cmax, AUCinf or AUClast of any one or more of the active agents that is about 80% to about 125% of the Cmax, AUCinf or AUClast of the active agent of the reference pharmaceutical composition having a geometric mean. In some embodiments, the pharmaceutical compositions of the invention comprise a pharmaceutical grade HFO-1234ze (E) propellant; a plurality of active agent particles; and a plurality of phospholipid particles comprising a perforated microstructure, and 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 composition of the invention and the reference pharmaceutical composition are administered by actuation of a metered dose inhaler, wherein each actuation of the pharmaceutical composition of the invention provides the same delivered dose of active agent as each actuation of the reference pharmaceutical composition. In some embodiments, the active agent particles comprise an active agent selected from the group consisting of a Long Acting Muscarinic Antagonist (LAMA), a long acting beta 2-agonist (LABA), a short acting beta-agonist (SABA), an Inhaled Corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent as described herein.

As used herein, cmax, AUCinf and AUClast are pharmacokinetic metrics used to determine the administration of an active agent. As used herein, cmax means the highest concentration of active agent in the blood after administration of a dose, e.g., via inhalation. As used herein, the area under the curve (AUC) is the constant integral of the curve describing the change in concentration of active agent in plasma as a function of time. As used herein, AUCinf means the area under the curve from the time of administration to the last measurable concentration and extrapolated to infinity. As used herein, AUClast means the area under the curve from the time of administration to the last measurable concentration.

In some embodiments, the pharmaceutical compositions of the invention exhibit a Cmax of budesonide that is about 80% to about 125% of the budesonide Cmax of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the invention exhibit a Cmax of glycopyrronium that is about 80% to about 125% of the Cmax of glycopyrronium of the reference pharmaceutical composition. In some embodiments, the pharmaceutical composition of the invention exhibits a Cmax of formoterol that is about 80% to about 125% of the Cmax of formoterol of the reference pharmaceutical composition. In some embodiments, cmax of budesonide is the geometric mean of the log-transformed values. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide and albuterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide, glycopyrrolate, and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide, glycopyrrolate, formoterol and roflumilast active agent particles.

In some embodiments, the pharmaceutical compositions of the invention exhibit an AUCinf of budesonide that is from about 80% to about 125% of the budesonide AUCinf of the reference pharmaceutical composition. In some embodiments, the pharmaceutical composition of the invention exhibits an AUCinf of formoterol that is about 80% to about 125% of the formoterol AUCinf of the reference pharmaceutical composition. In some embodiments, the AUCinf of budesonide is a geometric mean of the log-transformed values. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide and albuterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide, glycopyrrolate, and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide, glycopyrrolate, formoterol and roflumilast active agent particles.

In some embodiments, the pharmaceutical compositions of the invention exhibit an AUClast of budesonide that is from about 80% to about 125% of the budesonide AUClast of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the invention exhibit an AUClast of glycopyrrolate that is from about 80% to about 125% of the AUClast of glycopyrrolate of the reference pharmaceutical composition. In some embodiments, the pharmaceutical composition of the invention exhibits an AUClast of formoterol that is about 80% to about 125% of the AUClast of the reference pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the invention exhibit an AUClast of budesonide and formoterol that is about 80% to about 125% of the budesonide and formoterol AUClast of the reference pharmaceutical composition. In some embodiments, the AUClast of budesonide is a geometric mean of the log-transformed values. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide and albuterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of glycopyrrolate and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide, glycopyrrolate, and formoterol active agent particles. In some embodiments, the pharmaceutical compositions of the present invention comprise a combination of budesonide, glycopyrrolate, formoterol and roflumilast active agent particles.

Active agent particles

The active agent particles contained in the compositions described herein are formed of a material capable of being dispersed and suspended in a suspending medium, and are of a size that facilitates delivery of the respirable particles from the composition. Thus, in one embodiment, the active agent particles are provided as micronized particles, wherein at least 90% by volume of the active agent particles exhibit an optical diameter of about 7 μm or less. In some embodiments, at least 90% by volume of the active agent particles exhibit an optical diameter of about 5 μm or less. In other embodiments, at least 90% by volume of the active agent particles exhibit an optical diameter selected from the range 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% by volume of the active agent particles exhibit an optical 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, wherein at least 50% by volume of the active agent particles exhibit an optical diameter of about 4 μm or less. In a further embodiment, the active agent particles are provided as micronized particles, wherein at least 50% by volume of the active agent particles exhibit an optical diameter selected from about 3 μm or less, about 2 μm or less, about 1.5 μm or less, and about 1 μm or less. In yet a further embodiment, the active agent particles are provided as micronized particles, wherein at least 50% by volume of the active agent particles exhibit an optical diameter in the range selected from 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.

In certain embodiments, the active agent particles comprise glycopyrronium and at least 90% by volume of the active agent particles exhibit an optical diameter of about 7 μm or less. In certain embodiments, the active agent particles comprise budesonide, and at least 90% by volume of the active agent particles exhibit an optical diameter of about 7 μm or less. In certain embodiments, the active agent particles comprise formoterol, and at least 90% by volume of the active agent particles exhibit an optical 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 an optical diameter of about 5 μm or less.

The active agent particles may be formed entirely of the active agent, or they 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 completely or substantially crystalline. In another embodiment, the active agent particles may include active agents that exist in both crystalline and amorphous states. In yet another embodiment, the active agent particles may include active agents that exist in both crystalline and amorphous states. In yet another embodiment, when two or more active agents are present in the active agent particles, at least one such active agent may be present in crystalline or substantially crystalline form, and at least another active agent may be present in an amorphous state. In yet another embodiment, when two or more active agents are present in the active agent particles, each such active agent may be present in crystalline or substantially crystalline form. When the active agent particles described herein include 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 characteristics of the active agent used. Suitable excipients for formulating the active agent particles include, for example, lipids, phospholipids, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, synthetic or natural polymeric or surfactant materials.

Any suitable process may be employed to obtain micronized active agent particles for inclusion in the compositions described herein. Various processes may be used to produce active agent particles suitable for use in the formulations described herein, including but not limited to micronization, crystallization or recrystallization processes by grinding or milling processes, processes using precipitation from supercritical or near supercritical solvents, spray drying, spray freeze drying, or lyophilization. Patent references teaching 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 international patent publication No. WO 2007/009164. Where the active agent particles comprise an active agent material formulated with one or more excipients or adjuvants, the micronized active agent particles may be formed using one or more of the foregoing processes, and such processes may be used to obtain active agent particles having a desired size distribution and particle configuration.

The active agent particles may be provided in any suitable concentration within the suspension medium. The active agent contained in the active agent particles is substantially insoluble in the suspending medium. In some embodiments, the active agent, while substantially insoluble, exhibits measurable solubility in the suspending medium. However, the compositions described herein maintain the physical stability of such active agents even where the active agents exhibit measurable solubility in the suspending medium. In particular, in certain embodiments, the active agents included in the compositions described herein may exhibit sufficient solubility in the suspending medium such that up to 5% of the total active agent mass is dissolved in the suspending medium. Alternatively, the solubility of the active agent may result in up to 1% of the total active agent mass being dissolved in the suspension medium. In another embodiment, the solubility of the active agent may result in up to 0.5% of the total active agent mass being dissolved in the suspension medium. In another embodiment, the solubility of the active agent may result in up to 0.05% of the total active agent mass being dissolved in the suspension medium. In another embodiment, the solubility of the active agent may result in up to 0.025% of the total active agent mass being dissolved in the suspension medium.

Various therapeutic or prophylactic agents may be incorporated into the co-suspension compositions disclosed herein. Exemplary active agents include those that can be administered in the form of an aerosolized drug, and active agents suitable for use in the compositions described herein include those that can be present in a form that is dispersible in the selected suspending medium or can be formulated in a manner that is dispersible in the selected suspending medium (e.g., is substantially insoluble in the suspending medium or exhibits solubility that substantially maintains the co-suspending formulation), are capable of forming a co-suspension with suspended particles, and are inhaled in physiologically effective amounts. Active agents useful in forming the active agent particles described herein may have a variety of biological activities.

Examples of specific active agents that may be included in a composition according to the present description may be, for example, short-acting beta agonists (SABA), such as bittersweet, carboplatin, fenoterol, hexenalin, wheezil (isoprenaline), levalbuterol, oxacinline (metafluminellin), pirbuterol, procaterol, ramitrerol, salbutamol (salbutamol), terbutaline, tolterol, rapantel and epinephrine; long-acting β2 adrenergic receptor agonists ("LABA"), such as bambuterol, clenbuterol, formoterol, and salmeterol; super-long acting β2 adrenergic receptor agonists, such as carmoterol, mivirol, indacaterol and β2 agonists containing salicin or indole and adamantyl derivatives; corticosteroids such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone and triamcinolone; anti-inflammatory agents such as fluticasone propionate, beclomethasone dipropionate, flunisolide, budesonide, tripedane, cortisone, prednisone, prednisolone (prednisilone), dexamethasone (dexamethasone), betamethasone (betamethasone), or triamcinolone (triamcinolone acetonide); antitussives such as noscapine (noscapine); bronchodilators, such as ephedrine, epinephrine, fenoterol, formoterol, wheezin, metadoxypropyleneine, salbutamol, salmeterol, terbutaline; and muscarinic antagonists, including long acting muscarinic antagonists ("LAMA"), such as glycopyrrolate, dexpirronium, scopolamine, tolipomide (tropicamide), pirenzepine (pirenzepine), dimenhydrinate (DIMENHYDRINATE), tiotropium (tiotropium), daptomium (darotropium), aclidinium (aclidinium), trospium (trospium), ipratropium (ipatropium), atropine (atropine), benzathine (benzatropin), or oxitropium (oxitropium).

Where appropriate, the active agents provided in the compositions, including but not limited to those specifically described herein, may be used in the form of salts (e.g., alkali metal or amine salts or as acid addition salts) or as esters, solvates (e.g., hydrates), derivatives, or free bases thereof. Furthermore, the active agent may be in any crystalline form or in the form of an isomer or in the form of a mixture of isomers, for example as pure enantiomers, mixtures of enantiomers, as racemates or as mixtures 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 suspending medium.

Because the disclosed compositions are capable of reproducibly delivering 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 comprise one or more potent active agents that will be delivered at a dose selected from the group consisting of: the MDI is actuated between about 100 μg and about 100mg, between about 100 μg and about 10mg, and between about 100 μg and 1mg per actuation. In other embodiments, the compositions described herein may comprise one or more potent or highly potent active agents that will be delivered at a dose selected from the group consisting of: the MDI is actuated at most about 80 μg, at most about 40 μg, at most about 20 μg, between about 10 μg and about 100 μg, between about 5 μg and about 50 μg, and between about 1 μg and about 10 μg per actuation. Furthermore, in certain embodiments, the compositions described herein may comprise one or more highly potent active agents that will be delivered at a dose selected from the group consisting of: MDI is actuated between about 0.1 and about 2 μg, between about 0.1 and about 1 μg, and between about 0.1 and about 0.5 μg per actuation.

If desired, a composition as described herein may comprise a combination of two or more active agents. For example, a combination of two or more active agent particles may be co-suspended with a single class of suspended particles. Alternatively, the composition may comprise two or more types of active agent particles co-suspended with two or more different types of suspended particles. Even further, the compositions described herein may comprise two or more active agents combined within a single class of active agent particles. For example, where the active agent particles are formulated using one or more excipients or adjuvants other than the active agent material, such active agent particles may include a single particle comprising two or more different active agents.

In certain embodiments, the active agent included in the compositions described herein is a LAMA active agent. Where the composition includes a LAMA active agent, in particular embodiments, the LAMA active agent may be selected from, for example, glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, turnip ammonium, and daptominium, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. In some embodiments, the LAMA active agent is present at a concentration in the range of about 0.04mg/mL to about 2.25 mg/mL.

Glycopyrrolate is useful for the treatment of inflammatory or obstructive pulmonary diseases and conditions such as those described herein. As an anticholinergic, glycopyrrolate acts as a bronchodilator and provides an antisecretory effect which is beneficial for use in the treatment of pulmonary diseases and conditions characterised by increased mucus secretion. Glycopyrronium is a quaternary ammonium salt. Where appropriate, the glycopyrronium may be used in salt form (e.g. alkali metal or amine salts, or as acid addition salts) or as an ester or solvate (hydrate). Furthermore, glycopyrronium can be in any crystalline form or in the form of an isomer or a mixture of isomeric forms, for example pure enantiomers, mixtures of enantiomers, racemates or mixtures thereof. In this regard, the form of glycopyrronium can be selected to optimize the activity and/or stability of glycopyrronium and/or to minimize the solubility of glycopyrronium in the suspension medium. Suitable counter ions are pharmaceutically acceptable counter ions, 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-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate. In a particular embodiment of the compositions described herein, the bromide salt of glycopyrronium, 3- [ (cyclopentylpolylphenylacetyl) oxy ] -1, 1-dimethylpyrrolidinium bromide, also known as (RS) - [3- (SR) -hydroxy-1, 1-dimethylpyrrolidinium bromide ] - α -cyclopentylmandelate, is used and can be prepared according to the procedure described in U.S. patent No. 2,956,062.

Where the compositions described herein include glycopyrronium, in certain embodiments, the compositions may include glycopyrronium sufficient to provide a target delivered dose selected from the group consisting of: between about 1 μg and about 200 μg of MDI per actuation, between about 5 μg and about 150 μg of MDI per actuation, between about 10 μg and 100 μg of MDI per actuation, between about 5 μg and about 50 μg of MDI per actuation, between about 2 μg and about 25 μg of MDI per actuation, and between about 6 μg and about 15 μg of MDI per actuation. In other such embodiments, the formulation comprises glycopyrronium in an amount sufficient to provide a dose selected from the group consisting of: at most about 200 μg, at most about 150 μg, at most about 75 μg, at most about 40 μg, at most about 20 μg, or at most about 10 μg per actuation. In a further embodiment, the formulation comprises glycopyrronium in an amount sufficient to provide a dose selected from the group consisting of: 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 a target delivered dose as described herein, where the compositions described herein comprise glycopyrronium as an active agent, in particular embodiments, the amount of glycopyrronium included in the composition can be selected from, for example, between about 0.04mg/mL to about 2.25 mg/mL.

In other embodiments, tiotropium, including any pharmaceutically acceptable salt, ester, isomer, or solvate thereof, may be selected as a LAMA active agent for inclusion in the compositions described herein. Tiotropium is a known long-acting anticholinergic agent suitable for the treatment of diseases or conditions associated with pulmonary inflammation or obstruction, such as those described herein. Tiotropium, including crystalline and pharmaceutically acceptable salt forms of tiotropium, is 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. Where the compositions described herein comprise tiotropium, in certain embodiments, the compositions may comprise tiotropium in an amount sufficient to provide a delivered dose selected from the group consisting of: MDI is between about 2.5 μg and about 50 μg per actuation, between about 4 μg and about 25 μg per actuation, between about 2.5 μg and about 20 μg, between about 10 μg and about 20 μg, and between about 2.5 μg and about 10 μg. In other such embodiments, the formulation comprises tiotropium sufficient to provide a delivered dose selected from the group consisting of: the MDI is activated at most about 50 μg, at most about 20 μg, at most about 10 μg, at most about 5 μg, or at most about 2.5 μg per actuation. In a further embodiment, the formulation comprises tiotropium sufficient to provide a delivered dose selected from the group consisting of: the MDI actuated about 3 μg, 6 μg, 9 μg, 18 μg and 36 μg per actuation. In order to achieve a delivered dose as described herein, where the compositions described herein comprise tiotropium as an active agent, in particular embodiments the amount of tiotropium included in the compositions may be selected from, for example, between about 0.01mg/mL to about 0.5 mg/mL.

