AU2017201709A1 - Compositions, methods & systems for respiratory delivery of two or more active agents - Google Patents

Description

COMPOSITIONS, METHODS & SYSTEMS FOR RESPIRATORY DELIVERY OF TWO OR MORE ACTIVE AGENTS

Technical Field [0001] The present application is a divisional application of Australian Application No. 2015201037, which is incorporated in its entirety herein by reference.

[0001a] The present disclosure relates generally to compositions, methods and systems for respiratory delivery of two or more active agents. In certain embodiments, the present disclosure relates to compositions, methods, and systems for respiratory delivery of two or more active agents, wherein at least one of the active agents is selected from long-acting muscarinic antagonist (“LAMA”), long-acting β2 adrenergic agonist (“LABA”), and corticosteroid active agents.

Background [0001 b] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

[0002] Methods of targeted drug delivery that deliver an active agent at the site of action are often desirable. For example, targeted delivery of active agents can reduce undesirable side effects, lower dosing requirements and decrease therapeutic costs. In the context of respiratory delivery, inhalers are well known devices for administering an active agent to a subject’s respiratory tract, and several different inhaler systems are currently commercially available. Three common inhaler systems include dry powder inhalers, nebulizers and metered dose inhalers (MDIs).

[0003] MDIs may be used to deliver medicaments in a solubilized form or as a suspension. Typically, MDIs use a relatively high vapor pressure propellant to expel aerosolized droplets containing an active agent into the respiratory tract when the MDI is activated. Dry powder inhalers generally rely on the patient’s inspiratory efforts to introduce a medicament in a dry powder form to the respiratory tract. On the other hand, nebulizers form a medicament aerosol to be inhaled by imparting energy to a liquid solution or suspension.

[0004] MDIs are active delivery devices that utilize the pressure generated by a propellant. Conventionally, chlorofluorocarbons (CFCs) have been used as propellants in MDI systems because of their low toxicity, desirable vapor pressure and suitability for formulation of stable suspensions. However, traditional CFC propellants are understood to have a negative environmental impact, which has led to the development of alternative propellants that are believed to be more environmentsjiy-fnendly, such as perfluorinated compounds (PFCs) and hydfcflybroaikanes (HFAs). ipOOSj The active agent to be delivered by a suspension MDI is typically provided as a fine particulate dispersed within a propellant or combination of two or more propellants (l.e.. a propellant “system5*), in order to form the fine particulates, the active agent is typically micronized. Fine particles of active agent suspended in a propellant or propellant System tend to aggregate or flocculate rapidly. This is particularly true of active agents present in micronized form, in turn, aggregation or fioccuiation of these fine particles may complicate the delivery of the active agent. For example,: aggregation; or flocculation Pan lead to mechanical failures, such as those that might he caused by obstruction of the valve orifice of the aerosol container. Unwanted aggregation or flocculation of drug particles may also lead to rapid sedimentation or creaming of drug particles, and such behavior may result in inconsistent dose delivery, which can be particularly troublesome with highly potent, low dose medicaments. Another problem associated with such suspension MDI •formulations relates to crystal growth of the drug during storage, resulting in a decrease over time of aerosol properties and delivered dose uniformity of such fytDis, More recently, solution approaches, such as those disclosed In U.S. Patent No, 6,064,760, have been proposed for MD! formulations containing anticholinergics. [00061 One approach to improve aerosol performance in dry powder inhalers has been to incorporate fine particle carrier particles, such as lactose. Use of such fine 'no*;'jbe^i'"|[ί1γ®ΐδϊίϊ&^ΐ^ρ|! to any great extent for MDis. A recent report by Yeung et ah, “The influence of micronized particulates on the aerosotaflon properties of pressurized metered dese inhalers*; Aerosoi Science 40, pgs. 324-337 (2009), suggests that the use of such fine particle carriers in MDls actually result in a decrease in aerosol performs nee.

[0067] in traditional CFG systems, when the active agent present in an MDI formulation is suspended In the propellant or propellant system, surfactants are often used to coat the surfaces of the active agent In order to minimize or prevent the problem of aggregation and maintain a substantially uniform dispersion. The use of surfactants In this manner is sometimes referred to as “stabilizing- the suspension, However, many surfactants that: are soluble and thus effective in CFG systems are not effective in HFA and RFC propellant systems because such surfactants exhibit different solubility characteristics In non-GFC propellants,

Brief Description of the Drawings |00S8J FIG:, 1 is a graph, which depicts the delivered dose uniformity of a eo~' suspension fprmuistion containing giycopyrroiate and formoferoi fumarate prepared accord ing to the present description.

[0000] FIG, 2 is a graph, which depicts the .delivered dose ratio of the co-suspension formuiation of FIG, 1, 10010] FIG, 3Vis a graph, which depicts the delivered dose uniformity of a second co-su opens ion formulation prepared accord Ing to the presen t description [0011] FfG, 4 is a graph, which depicts the delivered dose ratio of the second cosuspension formulation of FIG- 3.

[0012] FIG, 5 is a graph, which depicts the delivered dose uniformity of giycopyrroiate and formoferol fumarate in a co-suspension formuiation prepared according to the present description upon storage under different conditions as indicated, [0013] FIG. 6 is a graph, which depicts the particle size distributions of exemplary co-suspension formulations prepared according to the present description upon storage under dliferent conditions, as indicated.

[0014] FIG. 7 provides graphs illustrating the particle size distributions achieved by an exemplary co-suspension inciuding a combination of giycopyrroiate and formoteroi fumarate, upon storage at Indicated conditions.

[001 Sj FIG. 8 provides graphs illustrating the particle size distribution achieved by an exemplary a>euspensibn including a combination of giycopyrroiate and formoteroi fumarate compared to particle size distributions achieved by formuiatlons including either giycopyrroiate or formoteroi fumarate atone, [0010] FIG. 9 is a graph, which depicts the serum giycopyrroiate and formoteroi concentration levels over time achieved after delivery of an exemplary co-suspensionjnciuding; giycopyrroiate and formoteroi fumarate prepared according to the present description. The serum concentration time profile of giycopyrroiate and formoteroi fumarate delivered from the exemplary combination formuiation is compared to that achieved by compositions containing and delivering giycopyrroiate or formoteroi fumarate alone, 10017] FfG, 10 is a graph that depicts the formoteroi particle size distribution achieved by a dual co-suspension prepared according to the present description, which included mierocyrstalllne formoteroi fumarate and giycopyrrolate active agent particles compared to a co-suspension only containing crystalline formoteroi fumarate.

[0018] FIG. 11 is a graph that depicts the giycopyrrolate particle size distribution achieved by a dual co-suspension prepared according to the present description, which included mlcrocrystafllne giycopyrrolate active agent particles and microerystalSine formoteroi fumarate active agent particles with two different particle size distributions (denoted "fine* and “coarse*) or spray dried formoteroi fumarate. [O019J FIG. 12 is a graph that depicts the formoteroi fumarate particle size distribution achieved by a second dual co-suspension prepared according to the present description, which included microcrystaiiine formoteroi fumarate and microcrystailihe giycopyrrolate active agent particles compared lo one that contained microcrystaiiine giycopyrrolate active agent particles and spray dried formoteroi fumarate particles. f0020] FIG, 13 is a graph, which depicts the delivered dose uniformity of giycopyrroiate and formoteroi fumarate in an exemplary dual co-suspension formulation prepared according to the present description.

[0021] FIG. 14 depicts the delivered dose uniformity for each active agent .included' in an: exemplary triple co-suspension composition, which included microcrystaiiine giycopyrroiate, formoteroi fumarate and mometasone female active agent parficies.

[0022] FIG. IS is a graph depicting the formoteroi fumarate aerodynamic particle size distributions achieved in a tripie eo-suspeosidn prepared according to the present description, which Included microcystaiiine giycopyrrolate, formoteroi fumarate and mometasone furcate active agent particles, compared to that achieved in a dual co-suspension which Included giycopyrrolate and formoteroi fumarate, [00231 16 is a graph depicting the giycopyrrolate aerodynamic particle size distributions achieved in a triple co-suspension prepared according to the present description, which included microcystaiiine giycopyrrolate, formoteroi fumarate and mometasone furcate active agent particles, compared to that achieved in a dual cosuspension which included giycopyrrolate and formoteroi fumarate.

[0024] FIG, 1 ? is a graph depicting the giycopyrrolate and tiotropium bromide aerodynamic particle size distributions achieved by a triple co-suspension prepared according to the present description, which, in addition to ether giycopyrrolate or tiotitpium bromide active agent particles, included formoteroi fumarate and mometasone fyroate microerysiaTne active agent particles.

[0625] FI©. 18 is a graph depicting the giycogyrrolafe aerodynamic size distribution achieved by a two dual and one single component co-suspension prepared according to the present description. The dose proportionality between the two dual co-suspensions as well as the equivalency between the dual and die single component co-suspension is displayed.

[0026] Fi©. 19 Is a graph depicting the fbrmofero! fumarate aerodynamic size distribution achieved by a two dual and two single component co-suspensions prepared according to the present description. The dose proportionality between the two dual and two single component co-suspensions as we!! as the equivalency between the dual and the single component co-suspension is displayed, 10627] FIG. 20 is a graph depicting the dose delivered uniformity of ultra low formotero! fumarate single component co-suspensions prepared according to the present description,

Detailed Description [0028] The present disclosure provides compositions, methods, and systems for respiratory delivery of two or more active agents, Specifically, in certain embodiments, the present disclosure includes pharmaceutical compositions, systems and methods for respiratory delivery of two or more active agents via an IMDI, and in particular embodiments ei least one of the active agents is selected from long-acting muscarinic antagonist ("LAMA"), long-acting p2 adrenergic agonist fLABA”|, and corticosteroid active agents, The compositions described herein may be formulated for pulmonary or nasal delivery via an MDI. The methods described herein include methods of stabilizing formulations including two or more active agents for respiratory delivery, as well as methods for pulmonary delivery of two or more active agents for treating a pulmonary disease or disorder via an fvIDI, Also described herein are "MDi systems for delivery of two or more active agents, as well as methods for preparing such systems.

[6029] Formulating pharmaceutical compositions incorporating two or more active agents is often challenging due to unpredictable or unexpected interactions between the active agents or changes to the formulations resulting from the incorporation of multiple active agents. Such Interactions are generally known as a Combination effootfrand In the context of suspension formulations delivered from an MPi, a combination affect may be manifest by, for example, a deviation from similarity between a formulation Including a single active agent and a formulation Including a combination of two or more active agents in one or more of the following areas: the aefoso! and: particle size distribution chafadertstics provided by the formulation; delivered dose uniformity for one or more of the active agents; deliverability or absorption of one or more of the active agents; or the dose proportionality observed for one or more of the active agents.

In specific embodiments^ the co·· suspension compostions described herein avoid combination effects associated with combination formulations. For purposes of the present description, a composition avoids combination effects where, for a selected active agent, the aerosol properties, particle size distribution characteristics, and delivered dose uniformity achieved by a combination formulation do not deviate from those achieved by a comparable formulation wherein the only active agent is the selected active agent, In some embodiments, the lack of a combination effect is evidenced for a selected active agent where the plasma concentration over time for a targeted dose of the selected active agent delivered from a eembioaion formulation does not deviate from the plasma concentration over time achieved when the selected active agent is delivered at the same dose from a comparable formulation wherein the only active agent Is the selected active agent [003If As used herein, the phrases “do not deviate*’ or “does not deviate” signify that: for a given parameter, the performance achieved by a combination formulation is ± 20% of that achieved by a comparable formulation including only one of the active agents included In the combination formulation. In certain embodiments, the performance achieved by a combination formulation does hot vary from that achieved by a comparable formulation including only one of the active agents included in the combination. For example, a ca-Sbspensidh as described herein, including two or more active agents, is considered to exhibit: no combination effect when, with respect to each such active agent at a given dose, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the piasma concentration over time achieved by the combination co-suspension are within ± 20% of those achieved by a comparable formulation including only a single active agent, in some embodiments, for each active agent at a give dose, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity,, and the plasma concentration ever time achieved by the fombination co-suspension compositions described herein are within ± 1S% of those achieved by a comparable formulation including oniy a single active agent, in yet other embodiments, for each active agent at a give dose, one or more of the aerosol properties, the particle Sim distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the Combination co-suspension compositions described herein are wihin ± 10¾ of those achieved by a comparable formulation including only a single active agent. in certain embodiments, with respect to each active agent at a given dose, the combinatidn ^-suspension compositions as described herein exhibit no difference to comparable formulations including only one of the active agents Included in the combination in one or more of the following areas: aerosol properties for the formulation; the particle size distribution characteristics; delivered dose uniformity for; and the plasma concentration over time. 100321 The combination of two or more active agents included in the compositions provided herein may, in some embodiments,, provide advantages over pharmaceutical formulations including only a single active agent. For instance, when a combination of two or more active agents is delivered simultaneously, the therapeuticaliy effective dose of both active agents may be relatively less than when any of the combined active agents Is delivered alone, thereby avoiding or reducing possible side effects. Moreover, combinations of two or more active agents may achieve a more rapid onset or longer duration of therapeutic benefit than can be achieved by delivering one of the combined active agents aione.

[00331 In specific embodiments, the methods described herein include methods for treating a pulmonary disease or disorder amenable to treatment by respiratory delivery of a co-suspension composition as described herein, For example, the compositions, methods and systems described herein can be used to treat inflammatory or obstructive pulmonary diseases or conditions, in certain embodiments; the compositions, methods and systems described herein can be used to treat patients suffering from a disease or disorder selected from asthma, chronic obstructive pulmonary disease (CORD), exacerbation of airways hyper reactivity conseguent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasdconstridtion, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, and any other respiratory disease, condition, trait, genotype or phenotype that can respond to the administration of, for sample, a LAMA, ΙΑΒΑ, cpdiee^teroid, 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 can be used to treat pulmonary Inflammation and obstruction associated with cystic fibrosis. As used herein, the terms “CORD” and “chronic obstructive pulmonary disease" encompass chronic obstructive lung disease (COLD), chronic obstructive airway disease pOAD), chronic airflow limitation (CAL) and chronic obstructive respiratory disease (‘€ORD) end include chronic bronchitis, bronchiectasis, and emphysema, As used herein, the term “asthma” refers to asthma of whatever type or genesis, including intrinsic |non~allerglc) asthma and extrinsic jallergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Asthma is also to be understood as embracing wheezy-infant syndrome, [0034] It will be readily understood that the embodiments, as generally described herein, are exemplary. The following more detailed description of various embodiments is not intended to limit the scope of the present disclosure, but is merely representative of various embodimenis. As such, the specifics recited herein may include independently patentable subject matter. Moreover, the order of the steps or actions of the methods described in connection with the embodiments disclosed herein may be changed by those skilled in the art without departing from the scope .of the present disclosure, in other words, unless a specific order of steps or actions is required for proper operation of the embodiment, the order or use of specific steps or actions may be modified.

[0035] Unless specifically defined ptheirwise, the technical terms, as used herein, have their normal meaning as understood in the art. The following terms are specifically defined for the sake of clarity.

[0030] The term “active agent* is used herein to include any agent, drug, compound, composition or other substance that may be used on, or administered to a human or animal for any purpose, including therapeutic, pharmaceutical, pharma colog sea I, diagnostic, cosmetic and prophylactic agents and immunomodufators. The term “active agent* may be used interchangeably with the terms, “#ugv" ^pharmaceutical,” “medicamentf "drug substancer or "therapeutic^ As used herein the "active agerif may a iso encompass natural or homeopath ic products that are not generally considered therapeutic, [0037] The terms "associate,” "associate with" or “association'' refers to an interaction or relationship between a chemical entityor structure: in a condition of proximity to a surface, such as the surface of another chemical entity. Composition, or structure. The association includes, for example, adsorption, adhesion, covalent bonding, hydrogen bonding:, ionic bonding and electrostatic attraction, Lifshitz-van der Waais Interactions and polar Interactions, The term "adhere” or “adhesion” is a form of association and is used as a generic term for all forces tending to cause a particle or mass to be attracted to a surface. "Adhere” also refers to bringing and keeping particles in contact with each other, such that there is substantially no visible separation between particles due to their different buoyancies in a propellant under normal conditions. In one embodiment, a partiele that attaches to or binds to a surface Is encompassed by the term “adhere;” Normal conditions may include storage at room temperature or under an accelerative force due to gravity. As described herein, active agent particles may associate with suspending particles to form a co-suspension, where there is substantially no visible separation between the suspending particles and the active agent particles or flocculates thereof due to differences in buoyancy within a propellant |003Sf "Suspending particles” refer to a material or combination of materials that is acceptable for respiratory delivery, and acts as a vehicle for active agent particles. Suspending particles interact with the active agent particles to facilitate repeatable dosing,: delivery or transport of active agent to the target site of delivery, i.e„ the respiratory tract. The suspending particles described herein are dispersed within a suspension medium including a propellant or propellant system, and can be configured according to any shape, size or surface characteristic suited fo achieving a desired suspension stability or active agent delivery performance. Exemplary suspending particles include particles that exhibit a particle size that facilitates respiratory delivery of active agent and have physics! configurations suited to formulation and delivery of the stabilized suspensions as described herein, [00391 The term: “co-suspension” refers to a suspension of two or more types of particles having different compositions: within a suspension medium:, Wherein one type of particle associates at: feast: partially with one or more of the other particle types, the asspGiatibn leads to an observable change In one or more onaractenstics of at least one of the individual particle types suspended in the suspension medium. Characteristics modified by the association may include, tor example*.one or more of the rate of aggregation or flocculation, the rate and nature of separation, i.e. sedimentation or creaming, density of a cream: or Sediment layer, adhesion to container walls, adhesion to valve components, and rate and the level of dispersion [130401 Exemplary methods for assessing whether a co-suspension is present can include the following: if one particle type has a pycnometric density greater than the ipmpellant and another particle type has a pycnometric density lower than the propellant, a visual observation of the creaming or sedimentation behavior can be employed to determine the presence of a co-suspension. The term “pycnometnc density'' refers to the density of a material that makes up a particle, excluding voids within the particle, in one embodiment, the materials can be formulated or transferred into a transparent vial, typically a glass via!, for visuai observation. After initial agitation the vial is left undisturbed for a sufficient time for -formation of a sediment or cream layer, typically 24 hours. If the sediment or cream layer is observed to be completely or mostly a uniform singie layer, a co-suspension is present- The term foG-suspenslon” includes partial co-suspensions, where a majority of the at least two particle types associate with each other, however, some separation (i.e-, Jess than a majority) of the at least two particie types may be observed, £0041J The exemplary co-suspension test may be performed at different propellant temperatures to accentuate the sedimentation or creaming behavior of particle types with a density close to the propellant density at room temperature-, If the different particle types-have the same nature of separation, i.e. all sediment or ail cream, the presence of a co-suspension can be determined by measuring other characteristics of the suspension, such as rate of aggregation or flocculation, rate of separation, density of cream or sediment layer, adhesion to container wails, adhesion to valve components, and rate and level of dispersion upon agitation, and comparing them to the respective characteristics of the similarly suspended individual particie types, Various analytical methods generally known to those skilled in the art can be employed to measure these characteristics. |0042| in the context of a imposition containing or providing respirable aggregates, particles, drops, etc., such as compositions described herein, the term “fine particle dos# or “PPD" refers to the dose, either in total mass or fraction of the nominal dose or metered dose, that is within a respirable range. The dose that is within the respirable range is measured in vitro to be the dose that deposits beyond the throat stage of a cascade impactor, be.,; the sum of dose delivered at stages 3 through filter in a Next Generation Impactor operated at a flow rate of 30 1/mSn, [00431 In the context of a composition containing or providing respirable aggregates, particles, drops, etc-, such as compositions described herein, the term “fine particle fraction* or “FRF55 refers to the proportion of the delivered material relative to the delivered dose {i.e., the amount that exits the actuator of a delivery device, such as an MDI) that is within a respirable range. The amount erf delivered material within the respirable range is measured in vitro as the amount of material that deposits beyond the throat stage of a cascade impactor, e.g., the sum of the meteriaS delivered at stages 3 through filter in a Next Generation Impactor operated at a flow rate of 30 l/min, [0:3441 As used herein, the term “inhibit” refers to a measurable lessening of the tendency of a phenomenon, symptom or condition to occur or the degree to which that phenomenon, symptom or condition occurs. The term “inhibit5' or any form thereof, is used In its broadest sense and Includes minimi;#, prevent, reduce, repress, suppress, curb, constrain, restrict, slow progress of and the like.

[004¾ “Mass median aerodynamic diameter or “MyAD* as used herein refers to the aerodynamic diameter of an aerosol below which 50% of the mass of the aerosol consists of particles with an aerodynamic diameter smaller than the MM AO, with the MMAD being calculated according to monograph 601 of the United States Pharmacopeia (“USP”), [0046J When referred to herein, the term “optical diameter” indicates the size of a particle as measured by the Fraunhofer diffraction mode using a iaser diffraction particle size analyzer equipped with a dry powder dispenser (e.g., Sym pa tec GmbH, ClausthahZellerfeld, Germany), 100471 the term solution mediated transformation refers to the phenomenon in which a more soluble form of a solid material (i.e. particles with small radius of curvature (a driving force for Ostwald ripening), or amorphous material) dissolves: and recijstaiiixes into the more stable crystal form: that can coexist in equilibrium with its saturated propellant solution, [0048] A "patienf refers to an animal in which a combination of active agents as described herein will have a therapeutic effect, in one embodiment, the patient is a human being.

[0049] “Perforated microstrucfores'' refer to suspending particles that include a structure! matrix that exhibits, defines or comprises voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations or hoies that allow the symoundiog suspension medium to permeate, fill or pervade the miorostrupture, such as those materials and preparations described in U .S, Patent No. 6,309,623 to Wears, at at. The primary form of the perforated microstructure is> generally, not essential, and any overall configuration that provides the desired formulation characteristics is contemplated herein. -Accordingly* in one embodiment:, the perforated microstructures may comprise approximately spherical shapes, such as hollow, suspending, spray-dried microspheres. However, collapsed, corrugated, deformed or fractured particulates of any primary form or aspect ratio may also be compatible.

[0050] As is true of suspending particles described herein, perforated microstructures may be fenced of any biocompatible material that does not substantially degrade or dissolve in the selected suspension medium. While a wide variety of materials may be used to form the particles, in some embodiments, the structural matrix is associated with, or includes, a surfactant such as, a phospholipid or fluonnsted surfactant. Although not required, the incorporation of a compatible surfactant in the perforated microstructure or, more generally, the suspending particles, can Improve the Stability of the respiratory dispersions, increase pulmonary deposition and facilitate the preparstion of the suspension.

[00511 The term “suspension medium” as used herein refers to a substance providing a continuous phase within which active agent particles and suspending particles can be dispersed to provide a co-suspension formulation. The suspension medium used in co-suspension formulations described herein includes propellant As used herein, the term “propellant” refers to one or more pharmacologically inert substances which exert a sufficiently high vapor pressure at normal room temperature to propel a medicament from the canister of an MDS to a patient on actuation of the MDi’s metering valve. Therefore, the term: “propellahf refers to both a single propellant and to a combination of two or more different propellants forming a “propel iant system,” (0052] the term "respirable” generally refers to particles, aggregates, drops:, etc. sized such that they can be inhaled and reach the airways of the lung.

[00531 When used to refer to co-suspension compositions described herein, the terms "‘physical stability” and “physically stable” refer to a composition that is resistant to one or mom of aggregation, flocculation, and particle size changes due to solution mediated transformations and Is capable of substantially maintaining the yyiAD of suspending particles and the fine particle dose. In one embodirnenf, physical stability may be evaluated through subjecting compositions to accelerated degradation conditions, such as by temperature cycling as described herein. {00541 When referring to active agents, the term “potent” indicates active agents that are therapeutically effective at or below doses ranging from about 0.01 mg/kg to about 1 mg/kg. Typical doses of potent active agents generally range from about 100 pg to about 100 mg.

[00551 When referring to active agents, the term “highly potent" indicates active agents that are therapeutically effective at or below doses of about 10 pg/kg, Typical doses Of highly potent active agents generally range up to about 100 pg.

[0058{ The terms "suspension stability" and “stable suspension" refer to suspension lormUiationb capable of maintaining the properties of a co-suspension of active agent particles and suspending particles over a period of time. In one embodiment, suspension stability may be measured through delivered dose uniformity achieved by co-suspension compositions described herein.

[00t»?| The term “substantially insoluble” means that a composition is either totally insoluble in a particular solvent or it is poorly soluble In that particular solvent The term “substantially insoluble’' means that a particular solute has a solubility of less than one part per 100 parts solvent, the term “substantially Insoluble” includes the definitions of “Slightly soluble” (from 100 to 1000 parts solvent per 1 part solute), “very slightly soluble" (from 1000 to 10,000 parts solvent per 1 part solute) and ''practically insoluble” (more than 10,000 parts solvent per 1 part solute) as given in Table 16-1 of Remington: The; Science and Practice of Pharmacy, 21 si ed, Lipplncott, Williams Wilkins, 2006, p. 212.

[0058] The term “surfactant" as used herein, refers to any agent which preferentially adsorbs to an interface between two immiscible phases, such as the interface between water and an organic polymer solution* a waier/air interface or organic solvent/air interface. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety* such that* upon adsorbing to microparticles* they tend to present moieties to the continuous phase that do not attract similarly-coated particles, thus reducing particle agglomeration. In some embodiments, surfactants may also promote adsorption of a drug and increase bioavailability of the drug, |005i] A “therapeutically effective amount” is the amount of compound which achieves a therapeutic effect by inhibiting a disease or disorder In a patient or by prophylacticaiiy inhibiting dr preventing the onset; of a disease or disorder. A therapeutically effective amount may be an amount which relieves to some extent one or more symptoms of a disease or disorder In a patient: returns to norma! either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder; and/or reduces the likelihood of the onset of the disease of disorder, [0060] The terms “chemically stable” and “chemical stability” refer to co-suspension formulations wherein the individual degradation products of active agent remain below the limits specified by regulatory regulrements during the shelf life of the product for human use focg.* 1% of total chromatographic peak ares per ICH guidance ^3B{R2:Ji and there is acceptable mass balance fe.g.< as defined in ICH guidance Q1E) between active agent assay and total degradation products. f00§1 j The compositiohs described herein are co-suspensions that include two or more active agents and include a suspension medium, one or more species of active agent particles, and; one dr more species of suspending particles, Of course, if desired, the compositions described herein may include one or more additional constituents, Moreover, variations and combinations of components of the compositions described herein they fee used, 1000¾ The co-suspension compositions according to the present description can be embodied by various different formulations. In certain embodiments, the compositions described herein include a first active agent provided In active agent particles that are co-suspended with at least one species of suspending particles that incorporate a second active agent. In Other embodiments, the compositions described herein include two or more active agents provided in two or more different species of active agent partieies op-suspended with at least one species of suspending particles that incorporate an "active agent different from that contained in any of the active agent partieies. In yet. further embodiments, the compositions described herein include two or more active agents provided in two or more different species of active agent partieies co-suspended; with at least one species of suspending particles that incorporate an active agent that may be the same as or different from that contained in any of the· active agent particles, in still farther embodiments, the compositions described herein include two or more active agents provided in two or more different species of active agent partieies eo-suspended with one or more species of suspending partieies that are free of active agent. Where the compositions described herein include two or more species of active agent partieies, such compositions may be referred to as “multi" co-suspensions. For example, a composition ineiudlng two species of active agent partieies co-suspended with one or more species of suspending particles may be referred to as a dual co-suspension, a composition including three species of active agent partieies co-suspended with one or more species of suspending particles may be referred to as a triple co-suspension, etc, [0063] In compositions according to the present description, even when multiple different species of active agent particles are present in the composition, the active agent particles exhibit an association with the suspending partieies such that the active agent particles and suspending particles co-locate within the suspension medium. Generally, due to density differences between distinct species of particles and the medium within which they are suspended (e.g., a propellant or propeiiant system), buoyancy forces cause creaming of particles with lower density than the propellant and sedimentation of particles with higher density than the propellant, therefore, in suspensions that consist of a mixture of different types of partieies with different density or different tendencies to flocculate, sedimentation or creaming behavior is expected to be specific to each of the different particle types and expected to lead to separation of the different particle types within the suspension medium.

[06641 However, the combinations of propeiiant, active agent particles, and suspending partieies described herein provide co suspensions including combinations of two or more active agents wherein the active agent partieies and suspending particles eo-iocate within the propeiiant (i.e., the active agent partieies associate with the suspending particles such that suspending particles and active adept particles do not exhibit substantial separation relative to each other, such as % differential sedimentation or creaming, even -after a time sufficient for the formation of a cream or sediment layer}, in particular embodiments, tor example, the compositions described herein form co-suspensions wherein the suspending particles-:-remain associated with active agent particles when subjected to buoyancy forces amplified by temperature fluctuations and/or centrifugation at accelerations up to and over, for example, 1 g, 10 g, 35 g, 50 gt and 100 g. However, the eo~ suspensions described herein need not be defined by a specific threshold force of association. For example, a co-suspension as contemplated herein may be successfully achieved where the active agent particles associate with the suspending particles such that there is no substantial separation of active agent particles and suspending particles within the continuous phase formed by the suspension medium under typical patient use conditions, |§06S| Co-suspensions of active agent particles and suspending particies according to the presen t description provide desirable chemical stability, suspension stability and active agent delivery characteristics. For example, in certain embodiments, when present within an MPt canister, co-suspensions as described herein can inhibit one or more of the following: fiocculation of active agent materiai; differential sedimentation or creaming of active agent particles and suspending particies; solution mediated transformation of active agent materiai; chemical degradation of a component of the formulation, including of active agent materiai ora surfactant; and loss of active agent to the surfaces of the container closure system, in particular the metering valve components. Such qualities work to achieve and preserve aerosol performance as the co-suspension fonoulatfon is delivered from an MDI such that desirable fine particle fraction, fine particle dose and delivered dose uniformity characteristics are achieved and substantialiy maintained throughout emptying of an MDI canister within: which the co-suspension formulation is contained. Additionally, co-suspensions according to the present description can provide a: physically and chemically stable formulation that provides consistent dosing characteristics for two or more active agents, even where such active agents are delivered at significantly different doses, while utilizing a relatively simple HFA suspension medium that does not require modification by the addition of, tor example, cosoivents, antisolvents, solubilizing agents or adjuvants. Even further, compositions prepared as described herein, when delivered from an MDl, eliminate or substantially avoid the phamiaceutical effects often experienced with formulations including multiple active agents. For example, as exemplified by specific enidodimante detailed herein, the combination terminations described herein provide delivery chsractensties: for each of the active agents contained therein comparable to delivery characteristics of the same active agents when formulated and delivered separately, pM8| Providing a co-suspension according to the present description may also simplify lormulationddelivery and dosing of the desired active agents. Without being bound by a particular theory , if is thdught that by achieving a co-suspension of active agent particles and suspending particles, the delivery, physical stability, and dosing of an active agent contained within such a dispersion may be substantially controlled through control of the size, composition, morphology and relative amount of the suspending particles, and Is less dependent upon the size and morphology of the particles of active agent. Moreover, in specific embodiments, the pharmaceutical compositions described herein can be formulated with a norvCFD propellant or propellant system substantially free of antisolvents, solubilizing agents, cosolvents, or adjuvants. |0S87] Co-suspension compositions formulated according to the present teachings can inhibit physical and chemical degradation of the active agents included therein. For example, in specific embodiments, the compositions described herein may inhibit oho or more of chemical degradation, flocculation, aggregation and solution mediated transformation of the active agents included in the compositions. The chemical and suspension stability provided by the co-suspension compositions described herein allows the compositions to be dispensed In a manner that achieves desirable delivered dose uniformity throughout emptying of an MDi canister (“DDU”) for muifiple active agents, even where at least one of the active agents to be delivered may be highly potent and the delivered doses of each of the active agents vary considerably.

[0060] Co-suspension compositions as described herein, which include: two or more active agents, can achieve a DDU of ± 30%, or better for each of the active agents included therein. In one such embodiment, compositions described herein achieve a DDU of ± 25%, or better, for each of the active agents included therein, in another such embodiment, compositions described herein achieve a DDU of ± 20%, or better, for each of the active agents included therein. Moreover, co-suspension compositions according to the present description serve to substantially preserve FPF and? FPD performance throughout emptying of an MDi canister, even after being subjected to accelerated degradation conditions, for instance, compositions according to the present description maintain as much as 80%, 90%, 95%, or more, of the original FPF or FPD performance, even after being subjected to accelerated degradation conditions.

[0069] Go-suspension compositions described herein provide the added benefit of achieving such performance while being formulated using non-CFC propellants, in specific embodiments, the compositions described herein achieve one or more of a targeted DOU, FPF or FPD, whiie being formulated with suspension medium Including only one or more non-CFC propellants and without the need to modify the characteristics of the non-CFO propellant:, such as by the addition of, for example, one or mere cosolvehi, antisolvent, solubilizing agent, adfuvant or other propellant modifying material.

Ill Suspension Medium P0?O] The suspension medium included in a composition described herein includes one or more propellants, in general, suitable propellants for use as suspension mediums are those propeliant gases that can be liquefied under pressure at room temperature, and upon Inhalation or topical use, are safe and toxicologicaSiy innocuous. Additionally, it is desirable that the selected propellant be relatively non-reactive with the suspending particles and active agent particles. Exemplary compatible propellants include hydrofiuoroaikanes (HFAs), pesliuonnated compounds (PFCs), and chlorofiuorocarbons (G FGs).

[09711 Specific examples of propellants that may be used to form the suspension medium of the co-suspensions disclosed herein include 1,1,1,2-tefrafluoroefhane {CF3CH2F) (HFA~134a), 1,1,1 (2,3,3,3-heptafluoro-n~propane PF3GHFCF3} (HFA-227¾ perfluoroeihane, monoch I oro-f l uofomeihane, 1,1 dlfluoroethane, and combinations thereof. Even further, suitable propellants include, for example: short chain hydrocarbons; Cm hydrogen-containing ehlorofiuorocarbons such as CHgCIF, GCfeFCMGiF, CF3CHCIF, CHF2CCIF2( CHCIFCHF2l CFaCFbCI, and CCiFaCH,; Cm hydrogen-contaihlng fluorocarbons [e,g„ HFAsj such as GHFyGHFs, GFsCHsF, CHF^CHs, and GF3GHFCF3; and perfluorocarfeons such as CF3CF3 and CF3CF;>CF:v [0072] Specific fluorocarbons, or classes of fluoridated eompoundst that may be used as suspension media include, but are not limited to, fluoroheptane, fiuorocycloheptane, f luoromethyl cyclohe ptan e, fluorohexane, fiuorocyclohexane, fiuoropentane, fiuorocyclopentane, f iuo ro m ef hyicyciopen ta ne, fluorodlmethyb cyclopentanes, fluorometbyicyeiobytane, fiuorodlmethyicyclobutane, fiuorotrimethyl· cydobutane, fluorobufane, fiuorocydobuiane, fluoropropane, fiuoroethers, fluoropolyethers and iiuorotriethylamines. These compounds may be used alone or in combination with more volatile propellants, [0073} In addition to the aforementioned fluorocarbons and h yd rof I uo ro a I ka n es, various exemplary chlorofluorocarbons and substituted fludnnated compounds may also be used as suspension media, in this respect,, FG-11 (GGbF), FC-11B1 (CBrCfeF), FC-11B2 (CBraCIF), FC12B2 {CF28r,}( FC21 (CHCFF), FC21B1 (CHBrCSF), FC-21B2 (CHBr#), FC-31B1 (CH2BrF), FC113A (CCFCIA), FG-122 (CCiF2CHCI*), FC-123 (CFjCHCF), FC432 (CHCi'FCHClF), FC-133 (CHCIFCHF2), FC-141 (CHsCICHCiF), FC-1418 (CChFCHs), FC-142 (CHF2CH;?Ci): FC-151 (CH^FCHaGi), FC-1 §2. {CH2FCH2F), FC-1112 {GGIF~CQF), FG4121 [CHCi~CF£!) and FC-1131 (CHCS-CHF) may also be used, while recognizing the possible attendant environmental concerns. As such, each of these compounds may be used, alone or in combination with other compounds (i.e., less volatile fluorocarbons) to form the stabilized suspensions disclosed herein.