In certain embodiments, the compositions described herein comprise LABA active agents. In such embodiments, the LABA active agent may be selected from, for example, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, miveterol, indacaterol, vilantro, and β ₂ agonists containing salicin or indole and adamantyl derivatives, and any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. In some embodiments, the LABA active agent is present at a concentration in the range of about 0.01mg/mL to about 1 mg/mL.

In certain such embodiments, formoterol is selected as the LABA active agent. Formoterol can be used for the treatment of inflammatory or obstructive pulmonary diseases and conditions such as those described herein. Formoterol has the chemical name (+ -) -2-hydroxy-5- [ (1 RS) -1-hydroxy-2- [ [ (1 RS) -2- (4-methoxyphenyl) -1-methylethyl ] -amino ] ethyl ] carboxanilide and is commonly used in pharmaceutical compositions as a racemic fumarate dihydrate salt. Formoterol can be used in the form of salts (e.g. alkali metal salts or amine salts, or as acid addition salts) or as esters or solvates (hydrates) where appropriate. Furthermore, formoterol can be in any crystalline form or in the form of an isomer or mixture of isomeric forms, for example pure enantiomers, mixtures of enantiomers, racemates or mixtures thereof. In this regard, the form of formoterol may be selected to optimise the activity and/or stability of formoterol and/or to minimise the solubility of formoterol in the suspension medium. Pharmaceutically acceptable salts of formoterol include, for example, salts of inorganic acids (such as hydrochloric, hydrobromic, sulfuric and phosphoric acid) and organic acids (such as fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p-methoxybenzoic, salicylic, o-hydroxybenzoic and p-hydroxybenzoic acids, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthoic acid). The hydrate of formoterol is described, for example, in U.S. patent No. 3,994,974 and U.S. patent No. 5,684,199. Specific crystalline forms of formoterol and other β2 adrenergic receptor agonists are described, for example, in WO95/05805, and specific isomers of formoterol are described in U.S. patent No. 6,040,344.

In a particular embodiment, the formoterol material used to form the formoterol particles is formoterol fumarate, and in one such embodiment, formoterol fumarate is present in the dihydrate form. Formoterol fumarate can be referred to as the chemical name N- [ 2-hydroxy-5- [ (1 RS) -1-hydroxy-2- [ [ (1 RS) -2- (4-methoxyphenyl) -1-methylethyl ] -amino ] ethyl ] phenyl ] carboxamide (E) -2-butenedioic acid salt dehydrate. Where the compositions described herein comprise formoterol, in certain embodiments, the compositions described herein may comprise formoterol at a concentration that achieves a target delivered dose selected from the group consisting of: the MDI is actuated between about 1 μg and about 30 μg, between about 0.5 μg and about 10 μg, between about 1 μg and about 10 μg, between about 2 μg and 5 μg, between about 2 μg and about 10 μg, between about 3 μg and about 10 μg, between about 5 μg and about 10 μg, and between 3 μg and about 30 μg per actuation. In other embodiments, the compositions described herein may comprise formoterol in an amount sufficient to provide a target delivered dose selected from the group consisting of: at most about 30 μg, at most about 10 μg, at most about 5 μg, at most about 2.5 μg, at most about 2 μg, or at most about 1.5 μg per actuation. In a further embodiment, the formulation comprises a dose of formoterol sufficient 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. In order to achieve a targeted delivered dose as described herein, where the compositions described herein comprise formoterol as the active agent, in particular embodiments the amount of formoterol included in the composition can be selected, for example, from between about 0.01mg/mL to about 1mg/mL, from between about 0.01mg/mL to about 0.5mg/mL, and from between about 0.03mg/mL to about 0.4 mg/mL.

Where the pharmaceutical compositions described herein comprise a LABA active agent, in certain embodiments, the active agent may be salmeterol, including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. Salmeterol is useful in the treatment of inflammatory or obstructive pulmonary diseases and disorders, such as those described herein. Salmeterol, pharmaceutically acceptable salts of salmeterol, and methods for preparing the same are described, for example, in U.S. patent No. 4,992,474, U.S. patent No. 5,126,375, and U.S. patent No. 5,225,445.

In the case of salmeterol as a LABA active agent, in certain embodiments, the compositions described herein may comprise salmeterol at a concentration that achieves a delivered dose selected from the group consisting of: the MDI is actuated between about 2 μg and about 120 μg, between about 4 μg and about 40 μg, between about 8 μg and about 20 μg, between about 8 μg and about 40 μg, between about 20 μg and about 40 μg, and between about 12 μg and about 120 μg per actuation. In other embodiments, the compositions described herein may comprise salmeterol in an amount sufficient to provide a delivered dose selected from the group consisting of: the MDI is activated at most about 120 μg, at most about 40 μg, at most about 20 μg, at most about 10 μg, at most about 8 μg, or at most about 6 μg per actuation. In order to achieve a targeted delivery dose as described herein, where the compositions described herein comprise salmeterol as the active agent, in particular embodiments the amount of salmeterol contained in the composition may be selected from, for example, between about 0.04mg/mL and about 4mg/mL, between about 0.04mg/mL and about 2.0mg/mL, and between about 0.12mg/mL and about 0.8 mg/mL.

Where the pharmaceutical compositions described herein comprise SABA active agent, in certain embodiments, the active agent may be bittersweet, carbopol, fenoterol, hexenalin, wheezin (isoprenaline), levosalbutamol, oxacinline (metaisoprenaline), pirbuterol, procaterol, ramitreterol, salbutamol (salbutamol), terbutaline, tolterol, rapterol and epinephrine, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In certain such embodiments, albuterol is selected as the SABA active agent. Salbutamol has the chemical name α ¹ - [ (tert-butylamino) methyl ] 4-hydroxy-meta-xylene- α, α' -diol and has the empirical formula C ₁₃H₂₁NO₃. Salbutamol may be used to treat inflammatory or obstructive pulmonary diseases and conditions such as those described herein. Salbutamol, pharmaceutically acceptable salts of salbutamol (such as salbutamol sulphate) and methods for preparing the same are described, for example, in U.S. patent No. 3,705,233.

In the case of salbutamol as SABA active agent, in certain embodiments, the compositions described herein may comprise salbutamol at a concentration that achieves a delivered dose selected from the group consisting of: the MDI is actuated between about 10 μg and about 200 μg, between about 20 μg and about 300 μg, between about 30 μg and 150 μg, between about 50 μg and about 200 μg, between about 30 μg and about 100 μg, and between about 1 μg and about 300 μg per actuation. In other embodiments, the compositions described herein may comprise albuterol in an amount sufficient to provide a delivered dose selected from the group consisting of: the MDI is activated at most about 300 μg, at most about 200 μg, at most about 150 μg, at most about 100 μg, at most about 50 μg, at most about 30 μg, at most about 20 μg, or at most about 10 μg per actuation. In a further embodiment, the formulation comprises albuterol in an amount sufficient to provide a dose selected from the group consisting of: 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. In order to achieve a targeted delivered dose as described herein, where the compositions described herein comprise albuterol as the active agent, in particular embodiments, the amount of albuterol contained in the composition may be selected from, for example, between about 0.1mg/mL to about 10mg/mL, between about 0.1mg/mL to about 5mg/mL, and between about 0.3mg/mL to about 4 mg/mL.

In other embodiments, the compositions described herein comprise 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 pharmaceutically acceptable salts, esters, isomers or solvates thereof. In some embodiments, the ICS active agent is present at a concentration in the range of about 0.1mg/mL to about 10 mg/mL.

Where the composition comprises an ICS active agent, in particular embodiments, mometasone may be selected. The preparation of mometasone, pharmaceutically acceptable salts of mometasone, such as mometasone furoate, and such materials is known and described, for example, in U.S. patent No. 4,472,393, U.S. patent No. 5,886,200, and U.S. patent No. 6,177,560. Mometasone is suitable for use in the treatment of diseases or conditions associated with pulmonary inflammation or obstruction, such as those described herein (see, e.g., U.S. patent No. 5,889,015, U.S. patent No. 6,057,307, U.S. patent No. 6,057,581, U.S. patent No. 6,677,322, U.S. patent No. 6,677,323, and U.S. patent No. 6,365,581).

Where the compositions described herein comprise mometasone, in particular embodiments, the compositions comprise mometasone (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) in an amount sufficient to provide the targeted delivery dose selected from the group consisting of: the MDI is actuated between about 20 μg and about 400 μg, between about 20 μg and about 200 μg, between about 50 μg and about 200 μg, between about 100 μg and about 200 μg, between about 20 μg and about 100 μg, and between about 50 μg and about 100 μg per actuation. In other embodiments, the compositions described herein may comprise mometasone (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) in an amount sufficient to provide the target delivery dose selected from the group consisting of: MDI is activated at most about 400 μg, at most about 200 μg, or at most about 100 μg per actuation.

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 inflammation or obstruction of the lung, such as those described herein. Fluticasone, pharmaceutically acceptable salts of fluticasone, such as fluticasone propionate, and the preparation of such materials are known and described, for example, in U.S. Pat. No. 4,335,121, U.S. patent No. 4,187,301, and U.S. patent publication No. US 2008125407. The chemical name of budesonide is (RS) -11 beta, 16 alpha, 17, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione and the cyclic 16, 17-acetal of butyraldehyde, which is also well known and described, for example, in U.S. patent No. 3,929,7688. In certain embodiments, the compositions described herein may comprise fluticasone (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) in an amount sufficient to provide a target delivery dose selected from the group consisting of: the MDI is actuated between about 20 μg and about 200 μg, between about 50 μg and about 175 μg, and between about 80 μg and about 160 μg per actuation. In other embodiments, the compositions described herein may comprise fluticasone (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) in an amount sufficient to provide a target delivery dose selected from the group consisting of: the MDI is activated at most about 175 μg, at most about 160 μg, at most about 100 μg, or at most about 80 μg per actuation. Where the compositions described herein comprise budesonide, in certain embodiments, the compositions described herein may comprise budesonide (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) at a concentration that achieves the target delivered dose selected from the group consisting of: the MDI is actuated between about 30 μg and about 240 μg, between about 30 μg and about 120 μg, between about 30 μg and about 100 μg, between about 50 μg and about 400 μg, between about 20 μg and about 600 μg, between about 50 μg and about 200 μg, between about 150 μg and about 350 μg, and between about 30 μg and about 50 μg per actuation. In other embodiments, the compositions described herein may comprise budesonide (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) in an amount sufficient to provide a target delivered dose selected from the group consisting of: the MDI is activated at most about 240 μg, at most about 160 μg, at most about 120 μg, at most about 80 μg, or at most about 50 μg per actuation. In a further embodiment, the formulation comprises budesonide in an amount sufficient to provide a dose selected from the group consisting of: 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. In order to achieve a target delivered dose as described herein, where the compositions described herein comprise budesonide as the active agent, in particular embodiments, the amount of budesonide contained in the composition can be selected from, for example, between about 0.1mg/mL and about 20mg/mL, between about 0.1mg/mL and about 5mg/mL, and between about 0.3mg/mL and about 6 mg/mL.

In further embodiments, the compositions described herein comprise non-corticosteroid anti-inflammatory agents, such as phosphodiesterase-4 (PDE-4) inhibitors and Janus kinase (JAK) inhibitors. Such anti-inflammatory agents may be selected from, for example, roflumilast, apremilast (apremilast), crizotinib (crisaborole), ruxotinib (ruxolitinib), tofacitinib (tofacitinib), olatinib (oclacitinib), baritinib (baricitinib), piracetatinib (peficitinib), fretinib (fedratinib), and Wu Pati ni (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 described, for example, in U.S. patent No. 8,604,064, U.S. patent No. 9,145,365, and U.S. patent No. 9,321,726. Roflumilast is suitable for use in the treatment of diseases or conditions associated with inflammation or obstruction of the lungs, such as those described herein. Roflumilast is sometimes used for the treatment of COPD, in particular severe COPD, and can be used as an oral medicament. Oral administration of roflumilast is common gastrointestinal side effects.

Where the compositions described herein comprise roflumilast, in certain embodiments, the compositions described herein may comprise roflumilast (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) at a concentration that achieves the target delivered dose selected from the group consisting of: the MDI is actuated between about 1 μg and about 100 μg, between about 5 μg and about 80 μg, between about 5 μg and about 50 μg, between about 5 μg and about 25 μg, between about 10 μg and about 25 μg, between about 30 μg and about 240 μg, between about 30 μg and about 120 μg, between about 30 μg and about 100 μg, between about 50 μg and about 400 μg, between about 20 μg and about 600 μg, between about 50 μg and about 200 μg, between about 150 μg and about 350 μg, and between about 30 μg and about 50 μg per actuation. In other embodiments, the compositions described herein may comprise roflumilast (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) in an amount sufficient to provide the target delivered dose selected from the group consisting of: the MDI is activated at most about 240 μg, at most about 160 μg, at most about 120 μg, at most about 80 μg, or at most about 50 μg per actuation. In a further embodiment, the formulation comprises roflumilast in an amount sufficient to provide a dose selected from the group consisting of: 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. In order to achieve a targeted delivered dose as described herein, where the compositions described herein comprise roflumilast as the active agent, in particular embodiments the amount of roflumilast included in the compositions can be selected from, for example, between about 0.1mg/mL and about 20mg/mL, between about 0.1mg/mL and about 5mg/mL, and between about 0.3mg/mL and about 6 mg/mL.

The compositions described herein may be formulated to include (and deliver) a single active agent. Alternatively, the compositions described herein may comprise two or more active agents. In particular embodiments comprising two or more active agents, the compositions described herein may comprise a combination of active agents selected from the group consisting of: 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 comprise three or more active agents. In certain such embodiments, the composition comprises a combination of active agents selected from the group consisting of LAMA, LABA, a combination of corticosteroid and non-corticosteroid anti-inflammatory active agents. For example, a composition as described herein may comprise a combination of active agents selected from the group consisting of: a combination of glycopyrrolate and formoterol, a combination of formoterol and budesonide, a combination of budesonide and salbutamol, glycopyrrolate, a combination of formoterol and budesonide, and a combination of glibenc Long An, formoterol, budesonide and roflumilast.

Those skilled in the art, with the benefit of this disclosure, will appreciate that a 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.

Suspended particles

The suspended particles included in the compositions described herein function to facilitate stabilization and delivery of the active agents included in the compositions. Although various forms of suspended particles may be used, the suspended particles are typically formed from pharmacologically inert materials that are acceptable for inhalation and are substantially insoluble in the propellant of choice. In general, most suspended particles are of a size within the respirable range. Thus, in particular embodiments, the MMAD of the suspended particles will not exceed about 10 μm, but not be below about 500nm. In alternative embodiments, the MMAD of the suspended particles is between about 5 μm and about 750 nm. In another embodiment, the MMAD of the suspended particles is between about 1 μm and about 3 μm. When used in embodiments for nasal delivery from MDI, the MMAD of the suspended particles is between 10 μm and 50 μm.

To obtain respirable suspended particles within the MMAD range, the suspended particles will typically exhibit a volume median optical diameter of between about 0.2 μm and about 50 μm. In one embodiment, the suspended particles exhibit a volume median optical diameter of no more than about 25 μm. In another embodiment, the suspended particles exhibit a volume median optical diameter selected from the group consisting of: 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.