[0074] In some embodiments, the suspension medium may be formed of a single propellant, in other embodiments, a combination of propellants may be used to form the suspension medium. In some embodiments, relatively volatile compounds may be mixed with lower vapor pressure components to provide suspension media having specified physieai characteristics selected to improve stability or enhance the bioavaiiabillty of the dispersed active agents., in some embodiments, the lower vapor pressure compounds will comprise fluorinated compounds (e.g. fluorocarbons) having a boiling point greater than about 25*C. In some embodiments, lower vapor pressure fluorinated compounds for use In the suspension medium may include periluorooclylbroniide CgFi?Br (PFOB or perflubron), dlchlorofluorooclane CgFisCi*. perfluorooctyiethane GsFi vGaHs (PFOE), perflyorodecylbromide CitjFstBr (PFDB) or pediuorobutyiethane G4FgC2Hs. In certain embodiments, these lower vapor pressure compounds are present in a relatively low level. Such compounds may be added direeMy to the suspension medium or may be associated with the suspending particles.

[OOJS] The suspension medium included in compositions as described herein may be formed of a propellant or propellant system that is substantiaiiy free of additional materials, including, for example, antisol vents, solubilizing agents, cosolvents or adjuvants. For example, In some embodiments, the suspension medium may be formed of a non-OFC propellant or propellant system, such as an HFA propellant or propellant system, that Is substantially free of additional materials. Such embodiments simplify the formulation and manufacture of pharmaceutical compositions suited forrespiratory delivery of the active agents included in the co-suspension compositions.

[9076J However, in other embodiments, depending on the selection of propellant, the properties of the suspending particles, or the nature of the active agents to be delivered, the suspension medium utilized may Include materials in addition to the propellant or propellant system. Such additional materials may include, for example, one or more of an appropriate antisolvenf, solubilizing agent, cosolvent or adjuvant to adjust, for example, the vapor pressure of the formulation or the stability, or solubility of suspended particles. For example, propane, ethanol, isopropyl alcohol, butane^ isobutane, pentane, isopentane or a dialkyl ether, such as dimethyl ether, may be Incorporated with the prdpefianf: in the suspension medium. Similarly, the suspension medium may contain a volatile fluorocarbon. In other embodiments, one or both of polyvinylpyrrolidone^ (“FVP") or pofyethyiehe glycol ΓΡΕ6") may be added to the suspension medium, Adding PVP or PEG to the suspension medium may achieve one or more desired functional characteristics, and In one example, PVP or PEG may be added to the suspension medium as a crystal growth inhibitor. In general, where a volatile cosolvent or adjuvant Is used, such an adjuvant or cosoivent may be selected from known hydrocarbon or fluorocarbon materials and may account for up to about 1% w/w of the suspension medium. For example, where a cosoivent or adjuvant Is incorporated In the suspension medium, the cosoivent or adjuvant may comprise less than about0.01%, 0.1% or 0.5% w/w of the suspension medium. Where PVP or PEG are Included in the suspension medium, such constituents may be Included at up to about 1 % w/w, or they may comprise less than about 0.01%, 0.1%, or 0.5% w/w of the suspension medium.

[0077] The active agent particles included in the co-suspensions described herein are formed of a material capable of being dispersed and suspended' within the suspension medium and are sized to facilitate delivery of respirable particles from the co-suspension, in one embodiment,..'therefore, the active agent particles are provided as a micronized material wherein at least 90% of the active agent parilcies by volume exhibit an optical diameter of about 7 pm or less. In other embodiments, the active agent particles are provided as a micronized material wherein at least 90% of the active agent parficies by volume exhibit :an optical diameter selected from a range of about 7 um to about 1 pms about 5 pm to about 2 pm, and about 3 pm to about 2 pm, in other embodiments, the active agent pedicles are provided as a micronized material wherein at least 90% of the active agent particles by volume exhibit an optical diameter selected from 6 pm or less, 5 pm or less, 4 pm or less, or 3 pm or less, in another embodiment, the active agent particles are provided: as a microhized matenai wherein at least 50% of the active agent particle material by volume exhibits an optical diameter of about 4 pm or less. In further embodiments^ the active agent particles are provided as a microhized materia! wherein at least 50% of the active agent particle material by volume exhibits an optical diameter selected from about 3 pm or less, about 2 pm or less, about i.5 pm or less, and about 1 um or loss. In still further embodiments, the active agent particles are provided as a micronized material wherein at least 50% of the active agent particles by volume exhibit an optical diameter selected from a range of about 4 pm to about 1 pro, about 3 pm to about 1 pm, about 2 pm to about: 1 pm, about 1,3 pm , and about 1,9 pm, [0078| The active agent particles may be formed entirely of active agent or they may be form:elated to include one or more active agents in combination with one or more excipients or adjuvants. In specific embodiments, an active agent present in the active agent particles may be entirely or substantially crystalline, Le., a majority of the active agent molecules are arranged in a regularly repeating pattern, over a long range of external face planes. In another embodiment, the active agent particles may include an active agent present in both crystal and amorphous states, in yet another embodiment, the active agent particles may include an active agent present in substantially an amorphous state, i.e., the active agent molecules are overall nohcrystailirte In nature and do not have a regularly repeating arrangement maintained over a long range, in yet a further embodiment, where two or more active agents are present as active agent particles, all such active agents may be present in crystalline or substantially crystalline form. In alternative embodiments with two or more active agents present, at least one such active agent may be present in crystalline or substantially crystalline term and at least another active agent may be present in an amorphous state,: p879] Where the active agent particles described herein include two or more active agents In combination with one or more excipients or adjuvants, the excipients and adjuvants can be selected based on the chemical and physical properties of the active agents used. Moreover, suitable excipients for the formulation of active agent particles include those described herein in association with the suspending particles, in specific embodiments, for example, active agent particles may be formulated with one or more of the lipid, phospholipid, carbohydrate, amino acid, organic salt, peptide, protein, alditols, synthetic or natural polymer, or surfactant materials as described, for example, in association With the suspending particles, 10080] In other embodiments, for example, an active agent may be added to a solution of one or more of the ilpidt: phospholipid!, carbohydrate, amino acid, metal sait, organic salt, peptide, protein, alditols, synthetic or natural polymer, or surfactant materials and spray-dried into a suspending particle that contains the active agent within the material forming the suspending particle. |0081] Any suitable process may he employed to achieve micronized active agent material for use as or inclusion in active agent particles or suspending particles as described herein. Such processes include, but are not limited to, micronizafion by milling or grinding processes, crystallization or reerystaization processes, and processes using precipitation from supercritical or near-supercritical solvents, spray drying, spray freeze-drying, or iyophiiization. Patent references teaching suitable methods for obtaining mlcronlzed active agent particles are described, for example, In U S. Patent No. 6,063,133, U.S. Paten? No. 5,858,410, U.S. Patent No. 5,851,453, U.S. Patent No. 5,833,391, U.S. Patent No. 5, 707,634, and international Patent Publication No. WO 2907/009164. Where the active agent particles include active agent material formulated with one or more excipient or adjuvant, micronized active agent particles can be formed using one or more of the preceding processes and such processes can be etliisted to achieve active agent particles having a desired size distribution and particle configuration.

[00823 The active agent particles may be provided in any suitable concentration within the suspension medium. For example, in some embodiments, the active agent particles- may be present in. concentrations· between about 0.01 mg/mi and about 2d mg/ml in certain such embodiments, the active agent particles may be present in a concentration selected from about 0.05 mg/mi to about 20 mg/ml about 0.05 mg/ml to about 10 mg/ml, and from about 0,05 mg/ml to about 5 mg/mi. |0O833 A variety of therapeutic or prophylactic agents can be utilized as active in the co-suspension compositions disclosed herein. Exemplary active agents include those that may be administered in the form of aerosolized medicaments, and active agents suitable for use in the compositions described herein include those that may be presented in a form or formulated' in a manner which is dispersible within the selected suspension medium (0.9., is substantially insoluble or exhibits a solubility in the suspension medium that substantially maintains a co-suspension formulation^ is capable of forming a co-suspension with the suspending particles, and is subject; to respirable uptake in physiologically effective amounts. The active agents that may be utilized in forming the active agent particles described herein can have a variety of biological activities. IQ084J Examples of specific active agents that may be included in a composition according to the present description may for example, short-acting beta agonists, eg., blfolterol, carbuteroi, fenoterol hexoprenaline, isoprenellne (isoproterenol}, levosalbutamol, orciprenaline (metaproterenol), pirbutero!, procaterol, rimiterot, saibutamoi (albuterol}, terbuiaiine, tulobuterof, reproterol, Ipratropium and epinephrine* long-acting 1¾ adrenergic receptor agonist flAB/V’}, e.g., bambuterol, cienbuierol, formoterol, saimeterol; ultra long-acting 8¾ adrenergiG receptor agonists, e.g.. carmoterol, mllveterol, indacaterol, and saligemn· or indole^ containing: and adamantyi-derived §2 agonists; corticosteroids,: e.g„ beclomethasone, budesonide, cieiesonide, flunisojide, fluticasone, methyi-predhispiohe, mometasone, prednisone and trlmacinoibne; anti~ihf|amhlaiorles! e.g. fluticasone propionate, bedomethasone dipropionate, flunisollde, budesonlde, tripedane, cortisone, prednisone, prednisilone, dexamethasorse, betamethasone, or triamcinolone acetonide; antitussives, e.g., noscapine: bronchodllarors, e,g<, ephedrlne, adrenaline, fenoteroi, formoterol isopronaiine, metaproterenol, saibutamoi, albuterol, saimeterol, tefbutsline; and fii^^gctrns' long-acting muscarinic antagonists (“LAMA"), glycopyrroiate, dextpirronium, scopolamine, troplcamide, pirenzepine, dimenhydrinate, tiotropium, chfotmplufo, aclldinium, trospfum, ipatro^iym,. atropine, benzatropin, Or oxitnspium. |0085J Where appropriate, the active agents provided in the composition, including hut not limited to those specificaliy described herein, may be used in the form of salts (e.g., alkali meiai or amine sails or as acid addition salts) or as esters, solvates (hydrates), derivatives, or a free base. Additionally, the active agents may be in any crystalHne form or isomeric form or mixture of isomeric forms, for example, as pure enantiomers, a mixture of enantiomers, as racemates or as mixtures thereof. In this regard, the form of the active agents may be selected to optimize the activity and/or siahiSity of the active agent and/or to, minimize:the solubility of the actie agent in the suspension medium. P086J Because the Compositions disclosed provide reproducible delivery of very low doses of active agents, In certain embodiments, the active agents Included in the compositions described herein may be selected from one or more potent or highly potent active agents. For example, In pertain embodiments, the compositions described herein may include one or more potent active agents that are to be delivered at a dose selected from between about 100 pg and about 100 mg per dose, about too pg and about 10 mg per dose, and about 100 pg and 1 mg per dose. In other embodiments, the compositions described herein may include a comblnatidn of two or more potent or highly potent active agents that are to be delivered at a dose selected from up to about 80 pg per dose, up to about 40 pg per dose, up to about 20 pg per dose, up to about 10 pg per dose or between about 10 pg and about 100 pg per dose. Additionally, in certain embodiments, the compositions described herein may include a combination of two or more highly potent active agents that are to be delivered at a dose selected from between about 0.1 and about 2 pg per dose, about 0.1 and about 1 pg per dose, and about 0.1 and about 0J M9 per dose, (0087] in certain embodiments, the compositions described herein include a LABA active agent. In one such embodiment, the composition Includes a LABA active agent in combination with a LAMA active agent or a corticosteroid active agent, in another such embodiment, the composition includes a LAMA active agent in combination with a LABA active agent and a corticosteroid. In such embodiments, a LABA active agent can be selected from, for example, bambuterol, cienbuterol, formoterof, salmeteroi, carmoterol, mllveterol, Indacaferoi, and sailgenin- or indole* containing and adamantybderived B? agonists, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In certain such embodiments, the active agent is selected from formoteroi and Its pharmaceutically acceptable salts, esters, isomers or solvates thereof, [0088J Formotero! can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as, for .example,, those described herein. Formoteroi has the chemical name RS^I 4iydroxy~2-(ld :methoxyphenyi)4miethyiethyiJ~amino]ethy!3 fermanlsde, and Is commonly used in pharmaceutical compositions as the racemic fumarate dihydrate salt Where appropriate, formoteroi may be used in the form of salts (e.g. alkali metal or amine salts or as acid addition salts) or as esters or as solvates (hydrates). Additionally, the formoteroi may be in any crystalline form: or Isomeric form: or mixture of isomeric forms, for example a pure enantiomer, a mixture of enantiomers, a racemate or a ^mixture thereof, in this regard:, the form of formoteroi may be selected to optimize the activity and/or stability of formoteroi and/or to minimize the solubility of formoteroi in the suspension medium, Pharmaceutically acceptable salts of formoteroi include, for example, salts of inorganic acids such as hydrochloric, hydrobromie, sulfuric and phosphoric acids, and organic acids such as fumade, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, trlcarbaliylic, oleic, benzoic, p~ mothoxybenzoic, saiicyHc, o~ and p-hydroxybenzolc, p-chlorobenzolc, methanesuifonic, pPoluenesuifonie and 3-hydroxy~2-naphthalene carboxylic acids, Hydrates of formoteroi are described, lor example, in U.S. Pat, No, 3,994,974 and U.S. Pat- No.· 5,684,199. Specific crystalline forms are described, far example, in VY095/05805, and specific isomers of formoteroi are described in U.S. Pat. No. 6,040.344.

[0089] in specific embodiments, the formoteroi material utilized to form the formoteroi particles is formoteroi fumarate, and in one such embodiment, the formoteroi fumarate is present in the dihydrate form;. Where the compositions described herein include fermoterol, in certain embodiments, the compositions described herein may Include formoteroi at a concentration that achieves a delivered dose selected from between about 0.5 pg and about iO pg, 0.5 pg and about 1 pg, about 1 pg and about 10 pg, about 2 pg and 5 pg, about 2 pg and about 10 pg, about δ pg and about 10 pg. and 3 pg and about 30 pg per actuation of an MO!, in other embodiments, the compositions described herein may Include formoteroi in an amount sufficient .to provide a delivered dose selected from up to about 30 pg, up to about 10 Mg, up to about 5 pg, up to about 2,5 pg, up to about 2 pg, or up to about 1.5 pg per actuation of an MDi In order fe achieve delivered doses as described herein, where compositions described herein inciude tormcteroi as the active agent, in specific embodiments, the amount: of formoteroSIneiuded in the eomposlibns may be selected from, for example, between about 0.01 mg/ml and about 1 rng/ml, between about 0.01 mg/mi and about 0.5 mg/ml, and between about 0.03 mg/rn! add about G.4 mg/mi. 10090] Where the pharmaceutical co-suspension compositions described herein include a IAEA active agent, id Certain embodiments,: the active agent Is selected tom salmeterob including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, Saimeteroi can be used to treat: inflammatory or obstructive pulmonary diseases and disorders such as, for example, those described herein. Again, where salmeriero! is included as the IAEA active agent, in some such embedimehts, the compositions may also Include a LAMA or corticosteroid active agent. In other such embodiments, the compositions include saimeteroi in combination with a LAMA active agent and a corticosteroid. Saimeteroi, pharmaceutically acceptable salts of satmeteroL and methods for producing the same are described, for example, in U.S, Patent No. 4,992,474, U.S. Patent No. 5,128,375, and U.S. patent 5,225,445.

[0091] Where saimeteroi is included as a IAEA active agent, In certain embodiments, the compositions described herein may Include saimeteroi at a concentration that achieves a delivered dose selected from between about 2 pg and about 120 pg, about 4 pg and about 40 pg, about 8 pg and 20 pg, about 8 pg and about 40 pg, about 20 pg and about 40 pg, and about 12 pg and about 120 pg per actuation of an MDI, in other embodiments, the compositions described herein may include saimeteroi in an amount sufficient to provide a delivered dose selected from up id about 120 pg, up fo about 40 pg, up to about 20 pg, up to about 10 pg, up to about 8 pg, or up to about 6 pg per actuation of an MDi. in order to achieve targeted delivered doses as described herein, whene compositions described herein include saimeteroi as the active agent, in specific embodiments, the amount of saimeteroi included in the compositions may he selected from, for example, between about 0.04 mg/ml and about 4 rng/ml, between about 0.04 mg/mi and about 2.0 mg/ml, and between about 0.12 mg/mi and about 0.8 mg/ml. For example, the compositions described herein may include sufficient gglrrseferol to provide a target delivered dose selected from between about 4 pg and about 120 pg, about 20 pg and about 100 pg, and between about 40 pg and about 120 pg per actuation of an MDS. in still other embodiments, the compositions described herein may include sufficient salmeteroi to provide a targeted delivered dose selected from up· to about 100 pg, up to about 40 pg, or up to about 15 pg per actuation of an MDL (0092] in certain embodiments^ the compositions described herein include a long·· acting muscarinic antagonist (LAfvlA) active agent. Examples of LAMA active agents that may be used In the compositions described herein include, giya>pyrrolate, dexlpirroriium, tiotropium, trospium, acMnium and darotropium, ineiuding any pbarmaceeficaiiy acceptable salts, esters, isomers or solvates thereof. In some embodiments, the compositions described herein include a LAMA active agent in combination with a LABA active agent or a corticosteroid, in other such embodiments, the compositions described herein include a ΙΑΜΑ- active agent in combination with both LABA and corticosteroid active agents. Where the compositions include a LAMA active agent, in particular embodiments, giycopyrroiate, including any pharmaceutically acceptabie salts, esters, isomers or solvates thereof, may he selected. |00i3] Giycopyrroiate can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as, for example,, those described herein. As an anticholinergic, giycopyrroiate provides an antlsecretcry effect, which is a benefit for use in the therapy of pulmonary diseases and disorders characterized by increased mucus secretions. Giycopyrroiate is a quaternary ammonium salt. Where appropriate, giycopyrroiate may be used In the form of salts: |e.g. alkali metal or amine salts, or as acid addition salts), esters, solvates (hydrates), or selected isomers. Additionally, the giycopyrroiate may be in any crystalline form or isomeric form or mixture of isomeric forms* for example a pure enantiomer, a mixture of enantiomers, a racemate or a mixture thereof, in this regard, the form of giycopyrroiate may be selected to optimise the activity and/or stability of giycopyrroiate and/or to minimize the solubility of giycopyrroiate in the suspension medium, Suitable counter ions are pharmaceutically acceptabie counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, tnfluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, rnafeate, succinate, benzoate, p-ehiorobenzoate, diphenyl-acetate or triphenylacetate, oArydioxybenzoate, p-hydroxybenzoate, 1"hydroxynaphiHabne-2·' carboxylate, 3-hydfoxynaph?haiene~2-carboxyiate, rneihanesulfonate and benzenesulfonate. in particular embodiments of the compositions described herein, the bromide sail of giycopyrrolate, namely 3-{(cyciopentyi-hydroxypheny1acetyi)oxy]-i ,1 -dimethyipyrroiidinium bromide, is used and can be prepared according to the procedures set out inU.S. Pat. Ho. 2,956,062.

[QQ94J Where the compositions described herein include giycopyrrolate, in certain embodiments, the compositions may include sufficient giycopyrrolate to provide a delivered dose selected from between about 10 pg and about 100 pg, about 15 pg and about 100 pg, about 15 pg and about 80 pg, and about 10 pg and about80 pg per actuation of an 'MDI. In other such embodiments, the formulations Include sufficient giycopyrrolate to provide a delivered dose selected from up to about 100 pg, up to about 80 pg. up to about 40 pg, up to about 20 pg, or up to about 10 pg per actuation of an MDL In yet further embodiments, the formulations include sufficient giycopyrroiate to provide a delivered dose selected from about 9 pg, 18 pg, 38 pg and 72 pg per actuation of the MDI. In order to achieve delivered doses asdescribed herein, where compositions described herein include giycopyrrolate as the active agent, in specific embodiments, the amount of giycopyrrolate included in the compositions may be selected from, for example» between about 0.04 mg/mi and about 2.25 mg/rni. £00953 lh other embodiments, tfotnopium, including any pharmaceutically acceptable salts, esters, corners or solvates thereof, may be selected as a LAMA active agent for inclusion in a composition as described herein. Tiotropium is a known long-act:ng anticholinergic drug suitable for use in treating diseases or disorders associated with pulmonary intism:mstibh or obstruction, such as those described herein. Tiotropium, including crystal and pharmaceutically acceptable salt forms of tiotropium, is described; for example. In y,S, Patent No. 5,610463, U.S. Patent No. RE39820, U.S. Patent No. 6,777,423, and U.S. Patent No, 6.906,928. Where the compositions described herein include tiotropium, in certain embodiments, the: compositions may include sufficient tiotifopium to provide a delivered dose selected from between about 2.5 pg and about 25 pg, about 4 pg and about 25 pg, about 2.5 pg and about 20 pg, and about 10 pg and about 2Θ pg per actuation of an MOI. in other such embodiments, the formuiatidns include sufficient tiotropium to provide a delivered dose selected from up to about 25 pg, up to about 20 pg, Up to about 10 Pi, up to about 5 pg, or up to about 2.5 pi per actuation of an Mpl, in yet further embodiments, the formulations include sufficient tiofropium to provide a delivered dose selected tom about 3 pg. δ pg, 9 pg, and 18 pg per actuation of the MDL in order to achieve delivered doses as described herein, where compositions described herein include tiofropium as the active agent, in specific embodiments, the amount of tidtropium included in the compositions may be selected tom, tor example, between about 0,01 mg/rni and about 0.5 rng/ml.

[0698] in still other embodiments, the compositions described herein include a corticosteroid. Such active agents may be selected from, for example., beciomethasone, budesonide, cielesonide, flunisolide, fluticasone, methyl· prednisolone, mometasone, prednisone and trimacinoione, including any pharmaceutically acceptabie salts, esters, isomers of solvates thereof. In some embodiments, such compositions Include a corticosteroid active agent in combination with a or LABA active agent. In other such embodiments, the compositions include a corticosteroid active agent in combination with a LAMA and a LABA active agent Where the compositions include a corticosteroid active agent, in 'particular embodiments, mometasone may be selected P0i?I Mometasone, pharmaeeuiicafly acceptabie salts of mometasone, such as mometasone furcate, and preparation of such materials are known, and described, for example, In U.S. Bat: No. 4,472,393, U.S. Pat. No. 5,888,200, and US. Pat. No. 6,177,560. Mometasone is suitable for use In treating diseases or disorders associated with pulmonary inflammation or obstruction, such as those described herein fsee, e,§., U.S. Pal. No. 5,889,015, U.S. Pat. No. 6,057,307, U.S. Pat. No. 8s057jS61, U.S. Pat, No. 6,677,322, U.S. Pat. No. 8,677,323 and U.S. Pat. No. 8,366,581), [0098] Where the compositions described herein include mometasone, in particular embodiments, the compositions include mometasone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, in so amount sufficient to provide a target delivered dose selected torn between about 20 pg and about 400 pg, about 20 pg and about 200 pg, about 50 pg and about 200 pg, about 100 pg and about 200 pg, about 20 pg and about 100 pg, and about 50 pg and about 100 pg, per actuation of an MDI. In still other embodiments, the compositions described herein may include mometasone, Including any pharmaceuticafiy acceptable salts, esters, isomers or solvates thereof in an amount sufficient to providea targeted delivered dose selected from up to about 4()0 pg, up to about 200 pg, or up to about 100 pg per actuation of an MDI. fprgij in other embodiments* the compositions described herein include, a corticosteroid selected tom fluticasone and budesonide, Both fluticasone and hudesonide are suitable lor use in treatment of conditions associated with pulmonary inflammation or obstruction* such as those described herein- Fluticasone* pharmaceutically acceptable salts of fluticasone, such as fluticasone propionate* and preparation of such materials are known, and described* for example, in U.S, Pat. No,: 4*335,1.21;* U.S: Pat No. 4,187,301, and U.S. Pad F>ub. No. US2008125407. Budesonide is also well known and described* for example, in U.S. Pat, No. 3,929768. In certain embodiments* compositions described herein may include fluticasone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof,: In an amount sufficient to provide a target delivered dose selected from between about 20 pg and: about 200 pg, about SCI pg and about 175 pg, and between about 80 pg and about 160 pg per actuation of an MDI. In other embodiments, the compositions described herein may include fluticasone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, in an amount sufficient to provide a targeted delivered dose selected from up to about 175 pg, up to about 160 pg, up to about 100 pg, or up to about 80 pg per actuation of an MDI, In particular embodiments* compositions described herein may indude budesonide, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof., in an amount sufficient to provide target delivered dose selected from between about 30 pg and about 240 pg* about 30 pg and about 120 pg, and between about 30 pg and about 50 pg per actuation of an MDi, In still other embodiments, the com described herein may include budesonide, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, In an amount sufficientto provide a targeted delivered dose selected from up to about 240 pg, up to about 120 pg, or up to about 50 pg per actuation of ah MDI, 10100] in each embodiment, a composition as described herein Includes two or more active agents. In some embodiments, the compositions include a combination of two or more species of active agent particles which may be eo-suspended with a single species of suspending particles. Alternatively, a composition may include two or more species of active agent particles eo-suspended with two or more different species of suspending particles. As yet another alternative* compositions as described herein may include a single species of active agent particles suspended with a single species of suspending particles, wherein the single species of active agent particles incorporates one or more active agents and the single species of suspending particles Incorporates one or more active agents. Even further, a composition as described herein may include two or more active agents combined within a single species of active agent particle. For example, where the active agent particles are formulated using one or more excipients or adjuvants in addition to the active agent material, such active agent particles may include individual particles that include two or more d ifferent active agents . fill Suspending Particles P101] The suspending particles included in the co-suspension compositions described herein work to facilitate stabilization and delivery of the active agent Included in the compositions. Though various forms of suspending particles: may be used, the suspending particles: are typically formed from pharmacologically inert material' that is acceptable for inhalation and is substantially insoluble in the propellant selected. Generally, the majority of suspending particles are sized within a mspirabie range, in particular embodiments, therefore, the MyAD of the suspending particles will not exceed about 10 pm bul ls not lower than about 500 era. In an alternative embodiment, the blMAD of the suspending particles is between about 5 pm and about 750 nm. In yet another embodiment, the MMAD of the suspending particles 1$ between about 1 pm and about 3 pm. When used In an embodiment for nasal delivery from an MDI, the MMAD of the suspending particles is between 10 pm and 50 pm, [0102] In order to achieve respirable suspending particles within the fdlvlAD ranges described, the suspending particles will typically exhibit a volume median optical diameter between about 0,2 pm and about 50 urn. In one embodiment, the suspending particles exhibit a volume median optical diameter that does not exceed about 25 pm. in another embodiment, the suspending -particles exhibit a volume median optical diameter selected from between about 0.5 pm and about 15 pm, between about l fo pm and about 10 pm, and between about 2 pm and about S pm.

[0105] The concentration of suspending particles included in a composition according to the present description can be adjusted, depending on, for example, the amount of active agent particles and suspension medium used, 'In one embodiment, the suspending parties are included in the suspension medium at a concentration selected from about 1 mg/ml to about 15 .mg/mi, about 3 mg/p to about 10 mg/ml,, 5 mg/ml to about 8 mg/ml, and about 8 mg/ml. In another embodiment, the suspending particles are Included In the suspension medium at a concentration of up to about 30 mg/mi. in yet another embodiment, the suspending particles are included in the suspension medium at a concentration of up to about 25 mg/mi, [0104] The relative amount of suspending particles to active agent particles is selected to achieve a co-suspension as contempiated Herein. A co-suspension composition may be achieved where the amount of suspending particles, as measured by mass, exceeds that of the active agent particles. For example, in specific embodiments, the ratio of the total mass of the suspending particles to the total mass of active agent particles may be between about 3:1 and about 15:1, or alternatively tom about 2:1 and 8:1. Alternately, the ratio of the total mass of the suspending particles to the total mass of active agent particles may be above about 1, such as up to about 1.5, up to about 5, up to about 10, up to about IS, up to about 1 ?, up to about 20, up to about 30. up to about 40, up to about SO, up to about 80, up to about 75, up to about 100, up to about 150, and up to about 200, depending on the nature of toe Suspending particles and active agent particles used. In further embodiments, the ratio of the total mass of the suspending particles to the total mass of the active agent particies 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 80, about 16, about 80, and about 170.

[0108] In other embodiments, the amount of suspending particies, as measured by mass, is iess than that of the active agent particies. For exampie, in particular embodiments, the mass of the suspending particies may be as low as 20% of the total mass of the active agent particles. However, in some embodiments, the total mass of the suspending particles may also approximate or equal the total mass of the active agent particies.

[0106] Suspending particles suitable for use in the compositions described herein may be formed of one or more pharmaceutically acceptable materials or excipients that are suitable for inhaled delivery and do not substantially degrade erdissoive In the suspension medium. In one embodiment, perforated microstructures, as defined herein, may be used as the suspending particles. Exemplary excipients that may be used in the formulation of suspending particles described herein include but are not limited to ia) carbohydrates, e.g., monosaccharides sued as fructose, galactose, glucose, D-mannose, sorbose, and the like; dlsaeeharides, suefi as sucrose, lactose, trehalose, ceilobiose, and the like' cyciodextrins.. such as gmybmxypropy!#-· eydodextnn; and polysaccharides, such as ralfinose, rnaltodextrins, dextrans, starches,, cbitln, chitosan, inuiln, and the like; .(b) amino acids, such as alanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, leudnei isoleucine, valine, and the like; (c) metal and organic sails prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, magnesium giuconate, sodium gluconate, tromethamin hydrochloride, and the tike: (d) peptides and proteins such as aspartame, thleucine, human serum aifeumin, collagen, gelatin, and the like; (e) alditols, such as mannitol, xyiitpi, and the like; (f) synthetic or natural polymers or combinations thereof, such as polylactides, polylactide-giyeolides. cyciodextrins; polyacryiates, methylceiluiose, carboxymethylceliuiose, poiyvinyi alcohols, polyanhydrides, polylactarhs, poiyvinyi pyrrolidones, hyaluronic acid, polyethylene glycols;: and (gj surfactants including fluorinated and nonfluorinated compounds such as saturated and unsaturated lipids, nonionic detergents, nonionlc block copolymers, Ionic surfactants and combinations thereof, in particular embodiments, suspending particles may include a calcium salt, such as calcium chloride, as described, for example, in U.S. Patent No. 7,442,388.

[0107] Additionally, phospholipids tom both natural and synthetic sources may be used in preparing suspending particles suitable tor use in the compositions described herein. In particular embodiments, the phospholipid chosen will have a gel to liquid crystal phase transition of greater than about 40*C, Exemplary phospholipids: are relatively long chain {i;e„ G16-C22} saturated lipids and may comprise saturated phospholipids, such as saturated phosphatidylcholines having acyl chain lengths of 16 C or 18 C {palmItoyl and siesroyl). Exemplary phospholipids include phosphogiycerides such as dipalmitoyiphosphatidyichoiine, distemySpbosphatidyichoiine, diarachldoyiphosphatidySoholine, dibahenoyiphosphatidylchpline, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethandiamtnes, long-chain saturated phosphatidyiserihes, long-chain saturated: phosphatidylgiycerois, and long-chain saturated phosphatidyllhpsitols, Additional excipients are disclosed In

International Patent Publication No. WO 98/32149 and U.S. Patent Nos. 6,356,530, 8,372,258 and 6,518,239. 101118] in particular embodiments, the suspending particles may he formed using one or more lipids, phospholipids or saccharides, as described herein. In some embodiments, suspending partieies include one or mom surfactants. The use of suspending partieies formed of or incorporating one or more surfactants may promote absorption of the selected active agent, thereby increasing bioavaiiability. The suspending particles described herein, such as, for example, suspending partieies formed using one or more lipids, can be formed to exhibit a desired surface rugosity (roughness}, which can further reduce inter-particle interactions and improve aerosolization by reducing the surface area available for particle-particle interaction, in further embodiments, if suitable, a lipid that is naturally occurring in the lung could be used In forming the suspending particles, as such suspending particles that have the potential to reduce opsonization (and thereby reducing phagocytosis by alveolar macrophages), thus providing a ionger-iived controlled release particle in the lung, [0109] in another aspect, the suspending particles utilized in the compositions described herein may be selected to increase storage stability of the selected active agent, similar to that disclosed in international Patent Publication No WO 2005/000287, For example, in one embodiment, the suspending particles my include pharmaceutically acceptable glass stabilization excipients having a Tg of at least 55 "C, at least 75 eC, or at least 100 "C. Giass formers suitable for use in compositions described herein include, but ate not limited to, one or more of trlieucine, sodium citrate, sodium phosphate, ascorbic acid, inuiin, cyciodextrin, polyvinyl pyrfoiidpne, mannitol, sucrose, trehalose, lactose, and, proline. Examples of addition a! glass-forming excipients are disclosed in U. S. Patent Nos. RE 37,872. 5,928,469. 6.258,341 „ and 6,39i,671. {91:10] The suspending partieies may be designed, sized and shaped as desired to provide desirable stability and active agent delivery characteristics, in one exemplary embodiment, the suspending particles comprise perforated microsiruetures as described herein. Where perforated mlcrostructures are used as suspending partieies in the compositions described herein, they may be formed using one or more excipients as described herein. For example, in particular embodiments, perforated microstruetures may include at least one of tbe following: lipids, phospholipids, nonionic detergents, non ionic block copolymers, ionic surfactants, biecompatibls fiuorinated surfactants and combinations thereof, particularly those approved for pulmonary use. Specific surfactants that may be Used in the preparation of perforated micmstructures· Include poloxamer 188. poioxafner 40? and poloxaroer 338. Other specific surfactants include oleic acid or 11$ si kali salts. In one embodiment, the perforated microstructures Include greater than about 10% w/w surfactant.. toil'll in some embodiments, suspending particles may be prepared by forming an oil- in- water emulsion, using a fluorocarbon oil (e.g., perOuoroociyl bromide, pedluorodecaiin) which may be emulsified using a surfactant such as a long chain saturated phospholipid. The resulting perfiuorocarbon in water emuision may be then processed using a high pressure homogemzer to reduce the oil droplet size. The perfiuorocarbon emuision may be fed into a spray dryer, optionally with an active agent solution, if it is desirable to include active agent within the matrix of the perforated microstructures. As is well known, spray drying is a one-step process that converts a liquid feed to a dried particulate form. Spray drying has been used to provide powdered pharmaceutical material for various administrative routes, including inhalation. Opefating conditions of the spray dryer (such as inlet and outlet temperature, feed rate, atomization pressure, flow rate of the drying air and nozzle configuration) can be adjusted to produce the desired particle size producing a yield of the resulting dry microstrudures. Such methods of producing exemplary perforated miprostructures are disclosed In U.S. Patent No. 6,309,623 to wears ef si-P112| Perforated microstrudures as described herein may also be formed through iyophilizatlon and subsequent milling or micronkation.· Lyophiiization Is a freeze-drying process In which Wafer is sublimed from: the composition after it is frozen. This process allows drying without elevated temperatures, in yet further embodiments, the suspending particles may be produced using a spray freeze drying process, such as is disclosed in U.S. Patent 5,727,333. pi 131 Furthermore, suspending particles as described heroin may include bulking agents, such as polymeric particles. Polymeric polymers may be formed from blocompatibie and/or biodegradable polymers, copolymers or blends:. in one embodiment, polymers capable of 'forming aerodynamiScatiy light particles may be used, such as functionalized polyester graft copolymers and biodegradable polyanhydrides. For example» bulk eroding polymers based on polyesters including pgiyChydroxy acids) can be used. Poiygiycoisc acid (PGA), polyectic acid (FLA) or copolymers thereof may be used to form suspending particles. The polyester may Include· a charged or functionafizable group, such as an amino acid. For example, suspending particles may be formed of polyCoA-laeiic acid) and/or poiy(D.L~i8Ctlc~eO' glycolic acid) (PLGA), which incorporate a surfactant such as DPPC. 101141 Other potential polymer candidates for use In suspending particles may include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, polyethylene glycol), polyethylene oxide), polyethylene terephihalate), poly vinyl compounds such as polyvinyl alcohols, polyvinyl ethers, and polyvinyl esters, polymers of acrylic and methaerylic adds, celluloses and other polysaccharides, and peptides or proteins, or copolymers or blends thereof. Polymers may be selected with,or modified to have the appropriate stability and degradation rates In vivo for different controlled drug delivery applications.