The concentration of suspended particles contained in a composition according to the present description may be adjusted depending on, for example, the amounts of active agent particles and suspending medium used. In one embodiment, the suspended particles are contained in the suspending medium at a concentration selected from the group consisting of: about 0.1mg/mL to about 15mg/mL, about 0.1mg/mL to about 10mg/mL, 1mg/mL to about 15mg/mL, about 3mg/mL to about 10mg/mL, 5mg/mL to about 8mg/mL, and about 6mg/mL. In another embodiment, the suspended particles are contained in the suspension medium at a concentration of up to about 30 mg/mL. In another embodiment, the suspended particles are contained in the suspension medium at a concentration of up to about 25 mg/mL.

The relative amounts of suspending particles to active agent particles are selected to achieve co-suspension as contemplated herein. When the amount of suspended particles (as measured by mass) exceeds the amount of active agent particles, a co-suspended composition can be obtained. For example, in particular embodiments, the ratio of the total mass of suspended particles to the total mass of active agent particles may be between about 3:1 to about 15:1, or alternatively between about 2:1 to 8:1. Alternatively, the ratio of the total mass of suspended particles to the total mass of active agent particles may be higher than about 1, such as up to about 1.5, up to about 5, up to about 10, up to about 15, up to about 17, up to about 20, up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150, and up to about 200, depending on the nature of the suspended particles and active agent particles used. In further embodiments, the ratio of the total mass of suspended particles to the total mass of active agent particles 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.

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

Suspended particles suitable for use in the compositions described herein may be formed from one or more pharmaceutically acceptable materials or excipients that are suitable for inhalation delivery and do not substantially degrade or dissolve in the suspending medium. In one embodiment, a perforated microstructure as defined herein may be used as suspended particles. Suspended particles and perforated microstructures for use as suspended particles and methods for their preparation are described in U.S. patent No. 8,815,258 and U.S. patent No. 9,463,161 and U.S. patent application publication 2011/0135737.

Phospholipids from natural and synthetic sources can be used to prepare suspended particles comprising perforated microstructures suitable for use in the compositions described herein. In particular embodiments, the selected phospholipids will have a gel-to-liquid crystal phase transition of greater than about 400 ℃. Exemplary phospholipids are relatively long chain (i.e., C16-C22) saturated lipids and may include saturated phospholipids, such as saturated phosphatidylcholine having an acyl chain length of 16C or 18C (palmitoyl and stearoyl). Exemplary phospholipids include phosphoglycerides such as dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, ditolyl phosphatidylcholine, 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 International patent publication No. WO 96/32149 and U.S. Pat. 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-phosphorylcholine (DSPC).

In another aspect, the suspended particles used in the compositions described herein may be selected to increase the storage stability of the selected active agent, similar to that disclosed in International patent publication No. WO 2005/000267. For example, in one embodiment, the suspended particles may include a pharmaceutically acceptable glass stabilizing excipient having a Tg of at least 55 ℃, at least 75 ℃, or at least 100 ℃. Glass formers suitable for use in the compositions described herein include, but are not limited to, one or more of trileucine, sodium citrate, sodium phosphate, ascorbic acid, inulin, cyclodextrin, polyvinylpyrrolidone, mannitol, sucrose, trehalose, lactose, and proline. Additional examples of glass forming excipients are disclosed in U.S. Pat. nos. RE 37,872, 5,928,469, 6,258,341, and 6,309,671. In particular embodiments, the suspended particles may include a calcium salt, such as calcium chloride, as described, for example, in U.S. patent No. 7,442,388.

In certain embodiments, the suspended particles are perforated microstructures comprising DSPC and calcium chloride. In some embodiments, the perforated microstructures comprise about 93% or more DSPC and about 7% or less calcium chloride. In some embodiments, the perforated microstructure comprises about 94% DSPC and about 6% calcium chloride. In some embodiments, the perforated microstructure comprises about 95% DSPC and about 5% calcium chloride.

The suspended particles may be designed, sized, and shaped as desired to provide the desired stability and active agent delivery characteristics. In one exemplary embodiment, the suspended particles comprise a perforated microstructure as 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, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof, particularly those approved for pulmonary use. Specific surfactants that can be used to prepare the perforated microstructures include poloxamer 188, poloxamer 407, and poloxamer 338. Other specific surfactants include oleic acid or its alkali metal salts. In one embodiment, the perforated microstructure includes greater than about 10% w/w surfactant.

Furthermore, the suspended particles as described herein may include fillers, such as polymer particles. The polymer may be formed from biocompatible and/or biodegradable polymers, copolymers or blends. In one embodiment, polymers capable of forming aerodynamic light particles, such as functionalized polyester graft copolymers and biodegradable polyanhydrides, may be used. For example, a bulk erosion polymer (bulk eroding polymer) based on polyesters 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 polyesters 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-co-glycolic acid) copolymers (PLGA) incorporating a surfactant such as DPPC.

Other possible polymer candidates for use in the suspended particles may include polyamides, polycarbonates, polyolefins such as polyethylene, polypropylene, poly (ethylene glycol), poly (ethylene oxide), poly (ethylene terephthalate), polyethylene compounds such as polyvinyl alcohol, polyvinyl ethers and esters, polymers of acrylic and methacrylic acid, cellulose and other polysaccharides, and peptides or proteins, or copolymers or blends thereof. For different controlled drug delivery applications, polymers with appropriate in vivo stability and degradation rate or polymers modified with appropriate in vivo stability and degradation rate may be selected.

In one embodiment of the compositions as described herein comprising one or more of glycopyrrolate, formoterol, budesonide and albuterol as active agents, the ratio of the total mass of the suspended particles to the total mass of the 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.

In some embodiments, the suspended particles may be prepared by forming an oil-in-water emulsion using fluorocarbon oils (e.g., perfluorobromooctane, perfluorodecalin) that may be emulsified using surfactants (such as long chain saturated phospholipids). The resulting perfluorocarbon-in-water emulsion may then be treated using a high pressure homogenizer to reduce the oil droplet size. The perfluorocarbon emulsion may be injected into a spray dryer. As is well known, spray drying is a one-step process that converts a liquid feed into a dry particulate form. Spray drying has been used to provide powdered pharmaceutical materials for a variety of routes of administration, including inhalation. In the case of spray drying, fluorocarbon oils (such as those described above) may be used as the blowing agent. The operating conditions of the spray dryer (such as inlet and outlet temperatures, feed rate, atomization pressure, flow rate of drying air, and nozzle configuration) can be adjusted to produce the desired particle size, resulting in a yield of the resulting dried microstructure. Such methods of producing exemplary perforated microstructures are disclosed in U.S. patent No. 8,815,258, U.S. patent No. 9,463,161, and U.S. patent application publication 2011/0135737.

The compositions described herein may comprise two or more types of suspended particles. For example, the compositions described herein may comprise a single class of active agent particles and two or more classes of suspended particles. Alternatively, in other embodiments, the compositions described herein may comprise two or more types of active agent particles in combination with two or more types of suspended particles.

Embodiments of the compositions

In one embodiment, the compositions described herein comprising a combination of two or more active agents may comprise budesonide, glycopyrrolate, and formoterol as the active agents. In one embodiment of the compositions as described herein comprising budesonide, glycopyrrolate and formoterol as the active agent, the ratio of the total mass of the suspended particles to the total mass of the active agent particles can 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. In all embodiments, the ratio of active agent to suspended particles is based on the free form (e.g., free acid or free base form) of the active agent. In one embodiment, the composition is administered by oral inhalation. In certain embodiments, the compositions described herein comprising budesonide, glycopyrrolate, and formoterol as active agents may be contained in a reservoir of a Metered Dose Inhalation (MDI) device. In some embodiments, the compositions described herein may comprise budesonide (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: between about 70 μg and about 170 μg, between about 75 μg and about 165 μg, and between about 80 μg and about 160 μg of budesonide per inhalation. In some embodiments, the compositions described herein may comprise glycopyrrolate (including any pharmaceutically acceptable salts, esters, isomers or solvates thereof) at a concentration that achieves a target delivered dose selected from the following: between about 5 μg and about 10 μg and between about 5 μg and about 15 μg of glycopyrrolate per inhalation. In some embodiments, the compositions described herein may comprise formoterol (including any pharmaceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: between about 1 μg and about 5 μg and between about 2 μg and about 4 μg of formoterol per inhalation. In some embodiments, the composition may be administered in two doses per day, with two inhalations per dose. In some embodiments, the compositions described herein comprise from about 0.240% to about 0.360% budesonide by weight (w/w), from about 0.010% to about 0.016% glycopyrrolate by weight (w/w), from about 0.007% to about 0.011% formoterol fumarate by weight (w/w), from about 0.410% to about 0.615% DSPC porous particles by weight (w/w) and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.268% to about 0.328% budesonide by weight (w/w), from about 0.012% to about 0.015% glycopyrrolate by weight (w/w), from about 0.008% to about 0.010% formoterol fumarate by weight (w/w), from about 0.461% to about 0.564% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.283% to about 0.314% budesonide by weight (w/w), from about 0.013% to about 0.014% glycopyrrolate by weight (w/w), from about 0.008% to about 0.010% formoterol fumarate by weight (w/w), from about 0.487% to about 0.538% DSPC porous particles by weight (w/w) and HFO-1234ze (E). Table 1 shows exemplary embodiments of compositions comprising a combination of two or more active agents, the compositions containing glycopyrrolate, formoterol and budesonide as active agents. In one embodiment, the exemplary compositions of Table 1 may provide a delivered dose of about 160 μg budesonide, about 9 μg glycopyrrolate, and about 4.8 μg formoterol fumarate per actuation of the metered dose inhaler.

TABLE 1 pressurized inhalation suspension of budesonide, glycopyrrolate and formoterol fumarate containing HFO-1234ze (E) propellant

Component (A)	Function of	Quantity (per pot)	Weight percent
				Micronized budesonide	API	31.05mg	0.2986
Micronized glycopyrronium bromide	API	1.40mg	0.0134
				Micronized formoterol fumarate	API	0.93mg	0.0090
Porous particles of DSPC	Suspended particles	53.30mg	0.5125
				HFO-1234ze(E)	Propellant agent	10.31g	99.1665

In one embodiment, the compositions described herein comprising a combination of two or more active agents may contain glycopyrrolate and formoterol as the active agents. In one embodiment of the compositions as described herein comprising glycopyrronium and formoterol as active agents, the ratio of the total mass of suspended particles to the total mass of active agent particles may be selected from between about 1 and about 25, between about 1 and about 20, 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. In all embodiments, the ratio of active agent to suspended particles is based on the free base form of the active agent. In one embodiment, the composition is administered by oral inhalation. In certain embodiments, a composition as described herein comprising glycopyrrolate and formoterol as active agents can be contained in the reservoir of a Metered Dose Inhalation (MDI) device. In some embodiments, a composition as described herein may comprise glycopyrrolate (including any pharmaceutically acceptable salts, esters, isomers or solvates thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: between about 5 μg and about 10 μg and between about 5 μg and about 15 μg of glycopyrrolate per inhalation. In some embodiments, a composition as described herein may comprise formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: between about 1 μg and about 5 μg of formoterol per inhalation. In some embodiments, the composition may be administered in two doses per day, with two inhalations per dose. In some embodiments, the compositions described herein comprise from about 0.011% to about 0.016% by weight (w/w) glycopyrrolate, from about 0.007% to about 0.011% by weight (w/w) formoterol fumarate, from about 0.411% to about 0.617% by weight (w/w) DSPC porous particles and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.012% to about 0.015% by weight (w/w) glycopyrrolate, from about 0.008% to about 0.010% by weight (w/w) formoterol fumarate, from about 0.411% to about 0.617% by weight (w/w) DSPC porous particles and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.013% to about 0.014% by weight (w/w) glycopyrrolate, from about 0.008% to about 0.010% by weight (w/w) formoterol fumarate, from about 0.488% to about 0.540% by weight (w/w) DSPC porous particles and HFO-1234ze (E). Table 2 shows exemplary embodiments of compositions containing glycopyrrolate and formoterol as active agents. In one embodiment, the exemplary compositions of table 2 may provide a delivered dose of about 9 μg glycopyrrolate and about 4.8 μg formoterol fumarate per actuation of the metered dose inhaler.

TABLE 2 pressurized inhalation suspension of glycopyrrolate and formoterol fumarate with HFO-1234ze (E) propellant

In one embodiment, the compositions described herein comprising a combination of two or more active agents may contain budesonide and salbutamol sulfate as active agents. In one embodiment of the compositions as described herein comprising budesonide and salbutamol sulfate as active agents, the ratio of the total mass of the suspended particles to the total mass of the active agent particles may be selected from between about 1 and about 25, between about 1 and about 20, 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. In all embodiments, the ratio of active agent to suspended particles is based on the free base form of the active agent. In one embodiment, the composition is administered by oral inhalation. In certain embodiments, a composition as described herein comprising budesonide and salbutamol sulfate as active agents may be contained in a reservoir of a Metered Dose Inhalation (MDI) device. In some embodiments, the compositions described herein may comprise budesonide (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: between about 35 μg and about 90 μg, between about 40 μg and about 85 μg, and between about 45 μg and about 80 μg of budesonide per inhalation. In some embodiments, the compositions described herein may comprise salbutamol sulphate (including any pharmaceutically acceptable salts, esters, isomers or solvates thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: between about 75 μg and about 95 μg and between 80 μg and about 90 μg salbutamol sulfate per inhalation. In some embodiments, the compositions described herein comprise from about 0.058% to about 0.088% budesonide by weight (w/w), from about 0.131% to about 0.197% salbutamol sulfate by weight (w/w), from about 0.267% to about 0.401% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.065% to about 0.080% by weight (w/w) budesonide, from about 0.147% to about 0.180% by weight (w/w) salbutamol sulfate, from about 0.301% to about 0.367% by weight (w/w) DSPC porous particles, and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.069% to about 0.077% budesonide by weight (w/w), from about 0.156% to about 0.172% salbutamol sulfate by weight (w/w), from about 0.317% to about 0.351% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.116% to about 0.175% by weight (w/w) budesonide, from about 0.131% to about 0.197% by weight (w/w) salbutamol sulfate, from about 0.266% to about 0.400% by weight (w/w) DSPC porous particles, and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.131% to about 0.161% budesonide by weight (w/w), from about 0.147% to about 0.180% salbutamol sulfate by weight (w/w), from about 0.300% to about 0.366% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.138% to about 0.153% by weight (w/w) budesonide, from about 0.156% to about 0.172% by weight (w/w) salbutamol sulfate, from about 0.316% to about 0.350% by weight (w/w) DSPC porous particles, and HFO-1234ze (E). Tables 3A and 3B show two exemplary embodiments of compositions containing budesonide and salbutamol sulfate as active agents. In one embodiment, the exemplary composition of Table 3A may provide a delivered dose of about 40 μg budesonide and about 90 μg salbutamol sulfate per actuation of the metered dose inhaler. In one embodiment, the exemplary composition of Table 3B may provide a delivered dose of about 80 μg budesonide and about 90 μg salbutamol sulfate per actuation of the metered dose inhaler.