[0115] The compositions described herein may include two or more species of suspending particles. Even further, compositions according to the present description can Include suspending particles that include one or more active agents incorporated into the suspending particles. Where active agent is incorporated info suspending particleSj the suspending particles will be of a respirable size and can be formulated and produced using, for example; the methods and materials: [0116] Compositions formulated according to the present teachings can inhibit degradation of active agent included therein. For example, in; specific embodiments, the compositions described herein inhibit one or more of flocculation, aggregation and the solution mediated transformation of active agent material included in the compositions. The pharmaceutical compositions described herein are suited for respiratory delivery via and MDI In a manner that achieves desirable delivered dose uniformity f'DDU'T of each active agent included in a combination of two or more active agents, even with combinations inciuding potent and highly potent actives. As is Illustrated in detail in the Examples included herein, even when delivering very low doses of two or more active agents, compositions described herein can achieve a DOU of + 30%, or better, for each active agent throughout emptying of an MDI canister, in one such embodiment, compositions described herein achieve a DOU of :± 25%, or better, for each active agent throughout emptying of an MDI canister:,, In yet another such embodiment, compositions described herein achieve a DDU for the active agent of ± 20%, or better, for each active agent throughout emptying of an MOl canister. ton?] Pharmaceutical compositions described herein also serve to substantially preserve FPF and FPD performance throughout: emptying of an MD1 canister, even after being subjected to accelerated degradation conditions. For instance, compositions according to the present description maintain as much as 80%, 90%, 95%, or more, of the original. FPF and FPD perforrnance throughout emptying of an MOl: canister, even after being subjected to accelerated degradation conditions. Compositions described herein provide the added: benefit of achieving such performance lie being formulated using non-CFC propellants and eliminating or substantially avoiding pharmaceutical effects often experienced with compositions incorporating multipie active agents. In specific embodiments, the compositions described herein achieve desired one or ell of a targeted DDU, FPF and FPD performance while being formulated with suspension medium including only one or more non-GFC propellants and without the heed to modify the characteristics of the non CFG propellant, such as by the addition of, for example, one or more cosolvent, antisofyenf, solubilizing agent, adjuvant or other propellant modifying material. 10118] in one embodiment a co-suspension composition deliverable from a metered dose inhaler according to the present description Includes the following; a suspension medium comprising a pharmaceutically acceptable HFA propellant; a first species of active agent particles comprising glyeopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended In the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrrolate of between about 15 pg and about 80 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising formoterol, Including any pharmaceutically acceptable salts, esters, Isomers or solvates thereof, suspended in the suspension medium: at a concentration sufficient to provide a delivered: dose of formoterol of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated: microstructures exhibiting a volume median optical diameter of between about 1,5 pm and about 10 pm, wherein the first and second species of active1 agent particles associate1 with the plurality of suspending particles to form a co-suspension. In one such embodiment, the ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles is seiecteci from betters about 3:1 and about 15:1 and between about 2:1 and 8:1 pi 19] In another embodiment, a co-suspension composition -deliverable from a metered dose inhaler according to the present description includes the following: a suspension medium comprising a pharmaceutically acceptable 'HjFA propellant; a first species of active agent particles comprising tlotropium,, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of tidtropium Of between about 8 pg and about 20 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising iormotenol, including any pharmaceutically acceptabie salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoieroi of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated mlcrostruciures exhibiting a volume median optical diameter of between about 1,5 pm and about 10 pm, wherein the first and second species of active agent particies associate with the plurality of suspending particies to form a eo-suspension. In one such embodiment, the ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

[0120] in another embodiment, a co-suspension composition deliverable from a metered dose inhaler according to the present description includes.-the- following: a suspension medium comprising a pharmaceutlcaiiy acceptable HFA propellant; a plurality of active agent particies comprising giycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium; at a concentration sufficient to provide a delivered dose of giycopyrroiate of between about 15 pg and about 80 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising formoieroi, including any pharmaceutically acceptabie salts, esters, isomers or solvates thereof, wherein the plurality of suspending particles exhibit a volume median optical diameter of between about 15 urn and about; 10 pm, are included In the suspension mediumat a concentration sufficient to provide a delivered close of formoteroi of between about 2 pg and about 10 pg per actuation of the metered dose intis'ler, and associate with" ithe plurality of active agent particles to form a co-suspension. in one such embodiment, the ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles is selected from between about 3:1 and about 1S;1 and between; about 2:1 and 6:1, [0121] in another embodiment, a eo-suspensloh composition deliverable from a metered dose inhaler according to the present description includes the following: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising tiotropium, including any pharmaceuticaily acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a cohcehtratidn sufficient to provide a delivered dose of tiofropium of between about 5 pg and about 20 pg per actuation of the metered dose inhaler; and a plurality of respirable: suspending particles comprising formoterol, including any pharmaceuticaliy acceptable sails, esters, isomers or solvates thereof, wherein the plurality of suspending particles exhibit a volume median opticai diameter of betweeh about 1,6 pm and about 10 prepare included in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol of between about 2 pg and about 10 pg per actuation of the metered dose Inhaler, and associate with the plurality of active agent particles to form a co-suspension. in one such embodiment, the ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles is selected from between about 3:1 and about 16:1 and between about 2:1 and 8:1, [012¾ in another embodiment, a co-suspension composition deliverable from a metered dose inhaler according to the present description includes the following: a suspension medium comprising a pharmaceuticaliy acceptable HFA propellant; a first species of active agent particles comprising giyeopyrroiate, including any pharmaceutically acceptable sails, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrroiafe of between about 15 pg and about 80 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising formoleroi, including any pharmaceutically ascepfabSe salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of fprmoterol of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; a third species of active agent particies comprising a corticosteroid selected from beciomethasone, budesonlde, ciciesonide, flunisoiide, fluticasone, mathyi-prednisoione, momefesone, prednisone and trimacinoionej including any pharmaceutically acceptable salts, esters, isomers or solvates thereof; and a plurality of respirable suspending particles comprising perforated microstructures exhibiting a volume median optical diameter of between about 1.5 pm and about 10 pm, wherein the first, second and third species of active agent particles associate with the plurality of suspending particles to form a co-suspension, in one such embodiment, at least 90% of the first, second, and third species of active agent particles by volume exhibit an optical diameter of less than 7 pm, and the ratio of the total mass of the suspending particles to the total mass of the first, second, and third species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 6:1.

[S123J In another embodiment, a co-suspensson composition deliverable from a metered dose inhaler according to the present description includes the following: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a first species of active agent particles comprising giycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of giycopyrrolate of between about IS pg and about 80 pg per actuation of the metered dose inhaler; a second species of active agent particles Comprising forrnoterol, Induding any pharmaceyflcally acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of fermotenbl of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; a third species of active agent particles comprising hudesonide, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium: at a concentration sufficient to provide a delivered dose of budesonide of between about 30 pg and about 50 pg per actuation of the metered dose Inhaler; and a plurality of respirable suspending particles comprising perforated microsiructures exhibiting a volume median optical diameter of between about 1,5 pm and about 10 pm, wherein the first, second and third species of active agent particles associate with the plurality of suspending particles to form a co-suspension. In one such embodiment, at least 90% of the first; second, and third species of active agent particles by volume exhibit an optical diameter of less than 7 pm, and the ratio of the total mess of the suspending particles to the total mass of the first, second, and third species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

[0124] In another embodiment, a co-suspension composition deliverable from a metered dose inhaler according to the present description includes the following: a suspension medium comprising a pharmaceutically acceptabie HFA propellant; a first species of active agent particles comprising tiotropium, including any Ipharmaceutically acceptable salts, asters, isomers or solvates thereof, suspended in the suspension medium at.a concentration sufficient to provide a delivered: dose: of tidtropsum df between about 5 pg: and about 20 pguper actuation of the metered dose inhaler; a second species of active agent particles comprising iormotenol, including any pharmaceuticaiiv acceptabie salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoferoi of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; a third: species of active agent particles comprising budesonide, Including any pharmaceutically acceptable salts, esters, isomem or solvates thereof suspended in the suspension medium; at a concentration sufficient to provide a delivered dose of budesonide of between about 30 pg and about 50 pg per actuation of the metered dose Inhaler; and a plurality of respirable suspending particles comprising perforated mierostructures exhibiting a volume median optical diameter of between about 1J> pm and about 10 pm, wherein the first, second and third species of active agent particles associate with the plurality of suspending particles to form a co-suspension, in one such embodiment, at least 90% of the first, second, and third species of active agent particles by volume exhibit an optical diameter of less than ? pm, and: the ratio of the total mass of the suspending particles to the total mass of the first, second, and third species of active agent particles is selected from between about 3:1 and about 13:1 and between about 2:1 and 8:1, pi2S] In another embodiment, a co-suspension composition deliverable horn a metered dose inhaler according to the present description inciudes the following: a suspension medium comprising a pharmaGeutically acceptable HFA propellant; a first species of active agent particles comprising glycopyrrolate, Including any pharmaceuticaiiy acceptable salts, esters, isomers or solvates thereof, suspended In the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrrolate of between about 15 pg and about 80 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising Ibrmeierol, inducting any pharmaceutically acceptabie salts, esters, Isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol of between about 2 μα and about 10 pg per actuation of the metered dose inhaler; a third species Of active agent particles comprising mometasone, including any pharmaceutically acceptable salts, esters, Isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient' to provide a delivered dose of mometasone of between about 20 pg and about 100 ug per actuation of the metered dose inhaler; and a plurality of respirable suspending ipadtcles GGrrsphsing perforated microstructures exhibiting a volume median optical diameter of between about 1 5 pm and about 10 pm, wherein the first, second and third species of active agent: particles associate with the plurality of suspending particles to form a co-suspension, in one such embodiment, at least 90% of the first, second, and third species of active agent particles by volume exhibit an optical diameter of less 7 pm, and the ratio of the total mass of the suspending particles to the total mass of the first, second; end third species of active agent particles Is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1, pi26] In another embodiment, a co-suspension composition deliverable from a metered dose inhaler according to the present description includes the following: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a first species of active agent particles comprising tiotropium, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended In the suspension medium at a concentration sufficient to provide a delivered dose of tiotropium of between about 5 pg and about 20 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, Isomers or solvates thereof, suspended In the suspension medium at a concentration sufficient to provide a delivered· dose of formoterol of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; a third species of active agent particles comprising mometasone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium: at a concentration sufficient to provide a delivered dose of mometasone of between about 20 pg and about 100 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated microstructures exhibiting a volume median optical diameter of between about 1 X> pm arid about 10 pm, wherein the first, second and third species of active agent particles associate with the plurality of suspending particles to form a co-suspension, in one such embodiment at least 90% of the first, second, and third species of agent particles by volume exhibit an optical diameter of less than 7 pm, and the ratio of the total mass of the suspending particles to the total mass of the first, second, and third species of active agent particles is selected from between about 3:1 and about 1i'1 and between about 2:1 and 8:1, [01271 in another embodiment, a co-suspension composition deliverable from a metered dose inhaler according to the present description includes the to!lowing: a suspension medium comprising a pharmaceutically acceptable NBA propellant; a first species of active agent particles comprising giycopyrroiate., including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of giycopyrroiate of between about 15 pg and about 80 pg per actuation of the metered dose Inhaler; a second species of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of 'formoterol of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; and a plurality of: respirable suspending particles comprising perforated microsiructureS: incorporating a corticosteroid selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone., mometasone, prednisone and trimadnelone, including, any .pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein the suspending partieies exhibit a volume median optical diameter of between about 1.5 pm and about 10 pm and associate with the first and second species of active agent particles to form a co-suspension. In one such embodiment, at least 90% of the first and second species of active agent particles by volume exhibit ah optica! diameter of less than 7 pm, and the ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles Is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1...

[8128] In another embodiment; a co-suspension composition deliverabie from a motored dose inhaler according to the present description includes the following: a suspension medium comprising a pharmaceutically acceptable NBA propellant; a first species of active agent partieies comprising giycopyrroiate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended In the suspension medium at a concentration sufficient to provide a delivered dose of giycopyrrolate of between about I S pg and about 80 pg per actuation of the metered dose inhaler; a second Species of active agent particles comprising formoteroi:, including any pharmaceutically acceptable salts, esters, isomers of solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoteroi of between about 2 pg and about 10 pg per actuation of the metered dose inhaler: and a plurality of respirable suspending particles comprising perforated m infostructures incorporating budesonide, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein the suspending particles include sufficient budesonide to provide a delivered dose of budesonide of between; about: 30 pg and about 50 pg per actuation of the metered dose inhaler, exhibit a volume median optical diameter of between about 1,5 pm and about 10 pm, and associate with the first and second spedes of active agent particles to form a co-suspension. In one such embodiment, at least 90% of the first and second species of active agent particles by volume exhibit an optical diameter of less than ? pm, and the ratio of the total mass of the suspending padicles to the total mass of the first and second species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1. :|01293 In another embodiment, a co-suspension composition deliverable from a metered dose inhaler according to the present description includes the following* a suspension medium comprising a pharmaceutlcaily acceptable HP A propellant; a first species of active agent particles comprising glycopyrrpiate, including any 'pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrrofate of between about 15 pg and about 80 pg per actuation of tie metered dose inhaler; a second species of active agent particles comprising formoteroi, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoteroi of between about 2 pg and about 10 pg per actuation of the metered dose inhaler: and a plurality of respirable suspending particles comprising perforated mieroStnjotyres incorporating mometasone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein the suspending particles include sufficient mometasone to provide a delivered dose of mpmetssone of between about 20 μα and about 100 pg per actuation of the metered dose inhaler, exhibit a volume median opticas diameter of between about 1.5 pm and about 10 μηι; and associate with the first and second species of active agent particles to form a co-suspension, in one such embodiment, at ieast 90% of the first arid second species of active agent particies by volume exhibit an optical diameter of less than Ψ pm, and the ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles is selected from between about 3:1 and about 15:1 and between about2:1 and 8:1, |013O] in another embodiment, a co-suspension composition deiiverabie from a metered dose inhaler according to the present description Includes the following: a suspension medium comprising a pharmaceutlcaliy acceptable HFA propellant; a first species of active agent particies comprising tiotrOpiuni, including any phamiaceuticaliy acceptable salts, esters, isomers or solvates thereof, suspended In the suspension medium at a concentration sufficient to provide a delivered dose of tloiropium of between about 5 pg and about 20 pg per actuation of the metered dose inhaler; a second species of active agent particies comprising fcrmoterol, including any pharmaceutically acceptable salts, esters, isomers or soivates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formolerol of between about 2 pg and about 10 pg per actuation of the metered dose Mhaler- and a plurality of respirable suspending particies comprising perforated microstructures incorporating a corticosteroid selected from beciomethasone, budesonide, ciciesonide, fiuhisdllde, fluticasone, methyl-prednisolone, mometasone, prednisone and tfimaeinoione, including any pharmaceutically acceptable sails, esters, isomers or soivates thereof, wherein the suspending partECies exhibit a volume median optical diameter of between about 1.5 pm and about 10 pm and associate with the first and second species of active agent particies to form a co-suspension, in one such ercboblmebt, at least 90% of the first and second species of active agent particies by volume exhibit an optical diameter of less than 7 pm, and the ratio of the total mass of the suspending particles to the total mass of the first end second species of active agent particles is selected from between about 3d and about 15:1 and between about 2:1 and 8:1. {0131] in another embodiment, a co-suspension composition deiiverabie from a metered dose inhaier according to the present description Includes the following:;: a suspension medium comprising a pharmaceutically acceptable HFA propeiiant; a first species of active agent particles comprising iiotropium, including any pharmaceutically acceptable satis, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of tiofropium of between about. 5 pg and about 2Q pg per actuation of the metered dose inhaler; a second species of active agent particles comprising: formoteroi, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose offormotenol of between about 2 pg and about 10 pg per actuation of the metered dose Inhaler; and a plurality of respirable suspending particles comprising perforated microstructures Incorporating budesonide, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein the suspending particles include sufficient budesonide to provide a delivered dose of budesonide of between about 30 pg and about 50 pg per actuation of the metered dose inhaler, exhibit a volume median optical diameter of between about 1,5 pm and about 10 pm, and associate with the first and second species of active agent particles io form a co-suspensiom in one such embodiment, at least 90% of the first and second species of active agent particles by volume exhibit an optical diameter of less than 7 pm, and the ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 5:1, [Q132J In another embodiment, a co-suspension composition deliverable fern a metered dose inhaler according to the present description includes the following: a suspension medium comprising a pharmaceutically acceptable H:FA: propellant; a first species of active agent particles comprising iiotropium,: ihciuding any pharmaceutically acceptable Salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of tiofropium of between about 5 pg and about 20 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising formoteroi, including any pharmaceuticaliy acceptable salts, esters, isomers or solvates thereof, suspended in the suspension;: medium at a concentration sufficient to provide a delivered dose of formoteml of between about 2 pg and about 10 pg per actuation of the metered dose Inhaler; and a plurality of respirable suspending particies comprising perforated microstructures incorporating mometasone, including any fiharmaceuticaily acceptable sails, esters, isomers or solvates thereof, wherein the suspending particles include sufficient mpmstssone to provide a delivered dose of mometasdne of between about 20 pg and about 100 pg par actuation of the metered dose inhaier, exhibit a volumemedian optical diameter of between about 1,5 pm and about 10 pm, and associate with the first and second species of active agent particles to form a co-suspension» In one such embodiment, at least 90% of the first and second species of active agent particles by volume exhibit an optical diameter of less than ? pm, and the ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles Is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1, 111. Petered Dose Inhaler Systems 101333 As described in relation to the methods provided herein, the cosuspension compositions disclosed herein may be used in an MDI system, MOSS are configured to deliver a specific amount of a medicament in aerosoi form. In one embodiment, an MO! system includes a pressurized, liquid phase formulaiion-fiiled canister disposed in an actuator formed with a mouthpiece. The MDI system may include the formulations described herein, which include a suspension medium, at least one species of active agent particles and at least one species of suspending particles. The canister used In the MDI may be of any suitable configuration, and in one exemplary embodiment, the canister may have a volume ranging from about 5 ml. to about 25 mi.., such as, for example a canister having a 19 ml volume. After shaking the device, the mouthpiece is inserted into a patient's mouth between the lips and teeth. The patient typically exhales deeply to empty the lungs and then takes a slow deep breath while actuating the cartridge.