TABLE 3 pressurized inhalation suspension of budesonide and salbutamol sulphate containing HFO-1234ze (E) propellant

TABLE 3 pressurized inhalation suspension of budesonide and albuterol sulfate with HFO-1234ze (E) propellant, 80/90 μg per actuation

In one embodiment, the compositions described herein comprising a combination of two or more active agents may contain budesonide and formoterol as active agents. In one embodiment of the compositions as described herein comprising budesonide and formoterol as the active agent, the ratio of the total mass of the suspended particles to the total mass of the active agent particles may be selected from between about 1 and about 25, between about 1 and about 20, 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. In all embodiments, the ratio of active agent to suspended particles is based on the free base form of the active agent. In one embodiment, the composition is administered by oral inhalation. In certain embodiments, a composition as described herein comprising budesonide and formoterol as active agents may be contained in a reservoir of a Metered Dose Inhalation (MDI) device. In some embodiments, the composition may comprise budesonide (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) at a concentration that achieves the target delivered dose selected from the group consisting of: between about 70 μg and about 170 μg, between about 75 μg and about 165 μg, and between about 80 μg and about 160 μg of budesonide per inhalation. In some embodiments, the composition may comprise formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: between about 1 μg and about 5 μg and between about 2 μg and about 4 μg of formoterol per inhalation. In some embodiments, the composition may be administered in two doses per day, with two inhalations per dose. In some embodiments, the compositions described herein comprise from about 0.238% to about 0.358% budesonide by weight (w/w), from about 0.007% to about 0.011% formoterol fumarate by weight (w/w), from about 0.410% to about 0.615% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.268% to about 0.329% budesonide by weight (w/w), from about 0.008% to about 0.010% formoterol fumarate by weight (w/w), from about 0.461% to about 0.564% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.283% to about 0.314% budesonide by weight (w/w), from about 0.008% to about 0.010% formoterol fumarate by weight (w/w), from about 0.487% to about 0.538% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.119% to about 0.180% budesonide by weight (w/w), from about 0.007% to about 0.011% formoterol fumarate by weight (w/w), from about 0.410% to about 0.616% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.134% to about 0.165% budesonide by weight (w/w), from about 0.008% to about 0.010% formoterol fumarate by weight (w/w), from about 0.462% to about 0.565% DSPC porous particles by weight (w/w), and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.142% to about 0.157% by weight (w/w) budesonide, from about 0.008% to about 0.010% by weight (w/w) formoterol fumarate, from about 0.487% to about 0.539% by weight (w/w) DSPC porous particles, and HFO-1234ze (E). Tables 4A and 4B show two exemplary embodiments of compositions containing budesonide and formoterol as active agents. In one embodiment, the exemplary composition of Table 4A may provide a delivered dose of about 160 μg budesonide and about 4.8 μg formoterol fumarate per actuation of the metered dose inhaler. In one embodiment, the exemplary composition of table 4B may provide a delivered dose of about 80 μg budesonide and about 4.8 μg formoterol fumarate per actuation of the metered dose inhaler.

TABLE 4 pressurized inhalation suspension of budesonide and formoterol fumarate with HFO-1234ze (E) propellant

In one embodiment, the compositions described herein comprising a combination of two or more active agents may comprise budesonide, glycopyrrolate, formoterol and roflumilast as active agents. In one embodiment of the compositions as described herein comprising budesonide, glycopyrrolate, formoterol and roflumilast as active agents, the ratio of the total mass of the suspended particles to the total mass of the 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. In all embodiments, the ratio of active agent to suspended particles is based on the free base form of the active agent. In some embodiments, the composition is administered by oral inhalation. In certain embodiments, the compositions described herein comprising budesonide, glycopyrrolate, formoterol and roflumilast as active agents may be contained in a reservoir of a Metered Dose Inhalation (MDI) device. In some embodiments, the composition may comprise budesonide (including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof) at a concentration that achieves the target delivered dose selected from the group consisting of: between about 70 μg and about 170 μg, between about 75 μg and about 165 μg, and between about 80 μg and about 160 μg of budesonide per inhalation. In some embodiments, the compositions described herein may comprise glycopyrrolate (including any pharmaceutically acceptable salts, esters, isomers or solvates thereof) at a concentration that achieves a target delivered dose selected from the following: between about 5 μg and about 10 μg and between about 5 μg and about 15 μg of glycopyrrolate per inhalation. In some embodiments, the compositions described herein may comprise formoterol (including any pharmaceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: between about 1 μg and about 5 μg and between about 2 μg and about 4 μg of formoterol per inhalation. In some embodiments, the compositions described herein may comprise roflumilast (including any pharmaceutically acceptable salt, ester, isomer, or solvate thereof) at a concentration that achieves a target delivered dose selected from the group consisting of: roflumilast is inhaled between about 1 μg and about 25 μg, between about 5 μg and about 20 μg, and between about 10 μg and about 15 μg per inhalation. In some embodiments, the compositions described herein comprise from about 0.024% to about 0.036% by weight (w/w) roflumilast, from about 0.238% to about 0.358% by weight (w/w) budesonide, from about 0.010% to about 0.016% by weight (w/w) glycopyrrolate, from about 0.007% to about 0.011% by weight (w/w) formoterol fumarate, from about 0.410% to about 0.615% by weight (w/w) DSPC porous particles, and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.026% to about 0.033% by weight (w/w) roflumilast, from about 0.268% to about 0.329% by weight (w/w) budesonide, from about 0.012% to about 0.015% by weight (w/w) glycopyrrolate, from about 0.008% to about 0.010% by weight (w/w) formoterol fumarate, from about 0.461% to about 0.564% by weight (w/w) DSPC porous particles, and HFO-1234ze (E). In some embodiments, the compositions described herein comprise from about 0.028% to about 0.031% by weight (w/w) roflumilast, from about 0.283% to about 0.314% by weight (w/w) budesonide, from about 0.013% to about 0.014% by weight (w/w) glycopyrrolate, from about 0.008% to about 0.010% by weight (w/w) formoterol fumarate, from about 0.486% to about 0.538% by weight (w/w) DSPC porous particles, and HFO-1234ze (E). Table 5 shows exemplary embodiments of compositions containing budesonide, glycopyrrolate, formoterol and roflumilast as active agents.

TABLE 5 pressurized inhalation suspensions of budesonide, glycopyrrolate, formoterol fumarate and roflumilast containing HFO-1234ze (E) propellant

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In one embodiment, a composition described herein comprising a combination of two or more active agents may comprise turnip ammonium bromide, valinate Luo San phenylacetate, and fluticasone furoate as active agents. In another embodiment, a composition described herein comprising a combination of two or more active agents may comprise turnip ammonium bromide and vilantt Luo San phenylacetate as active agents. In one embodiment, a composition described herein comprising a combination of two or more active agents may comprise glycopyrrolate, indacaterol acetate and mometasone furoate as active agents. In another embodiment, a composition described herein comprising a combination of two or more active agents may comprise glycopyrrolate and indacaterol acetate as active agents. In one embodiment, the compositions described herein comprising a combination of two or more active agents may comprise glycopyrrolate, formoterol and beclometasone dipropionate as active agents. Compositions formulated in accordance with the present teachings can inhibit degradation of the active agent contained therein. For example, in certain embodiments, the compositions described herein inhibit one or more of flocculation, aggregation, and solution-mediated transformation of active agent materials contained in the compositions. The pharmaceutical compositions described herein are suitable for respiratory tract delivery via MDI in a manner that achieves the desired delivered dose uniformity ("DDU") for each active agent contained in the combination of two or more active agents, even though the combination comprises both potent and highly potent active agents. As detailed in the examples contained herein, the compositions described herein can achieve ± 30% or better DDU of each active agent throughout the process of evacuating an MDI canister, even when very low doses of two or more active agents are delivered. In one such embodiment, the compositions described herein achieve ± 25% or better DDU of each active agent throughout the process of evacuating the MDI canister. In another such embodiment, the compositions described herein achieve ± 20% or better active agent DDU per active agent throughout the process of emptying the MDI canister. In further embodiments, the compositions described herein achieve ± 15% or better active agent DDU per active agent throughout the process of evacuating an MDI canister. In still further embodiments, the compositions described herein achieve ± 10% or better active agent DDU per active agent throughout the process of emptying the MDI canister.

The pharmaceutical compositions described herein also serve to substantially maintain FPF and FPD performance throughout the process of evacuating an MDI canister, even after undergoing accelerated degradation conditions. For example, compositions according to the present disclosure maintain initial FPF and FPD performance of up to 80%, 85%, 90%, 95% or more throughout the process of evacuating an MDI canister, even after experiencing accelerated degradation conditions. The compositions described herein provide the additional benefit of achieving this property when formulated with non-CFC and non-HFA propellants, and eliminate or substantially avoid the combined effects often experienced by compositions incorporating multiple active agents. In certain embodiments, the compositions described herein achieve one or all of the targeted DDU, FPF, and FPD performance when formulated with a suspension medium comprising only one or more HFO propellants, and do not require modification of the HFO propellant characteristics, such as by the addition of, for example, one or more latent solvents, anti-solvents, solubilizing agents, adjuvants, or other propellant modifying materials.

Method of

Compositions formulated in accordance with the present teachings can inhibit degradation of the active agent contained therein. For example, in certain embodiments, the compositions described herein inhibit one or more of flocculation, aggregation, and ostwald ripening of the active agent contained in the composition. The stability provided by the compositions described herein enables the composition to be dispensed in a manner that achieves the desired delivered dose uniformity ("DDU") throughout the process of emptying the MDI canister, even where the active agent to be delivered is highly effective and the delivered dose of the active agent is selected from, for example, one of MDI actuation less than 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 actuation. As detailed in the examples contained herein, the compositions described herein can achieve DDU of ±30% or better for each active agent contained in the composition even at low doses of highly potent active agents. In alternative embodiments, the compositions described herein achieve ± 25% or better DDU 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.

Furthermore, the composition according to the present description is used to substantially maintain FPF and FPD performance throughout the process of evacuating an MDI canister, even after being subjected to accelerated degradation conditions. For example, compositions according to the present description maintain initial FPF and FPD performance of up to 80%, 85%, 90%, 95% or more, even when they incorporate multiple active agents. The compositions described herein provide the additional benefit of achieving this property when formulated with non-CFC and non-HFA propellants. In certain embodiments, the compositions described herein achieve one or all of the desired target DDU, FPF, and FPD properties when formulated with a suspension medium comprising only one or more HFO propellants, and do not require modification of the HFO propellant characteristics such as by the addition of, for example, one or more latent solvents, anti-solvents, solubilizing agents, adjuvants, or other propellant modifying materials.

The stability and physical characteristics of the compositions described herein support several methods. For example, in one embodiment, provided herein are methods of formulating pharmaceutical compositions for respiratory delivery of an active agent. The method involves the steps of providing a suspension medium comprising an HFO propellant, one or more types of active agent particles, and one or more types of suspension particles as described herein, and combining such ingredients to form a composition, wherein the active agent particles associate with the suspension particles to form a co-suspension as described herein. 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 buoyancy forces in the propellant. As will be appreciated, the method of formulating a pharmaceutical composition as described herein may include providing two or more types of active agent particles in combination with one or more types of suspended particles. Alternatively, the method may comprise providing two or more suspended particles in combination with one or more types of active agent particles.

In further embodiments, the compositions described herein support methods, e.g., for forming stable formulations of active agents for pulmonary delivery, methods for maintaining FPF and/or FPD throughout the process of evacuating MDI canisters, methods for pulmonary delivery of active agents that are effective or highly effective, and methods of achieving DDU selected from ±30% or better, ±25% or better, ±20% or better, ±15% or better and ±10% or better of effective and highly effective drugs administered by pulmonary delivery.

In methods involving pulmonary delivery of an active agent using the compositions described herein, the compositions may be delivered by MDI. Thus, in particular embodiments of such methods, an MDI loaded with the composition described herein is obtained and the desired active agent is administered to the patient by pulmonary delivery by actuating the MDI. For example, in one embodiment, after shaking the MDI device, a spout (mouthpiece) is inserted into the mouth between the patient's lips and teeth. The patient typically exhales deeply to empty the lungs and then breathes slowly deeply when the cartridge of the MDI is actuated. When actuated, a prescribed volume of the formulation travels to the expansion chamber, exits the actuator nozzle, and becomes a high-velocity spray that is inhaled into the patient's lungs. In some embodiments, the dose of active agent delivered throughout the process of emptying the MDI canister is no more than 20% greater than the average delivered dose and no less than 20% less than the average delivered dose. In some embodiments, the dose of active agent delivered throughout the process of emptying the MDI canister is no more than 15% greater or less than the average delivered dose. In some embodiments, the dose of active agent delivered throughout the process of emptying the MDI canister is no more than 10% greater or less than the average delivered dose.

In particular embodiments of methods for providing stable formulations of active agents for pulmonary delivery, the present disclosure provides methods for inhibiting solution-mediated transformation of active agents in pharmaceutical formulations for pulmonary delivery. In one embodiment, a suspension medium as described herein, such as a suspension medium formed from HFO propellants, is obtained. Suspended particles are also obtained or prepared as described herein. One or more types of active agent particles as described herein are also obtained, and the suspending medium, suspending particles, and active agent particles are combined to form a co-suspension, wherein the active agent particles are associated with the suspending particles in a continuous phase formed by the suspending medium. Co-suspensions according to the present description have been found to exhibit a higher tolerance to solution-mediated transformations and irreversible crystal aggregation when compared to active agents contained in the same suspension medium in the absence of suspended particles, and thus may lead to improved stability and dosing uniformity, allowing for the formulation of active agents that are physically somewhat unstable in the suspension medium alone.

In particular embodiments of the methods for preserving FPF and/or FPD, there is provided a pharmaceutical formulation for pulmonary delivery of an inhalable co-suspension as described herein that is capable of maintaining the FPD and/or FPF within ± 20%, ±15%, ±10% or even ± 5% of the original FPD and/or FPF, respectively, throughout the process of evacuating the MDI canister. This property can be achieved even after the co-suspension has been subjected to accelerated degradation conditions. In one embodiment, a suspension medium as described herein, such as a suspension medium formed from HFO propellants, is obtained. Suspended particles are also obtained or prepared as described herein. One or more types of active agent particles as described herein are also obtained, and the suspension medium, the suspension particles, and the active agent particles are combined to form a co-suspension, wherein the active agent particles are associated with the suspension particles within 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 corresponding values measured prior to exposure of the composition to the one or more temperature cycling events.

Provided herein are methods for treating a patient suffering from an inflammatory or obstructive pulmonary disease or condition. In certain embodiments, such methods comprise 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 accomplished by using an MDI delivery composition. In certain embodiments, the compositions, methods, and systems described herein are useful for treating a patient suffering from a disease or disorder selected from the group consisting of: asthma, chronic Obstructive Pulmonary Disease (COPD), exacerbations of airway hyperresponsiveness caused by other drug therapies, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergy, respiratory distress syndrome, pulmonary arterial hypertension, pulmonary vasoconstriction, and any other respiratory disease, condition, trait, genotype, or phenotype that may be responsive to administration of, for example, LAMA, LABA, SABA, ICS, a non-corticosteroid anti-inflammatory agent, or other active agent as described herein, whether alone or in combination with other therapies. In certain embodiments, the compositions, systems, and methods described herein are useful for treating pulmonary inflammation and obstruction associated with cystic fibrosis. In particular embodiments of a method for treating a patient having an inflammatory or obstructive pulmonary disease or condition, the pulmonary disease or condition is selected from those specifically described herein, and the method comprises pulmonary delivery of a composition according to the present specification to the patient via an MDI, wherein pulmonary delivery of such composition comprises administration of one or more active agents at a dose or dose range as described in connection with the compositions disclosed herein.

Metered dose inhaler system

As described with respect to the methods provided herein, the compositions disclosed herein may be used in MDI systems. MDI is configured to deliver a specific amount of 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 spout. The MDI system may include a formulation as described herein including a suspension medium including an HFO propellant, at least one type of active agent particles, and at least one type of suspension particles. The canister used in the MDI is any of a number of suitable configurations, and in one exemplary embodiment the volume of the canister may be in the range of about 5ml to about 25ml, such as a 19ml volume canister. After shaking the device, the spout is inserted into the mouth between the patient's lips and teeth. The patient typically exhales deeply to empty the lungs and then breathes slowly deeply when the cartridge is actuated.

Within the exemplary cartridge is a metering valve comprising a metering chamber capable of containing a defined volume of formulation (e.g., 63 μl or any other suitable volume available in commercially available metering valves) that, when actuated, is released into an expansion chamber at the distal end of the valve stem. The actuator houses the canister and may also include a port having an actuator nozzle for receiving the valve stem of the metering valve. When actuated, a prescribed volume of the formulation travels to the expansion chamber, exits the actuator nozzle, and becomes a high-velocity spray that is inhaled into the patient's lungs.

Examples of suitable MDIs are shown and described in international application publication No. WO 2019/074799 (which is hereby incorporated by reference in its entirety). Suitable MDI may include, for example, an aerosol delivery unit 100 as shown in fig. 1-3B for selectively delivering a dose of aerosolized substance, which includes structure and related functions for exposing the discharge channel of the inhaler to a desiccant material at least during storage of the inhaler.

Referring to fig. 1-3B, the aerosol delivery unit 100 includes a base housing 104 and a canister 110 received in the base housing 104, the canister 110 being displaceable from an initial position I as shown in fig. 3A to a discharge position D as shown in fig. 3B for selectively discharging a dose of aerosolized substance for inhalation by a user. The canister 110 includes a canister body 116 and an outlet valve 112, the canister body 116 containing the substance to be expelled, the outlet valve 112 including a movable valve stem 114 extending from the canister body 116. The valve stem 114 defines a portion of the discharge passage 120, which discharge passage 120 extends from the canister body 116 to a discharge orifice 122 provided within the aerosol delivery unit 100, which discharge orifice 122 in turn leads to an inhalation passage 126, through which inhalation passage 126 the atomized material passes and then out through a nozzle orifice 128 for inhalation by a user during an inhalation event. The discharge channel 120 and the intake channel 126 may be collectively referred to as a drug delivery channel. As will be appreciated by those of ordinary skill in the relevant art, as shown in fig. 3B, when the valve stem 114 is displaced relative to the canister body 116, a metered dose of substance contained by the canister body 116 will be expelled through the discharge orifice 122 for inhalation by a user via the inhalation passage 126.

Referring to fig. 1, the aerosol delivery unit 100 may further comprise a dose counter part 107, which dose counter part 107 is fixed below the upper part of the canister 110 to provide a dose counting function and to provide a user interface for pressing the canister 110. The aerosol delivery unit 100 may further comprise a cap 105 to cover the spout aperture 128 of the aerosol delivery unit 100 when the unit 100 is stored. The cap 105 may be completely separate from the base housing 104 or may be connected to the base housing 104 by a tether 106, the tether 106 enabling the cap 105 to be removed from the spout aperture 128 while still remaining connected to the base housing 104.

Referring to fig. 3A and 3B, the aerosol delivery unit 100 further comprises a desiccant chamber 150, the desiccant chamber 150 containing a desiccant material 152, the desiccant material 152 being in fluid communication with the discharge channel 120 at least when the aerosol delivery unit 100 is in the storage configuration and not actively discharging the atomized substance. For example, according to the exemplary embodiment shown in fig. 3A and 3B, a desiccant chamber 150 is provided at the end of the canister 110, between the lower end of the canister body 116 and a separate desiccant housing 154 and a stem seal 156, the separate desiccant housing 154 and stem seal 156 being connected to the end of the canister 110. The desiccant material 152 may be provided in a semi-annular form (as shown in fig. 2) and may include a central passage 153 through which the valve stem 114 of the canister 110 extends. The stem seal 156 may be an annular seal integrally formed with the desiccant housing 154, such as via a multi-shot injection molding process, or may be otherwise provided as a separate sealing member connected to the desiccant housing 154. In some cases, the stem seal 156 may be provided as a bellows-type seal that is secured between the valve stem 114 and the desiccant housing 154 to provide a desiccant chamber 150, the desiccant chamber 150 having a volume that varies as the stem seal 156 deforms as the canister 110 displaces during an inhalation event. In other cases, such as the exemplary embodiment shown in fig. 3A and 3B, the desiccant chamber 150 may have a fixed volume.

As can be appreciated from fig. 3A, the desiccant material 152 within the desiccant chamber 150 is in fluid communication with the drain channel 120 through an aperture 124 on one side of the valve stem 114, the aperture 124 otherwise serving to pass the substance contained in the canister body 116 toward the drain aperture 122 when the valve stem 114 is displaced during an inhalation event. In this manner, the drain channel 120 remains exposed to the desiccant material 152 when the canister 110 is in the initial position I, such as when the unit 100 is stored. In some cases, the desiccant material may be sufficient to keep the discharge channel dry between uses (e.g., <25% rh) for substantially the entire product life of the canister of material to be discharged.

Advantageously, the desiccant housing 154 may be connected with an end or collar (collar) of the canister 110 to form a cartridge 160 (fig. 2) that is easily removable from the base housing 104. In this manner, the desiccant housing 154 and canister 110 may be easily removed from the base housing 104 to replace the canister 110 when depleted and/or the desiccant material 152 as needed. The desiccant housing 154 may be connected to the end or collar of the canister 110 via elastic bands, clips, detents, or other fastening devices or techniques, including friction fit or interference fit arrangements. Although the desiccant chamber 150 is shown in the exemplary embodiment of fig. 3A and 3B as being connected to the lower end or collar of the canister 110, it should be understood that in other embodiments the desiccant chamber may be provided in a separate desiccant housing that is connected to the base housing 104, separate from the canister 110, the desiccant chamber may be integrally formed in the base housing itself, or the desiccant chamber may be provided in a separate component that is attached to the base housing 104. Furthermore, the desiccant material may be provided in a variety of different forms, such as gel form, powder form, particle form or molded form, and may be composed of or comprise different materials, such as silica, activated carbon, calcium sulfate or calcium chloride.

According to the exemplary embodiment of fig. 1-3B, a desiccant housing 154 may be connected with an end or collar of the canister 110 to form a cartridge 160, which cartridge 160 may be mounted in the base housing 104 for engagement with a stem seat/nozzle assembly 132 disposed therein. Further details of the components of the cartridge 160 and stem block/nozzle assembly 132 can be seen in the exploded view of fig. 2. As shown in fig. 2, the desiccant housing 154 may form a cup-like structure having a generally cylindrical sidewall that is sized and shaped to receive the lower end of the canister 110. The desiccant material 152 may be provided in molded form. The desiccant material 152 may be configured to be positioned at a lower end of the desiccant housing 154. The desiccant housing 154 may include one or more locating or coupling features to help couple or otherwise locate the desiccant material 152 within the desiccant housing 154. The desiccant material 152 may be shaped to not block stem apertures of a stem seal 156 provided in the desiccant housing 154 for receiving the stem 114 of the canister 110. For example, the desiccant material 152 may have a semi-annular shape with a central channel 153 or other gap for the valve stem 114. In some cases, such as in the exemplary embodiment shown in fig. 1-3B, the desiccant material 152 may be shaped to partially surround the valve stem 114 and may extend beyond the terminal end of the valve stem 114. The desiccant housing 154 and desiccant material 152 may also be shaped accordingly and may each extend beyond the terminal end of the valve stem 114. In this manner, the desiccant material 152 may substantially fill the desiccant chamber 150 and provide a relatively large volume of desiccant material suitable for continuously removing moisture from at least the passage of the valve stem 114 throughout the useful life of the material (e.g., pharmaceutical formulation) contained in the canister 110.

Referring to fig. 3A and 3B, a canister seal 117 may be positioned around the canister body 116, such as around the lower neck of the canister body 116, to provide a resilient element between the canister body 116 and the desiccant housing 154 that may be compressed when the canister 110 and the desiccant housing 154 are connected together. The canister seal 117 may provide a sealing position to help isolate the desiccant chamber 150 when the aerosol delivery unit 100 is fully assembled and to prevent moisture from entering the desiccant chamber 150 through a pathway other than the exhaust channel 120. In a similar manner, the stem seal 156 may provide a sealing position to help isolate the desiccant chamber 150 and prevent moisture from entering the desiccant chamber 150 when the aerosol delivery unit 100 is fully assembled. In this manner, the desiccant chamber 150 is effectively isolated from the external environment except for the drain channel 120, which drain channel 120 may be exposed to the external environment through the intake channel 126 when the spout cap 105 is removed from the base housing 104.

As can be appreciated from a comprehensive review of fig. 3A and 3B, when the valve stem 114 is in the expanded position, the portion of the vent passage 120 defined by the valve stem 114 is in fluid communication with the desiccant chamber 152 via the aperture 124 on one side of the valve stem 114. Conversely, when the valve stem 114 of the canister 110 is fully depressed, the desiccant chamber 152 is temporarily isolated from the exhaust passage 120 defined by the valve stem 114.

Further, with the canister 100 loaded in the desiccant housing 154, the valve stem 114 protrudes from its lower end and is then received in a stem seat/nozzle assembly 132 provided in the base housing 104. According to the exemplary embodiment of fig. 2, a stem seat/nozzle assembly 132 may be provided in a spout unit 131, the spout unit 131 being connectable with the base housing 104 and comprising a inhalation passage 126 and a spout aperture 128 for delivering the nebulized substance to a user. As shown, upon installation of the cartridge 160, the desiccant material 152 may extend from a position above the discharge orifice 122 of the stem seat/nozzle assembly 132 to a position below the discharge orifice 122, and may substantially fill the desiccant chamber 150 within the desiccant housing 154 to provide a relatively large volume of desiccant material suitable for continuously removing moisture from at least the passageway of the valve stem 114 throughout the useful life of the material (e.g., pharmaceutical formulation) contained in the canister 110. In this manner, embodiments may be particularly suitable for eliminating, reducing, or minimizing the presence of moisture in the vent channel 120, and particularly suitable for eliminating, reducing, or minimizing any soil associated therewith, even when the vent channel 120 is not completely isolated from the external environment after venting material during an inhalation event.

According to some embodiments, an MDI is provided, such as the aerosol delivery unit 100 shown in fig. 1-3B, wherein one or more internal components of the outlet valve 112 are at least partially composed of a bromobutyl material (e.g., bromobutyl rubber).

For example, fig. 4 shows an outlet valve 200 of a tank 201 containing MDI of a formulation to be expelled, wherein the outlet valve 200 is provided with one or more internal components comprising or consisting of a brominated butyl material (e.g. brominated butyl rubber). For example, the outlet valve 200 includes a core 202 and a valve stem 204 that are movably displaceable relative to a valve body 206 and a metering chamber 208 to dispense metered amounts of the formulation through a discharge passage 205 of the outlet valve 200 during operation of the MDI device. The inner core 202 and the valve stem 204 are biased toward the extended position by a spring element 207 and can be selectively depressed to dispense a metered dose of the formulation.

To help establish consistent metered doses of formulation to be expelled, the outlet valve 200 further includes a plurality of gaskets to seal the interior cavity of the metering chamber 208 and isolate the canister 201 from the valve body 206 and the interior formulation cavity of the canister 201 and from the external environment. More specifically, upper and lower seat gaskets 212a, 212b are provided that slidably engage the inner core 202 and the valve stem 204 to seal the interior cavity of the metering chamber 208 and isolate the valve body 206 and canister 201 from each other. As shown in fig. 4, an upper seat gasket 212a is disposed between the metering chamber 208 and the valve body 206 and surrounds and seals against a portion of the displaceable core 202. A lower seat gasket 212b is disposed between the metering chamber 208 and the canister 201 and surrounds and seals against a portion of the displaceable valve stem 204 that protrudes from the canister 201. Advantageously, one or more of the seat washers 212a, 212b may comprise or consist of a brominated butyl material (e.g., brominated butyl rubber). In addition, as further shown in fig. 4, a neck gasket 214 is disposed between the valve body 206 and the canister 201 to further help seal the internal formulation cavity from the external environment. Advantageously, neck gasket 214 may comprise or consist of a brominated butyl material (e.g., brominated butyl rubber).

It has been shown that by forming the internal gasket, i.e. the one or more seat gaskets 212a, 212b and/or the neck gasket 214, of the outlet valve 200 comprising or consisting of a bromobutyl material (e.g. bromobutyl rubber), the outlet valve 200 is particularly effective in expelling and maintaining a consistent metered dose of formulation over time throughout operation and in avoiding fouling or clogging of the discharge outlet of the MDI device. Furthermore, the outlet valve 200 is particularly effective in avoiding loss of formulation weight over time as compared to other suitable gasket materials. Thus, MDI of this configuration is particularly suitable for delivering formulations to users.

As an example, fig. 5 shows a CT scan of the discharge channel of an MDI having a formulation tank with an outlet valve comprising an internal seat gasket and neck gasket composed of brominated butyl material (e.g., brominated butyl rubber), wherein the MDI is used to repeatedly discharge the formulation under controlled environmental conditions (25 ℃/60% RH). Notably, fig. 5 shows the exit orifice of MDI that is substantially free of deposited or accumulated material despite repeated use of MDI to dispense the formulations described herein.

Fig. 6 provides a comparison of the loss of formulation weight over time for different valve seat gasket and valve neck gasket materials. As can be appreciated from fig. 6, a configuration in which the valve neck gasket comprises a brominated butyl material (e.g., brominated butyl rubber) always shows a significant reduction in weight loss over time as compared to the control configuration (leftmost column in the graph). Further, when the valve seat portion gasket also contains a brominated butyl material, such as brominated butyl rubber (rightmost column in the graph), the weight loss over time is nearly 0%. Thus, an internal gasket composed of a brominated butyl material (e.g., brominated butyl rubber) is provided that exhibits unexpected properties.

The following abbreviations are used throughout this disclosure, including the figures and examples:

AB: salbutamol

AS: salbutamol sulfate

BD: budesonide

FF: formoterol fumarate

GP: glycopyrronium salt

RF: roflumilast

BDA: budesonide/salbutamol (combination)

BGF: budesonide/glycopyrrolate/formoterol (combination)

GFF: glycopyrrolate/formoterol fumarate (combination)

BFF: budesonide/formoterol fumarate (combination)

BGFR: budesonide/glycopyrrolate/formoterol fumarate/roflumilast (combination)

BDA-1234ze: budesonide/salbutamol (combination) in HFO-1234ze (E) formulation

BDA-134a: budesonide/salbutamol (combination) in HFA-134a formulation

BFF-1234ze: budesonide/formoterol fumarate (combination) in HFO-1234ze (E) formulations

BFF-134a: budesonide/formoterol fumarate (combination) in HFA-134a formulations

CFC-11: trichlorofluoromethane

CFC-113:1, 2-trichloro-1, 2-trifluoroethane

CFC-114:1, 2-dichloro-tetrafluoroethane

HCFC-124: 1-chloro-1, 2-tetrafluoroethane

HFA-227ea:1, 2, 3-heptafluoropropane

HFC-125: pentafluoroethane, also known as1, 2-pentafluoroethane

HFC-152a:1, 1-difluoroethane

HFC-245cb:1, 2-pentafluoropropane

HFO-1225ye (Z): cis-1, 2, 3-pentafluoropropene

HFO-1225ye (E): trans-1, 2, 3-pentafluoropropene

HFO-1234yf:2, 3-tetrafluoropropene

HFO-1234ze (Z): cis-1, 3-tetrafluoroprop-1-ene

PP: porous particles of phospholipids

Detailed description of the preferred embodiments

In one aspect, the present disclosure provides the following specific embodiments:

Embodiment 1.A pharmaceutical composition deliverable from a metered dose inhaler, the pharmaceutical composition comprising:

pharmaceutical grade (1E) -1, 3-tetrafluoro-1-propene (HFO-1234 ze (E)) propellants;

A plurality of active agent particles; and

A plurality of phospholipid particles comprising a perforated microstructure;

wherein the active agent particles comprise an active agent selected from the group consisting of a Long Acting Muscarinic Antagonist (LAMA), a long acting beta 2-agonist (LABA), a Short Acting Beta Agonist (SABA), an Inhaled Corticosteroid (ICS) and a non-corticosteroid anti-inflammatory agent.