[01341 Inside an exemplary cartridge Is a metering valve including a metering chamber capabie of holding a defined volume of the formulation (e.g., 63 μ! or any other suitable volume available in commercially available metering valves), which is released into an expansion chamber at the distal end of the valve stem when actuated. The actuator retains the canister and may also include a port with an actuator nozzle for receiving the vaive stem of the metering valve. When actuated, the specified volume of formulation travels to the expansion chamber, out the actuator nozzle and into a high-velocity spray that is drawn into the lungs of a patient. IV, Methods |013§] Methods of formulating a pharmaceutical, composition for respiratory delivery of at least two active agents ere provided herein,: In one f mbodimept, the method Involves the steps of providing a suspension medium, one or more species of active agent particles and one or more species of suspending particles, and combining such constituents to form a composition wherein the active agent particles associate with the suspending particies and co-iocate with the suspending particies within the suspension medium such that a co-suspension as described herein is formed, in one such embodiment, the association of the active agent particies and the suspending particies is such that they do not separate due to their different buoyancies: in a propellant. As will: be appreciated, a method^ of formulating a pharmaceutical composition as described herein can include providing two or more species: of active agent particles in combination with one or more species of suspending particies. In further embodiments, the method may include providing two or more species of suspending particies in combination with two or more species of active agent particles in a manner which results in a co-suspension, in stilt other embodiments, one or more species of active agent particles may be combined with one or more species of suspending particles, as described herein, in particular embodiments; the active agent material included in the active agent particles is selected from one or more of LABA, LAMA or corticosteroid active agents, in certain embodiments, the active agent particles consist essentially of active agent material, and are free of additional excipients, adjuvants, stabilizers, etc, 10136J In specific embodiments of methods for providing a stabilized composition of a combination of two or more active agents, the present disclosure provides methods for Inhibiting; the solution mediated transformation of the active agents in a pharmaceutical composition for pulmonary delivery. In one embodiment, a suspension medium as described herein, such as a suspension medium formed by an HFA propellant. Is obtained. Suspending pertieies are also obtained or prepared as described herein. Active agent particles are also obtained, and the suspension medium , suspending particles and active agent particles are combined to form a cosuspension wherein the active agent particles associate with suspending particles and eo-locate with the suspending particles within the continuous phase formed by the suspension medium. When compared to active agent particies contained in the same suspension medium in the absence of suspending particles, co-suspensions according to the present description have been found to exhibit a higher tolerance to solution mediated phase transformation that leads to irreversible crystal aggregation, and thus may lead fo improyed stability and dosing uniformity. £0137] In further embodiments, methods for form mg stabilized compositions including two or more active agents for pulmonary delivery include preserving the FPF and/or FPO cf the composition throughout emptying of an MDI canister. In specific embodiments of methods tor-preserving foe FPF and/or FPD provided by a pharmaceutical composition for pulmonary delivery, a respirable co-suspension as described herein is provided which is capable of maintaining the FPD and/or the FPF to within ± 20%, ± 10%, or even ± 5% the initial FPD and/or FPF, respectively, throughout emptying of an MDf canister. Such performance can be achieved where two or more active agents are Incorporated into the co-suspension and even after the co-suspension is subjected to accelerated degradation conditions, In one embodiment, a suspension medium as described herein, such as a suspension medium formed by an HFA propellant, is obtained. Suspending particies are also obtained or prepared as described herein,· Active agent particies are also obtained, and the suspension medium, suspending particles and active agent particies are combined to form a co-suspension wherein the active agent particles associate with suspending particies and co-ioeate with the suspending particies within the suspension medium. Even after exposure of such composition to one or more temperature eyciing events, the co-suspension maintains an FPD or FPF within ± 20%, ± 10%, or even ± 5% of tine respective values measured prior to exposure of the composition to multiple temperature cycling events, [0138J Methods tor preparing an MD! for respiratory deiivery of two or more active agents are disclosed. In certain embodiments, such a method may indude loading a canister, as described herein, with active agent particles and suspending particies. An actuator valve can be attached to an end of the canister and the canister sealed. The actuator valve may be adapted for dispensing a metered amount of the active agents included in the co-suspension composition per actuation •of the MDf. The canister can be charged with a pharmaceutically acceptable suspension medium, such as a propellant as described herein, whereupon the active agent particies and suspending particies yield a stable co-suspension In the suspension medium. |0i3i| Sn methods involving respiratory delivery of two or more active agents using eomppsiiions described herein, the compositions may be delivered by an MPf, Therefore;, in particular embodiments of such methods, an fvtOI loaded with a composition described herein is obtained, and two or more active agents are administered to a patient via respiratory delivery through actuation of the MPl For example, in one embodiment Involving pulmonary delivery of two or more active agents, after shaking the MDi device, the mouthpiece is inserted into a patient's mouth between the lips and teeth, The patient fypically exhales deeply to empty the lungs and then takes a slow deep breath while actuating the cartridge of the MDi, When actuated, the specified volume of formulation travels to the expansion chamber, out the actuator nozzle and Into a high-velocity spray that Is drawn Into the lungs of a patient, in one embodiment the dose of each active agent delivered throughout emptying of an MDi canister Is not more than 303δ greater then the mean delivered dose and is not less than 30% less than the mean delivered dose. Therefore, methods of achieving a desired DDU of two or mom active agents delivered from an MDi are also provided, in such embodiments, the method may include achieving a DDU for each of the two or more active agents delivered from an MDL selected from, for example, a DDU of ± 30%, or better, a DDU of ± 25%, or better, and a DDU of ± 20%,. or better throughout emptying of the MDi. canister from whIch the co-suspension composition is delivered. P148j Methods for treating patients suffering from an inflammatory or obstructive pulmonary disease of condition are provided herelny In specific embodiments,: such methods include pulmonary delivery of a pharmaceutical composition described herein, and in certain such embodiments, pulmonary administration of the; pharmaceutical composition is accomplished by delivering the composition using an MDI, The disease or condition to be treated can Pe selected from any Inflammatory or obstructive pulmonary disease or condition that responds to the administration of. for example, the active agents described herein. In some embodimehis, the combination of active agents includes at least one active agent selected from LAMA, LABA or corticosteroid active agents. In particular embodiments, the pharmaceutical compositions described herein may be used in treating a disease or disorder selected from asthma, CORD, exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, .emphysema, and any other respiratory disease, condition, trait, genotype or phenotype that can respond to the administration of combinations of active agents described herein, in certain embodiments, the pharmaceuticai compositions described herein may be used In treating pulmonary inflammation and obstruction associated with cystic fibrosis, |0141] Additionatiy, pharmaceutical compositions according to the present description delivered from an MDI provide desirable pharmacodynamic (PO) performance, in particular embodiments, pulmonary delivery of the pharmaceuticsl compositions described herein results in rapid, significant improvement in the lung capacity, which can be characterized by an Improvement in the patient's forced expiratory volume in one second (FEVt). For example, in partieuiar embodiments, methods for achieving a clinically relevant increase In FEVj are provided, wherein such methods include providing a co-suspension composition comprising two or more active agents, wherein at least one of those active agents is selected from a ΙΑΒΑ, LAMA or corticosteroid active agents, as described herein, and administering such composition to a patient experiencing pulmonary inflammation or obstruction via an MDI, in one such embodiment, the active agents included in the composition include a combination selected from one of a combination of LABA and LAMA active agents, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA, LAMA and corticosteroid active agents. For purposes of the present disclosure, a clinically relevant increase in FEV, is arty increase of 100 ml or greater, and in certain embodiments of the methods described herein, administration of compositions: according to the present description to patient results in a clinically significant increase in FEV; within 1 hour or less. Id,Other such embodiments, methods, for administering a composition as described herein to a patient via an MD! result in a cilhlcaily significant increase in FEV1 with ip 0 5 hours or less, 10142] In further embodiments, methods are provided for achieving an Increase in FEU* greater than 100 mi, For example, in certain embodiments, the methods described herein include methods for achieving an FE\A of 150 mi or greater within a period of time selected from 0,5 hours or less, 1 hour or less, and 1,5 hours or less. In other embodiments, the methods described herein include methods for achieving an FEVt of 200 ml or greater within a period # time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less, and 2 hours or less, in certain such embodiments, the active agents included in the composition Include a combination selected from one df a combination of LABA and LAMA active agents, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA, LAMA and corticosteroid active agents, wherein the composition isddlivered to the patient via an MOL p143] In still further embodiments, methods for achieving and maintaining a clinically significantly increase in ΕΕΜϊ are provided, In particular embodiments, upon administration of a single dose of a combination of active agents formulated In a composition as described herein to a patent vsa an MDL a ctinioaliy significant Increase in FEV'i is achieved in a period of time selected from 0,5 hours or less, 1 hour or less, and 1.5 hours or less, and the clinically significant increase in F EV't Is maintained for up 12 hours or more. In certain such embodiments, the increase in FEV j may be selected from an Increase of 150 ml or greater, 200 ml or greater and 250 ml or greater, and the increase in FEV; remains clinically significant for a time period selected from up to 4 hours, up to 6 hours, up to 8 hours, up to 10 hours, and up to 12 hours, or more. In certain such embodiments, the active agents included in the composition include a combination selected tom one of a combination of LABA and LAMA active agents, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid: active agents, and a combination of LABA, LAMA and corticosteroid active agents, wherein the composition is delivered to the patient via an MDI. £0144! Compositions,; Systems add methods described herein are not only suited to achieving desirable pharmacodynamic performance In short periods Of time, but will achieve such results in a high percentage of patients, For example, methods are provided herein for achieving a 10% or greater increase in FEMtJn 50% or more of patients experiencing pulmonary Inflammation or obstruction. For example, in particular embodiments, methods for achieving a 10% or greater increase in FEVi in a patient include: providing a co-suspension composition comprising a combination of active agents, wherein at least one active agent is selected from: LABA, LAMA, and pdrticosteroid active agents as described herein, and administering such composition via an MOHo a patient experiencing pulmonary inflammation or obstruction, in certain such embodiments, administration of the composition results in 10% or greater increase in FEVI within a period of time selected from 0,5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours In 50% or more of patients. In other such of the composition results in 10% or greater increase in FEV* with in a period of time selected from 0,5 hours or less, 1 hour or less, 1.5 hours or less, and 2 or less hours In 60% or more of patients, in still other such embodiments,: administration of the composition results In 10% or greater increase In FEV·; within a period of time selected from 0.5 hours or less, 1 hour or less, i ,5 hours or less, and 2 hours or less In ?0% or more of patients. In yet ether such embodiments, administration of the composition results in 16% or greater increase In FEV* within a period of time selected from 6.6 hours or less, 1 hour or less, 1.5 hours or less, and 2 or less hours in 80% or more of patients. In certain such embodiments, the active agents included in the composition include a combination selected from one of a combination of IAEA and LAMA active agents, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA, LAMA and corticosteroid active agents, wherein the composition Is delivered to the patient via an MDI. fS145| In specific embodiments, the methods described herein facilitate treatment of patients experiencing pulmonary inflammation or obstruction, wherein such methods include providing a co-suspension composition comprising a combination of active agents as described herein and administering such composition to a patient experiencing pulmonary inflammation or obstruction via an MDI, and administration of the composition via an MDI results In patients experiencing either an increase from baseline in FEV* of at least 200 ml or a 12%, or greater, increase from baseline in FEV; coupled with total increase in FEV* of at least 1 §6 mil. in certain such embodiments, administration of the composition results in either an Increase from baseline in FEV? of at least 200 ml ora 12%, or greater, increase tom baseline in FEVi coupled with total increase in FEV, of at least ISO ml within a period of time selected from 1 hour, or less, 1,5 hours or less, 2 hours, or less, and 2.5 hours, or less, in 50% of more of patients, in other such embodiments, admin istrdtsors of the composition results in ah increase from baseline in FEV; of at least 200 mi or a 12%, or greater, increase from baseline in FEV* coupled with total increase In FEV* of at least 156 ml Within a period of time selected from: 1 hour, or less, 1,5 hours, of less, 2 hours, or less, and 2:5 hours, or less, in 60% or more of patients. In still other such embodiments, adminSstration of the composition results in either an increase from baseline in FEV5 of at least 200 ml or a 12%, or greater, increase from baseline in FEVi coupled with total increase in.FEVi of at Seas! 150 mi within a period of time selected from 1,5 hours, orfess, 2 hours, or less, 2.5 hours, or less, and 3 hours, or less, in 70% or more of patients. In yet other such embodiments, administration of the com pos ition results in either an increase from basel ine in FEVi of at least 200 mi or a 12%, or greater, increase from baseline in FEVi coupled with total Increase In ΡΕ¥1: of at least 150 mil within a period of time selected from 1.5 hours, or less, 2 hours sor less, 2.5 hours ,or less, and 3 hours, or less in 80% or more of patients. In certain such embodiments, the active agents included in the composition include a combination selected from one of a combination of ΙΑΒΑ and LAMA active agents, a combination of ΙΆΒΑ end corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LASA, LAMA and corticosteroid active agents, wherein the composition is delivered to the patient via an MDL [Q146J The specific examples included herein are for illustrative purposes oniy and are not to be considered as limiting to this disclosure. Moreover, the compositions, systems and methods disclosed herein have been described in relation to certain embodiments thereof, and many detail# have been set forth for purposes of illustration, it will be apparent to those skied in the art that the invention is susceptible to additional embodiments and that-certain of the details described herein may be varied without departing from the basic principles of the invention. Any active agents and reagents used in the following examples are either commercially available or can be prepared according to standard literature procedures by those skilled in the art of organic synthesis. The entire contents of all publications* patents, and patent applications referenced herein are hereby incorporated herein by reference.

Example 1 £614?] An exemplary co-suspension composition as described herein was prepared and evaluated. The composition Included a combination of gSycopyrrolate (GP) and formoteroi fumaraie (FF) active agents. GF was present in the propeiiant as micronized, crystalline active agent: particles., it was co-suspended with spray dried suspending particles that included FF disposed within the material forming the suspending particle. To achieve this,: FF was dissolved in the feedstock used to manufacture the lipid-based suspending particles. |0148| GP active agent particles were formed by micro sizing glycopyrroiate using a jet mill. The particle size distribution of the giycopyrrolate active agent particles was determined by laser diffraction using a laser diffraction padicie size analyzer, Fraunhofer diffraction mode, equipped with a dry powder dispenser {e.g.« Sympaiee GmbH, Clausthai-Zelierteid, Germany), '&amp;M by volume of the active agent particles exhibited an optical diameter smaller than 1,7 pm, and 90% by volume exhibited an optical diameter smaller than 3,5 pm, |0149] FF-containing suspending particles were manufactured as follows* 554 ml of a fluoraearhondh-water emulsion of PFDB (perfluorooctyi bromide) stabilized by a phospholipid was prepared; 26,5 g of the phospholipid, DSPC 0^-distero^Fsfy· glyoem^-phosphochoiina), and 2,4 g of calcium chlorideywere homogenized in 276 ml of hot water (80°C) using a high shear mixer; and 142 ml of PFOB were added slowly during homogenization,. The resulting coarse emulsion was then further homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, GA) at pressures of up |q 170 KfPa for 5 passes, 552 mg FF was dissolved in 273 mi of warm water (5£PG) and most of the solution was combined with the emulsion using a high shear mixer, The emulsion was spray dried In nitrogen using tne following spray drying conditions: inlet temperature 95X; outlet temperature 68¾ emulsion feed rate 2.4 ml/min; and total gas flow 498 i/mln. The final mass fraction of formoteroi in the spray dried powder was 2%.

[0150] A second lot of FF-containing suspending particles was manufactured in a Similar fashion. The mass fraction of FF In the spray dried powder was 1% for this lot. A third lot of suspending particles was manufactured without FF.

[0151] The particle sizedistribution of the suspending particles (VfvID) was determined by laser diffraction. For both lots of FF containing suspending particles, 50% by volume were smaller than 3,5 urn and the Geometric Standard Deviation of the distribution was 1.7, For the suspending particles without FF, 50% by volume were smaller than 3,2 pm and the Geometric Standard Deviation of the distribution was 1.8, [0152] MOla containing FF, GP or both were prepared by weighing the target masses of active agent particles and suspending particles into fluonnated ethylene polymer (PEP) coated: aluminum canisters (Presspsm Biackbum, UK) with a 19 ml volume. The canisters were crimp sealed with 63 μ! valves {# BK 357, Bespate, King's Lynn, UK) and filled with 12.4 g of HFA 134a (1,1,1 ;24etrafiuoroethane) (Ineos Fluor, Lyndhurst, UK) by overpressure through tne valve stem. The resulting suspension concentrations and the target delivered dose assuming 20% actuator deposition are given In Table la for three different configurations {configurations iA through 10),. After injecting the propellant the canisters were sonicated for 15 seconds and agitated on a wrist action shaker for 30 minutes. The canisters were fitted with polypropylene actuators with a 0.3 mm orifice (# BK 638, Bespak, King's Lynn, UK).