Embodiment 2. The pharmaceutical composition according to embodiment 1, wherein the plurality of active agent particles comprises two or more types of active agent particles, wherein each type of active agent particle comprises a different active agent selected from the group consisting of: long Acting Muscarinic Antagonists (LAMA), long acting beta 2-agonists (LABA), short Acting Beta Agonists (SABA), inhaled Corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.

Embodiment 3. A pharmaceutical composition deliverable from a metered dose inhaler, the pharmaceutical composition comprising:

A plurality of active agent particles of a first species;

a plurality of active agent particles of a second species; and

A plurality of phospholipid particles comprising a perforated microstructure;

Wherein the first class of active agent particles comprises a first active agent and the second active agent particles comprises a second active agent, and wherein the first active agent and the second active agent are selected from the group consisting of a Long Acting Muscarinic Antagonist (LAMA), a long acting beta 2-agonist (LABA), a Short Acting Beta Agonist (SABA), an Inhaled Corticosteroid (ICS), and a non-corticosteroid anti-inflammatory agent.

Embodiment 4. The pharmaceutical composition according to embodiment 3, further comprising a plurality of active agent particles of a third species; wherein the third class of active agent particles comprises a third active agent selected from the group consisting of a Long Acting Muscarinic Antagonist (LAMA), a long acting beta 2-agonist (LABA), a Short Acting Beta Agonist (SABA), an Inhaled Corticosteroid (ICS) and a non-corticosteroid anti-inflammatory agent.

Embodiment 5 the pharmaceutical composition according to embodiment 4, further comprising a plurality of active agent particles of a fourth species; wherein the fourth class of active agent particles comprises a fourth active agent selected from the group consisting of a Long Acting Muscarinic Antagonist (LAMA), a long acting beta 2-agonist (LABA), a Short Acting Beta Agonist (SABA), an Inhaled Corticosteroid (ICS) and a non-corticosteroid anti-inflammatory agent.

Embodiment 6. The pharmaceutical composition according to any one of embodiments 1 to 5, wherein LAMA is present at a concentration ranging from about 0.04mg/mL to about 2.25 mg/mL.

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

Embodiment 8 the pharmaceutical composition according to any one of embodiments 1 to 5, wherein the ICS is present at a concentration ranging from about 0.1mg/mL to about 20 mg/mL.

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

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

Embodiment 11. The pharmaceutical composition according to any of embodiments 1 to 10, wherein the perforated microstructure comprises 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC) and calcium chloride.

Embodiment 12. The pharmaceutical composition according to any one of embodiments 1 to 11, wherein the phospholipid particles exhibit a volume median optical diameter selected from the group consisting of: 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.

Embodiment 13. The pharmaceutical composition according to any of embodiments 1 to 12, wherein the total mass of phospholipid particles exceeds the total mass of:

i) A plurality of active agent particles of embodiment 1;

ii) any of the first, second, third or fourth species of active agent particles; or (b)

Iii) A combination of any two of the first, second, third and fourth types of active agent particles.

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

Embodiment 15 the pharmaceutical composition according to any one of embodiments 4 to 13, wherein the first active agent is LAMA; the second active agent is a LABA; and the third active agent is ICS.

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

Embodiment 17 the pharmaceutical composition according to any one of embodiments 3 to 13, wherein the first active agent is SABA; and the second active agent is ICS.

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

Embodiment 19 the pharmaceutical composition according to any one of the preceding embodiments, wherein LAMA is selected from glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, turnidiammonium, and daptominium; or a pharmaceutically acceptable salt or solvate thereof.

Embodiment 20. The pharmaceutical composition according to any of the preceding embodiments, wherein the LABA is selected from the group consisting of bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, miveterol, indacaterol, vilantro and β ₂ agonists containing salicin or indole and adamantyl derivatives; or a pharmaceutically acceptable salt or solvate thereof.

Embodiment 21 the pharmaceutical composition according to any one of the preceding embodiments, wherein SABA is selected from the group consisting of bittersweet, carbopol, fenoterol, hexenalin, wheezin (isoprenaline), levalbuterol, oxacinnoline (metazipraline), pirbuterol, procaterol, ramiterol, salbutamol (salbutamol), terbutaline, tulobuterol, rapoterol, and epinephrine; or a pharmaceutically acceptable salt or solvate thereof.

Embodiment 22. The pharmaceutical composition according to any of the preceding embodiments, wherein the ICS is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone, and triamcinolone; or a pharmaceutically acceptable salt or solvate thereof.

Embodiment 23. The pharmaceutical composition according to any of the preceding embodiments, wherein the non-corticosteroid anti-inflammatory agent is roflumilast or a pharmaceutically acceptable salt or solvate thereof.

Embodiment 24. The pharmaceutical composition according to any of the preceding embodiments, which exhibits enhanced robustness in a Simulated Use Test (SUT).

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

Embodiment 26 the pharmaceutical composition according to any of the preceding embodiments, comprising:

Pharmaceutical grade HFO-1234ze (E) propellant;

A plurality of glycopyrronium particles;

A plurality of formoterol particles; and

A plurality of phospholipid particles comprising a perforated microstructure.

Embodiment 27 the pharmaceutical composition according to any one of the preceding embodiments, comprising:

Pharmaceutical grade HFO-1234ze (E) propellant;

A plurality of glycopyrronium particles;

A plurality of formoterol particles;

A plurality of budesonide particles; and

A plurality of phospholipid particles comprising a perforated microstructure.

Embodiment 28 the pharmaceutical composition according to any of the preceding embodiments, comprising:

Pharmaceutical grade HFO-1234ze (E) propellant;

A plurality of albuterol particles;

A plurality of budesonide particles; and

A plurality of phospholipid particles comprising a perforated microstructure.

Embodiment 29 the pharmaceutical composition according to any of the preceding embodiments, comprising:

Pharmaceutical grade HFO-1234ze (E) propellant;

A plurality of formoterol particles;

A plurality of budesonide particles; and

A plurality of phospholipid particles comprising a perforated microstructure.

Example 30 a pharmaceutical composition according to any of the preceding embodiments, comprising:

Pharmaceutical grade HFO-1234ze (E) propellant;

A plurality of glycopyrronium particles;

A plurality of formoterol particles;

a plurality of budesonide particles;

A plurality of roflumilast particles; and

A plurality of phospholipid particles comprising a perforated microstructure.

Embodiment 31 the pharmaceutical composition according to any of the preceding embodiments, wherein the concentration of glycopyrrolate active agent particles in the propellant is sufficient to provide a delivered dose of glycopyrrolate per actuation of a metered dose inhaler selected from the following: 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.

Embodiment 32. The pharmaceutical composition according to any of the preceding embodiments, wherein the concentration of glycopyrrolate in the propellant is between about 0.04mg/mL to about 2.25 mg/mL.

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

Embodiment 34. The pharmaceutical composition according to any one of the preceding embodiments, wherein the formoterol active agent particles are included in the composition in a concentration sufficient to provide a formoterol delivery dose selected from: the metered dose inhaler is between about 1 μg and about 30 μg, between about 0.5 μg and about 10 μg, between about 2 μg and 5 μg, between about 3 μg and about 10 μg, between about 5 μg and about 10 μg, and between 3 μg and about 30 μg per actuation.

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

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

Embodiment 37 the pharmaceutical composition according to any one of the preceding embodiments, wherein the budesonide active agent particles are included in the composition in a concentration sufficient to provide a budesonide delivery dose selected from the group consisting of: the metered-dose inhaler is 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.

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

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

Embodiment 40. The pharmaceutical composition according to any of the preceding embodiments, wherein the albuterol active agent particles are comprised in the composition in a concentration sufficient to provide a delivery dose of albuterol selected from the group consisting of: the metered-dose inhaler is 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.

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

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

Embodiment 43 the pharmaceutical composition according to any one of the preceding embodiments, wherein the roflumilast active agent particles are included in the composition in a concentration sufficient to provide a roflumilast delivered dose selected from the group consisting of: the metered-dose inhaler is 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.

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

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

Embodiment 46. The pharmaceutical composition according to any of the preceding embodiments, wherein the glycopyrrolate particles comprise glycopyrronium or a pharmaceutically acceptable salt thereof.

Embodiment 47. The pharmaceutical composition according to embodiment 46, wherein glycopyrrolate or a pharmaceutically acceptable salt thereof is in crystalline and/or micronized form.

Embodiment 48. The pharmaceutical composition according to any of the preceding embodiments, wherein the formoterol particles comprise formoterol or a pharmaceutically acceptable salt thereof.

Embodiment 49 the pharmaceutical composition according to embodiment 48, wherein the formoterol or a pharmaceutically acceptable salt thereof is in crystalline and/or micronized form.

Embodiment 50. The pharmaceutical composition according to any of the preceding embodiments, wherein the albuterol particles comprise albuterol or a pharmaceutically acceptable salt thereof.

Embodiment 51. The pharmaceutical composition according to embodiment 50, wherein albuterol or a pharmaceutically acceptable salt thereof is in crystalline and/or micronized form.

Embodiment 52 the pharmaceutical composition according to any of the preceding embodiments, wherein the budesonide particles comprise budesonide in crystalline and/or micronized form.

Embodiment 53. The pharmaceutical composition according to any of the preceding embodiments, wherein the roflumilast particles comprise roflumilast or a pharmaceutically acceptable salt thereof.

Embodiment 54. The pharmaceutical composition according to embodiment 53, wherein roflumilast or a pharmaceutically acceptable salt thereof is in crystalline and/or micronized form.

Embodiment 55. A metered dose inhaler comprising a canister having an outlet valve comprising an actuator for dispensing a metered dose of the pharmaceutical composition according to any one of embodiments 1 to 54, wherein the canister comprises the pharmaceutical composition.

Example 56 a metered dose inhaler according to embodiment 55, which exhibits enhanced robustness in a Simulated Use Test (SUT).

Embodiment 57. The metered dose inhaler according to embodiment 55 or 56, which exhibits less than about 10%, 9%, 8%, 7%, 6% or 5% reduction in injection weight per actuation throughout the process of emptying the canister.

Embodiment 58 the metered dose inhaler according to any one of embodiments 55-57 exhibiting a weight loss of less than about 1.0%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% per year at 25 ℃/60% RH.

Example 59. The metered dose inhaler according to any one of embodiments 55-58, wherein the at least one internal gasket of the outlet valve is constructed at least in part from bromobutyl material.

Example 60 the metered dose inhaler according to any one of embodiments 55-59, wherein the outlet valve comprises a neck gasket and at least one seat gasket; and the neck gasket and/or the at least one seat gasket are constructed of bromobutyl material.

Embodiment 61 the metered dose inhaler according to any one of embodiments 55-60, which exhibits a Delivered Dose Uniformity (DDU) of a pharmaceutical formulation selected from the group consisting of: 20% or better DDU, ±15% or better DDU, and 10% or better DDU.

Embodiment 62. The metered dose inhaler according to any one of embodiments 55-61, which dispenses the pharmaceutical composition at an initial fine particle fraction and substantially maintains the initial fine particle fraction dispensed from the metered dose inhaler such that the fine particle fraction delivered from the metered dose inhaler is maintained within 85% of the initial fine particle fraction throughout the process of evacuating the canister.

Embodiment 63. The metered dose inhaler according to embodiment 62, wherein the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.

Embodiment 64 a method of treating a pulmonary disease or disorder in a patient comprising administering to the patient a pharmaceutical composition according to any one of embodiments 1 to 54 by actuating a metered dose inhaler; wherein the metered dose inhaler comprises a pharmaceutical composition.

Embodiment 65 the method of embodiment 64, wherein the pulmonary disease or disorder is selected from at least one of asthma, chronic Obstructive Pulmonary Disease (COPD), allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergy, respiratory distress syndrome, pulmonary arterial hypertension, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis.

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

Embodiment 67. The method of any of embodiments 64 to 66, wherein the metered-dose inhaler is described in accordance with any of embodiments 54 to 63.

Embodiment 68 the pharmaceutical composition according to any one of embodiments 1 to 54 for use in the manufacture of a medicament for the treatment of a pulmonary disease or disorder.

Embodiment 69 the pharmaceutical composition according to any one of embodiments 1 to 54 for use in the treatment of a pulmonary disease or disorder.

Embodiment 70 the pharmaceutical composition according to any one of embodiments 1 to 54, which exhibits a Cmax, AUCinf or AUClast of any one or more of the active agents that is about 80% to about 125% of the Cmax, AUCinf or AUClast of one or more of the active agents of the reference pharmaceutical composition.

Embodiment 71 the metered dose inhaler of any one of embodiments 55-63, wherein the pharmaceutical composition exhibits a Cmax, AUCinf or AUClast of any one or more of the active agents that is about 80% to about 125% of the Cmax, AUCinf or AUClast of one or more of the active agents of the reference pharmaceutical composition.

Embodiment 72 the method of any one of embodiments 64 to 67, wherein the pharmaceutical composition exhibits a Cmax, AUCinf or AUClast of any one or more of the active agents that is about 80% to about 125% of the Cmax, AUCinf or AUClast of one or more of the active agents of the reference pharmaceutical composition.

The specific embodiments included herein are for illustrative purposes only and should not be construed as limiting the present disclosure. Furthermore, the compositions, systems, and methods disclosed herein have been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the disclosure is susceptible to additional embodiments and that certain of the details described herein can be varied without departing from the basic principles of the disclosure. Any of the active agents and reagents used in the following examples are commercially available or may be prepared by one of ordinary skill in the art in accordance with standard literature procedures, given the teachings provided herein. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Examples

Example 1

Suspended particles were prepared by spray drying an emulsion of PFOB (perfluorobromooctane) stabilized by DSPC (1, 2-distearoyl-sn-glycero-3-phosphorylcholine) and water. Detailed preparation procedures can be found in WO 2010/138862, WO 2010/138868 and WO 2010/138884, the contents of which are incorporated herein by reference in their entirety. The particle size distribution of the suspended particles was determined by laser diffraction. 50% by volume of the suspended particles are smaller than 2.9 μm and the geometric standard deviation of the distribution is 1.8.

The active agent particles formed from glycopyrronium (3- [ (cyclopentylpolylphenylacetyl) oxy ] -1, 1-dimethylpyrrolidinium bromide) are formed by micronizing glycopyrronium using a jet mill. The particle size distribution of the micronized Glycopyrronium (GP) was determined by laser diffraction. 50% by volume of the micronized particles exhibit an optical diameter of less than 2.1 μm and 90% by volume of the micronized particles exhibit an optical diameter of less than 5 μm.

Formoterol fumarate micronized by manufacturer (Inke) (±) -2-hydroxy-5- [ (1 RS) -1-hydroxy-2- [ [ (1 RS) -2- (4-methoxyphenyl) -1-methylethyl ] -amino ] ethyl ] formanilide fumarate, also known as (+ -) -2' -hydroxy-5- [ (RS) -1-hydroxy-2- [ [ RS) -p-methoxy- α -methylphenylethyl ] -amino ] ethyl ] formanilide fumarate, was obtained and used as an active agent particle. The particle size distribution of micronized Formoterol Fumarate (FF) was determined by laser diffraction. 50% by volume of the micronized particles exhibit an optical diameter of less than 1.6 μm and 90% by volume of the micronized particles exhibit an optical diameter of less than 3.9 μm.

Active agent particles formed from budesonide (16, 17- (butylidenebis (oxy)) -11, 21-dihydroxy- (11-beta, 16-alpha) -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 exhibit an optical diameter of less than 1.9 μm and 90% by volume of the micronized particles exhibit an optical diameter of less than 4.3 μm.

The active agent particles formed from albuterol sulfate were formed by micronizing albuterol sulfate using a jet mill. The particle size distribution of salbutamol sulphate (AS) was determined by laser diffraction. 50% by volume of the micronized particles exhibit an optical diameter of less than 1.5 μm and 90% by volume of the micronized particles exhibit an optical diameter of less than 3.3 μm.

The active agent particles formed from roflumilast are formed by micronizing roflumilast using a jet mill. The particle size distribution of Roflumilast (RF) was determined by laser diffraction. 50% by volume of the micronized particles exhibit an optical diameter of less than 1.0 μm and 90% by volume of the micronized particles exhibit an optical diameter of less than 2.4 μm.

Metered dose inhalers are prepared by first dispensing the appropriate amount of suspended particles and active agent particles into an Addition Vessel (AV) and adding the appropriate amount of HFO-1234ze (E) (1, 3-tetrafluoropropene) propellant. The mixture is agitated to promote wetting of the powder and then transferred to a pressure vessel where the suspension is mixed. A valve comprising a 50 μl metering chamber (BK 357, bespak, king's Lynn, UK) was pressed onto an aluminum can (PRESSPART, blackburn, UK) coated with Fluorinated Ethylene Polymer (FEP) and then the suspension was filled by valve pressure. The canister was equipped with a polypropylene actuator (# 10024269,Bespak,King's Lynn,UK) with 0.32mm holes.

Example 2

A metered dose inhaler is prepared containing a triple co-suspension composition comprising glycopyrrolate, budesonide and formoterol active agent particles, wherein each type of active agent particle is provided as a micronized crystalline API material. The active agent particles are suspended in HFO-1234ze (E) propellant with or without phospholipid particles. In formulations containing phospholipid particles, as shown in fig. 7, the three types of active agent particles exhibit a uniform deposition profile. The three types of active agent particles exhibit respective deposition profiles in formulations that do not contain phospholipid particles.

Example 3

A metered dose inhaler is prepared containing a triple co-suspension composition comprising glycopyrrolate, budesonide and formoterol active agent particles, wherein each type of active agent particle is provided as a micronized crystalline API material. The active agent particles are suspended in either HFA-134a propellant or HFO-1234ze (E) propellant that is free of phospholipid particles. The deposition profile of budesonide in each formulation was tested at relative humidity of 0% and 50%. Compared to HFO-1234ze (E) propellants, HFA-134 propellant formulations exhibit a greater relative humidity effect on the deposition distribution.

Example 4

A metered dose inhaler is prepared containing a dual co-suspension composition comprising budesonide and formoterol active agent particles, wherein each type of active agent particle is provided as a micronized crystalline API material. The active agent particles are suspended in HFO-1234ze (E) propellant with or without phospholipid particles. As shown in fig. 15, both types of active agent particles and suspended particles exhibit a uniform deposition distribution. Table 6 provides FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition as characterized by NGI (new generation impactor). As shown in fig. 16 and 17, budesonide and formoterol fumarate respectively produced an aPSD (aerodynamic particle size distribution) in HFO-1234ze (E) through NGI similar to that in HFA-134 a. Table 7 provides FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition as characterized by NGI (new generation impactor). As shown in fig. 18, 19 and 20, the aPSD of each of budesonide, formoterol fumarate and suspended particles described as DSPC was stable for 12 months when stored closed and protected at 25 ℃/60% RH. Table 8 provides FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition as characterized by NGI (new generation impactor). As shown in fig. 21, budesonide and formoterol fumarate exhibited consistent delivered doses expressed as% LC (percent of label claim) and were stable for 12 months when stored closed and protected at 25 ℃/60% RH.

TABLE 6 micro particle fraction (FPF), micro particle dose (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition of BD, FF, and DSPC of BFF-1234ze

TABLE 7 micro-particle fraction (FPF), micro-particle dose (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition of BD and FF of BFF-1234ze and BFF-134a formulations as characterized by NGI

TABLE 8 micro particle fraction (FPF), micro particle dose (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition stability data for BD, FF, and DSPC of BFF-1234ze

In formulations without phospholipid particles, both types of active agent particles exhibit respective deposition profiles, while in formulations with phospholipid particles, both types of active agent particles exhibit consistent deposition profiles.

Example 5

A metered dose inhaler is prepared containing a dual co-suspension composition comprising budesonide and albuterol active agent particles, wherein each type of active agent particle is provided as a micronized crystalline API material. The active agent particles are suspended in HFO-1234ze (E) propellant with or without phospholipid particles. As shown in fig. 22, both types of active agent particles and suspended particles exhibit a uniform deposition distribution. Table 9 provides FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition as characterized by NGI (new generation impactor). As shown in fig. 23 and 24, budesonide and salbutamol produced an aPSD (aerodynamic particle size distribution) in HFO-1234ze (E) through NGI similar to that in HFA-134a, respectively. Table 10 provides FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition as characterized by NGI (new generation impactor). As shown in fig. 25 and 26, the respective asds of budesonide and albuterol were stable for 12 months when stored closed and protected at 25 ℃/60% RH. Table 11 provides FPF (fine particle fraction), FPD (fine particle dose), MMAD (mass median aerodynamic diameter) and throat deposition as characterized by NGI (new generation impactor). As shown in fig. 27, budesonide and albuterol exhibited consistent delivered doses in% LC (percent of label claim) and were stable for 12 months when stored closed and protected at 25 ℃/60% RH.

TABLE 9 micro particle fraction (FPF), micro particle dose (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition of BD, AB, and DSPC of BDA-1234ze

TABLE 10 micro-particle fraction (FPF), micro-particle dose (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition of BD and AB as characterized by NGI for BDA-1234ze and BDA-134a formulations

TABLE 11 micro particle fraction (FPF), micro particle dose (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition stability data for BD and AB of BDA-1234ze

Example 6

A metered dose inhaler is prepared containing a dual co-suspension composition comprising glycopyrrolate and formoterol active agent particles, wherein each type of active agent particle is provided as a micronized crystalline API material. The active agent particles are suspended in HFO-1234ze (E) propellant with or without phospholipid particles. As shown in fig. 28, both types of active agent particles and suspended particles showed a uniform deposition distribution in the formulation containing phospholipid particles.

Example 7

A metered dose inhaler is prepared containing a triple co-suspension composition comprising glycopyrrolate, budesonide and formoterol active agent particles, wherein each type of active agent particle is provided as a micronized crystalline API material. The active agent particles are suspended in either HFA-134a or HFO-1234ze (E) propellant and formulated with or without phospholipid particles.

The deposition profile of formoterol active particles was tested at several different ambient humidity (RH) levels ranging from 0% to 100%. The formoterol active particles in formulations without phospholipid particles showed increased throat and stage 3 deposition in HFO-1234ze (E) compared to HFA-134 a. However, this difference was not observed in the formulations comprising phospholipid particles, which showed similar formoterol deposition profiles in HFO-1234ze (E) (FIG. 8, lower panel) and HFA-134a (FIG. 8, upper panel).

The deposition profile of the budesonide active particles was tested at several different ambient humidity (RH) levels ranging from 0% to 100%. The budesonide deposition profile in HFA-134a formulations without phospholipid particles is more sensitive to RH levels than HFO-1234ze (E) formulations without phospholipid particles. Both HFA-134a and HFO-1234ze (E) formulations were more sensitive to RH in the presence of phospholipid particles than formulations without phospholipid particles, and both formulations showed similar changes in deposition profile based on RH levels (FIG. 9).

The deposition profile of glycopyrronium active agent particles was tested at several different ambient humidity (RH) levels ranging from 0% to 100%. Both HFA-134a and HFO-1234ze (E) formulations were more sensitive to RH in the presence of phospholipid particles than formulations without phospholipid particles, and both formulations showed similar changes in deposition profile based on RH levels.

Example 8

After storing the MDI for various periods of time under various temperature and relative humidity conditions, the Fine Particle Fraction (FPF) present in the delivered dose upon actuation of the MDI containing the budesonide, formoterol or glycopyrrolate active agent particles and phospholipid particles is measured. (FIGS. 10A, 10B, 10C)

After storing the MDI for various periods of time under various temperature and relative humidity conditions, the mass of Fine Particles (FPM) present in the delivered dose upon actuation of the MDI containing budesonide and phospholipid particles was measured. (FIGS. 11A, 11B, 11C)

Example 9

After storing MDI for various periods of time under various temperature and relative humidity conditions, the degradation of the active agent particles of budesonide (fig. 12A, 12B, 12C) and glycopyrrolate (fig. 13A, 13B, 13C) in MDI canisters containing the active agent particles and phospholipid particles was measured.

Example 10

After storing the MDI for various periods of time under various temperature and relative humidity conditions, the delivered dose uniformity upon actuation of the MDI containing the budesonide active agent particles and the phospholipid particles was measured. (FIGS. 14A, 14B, 14C)

Example 11

A metered dose inhaler is prepared containing a quadruple co-suspension composition comprising glycopyrrolate, budesonide, formoterol and roflumilast active agent particles, wherein each type of active agent particle is provided as a micronized crystalline API material. The active agent particles are suspended in HFO-1234ze (E) propellant and formulated with phospholipid particles. The deposition profile of each type of active agent particle of freshly prepared MDI was tested after three months of storage at 25 ℃ and 75% relative humidity, and after three months of storage at 40 ℃ and 75% relative humidity. The quadruple formulation exhibited a consistent aerosol distribution for each of the four types of active agent particles, and this distribution was consistent after three months of storage at the temperature and relative humidity levels tested.

Example 12

Randomized, single blind, 3 cycle, 3 course, single dose, crossover studies were performed to assess the relative bioavailability of BGF MDI HFO-1234ze (E) and BGF MDI HFC-152a compared to BGF MDI HFA-134a in healthy subjects.

The study pharmaceutical products included (1) a test product of budesonide/glycopyrrolate/formoterol (BGF) Metered Dose Inhalers (MDI) formulated with HFO-1234ze (E) propellant and (2) a reference product of budesonide/glycopyrrolate/formoterol (BGF) Metered Dose Inhalers (MDI) formulated with HFA-134a propellant. The indication studied is Chronic Obstructive Pulmonary Disease (COPD) and the stage of development is stage 1.

Study purposes:

The main purpose is as follows:

To evaluate the relative bioavailability of a Fixed Dose Combination (FDC) of budesonide, glycopyrrolate, and formoterol between a test formulation and a reference formulation when administered as a Metered Dose Inhaler (MDI) with 3 different propellants.

The secondary purpose is as follows:

To determine the Pharmacokinetic (PK) parameters of BGF when administered as 3 different propellant formulations. To assess safety and tolerability of the combination of BGF in healthy subjects when administered as a single dose of 3 different propellant formulations.

Study design:

the study was a randomized, single blind, 3 cycle, 3 course of treatment, single dose, single center, crossover study. The study included evaluating the PK profile of BGF MDI formulated with 3 different propellants: hydrofluoroolefins (HFO-1234 ze (E)) -treatment A (test), hydrofluorocarbons (HFC-152 a) -treatment B (test), and hydrofluoroalkanes (HFA-134 a) -treatment C (reference).

The study included:

Screening period: up to 28 days prior to the first administration.

Three treatment periods, each of which is up to 3 days: the subjects were hospitalized starting in the morning from the day prior to the first administration of BGF MDI in treatment phase 1 (day-1), throughout all treatment and elution phases, until discharge on day 2 of treatment phase 3.

Follow-up: the last administration of BGF MDI was within 3 to 7 days. There is a 3 to 7 day washout period between each administration. After at least 8 hours of overnight fast, each subject received 3 single doses of BGF MDI (1 dose of HFO-1234ze (E) [ treatment A ];1 dose of HFC-152a [ treatment B ] and 1 dose of HFA-134a [ treatment C ]).

Mainly includes the standard:

Healthy, non-smoking male subjects aged 18 to 60 years have veins suitable for catheterization or repeated venipuncture. The Body Mass Index (BMI) of the subject must be between 18 and 30kg/m2 (inclusive) and body weight of at least 50kg and not more than 100kg (inclusive). The one second effort expiratory volume (FEV 1) of the subject must be > 80% of the predicted value in terms of age, height and race at the screening visit.

Study drug:

Treatment a (test): BGF MDI HFO-1234ze (E) at an intensity/concentration of 160/7.2/4.8 μg per actuation.

Treatment B (test): BGF MDI HFC-152a, intensity/concentration 160/7.2/4.8 μg per actuation.

Treatment C (reference): BGF MDI HFA-134a, intensity/concentration 160/7.2/4.8 μg per actuation.

Duration of the study

Each subject will participate in this study for up to 53 days.

Treatment compliance:

Administration was performed at Parexel EARLY PHASE CLINICAL Unit in los Angeles. Administration of all study drugs (IMPs) was recorded in the Parexel electronic primary data acquisition and information management system (ClinBase ^TM). Compliance is ensured by direct supervision and witnessing of IMP administration.

Evaluation criteria:

pharmacokinetic parameters:

Major PK parameters: cmax, AUCinf and AUClast for test and reference treatments.

Secondary PK parameters: tmax, t ¹/₂ λz, MRT, λz, CL/F, vz/F, TRCmax, TRAUCinf and TRAUClast.

Security variables:

Adverse Event (AE)/Serious Adverse Event (SAE).

Vital signs (systolic and diastolic blood pressure, pulse rate, body temperature, oxygen saturation and respiratory rate).

12-Lead security and digital Electrocardiogram (ECG) and cardiac telemetry

Physical examination.

Laboratory assessment (hematology, clinical chemistry and urine analysis)

Spirometry.

Taste assessment.

The statistical method comprises the following steps:

determination of sample size:

This is a preliminary PK study to determine the relative bioavailability between 2 BGF MDI test formulations compared to conventional formulations. Therefore, no sample size calculation was performed.

It is expected that 48 healthy subjects (subject numbers increased from 24 to 48 to account for replacement subjects due to dose bias involving the first 23 subjects according to protocol modification 2) will be randomly assigned to a 3-cycle and 3-course 6-sequence Williams design: ABC, BCA, CAB, ACB, BAC and CBA to ensure that at least 20 subjects are assessed at the end of the last treatment period.

A subject is considered to be evaluable if it has an evaluable PK profile, i.e., (1) has received positive treatment, (2) has no significant violation of the inclusion or exclusion criteria for the regimen, or significant deviation from the regimen, and (3) has no unavailable or incomplete data that may affect PK analysis, pharmacokinetic data presentation, and analysis:

Unless otherwise specified, the PK analysis set presented all PK concentrations, parameter totals and statistical analysis. The safety analysis set presents a list of PK concentrations and parameters, and includes all reportable individual PK results. Individual PK concentrations and parameter data for any subject not included in the PK analysis set or excluded from the descriptive summary table, graph and/or inference statistical analysis are included in the list and labeled with the appropriate footnotes.