Table la: Configurations of the glycopyrroiate - fpfmbterpi fumaraie combination co-suspensions of Example 1

J01S3] The filled MBIs were stored valve down at two different conditions: refrigerated at 5*C without overwrap and controlled room temperature at 25*0/60% RH with a foil overwrap. Aerosol performance and delivered dose uniformity tests were carried out at different time points. Aerosol performance was assessed after manufacturing in accordance with USP <601> (United States Pharmacopoeia Monograph 801). A Next Generation Impactor (Net) operated at a flow rate of 30 i/min was used for determination of particle size distribution. Sample canisters were seated into an actuator with two waste actuations and two additional waste priming actuations. Five actuations were collected .In the NGi with a USP throat attached. The valve, actuator, throat, NGl cups, stages, and filter were rinsed with Soiumetrically dispensed solvent. The sample solutions were assayed using a drug-specific chromatographic method. The fine particle fraction was defined using the sum of stages 3 through filter. Delivered dose uniformity through use testing was performed using a Dose Uniformity Sampling Apparatus as described by USP <601 >. inhalers were seated and primed as described before. Two actuations were collected and assayed at beginning, middle and end of use.

No trends in aerosol performance or delivered dose uniformity were observed lor the duration of the study (3 months) or as a function of storage temperature. Hence* all aerosol performance test results were pooled. Table lb lists the average performance of the different configuration. The fine particle dose is the sum of collected mass on stages 3 to filter of the impactor, normalised by the metered dose. The average aerosol performance for ail three configurations was equivalent.

Table 1 b: Average aerosol performance for co-suspensions in Example 1

[0105] Dose content uniformity was tested through canister life for both actives of the combination product. Figures T and 2 show the ex-actuator dose for configuration lA and 18, respectively,, normalized by the actual metered doses of the canister, Assuming an actuator deposition Of 20% the target ex-actuator doses for both actives were 80%. The individual FF and ΘΡ doses are represented by dots and triangles, respectively. The closed line denotes the mean of the formoteroi doses, and the broken line denotes the mean of the giycopyrrolate doses. Figures 3 and 4 show the ratio of the normalized ex actuator doses for configuration 1A and irrespectively. The result indicates that the dose ratio remained constant through canister life. Furthermore the variability of the dose ratio is much lower than that of the individual doses, indicating that a cofoyspension with a consistent carrier to active ratio was formed and maintained through container life.

The results show that, when formulated according to the disclosure provided herein* combination product co-suspensions are formed with suspending particles containing one of: the active pharmaceutical ingredients,; ;in this case FF. Suspending particle to active agent particle ratios can be adjusted to achieve targeted dose content uniformity while maintaining Similar aerosol performance.

Example 2 [8156] MDis containing FF, GF or both were prepared at target concentrations of 2,4 and 18 pg per actuation for FF and ΘΡ respectively. GP active agent was mJcronized and had a dies d®, d® and span of 0.6, 1.7, 3.6 and l .9 um respectively as measured by laser diffraction as described Example 1. FF was incorporated into spray dried suspending particles and prepared as described in Example 1 , with a composition of 2% FF, 91.5% DSPC and 6.5% CaCb. The GP, FF and GP - FF fdDls were prepared by weighing the target masses of active agent particles and suspending particles into dudrinated ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) with a 19 mL volume. The canisters were crimp sealed; with 5D pi valves (# 6K 357, Bespak, King’s Lynn, UK) and filled with 19.2 g of HFA 134a (1 <1,1:2-tetrafluoroetha.ne) (Ineos Fluor, LyniShurst, OK) by overpressure through the valve stem. After Injecting the propellant* the canisters were sonicated for 15 seconds and agitated on a wrist action shaker for 30 minutes. The canisters were fitted with polypropylene actuators with a 0.3 mm ©nice {# 8K 636, Bespak, King’s Lynn, UK). 10157] Long term aerosol stability and delivery characteristics ot the MDI compositions were assessed. In particular the aerosol particle size distribution and delivered dose characteristics of such compositions were evaluated as in accordance with USP «691 > as described in Example 1, under various conditions and, in some instances, for periods of time extending up to 12 months. For example, as is shown in Figure 5, the delivered dose uniformity provided by the compositions prepared according to Example 1 was substantially preserved, even after 12 months storage of such compositions at 5’5C or after 4.5 months at 26 <:C and 60 % relative humidity (RH) for samples stored inside aluminum foil pouches to minimize water ingress Into the klDI canister (Le,, “protected storageM). IPISSj The aerosol performance of such compositions was also evaluated throughout unprotected storage conditions extending up to 12 months and protected storage conditions extending up to 6 monthsy As is shown in Figure 6, the GP and FF particle size distributions proylded by this co-suspension composition were substantially preserved after 12 months of protected storage at 5eC and six months of unprotected storage conditions at 25°C and 60% RB. As is shown in Figure 7, even under stressed conditions (40° C, 75% RH), the compositions showed no noticeable degradation in the particle size distribution .of GP and FF delivered from the metered dose inhalers after six months.

[0169] in order to evaluate whether the combination of GP and FF within a single formulation would result in the degradation of the aerosol properties relative; to compositions including a single active agent, the aerosol properties of co-suspension •compositions were assessed relative to suspension compositions including only a single active agent.

[¢160] As can be seen in Figure 8,: the aerosol performance of the combination co-suspension composition including both GP and IFF active agent was no different than the serose! performance achieved by suspension compositions including either GP or FF atone demonstrating that the aerosol properties of the individual active agents are substantially the same when achieved from the single component or dual combination co-suspensions.

[0161] The pharmacokinetics and safety of a combination coreuspension metered dose inhafer containing glycopyrrojate and formoieroi fumarate were evaluated in a clinical trial. The clinical trial was a single-center, randomized, double-blind, single dose, four-period, four-treatment crossover study used to evaluate four inhaled treatments administered by MOL The four treatments included a FormoferoS Fumarate (FF) Inhalation Aerosol, a Giycopyrrofate (GP) inhalation Aerosol, a GP * FF inhalation Aerosol, and consecutive delivery of the GP Inhalation Aerosol followed immediately by delivery of the FF Inhalation Aerosol. The GP t FF inhaiation Aerosol as well as the FF inhalation Aerosol and GP inhalation Aerosol were prepared as described in Example 2. The GP+FF Inhalation Aerosol was also labeled the iixed” combination of GP and FF, while the treatment calling for consecutive delivery of the GP inhalation Aerosol feilowod immediately by delivery of the FF inhalation Aerosol was labeled the Toose" combination of GP and FF.

[6162] Subjects were randomized in to the study and assigned one of four treatment seguenoes, with each treatment sequence including ail four study treatments. Each subject received:four single dose treatments separated by 7 to 21 days. Sixteen subjects were enrolled and analyzed for safety. Three subjects were excluded from the P&amp; analysis as a result of not receiving one or more of the lour treatments, and an additional two subjects wore excluded from the PK analysis as non-evaiuabie clue to dosing errors arising from poor inhalation technique. (0163J The 6P + FF Inhalation Aerosol was administered to provide each subject a 72 pg dose of GP and a 9.6 pg dose of FF (four actuations. 16 pg 8P arid 2,4 pg FF per actuationj. The GP Inhalation Aerosol was administered to provide each subject a 72 pg dose of GP (four actuations, 18 pg GP per actuation). The FF Inhalation Aerosol was administered to provide each subject a 9.6 pg dose of FF (four actuations, 2.4 pg FF per actuation). For blinding purposes each of the preceding three treatments were preceded by four actuations of placebo M.DI. The loose combination of GP inhalation Aerosol followed by FF inhaiation Aerosoi was administered to provide each subject a 72 pg dose of GP and a 9.6 pg dose of FF (four actuations, 16 pg GP per actuation followed by four additional actuations, 2.4 pg FF per actuation). (0164] Both the ioose and fixed combinations of GP and FF were safe and weil-tolerated, with the fixed combination providing a safety profile simliar to that observed for the other three treatments evaluated in the trial. Blood samples were collected pre-dose and at 2, 5, 15, and 30 minutes, as well as 1, 2, 4, 6,(8, and 12 hours post-dose for determining the plasma concentrations of GP and FF that were used to calculate various PK parameters. Plasma concentration time profiles for both GP and FF in the 12 hour period Immediately following dosing are provided In Figure 9. As can be seen in Figure 9; administration Of GP and FF from the fixed combination resulted in plasma concentrations of GP and FF foliowing ad ministration comparable to those resulting from administration of the loose combination of GP and FF, As was noted for the in-vitro delivered dose and particle size distribution performance described in Example 2, no combination effect was observed in-vivo for the fixed combination GP * FF Inhalation Aerosol. (0165] An exemplary dual co-suspension composition according to the present description was produced and metered dose inhalers incorporating the composition were prepared. The composition (included a combination of giycopyrroiafe (GP) and fbrmoterol fumarate (FF). with each being provided as a micronized, crystalline materia!, A combination crystalline co-suspension MDI was manufactured by semi-automated suspension filling..The dual co-suspension consisted of a combination of two microcrystafline active pharmaceutical Ingredients (also referred to as TAPIs" or "ΑΡΓ* in the singular):, GP and FF, co-suspended with suspending particles in HFA 134a propellent. The dual co^suspension was formulated to provide a delivered dose of 18 ug GP per actuation and 4,8 pg ff per actuation. In preparing the dual co-'Suspension compositions, in certain compositions, the FF API material used; was denoted as “coarse", while in other compositions, the FF API material used was denoted as %η07 Whether the co-suspehSion compositions Incorporated course or fine FF, the compositions were formulated to provide a delivered FF dose of 4,8 pg per actuation. The particle size eharactenstics for the course FF, fine FF and GP API materials used in formulation the co-suspension compositions described In this Example are detailed in Table 2. In addition to the dual co-suspension compositions, a monotherapy co-suspension composition Incorporating oniy FF active agent material was formulated. The FF monotherapy co-suspension utilized coarse FF API. A monotherapy MDI was manufactured using such FF monotherapy co-suspension, and the FF monotherapy MDi was formulated and manufactured provide a delivered dose of 4 J pg FF per actuation..

[0168] Suspending particles were manufactured via spray dned emulsion at a feed stock concentration of 80 mg/ml with a composition of 93.44% DSPC (1,2-Distearoyi-sn-Giycero-3~Phosphocholine) and 8.56% anhydrous calcium chloride (equivalent to a 2:1 DSPCtCaCIa ffidie/mole ratio;), During the emulsion prep, DSPC and CaCh was dispersed with a high shear mixer at 8000-10000 rpm in a vessel containing heated water (80 ± 3 °C) with PFOB slowly added during the process. The emulsion was then processed with 8 passes in a high pressure homogenize?· (10000-25000 psi). The emulsion was then spray dried via a Spray dryer fitted with a 0.42" atomizer nozzle with a set atomizer gas flow of 18 SOFM, The drying gas flow rate was set to 72 SGFM with an Inlet temperature of 135 -C, outlet temperature 70 °C, and an emulsion JOw rate of 58 mh/mfa, [0167] For the MDi manufacturing, a drug addition vessel (DAV) was prepared for suspension filling In the following manner: first adding half of suspending parties© quantity, next fling micrecrystailine materials, and lastly adding the remaining half of suspending particles to the top. Materials were added to the vessel in a humidity oontrofied environment of <10% RH. The DAV was then connected to a 4 L suspension vessel and flushed with HFA 134a propellant and then mixed with gently to form a slurry, The slurry is then transferred baek to the suspension mixing vessel and diluted with additional BFA434.8 to form the final suspension at target concentration stirring gently with an impeller. The temperature inside the vessel was maintained at 21-23 X throughout the entire hatch production. After recirculation for 30 min the suspension was filled into 14 ml. tluorlnated ethylene polymer (PEP) coated aluminum canisters (Presspatt, Blackburn, UK) through 50 pi: valves (Bespak, King’s Lynn, UK). Sample canisters were the selected at random for total canister analysis to ensure correct formulation quantities. The optical diameter and particle size distribution of two lots of mieronized formoterol particles was determined by laser diffraction as described in Example 1. , Table 2 lists the dto, dso and dm values for the different lots of mieronized material used, d 50, d^ and dso denote the particle size at which the cumulative volume distribution reported by the particle sizing instrument reaches 10%, 50% and 90%, respectively. 101683 The particle size distributions provided by both dual co-suspension formulations prepared in accordance with this Example 4 were compared to the particle size distribution provided by a co-suspension compositions prepared according to Example 1. The results of this comparison are provided in Table 3, where N%FPF FF” and “%FPF GP* represent the fine particle mass 0f the specified active agent on Stages 3 through filter of an NG1, divided by actuator mass, and multiplied: by ioo.

Table,. 2: Particle Size Distributions for mieronized Formoteroi Fumarate and Glyeopyrrolsie used to prepare Dual Co-Suspensions

JibieS: Particle Size Distributbnslbr Different, Exemplary GP/FF Co-susoensions

pi®9J Tlie aerosol performance of

the dual co-suspension compositions prepared according to this Example was evaluated and cximpared to the cosuspension composition prepared according to Example 1, with aerosol performance being assessed as described in Example 1, The results pf such comparisons are provided in Figure 10 through Figure 12. As is easily appreciated by reference to these figures, regardless of whether the crystalline formoteroi materia! used in providing the dual co-suspension was fine or coarse:, the FF and GP pedicle size distributions for the dual co-suspension compositions were substantially the same as those achieved by the co-suspension composition prepared according to Example 1,.-[0178] In addition, the delivered dose uniformity for GP and FF provided by the dual co-suspension compositions as described in this Exampie was assessed in as described in Exampie 1. The results of this assessment are iiiustrated in Figure 13, The dual co-suspension formulations provided desirable DDU characteristics for both GP and PF as ail actuations delivered the expected dose within ± 25% of the mean.

Example 5 £01711 The formulation Of a dual co-Suspensioh composition of saimeterol xinafoate (SX) active agent particles and fluticasone propionate [FP) active agent particles is described. Both FP and SX are present in the pfopeliant as a micronized, crystalline particles. The two species of micrOnized active agent particles are co-suspended with spray dried suspending particles. 10172] Micron ized SX {4-hydroxy-a1-lP-{4-phenyibutoxy)hexyi]amino] methyl]-1,3-benzenedimethanol, 1-hydroxy-2~naphfoalenecarboxylate) was received by the manufacturer finke SA, Germany) and used as active agent particles. The particle size distribution of the SX was determined by laser diffraction. 50% by volume of the micronized particles exhibited an optical diameter smaller than 2 pms and 90% by volume exhibited an optical diameter smaller than 3,9 urn. 101731 Wicrorsized: FP uoromelhyi)6t!,9-dif!uoro-11SM 7-dihydroxy-16a-methyl- 3“OxoandfOsta-1 ^-dlene-lTfocarbofhioate, 17-propfonate) was received as micron ized by the manufacturer (Hovione FarmaCiencla SA, Loures Portugal) and used as active agent particles. The particle size distribution of the FP was determined by laser dihracflon, -&amp;M by volume of the mlcronlzed particles exhibited an optical diameter smaller than 2.6 pm, and 90% by volume exhibited an optical diameter smaller than 6.6 urn. £0174! Suspending particles were manufactured as follows: 160 mb of a tiuorocar bon- in-water emulsion of PFOB (perfluorooctyl bromide) stabilized by a phospholipid was prepared; 12.3 g of the phospholipid, DSPS (1 (2-0ίΡίβίθ^^η~ glycem^phosphochoiine) and 1.2 g of calcium chloride were homogenized in 100 ml of hot water (7Q°C) using a high shear mixer; and 65 ml of PFOB were added slowly during homogenization. The resulting coarse emulsion was then further homogenized using a high pressure homogenizer (Mode! 03, A vest in, Ottawa, CA) at pressures of up to 140 MPa for 3 passes. |0175| The emulsion was spray dried in nitrogen using the following spray drying conditions: Inlet temperature 90°0; outlet temperature 69°C; emulsion feed rate 2.4 mi/mln; and total gas flow 498 l/min. The particle size distribution of the suspending particles, VMD, was determined by laser diffraction, 50% by volume of the suspending particies were:.smaller than 2.7 pm, the Geometric Standard Deviation of the distribution was 2.0. Additionally, the aerodynamic particle size distribution of the Suspending particies was determined with a time-of-flight: particle sizer. 50% by volume of the suspending particies had an aerodynamic particle diameter smaller than 1,6 pm. The large difference between aerodynamic particle diameter and optica! particle diameter indicates that the suspending particles had a low particle density < 0,5 kg/ί. This was verified by electron microscopy: which confirmed that: the suspending particles exh ibited a hollow, thin-walled morphology.

[01761 MDIs were prepared by weighing the target masses of micronized FP, SX, and suspending particles info fidpflnated ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) with a 19 mb volume. The canisters Were crimp sealed with 63 pi valves: 0 BK 357, Bespak, King’s Lynn, UK) and filled with 10 ml of HFA 134a {1,1,1,2~tefrafluoroethahe} (Ineos Fluor, Lyndhurst, UK) by overpressure through the valve stem. After Injecting the propellant, the canisters were sonicated for 15 seconds and agitated oh a wrist action shaker for 30 minutes. The canisters were fitted with polypropylene actuators with a 0.3 mm orifice {# BK 636, Bespak, King’s Lynn, UK), Aerosol performance was assessed shortly alter manufacturing in accordance with USP 801 , as described in Example i. Results are reported below In Table 4.