For each analyte, test treatments (treatments A and B (BGF MDI HFO and BGF MDI HFC, respectively)) were compared to the reference treatment (treatment C (BGF MDI HFA)), respectively. Statistical analysis was performed using a linear mixed effect anova model, using the natural logarithms of Cmax, AUCinf and AUClast as response variables, sequence and period, treatment as fixed effects, and subjects nested in sequence as random effects. Converted back from the logarithmic scale, the geometric mean of Cmax, AUCinf and AUClast, and intra-subject coefficient of variation Confidence Interval (CI) are estimated and presented (double 95%). In addition, the geometric mean and the ratio of CI (90% on both sides) are estimated and presented.

Furthermore, the median difference in unconverted tmax between the test and reference treatments for each analyte, and the corresponding 90% CI of the median difference for each analyte, was calculated using a non-parametric hodgkin-man method.

Presentation and analysis of security and eligibility data:

Security data (both intra-and extra-planned) is presented in the data list. Continuous variables were summarized by treatment using descriptive statistics (n, mean, standard deviation [ SD ], minimum, median, maximum). The classification variables are summarized in a frequency table (frequency and ratio) by treatment, as applicable. The analysis of the security variables is based on a security analysis set.

Adverse events were summarized in terms of Preference (PT) and System Organ Classification (SOC) using the supervision active medical dictionary (Medical Dictionary for Regulatory Activities) (MedDRA) vocabulary. In addition, a list of SAEs and AEs that resulted in withdrawal was made and the number of subjects with any AE, SAE, AE that resulted in withdrawal and AE with severe intensity was summarized. Adverse events occurring prior to dosing were reported separately.

Data tables and lists of vital signs, clinical laboratory tests, digital ECG and 12-lead safety ECG (list only), telemetry (list only) and spirometry are presented. The results from the taste assessment are presented solely in the list. Any new or aggravated clinically relevant abnormal medical physical examination findings are reported as AEs compared to the baseline assessment. The observed data for each planned evaluation is summarized, along with the corresponding change from baseline when the baseline is defined. Clinical laboratory data is reported in units provided by the clinical laboratory for the Safety Review Committee (SRC) conference and in International units (SI) units in clinical research reports (CSR).

The safety laboratory assessed overstep values are marked in separate lists and are descriptive summarized using agreed standard reference ranges and/or extended reference ranges (e.g., astraZeneca, project or laboratory range).

Scheme deviation:

a total of 26 (55.3%) subjects reported significant protocol bias during the study:

For treatment a (HFO propellant): 23 (48.9%) subjects were reported with other important regimen deviations (subjects were not dosed with self-inhaler as described in the regimen. Nurses performed dosing).

For treatment B (HFC propellant): 23 (48.9%) subjects were reported other significant regimen deviations (subjects were not dosed with self-inhaler as described in the regimen the nurses performed dosing) and 2 (4.3%) subjects did not receive the expected full dose due to problems during inhalation.

For treatment C (HFA propellant): 23 (48.9%) subjects were reported other significant regimen deviations (subjects were not dosed with self-inhaler as described in the regimen the nurses performed dosing) and 1 (2.1%) subject did not receive the expected full dose due to problems during inhalation.

According to protocol modification 2, the number of subjects increased from 24 to 48 to account for replacement subjects due to dose bias involving the first 23 subjects.

23 Subjects were excluded from the PK analysis set due to reported protocol bias. Significant protocol bias associated with COVID-19 was not reported during the study.

Pharmacokinetic results:

systemic exposure of budesonide from BGF MDI HFO was comparable to BGF MDI HFA, with Cmax, AUCinf and AUClast GMR and 90% CI being 111.7% (91.01%, 137.1%), 104.7% (91.95%, 119.2%) and 107.2% (94.53%, 121.9%) respectively.

Glycopyrrolate systemic exposure from BGF MDI HFO is comparable to BGF MDI HFA, with Cmax and AUClast GMR and 90% CI of 108.3% (85.50%, 137.3%) and 106.1% (86.18%, 130.6%) respectively.

Formoterol systemic exposure from BGF MDI HFO was comparable to BGF MDI HFA, with Cmax, AUCinf and AUClast GMR and 90% CI of 109.1% (97.02%, 122.7%), 96.00% (70.33%, 131.0%) and 98.13% (86.44%, 111.4%) respectively.

Security results:

Death, SAE or AE that led to termination of IMP were not reported during this study.

No new safety signal was observed, no clinically relevant trends in vital signs, physical examination, laboratory results, spirometry and taste assessment were observed, and no abnormal clinically significant 12-lead safety and digital ECG and cardiac telemetry findings were reported.

The combination of budesonide, glycopyrrolate and formoterol exhibits an acceptable safety profile when administered as a single dose in 3 different propellant formulations and is well tolerated in the study population.

In view of this clinical study, the systemic exposure of budesonide, glycopyrrolate and formoterol was similar for BGF MDI HFO-1234ze (E) compared to the reference product BGF MDI HFA-134 a. In this taste assessment, there was no indication that there was a meaningful difference between the products. The combination of budesonide, glycopyrrolate and formoterol exhibits an acceptable safety profile when administered as a single dose in HFO-1234ze (E) and HFA-134a formulations and is well tolerated in the study population.

Example 13

Figure 34 depicts the aerosol particle size distribution (aPSD) measured by a New Generation Impactor (NGI) of Formoterol Fumarate (FF) active agent particles from an MDI comprising a dual fixed dose combined co-suspension of formoterol fumarate and budesonide active agent particles suspended in HFA-134a (a formulation known as BFF-134 a) or HFO-1234ze (E) (a formulation known as BFF-1234 ze) propellant together with phospholipid suspension particles, as a percentage of total recovered mass. The profile shows a similar aerosol distribution of the two active agent particles between HFA-134a and HFO-1234ze (E).

Figure 35 depicts the aPSD measured by NGI of formoterol (FF) active agent particles from MDI comprising a triple fixed dose combined co-suspension of budesonide and formoterol fumarate active agent particles suspended in HFA-134a (a formulation known as BFF crystal-134 a) or HFO-1234ze (E) (a formulation known as BFF crystal-1234 ze) propellant without phospholipid suspension particles, as a percentage of total recovered mass. The profile shows a unique aerosol distribution of the two active agent particles between HFA-134a and HFO-1234ze (E).

Table 12 provides a summary of the number of fine particle fractions, <6.4 μm (FPF), fine particle dose, <6.4 μm (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition of budesonide and formoterol fumarate calculated from the NGI dataset of BFF-134a, BFF-1234ze, BFF crystal-134 a, and BFF crystal-1234 ze.

TABLE 12 micro-particle fraction (FPF), micro-particle dose (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition of BD and FF of BFF-134a, BFF-1234ze, BFF-134a and BFF-crystal-1234 ze

Example 14

Figure 36 depicts the aerosol particle size distribution (aspsd) measured by a New Generation Impactor (NGI) of formoterol (FF) active agent particles from MDI containing a triple fixed dose combined co-suspension of budesonide, glycopyrrolate, and formoterol active agent particles suspended in HFA-134a (a formulation known as BGF-134 a) or HFO-1234ze (E) (a formulation known as BGF-1234 ze) propellant together with phospholipid suspension particles, as a percentage of total recovery mass. The profile shows a similar aerosol distribution of all active agent particles between HFA-134a and HFO-1234ze (E).

Figure 37 depicts the asds measured by NGI of particles of Budesonide (BD), glycopyrrolate (GP), and Formoterol Fumarate (FF) active agents actuated from MDI containing triple fixed dose combined co-suspensions of budesonide, glycopyrrolate, and formoterol fumarate active agent particles suspended in HFA-134a (a formulation called BGF crystal-134 a) or HFO-1234ze (E) (a formulation called BGF crystal-1234 ze) without phospholipid suspension particles as a percentage of total recovered mass. The profile shows a unique aerosol distribution of all active agent particles between HFA-134a and HFO-1234ze (E).

Table 13 provides a summary of the fine particle fractions of budesonide, glycopyrrolate, and formoterol fumarate, <6.4 μm (FPF), fine particle dose, <6.4 μm (FPD), mass Median Aerodynamic Diameter (MMAD), and throat deposition calculated from the NGI dataset of BGF-134a, BGF-1234ze, BGF crystal-134 a, and BGF crystal-1234 ze.

TABLE 13 micro-particle fractions for BD, GP and FF for BGF-134a, BGF-1234ze, BGF crystal-134 a and BGF crystal-1234 ze, <6.4 μm (FPF), micro-particle dose, <6.4 μm (FPD), mass Median Aerodynamic Diameter (MMAD) and throat deposition

The various embodiments described above may 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 indicated herein. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments.

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 the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the present disclosure.

Claims

1. A pharmaceutical composition deliverable from a metered dose inhaler, the pharmaceutical composition comprising:

A pharmaceutical grade (1E) -1, 3-tetrafluoro-1-propene (HFO-1234 ze (E)) propellant having a purity of at least about 99.90%;

a plurality of one or more types of active agent particles; and

A plurality of phospholipid particles comprising a perforated microstructure;

Wherein the one or more active agents are selected from the group consisting of Long Acting Muscarinic Antagonists (LAMA), long acting beta 2-agonists (LABA), short acting beta-agonists (SABA), inhaled Corticosteroids (ICS) and non-corticosteroid anti-inflammatory agents.

2. The pharmaceutical composition of claim 1, comprising

A plurality of active agent particles of a first species; wherein the active agent is LAMA selected from the group consisting of: glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, turnidiammonium, and daptomide; or a pharmaceutically acceptable salt or solvate thereof; and

A plurality of active agent particles of a second species; wherein the active agent is a LABA selected from the group consisting of: bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, miveraterol, indacaterol, vilantro and β ₂ agonists derived from salicin or indole and adamantyl; or a pharmaceutically acceptable salt or solvate thereof.

3. The pharmaceutical composition of claim 2, wherein the LAMA is glycopyrrolate or a pharmaceutically acceptable salt or solvate thereof; and the LABA is formoterol or a pharmaceutically acceptable salt or solvate thereof.

4. The pharmaceutical composition of claim 1, comprising

A plurality of active agent particles of a first species; wherein the active agent is LAMA selected from the group consisting of: glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, turnidiammonium, and daptomide; or a pharmaceutically acceptable salt or solvate thereof;

A plurality of active agent particles of a second species; wherein the active agent is a LABA selected from the group consisting of: bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, miveraterol, indacaterol, vilantro and β ₂ agonists derived from salicin or indole and adamantyl; or a pharmaceutically acceptable salt or solvate thereof; and

A plurality of third species of active agent particles; wherein the active agent is an ICS selected from the group consisting of: beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone and triamcinolone, or a pharmaceutically acceptable salt or solvate thereof.

5. The pharmaceutical composition of claim 4, wherein the LAMA is glycopyrrolate or a pharmaceutically acceptable salt or solvate thereof; the LABA is formoterol or a pharmaceutically acceptable salt or solvate thereof; and the ICS is budesonide or a pharmaceutically acceptable salt or solvate thereof.

6. The pharmaceutical composition of any one of claims 1-5, wherein the LAMA is present at a concentration in the range of about 0.04mg/mL to about 2.25 mg/mL.

7. The pharmaceutical composition of any one of claims 1-5, wherein the LABA is present at a concentration in the range of about 0.01mg/mL to about 1 mg/mL.

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein the ICS is present at a concentration ranging from about 0.1mg/mL to about 20 mg/mL.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the perforated microstructure comprises 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC) and calcium chloride.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the phospholipid particles are present at a concentration ranging from about 0.1mg/mL to about 10 mg/mL.

11. The pharmaceutical composition according to any one of claims 1 to 10, comprising:

a pharmaceutical grade HFO-1234ze (E) propellant having a purity of at least about 99.90%;

A plurality of glycopyrronium particles;

A plurality of formoterol particles; and

A plurality of phospholipid particles comprising a perforated microstructure.

12. The pharmaceutical composition according to any one of claims 1 to 10, comprising:

A plurality of glycopyrronium particles;

A plurality of formoterol particles;

A plurality of budesonide particles; and

A plurality of phospholipid particles comprising a perforated microstructure.

13. The pharmaceutical composition of claim 11 or 12, wherein the concentration of the glycopyrrolate particles in the propellant is sufficient to provide a delivered dose of glycopyrrolate per actuation of the metered dose inhaler selected from the following: 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.

14. The pharmaceutical composition according to any one of claims 11 to 13, wherein the glycopyrrolate particles comprise micronized and crystalline glycopyrrolate.

15. A pharmaceutical composition according to claim 11 or 12, wherein the formoterol particles are included in the composition in a concentration sufficient to provide a formoterol delivery dose selected from: the metered dose inhaler is between about 1 μg and about 30 μg, between about 0.5 μg and about 10 μg, between about 2 μg and 5 μg, between about 3 μg and about 10 μg, between about 5 μg and about 10 μg, and between 3 μg and about 30 μg per actuation.

16. The pharmaceutical composition according to any one of claims 11, 12 and 15, wherein the formoterol particles comprise micronized and crystalline formoterol fumarate.

17. The pharmaceutical composition of claim 12, wherein the budesonide particles are included in the composition in a concentration sufficient to provide a budesonide delivery dose selected from the group consisting of: the metered dose inhaler is 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.

18. The pharmaceutical composition of any one of claims 11, 12 and 17, wherein the budesonide particles comprise micronized budesonide.

19. The pharmaceutical composition of any one of claims 11, 12 and 17, wherein the phospholipid particles are included in the composition in a concentration sufficient to provide a delivered dose of phospholipid particles selected from between about 50 μg to about 400 μg.

20. The pharmaceutical composition of any one of claims 1 to 18, which exhibits a Cmax, AUCinf or AUClast of any one or more of the active agents that is about 80% to about 125% of the Cmax, AUCinf or AUClast of the active agent of a reference pharmaceutical composition comprising a pharmaceutical grade HFA-134a propellant.

21. A metered dose inhaler comprising a canister having an outlet valve comprising an actuator for dispensing a metered amount of the pharmaceutical composition according to any one of claims 1 to 20, wherein the canister contains the pharmaceutical composition.

22. The metered dose inhaler of claim 21, wherein said outlet valve comprises a neck gasket and at least one seat gasket; and the neck gasket or the at least one seat gasket is constructed of bromobutyl material.

23. The metered dose inhaler of claim 21 or 22, exhibiting a reduction in injection weight per actuation of less than about 10%, 9%, 8%, 7%, 6% or 5% throughout the process of emptying the canister.

24. A metered dose inhaler as claimed in any one of claims 21 to 23 exhibiting a weight loss of less than about 1.0%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% per year at 25 ℃/60% rh.

25. The metered dose inhaler of any one of claims 21-24, which exhibits drug formulation Delivery Dose Uniformity (DDU) throughout the process of emptying the canister selected from the group consisting of: 20% or better DDU, ±15% or better DDU, and 10% or better DDU.

26. A method of treating a pulmonary disease or disorder in a patient, comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 20 by actuating a metered dose inhaler; wherein the metered dose inhaler comprises the pharmaceutical composition.

27. The method of claim 26, wherein the pulmonary disease or disorder is asthma or COPD.

28. The method according to claim 26 or 27, wherein the metered dose inhaler is according to any one of claims 21 to 25.

29. The pharmaceutical composition according to any one of claims 1 to 20 for use in the manufacture of a medicament for the treatment of a pulmonary disease or disorder.

30. The pharmaceutical composition according to any one of claims 1 to 20 for use in the treatment of a pulmonary disease or disorder.