Table 4: Results for a co-suspension of Fluticasone Propionate (FP> and Saimeterol Xinafoate (SX) of Example 5

*no trend observed [01773 The delivered dose uniformity through use was tested and all individual delivered doses were within ±20% of mean, at 6,1% relative standard deviation (also referred to as “RSD”), Visual observation Of the co-suspension was conducted in glass vials and no sedimentation of active agent particles was observed^ The vials were left to settle for 24 hours without agitation. The suspension flocculated slowly and formed a homogeneous, single cream layer.

Example 6 [0178J The formulation of a combination co-suspension composition of saimeterol xinafoate (SX) active agent particles and fluticasone propionate {FP} suspending particles Is described. SX Is present in the propellant as a micronixed, crystalline particle, it is co-suspended with spray dried suspending particles that have micron ized FP disposed into the material forming the suspending particles. To achieve this, FP crystals are suspended In the feedstock used to manufacture the lipid-based suspending particles. The FP and SX used to form the active agent particles and suspending particles referenced in this example were as described In Example 5, [01793 FP'Containing suspending particles: were manufactured as follows: 200 rnt of a fluorocarbon-in-water emulsion of PFGB stabilized by a phospholipid was prepared; 3.¾ of the phospholipid (QSPC) and O.Bg of miemnixed FP were dispersed and G.3g of calcium chloride dihydrate was dissolved in 100ml of warm water (?0°C) using a high shear mixer; and 44mL of PFGB was added slowly during dispersion, The resulting coarse emulsion was then further homogenized using a high pressure homogenizer at 140 MPa for 3 passes. The homogenization reduced the particle size of the suspended FP crystals. The emulsion was spray dried in nitrogen using the fbiiowing spray drying conditions: inlet. temperature SSX; outlet temperature 72*C; emulsion feed rate 2.4 mi/mln; and total gas flow 525 i/niin.

[0180] MDIs were prepared by weighing the target masses of micronized SX active agent particles and FP-ooniaining suspending particles into fluorinated ethylene polymer (PEP) coated aluminum canisters (Presspart, Blackburn, UK) with a 19 mi volume. The canisters were crimp sealed with 63 pi valves (# BK 367, Bespak, Xing's Lynn, UK) and filled with 10 ml of HFA 134a (1,1,1,2-tetraflueroethane) (Ineos Fluor, Lyndhurst, UK) by overpressure through the valve stem. After injecting the propellant, me canisters were sonicated 15 seconds and agitated on a wrist action shaker for 30 minutes. The canisters were tilted with polypropylene actuators with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK), Aerosol performance was assessed shortly after manufacturing in accordance with USP 601 as previously described in Example 1. Results are reported below In Table 5.

Table 5: Results for a Oorsuspension of Salmeterol Xinafoate (SX) Active Agent Particles with Fluticasone Propionate-containing Suspending Particles,

*with a slight upward trend 18181] The delivered dose uniformity through use was tested and ail individual delivered doses were within ±25% of mean, at 9.0% RSD for FP and 13% RSB for SX. Visual observation of the co-suspension was conducted in glass vials and no sedimentation of active agent particies was observed. The vials were left to settle for 24 hours without agitation. The suspension flocculated slowly and formed a homogeneous, single cream layer, shewing no indication of separation of SX and suspending particles.

[01823 The formulation of a dual ^suspension composition including budesonide active agent particles; and momeissone fufpate active agent particles is described. Budesonide (8D) and moroetasone funoata (MF) were present in Ida propellant as a micronlzedi; crystalline particles arid are co-suspended with spray dried suspending particles, [01821 BD, 18,1 ?“(butyl!denebis(OKy))~11,21 -dihydroxy-, (11 -fM'8~o)-pregna-1,4-diene-3,20-dsone, was received micronized by the manufacturer (AARTI, Mumbai, India) and used as active agent particles. The particle size distribution of the BO was determined by laser diffraction, §0% by volume of the mlcfonized particles exhibited an optical diameter smaller than 1.9 pm, and 90% by volume exhibited an optical diameter smaller than 4,3 pm, [0184] MF, 9«, 21 -dichioro-11 β, 17-d ih ydroxy-18 came thyl pregn a-1,4~diene~3,20~ dione 1 ?-(2~furoate), was received mieronized by the manufacturer (AARTI, Mumbai, India) and used as active agent particles. The particle size distribution of the MF was determined by laser diffraction, 50% by volume of the mieronized particles exhibited an optical diameter smaller than 1,6 pm, and 90% by volume exhibited an optical diameter smaller than 3.5 pm, [0185] Suspending particles were manufactured as follows: 500 ml of a fluorocarbon-in-water emulsion of PFOB (periluoroociyl bromide) stabilized by a phospholipid was prepared: 18,7 g of the phospholipid, DSPC (1 t2-dieferoyl-sh~ glycero-3-phosphooholine) and 1.3 g of calcium chloride were homogenized in 400 nil of hot water (75°C) using a high shear mixer; and 100 ml of PFOB were added slowly during homogenization. The resulting coarse emulsion was then further homogenized using a high pressure homogenizer (Model £3, Avestin, Ottawa, GA) at pressures of up to 170 MPa for 5 passes. The emulsion was spray dried In nitrogen using the following spray drying conditions: inlet temperature 95°C; outlet temperature 72°C; emulsion feed cafe 2 .4 ml/min; and total gas flow 498 i/min.

[0186] MDls were prepared by weighing the target masses of mieronized active and suspending particles into coated glass vials with a 15 ml volume. The canisters were crimp sealed with 63 μ! valves (Valois, Las VaudreuiS, France) and filled with 9.2 g of HFA 134a (1,1,1 ^Aetrafluoroethane) (Inees Fluor, Lyndhurst, UK) by overpressure through the valve stem. After Injecting the propellant* the canisters were sonicated for IS seconds and agitated on a wist action shaker ter 30 minutes. The suspension canceniratiens were 0.8 mg/mi for BD active agent particles, 11 mp/ml for yF active agent, paftlciesi and 0 mg/ml tor the suspending particles. The suspending particle to active agent particle ratio was 7.5 for BD and 5.5 for MF. Target ex actuator doses were 40 pg for BD and 55 pg for IV1F.

[0187] Visual observation of the co-suspended configurations showed no sedimentation of active agent particles. The vials were left to settle for 16 hours without agitation. No active agent particles were visible at the bottom of the co-suspension vials. the results showed that crystalline budesenide and mometaspne flsroate material forming the different species of active agent particles associated with the suspending particles., formed a co-suspension in the configurations disclosed herein. The association between active agent particies and suspending particles was strong enough to overcome buoyancy forces as settling of the active agent particies was successfully inhibited.

Example 8 [51881 Dual co-suspension compositions were prepared with suspending: particles including either mometaspne furcate (MF) or budesonide (BD), and MD-te Incorporating the composition were prepared,: the co-suspension composition included a combination :pf crystalline giycopyrrolate (GP) and formoterdl fumarate (FF) active agent particles co-suspended with suspending particles Including either jyjF or BD. Each of the APIs were provided as a micron ized, crystalline material. [0189] Suspending particies containing 60% (w/w) of either BD or ME were manufactured as follows: high shear homogenisation of a dispersion containing 2.8 g of DSF'C {l.g-Distearoyl-sn-Giycero-S-Phosphocholihe}» and 0,26 g of caicium chloride in 400 mb of hot water (75 *€} using a high shear mixer was performed while 55-6 § of PFOB were added: slowly. Micronszed IVIE or BD (in 1:1 weight: proportion to DSPC) was added to the: resulting coarse emulsion, which was further homogenised using a high pressure homogenlzer (yodel C3, Avast in, Ottawa, DA) at pressures of up to 170 MPa for 3 to 5 passes. The emulsion was spray dried using the following spray drying conditions: inlet temperature 90-95 *0; outlet temperature 95-72 emulsion feed rate 2-8 mUmin; total dry nitrogen flow 525-850 L/rnin, The particle size distribution of the resulting powders was determined by laser diffraction, 50% by volume of the suspending particles were smaller than 1.6 pm, the span of the distribution was 1.6 pm. $3190] Canisters containing either 50% |w/w>: MF or BD containing suspending particles were fiilbdi'With HFA 134a propellent, targeting a 50 or 100 pg/actuation of MF or BP, respectively. Their aerosol particle size distributions were determined according to the methods described in Example 1, and results are shown in Table 6, A comparable series of canisters: containing MF or BD containing suspending particies in combination with GP and FF active agent particles were: produced. Sufficient micron ized GP and FF API materia! was added to such canisters in amounts sufficient to provide targeted delivered doses of 36 pgfactuation and 6 pg/actuetson for GP and FF, respectively. Additional placebo suspending particies prepared as described herein but free of any active agent (also referred to as "piacebo’· suspending particies) were added to certain to reach a total co-suspension concentration of 5.5 m|/mi.

The aerosol particle size distributions provided by the co-suspension compositions prepared according to this Example were determined as described in Example 1, with the results are shown in Table 7. The mass mean aerodynamic diameter of the corticosteroid In the single component suspensions is equivalent to the one obtained in the triple combination formulations prepared with two different species of active agent particies co-suspended with BD or MF containing suspending particles. As was tree of the co-suspension compositions containing a combination of two different active agents, the triple co-suspension compositions prepared according to the present description avoided a combination effect.

Table 6: Suspension fviDis in HFA 1340 propellant containing corticosteroid suspending particies. Aerosol properties, mass aerodynamic diameter and fine particle fraction determined by drug specific cascade Impaction.

table 7: triple combination suspension MQ\s in HFA 134a propellant including corticosteroid containing suspending particles (Mometasone Furcate or Budesonide), a. LAMA (Glycopyrroiate) and a LABA (Formoteroi Fumarate}, Aerosol properties, mass mean aerodynamic diameter and fine particle fraction determined by drug specific cascade impaction. added placebo suspending parades

Example 9 10192] A triple co-suspension composition according to the present description was produced and MOIs incorporating the composition were prepared. the composition included a combination of glycopyrroiate (GP), formoteroi fumarate (FF), and mometasone furcate (MF) active agent partides, with each being pfpvided as a micronized, crystalline API materiai, 10193] A triple co-suspension MDI was manufectyred by semi-automated suspension filling, the triple co-suspension consisted of a combination of three microorysfafiihe active pharmaceuicaS Ingredients forming three different species of active agent particles: MF (corticosteroid);: GP (LAMA); end: FF (LABA). These three different species of active agent particles were co-suspended with suspending particles in HFA 134a propellant. The triple co-suspension was formulated to the following delivered dose targets: 50 pg per actuation MF;: 36 ug per actuation GP; and 4.3 pg per actuation FF. In addition to the triple co-suspension, a monotherapy co-suspension including only MF was produced. The monotherapy MF co-suspension included MF active agent particles co-suspended in tie·, propellant with suspending particles as described in this Example, and was formulated to provide a target delivered dose of 50 pg per actuation MF.

[0194] Suspending particles were manufactured via spray dried: emulsion at a lead stock concentration of 80 mg/mt with a composition of 93.44% DSPC (1,2-Disteanoyi-so-Glycero-S-Phosphoeholine} and 6,58% anhydrous caicium chloride (equivalent to a 2:1 DSPCiCaCia moie/mole ratio). During the emuision prop, DSPC and CaCh were dispersed with a high shear mixer at 8000-10000 rpm in a vessel containing Heated water (80 ± 3 °C) with PFOB slowly added during the process. The emulsion was then processed with 0 passes in a high pressure homogenlzer (10000--25000 psi). The emuision was then spray dried via a spray dryer fitted with a 0,42-atomizer nozzle with a set atomizer gas How of 18 SCFM, The drying gas flow rate was set to 72 SCFM with an inlet temperature of 135 *0, outlet temperature 70 °C, and an emulsion flow rate of 58 mL/min.

[0195] For MDI manufacturing, a drug addition vessel (DAV) was prepared for suspension filling in the fallowing manner: first adding half of suspending particle quantity, next filling microcrystalline materials, and lastly adding the remaining half of suspending particles to the top. Materials were added to the vessel in a humidity controlled environment of <40% RH. The DAM was then connected to a 4 L suspension vessel and flushed with HFA 134a propellant and then mixed with a magnetic stir Par. The temperature inside the vessel was maintained at 21-23 *0 throughout the entire batch production.,· After recirculation of the batch for 30 min canisters were filled with the suspension mixture through SO μΐ EPDM valves. Sample canisters were the selectedtat:'Mhdd!pi: for Total Canister An a lysis to ensure correct formulation quantities. The freshly manufactured tripie co-suspension MDI batch was then placed on one week quarantine before initial product performance analysis. The mometasone furoate only MDI was manufactured by suspension filling in the same manner, pti6] The primary particle size distribution of all microcrystalline APIs was determined by laser diffraction as described in Example 1, results are shown in Table 9. Aerodynamic particle size distribution and mass mean aerodynamic diameter of all components upon actuation of the suspension MDfs was determined by drug specific cascade impaction as described In Example 1 and are shewn In Table 9.

Table 9: Triple microcrystalline Co-Suspension in HFA 134a propellant MDI.. Primary particle size distribution determined by laser diffraction (Sympafee),

Table 10: Triple co-suspension MPfs in HFA 134a propellant containing microerystaliine Corticosteroid (Mometasone Furcate), LABA (Forrnoteroi Fumarate) and a TAMA {Glycopyrroiate}. Aerosol properties, mass mean aerodynamic diameier add fine particle fraction were determined by drug specific cascade impaction (NGi).

101971 Aerosol performance and delivered cose uniformity achieved by the triple co-suspensions prepared according to this Example were evaluated according to the description provided in Example 1, Figure 14 illustrates the GP, FF and MF ODU achieved from two canisters containing MF only and two canisters containing MF, GP and FF prepared according to this Example. The DDU of MF deilvered from the MF monotherapy configuration Is equivalent to the one achieved with the tripie co-suspension composition. The aerosol performance of the triple co-suspension composition prepared according to this example was also assessed relative to formulations containing a combination of only two active agents, FF and GP, The aerodynamic particle size distribution of FF and GP are equivalent whether delivered from the compositidns containing two: active agents or three active agents as shown in Figures 15 and 16, respectively. |8198| As was true of the co-suspension compositions containing a combination of two different active agents, the triple co-suspension compositions prepared aooording to the present description avoided: a combination effect.

Example 10 p199] Exemplary triple co-suspension compositions according to the present description were produced and metered dose inhalers incorporated in the composition were prepared. The tripie co-suspensions included glycopyrrolate (GP) or tiotropium bromide (TB) in combination: with farmoteroi fumarate (FF)f and morrteiasorie furcate (MF) active agents, with each API being used as micronized, crystalline material. P200] Two separate suspension MDI batches containing three active pharmaceutical ingredients (APis), a corticosteroid, a LAMA and a LABA were prepared. The APIs were provided as microerystaiiine materiais that served as the active agent particles co-suspended with suspending particles prepared as described herein. The triple co-suspension compositions prepared as described in this Example were prepared by adding the active agent particles and suspending particles to an HFA 134a propellant.

[0201] The first triple co-suspension batch (Triple GFM) was formulated to the following delivered dose targets: 40 pg per actuation MF; 13 ug per actuation GP; and 4.8 pg per actuation FF. The active agent particles were co-suspended with suspending particles manufactured using ran emulsion composed of 93,46% DSPC (i!2-pisieafoyl-sn-Glycerd‘-3-Phosphoc.holine} and 8.54% anhydrous calcium chloride spray dried with an SO mg/hii feed concentration. The DSPC;CaCb molar ratio of the suspending particles was 2:1. The suspending particles were combined with the active agent particles in propellant for a formulation, target of 6 mg/ml suspending particle concentration. The primary particle sizes of the microerystaiiine active agent particles, determined by Sym pa tec laser diffraction measurements as described in Example 1, are displayed below in Table 11, [0202] The second triple co-suspension batch (TFM) was prepared using a different LAMA API:, anhydrous tiotropium bromide (TB) to replace GP, The second tripie cd-suspension was formulated to the following delivered dose targets: 50 pg per actuation MF; 9 pg per actuation TB; and 4,8 pg per actuation FF. The suspending particles were prepared as described in relation to the Triple GFM cosuspension, and the active agent particles were co-suspended with the suspending particles at a targeted suspension concentration of 6 mg/mL The primary particle sizes of the mieroerysfaiiine active agent particles, determined by Sympatec laser diffraction measurements as described In Example 1.. are displayed below in Table 12. £0203] fd Die were prepared using the Triple GFM and Triple TFM co-suspension compositions, and the aerosol properties, fine particle fraction, and mass median aerodynamic:· diameter were determined as described in Example 1, Table 13 sets out the MMAD and FPF performance lor Triple GF!v1 and Triple TFM,. while the desirable aerosol properties achieved by the Triple GFM and Triple TFM co-suspensions are shown in Figure i? (showing the aerodynamic particle size distribution of GP and TB obtained from Triple GFM and Triple TFM, respectively),

Tabie 11r Triple GFM primary particle size distribution determined by laser diffraction {Sympatec),

Tabid 12i Triple TFM primary particle Size distribution determthed by laser diffraction (Sympatec),

Tabie 13: Triple GFM and Triple TFM aerosol properties, mass mean aerodynamic diameter and fine particle fraction determined by drug specific cascade impaction

P&amp;Q43 Exemplary dual co-suspension compositions according to the present description were produced and MDls incorporating the dual co-suspension compositions were prepared. The compositions included a combination of giycopyrroiate (GP) and forrnoteroi furnarate (FF), with each being provided as a mJcronized, crystalline material with particle size distribution as shown in Table 14, The mlcroerysialfine GP and FF materials provided two species of active agent particles, while suspending particles were prepared as described in Example 4. In preparing the dual co-suspensions described in this Example, the GP active agent particles, FF active agent particles, and suspending particles were combined in an HFA 134a propellant. |020S| The dual co-suspensions described In this example were prepared by first dispensing the appropriate quantities of GP and FF active agent particles and suspending particles into a drug addition vessel (DAV) Inside a humidity controlled chamber (RH < -5%). the DAV is then sealed under a nitrogen atmosphere and connected to the suspension vessel containing 12 kg of HFA~134a, A slurry was then formed by adding Q,S~1 kg of H FA-134 a Into the DAV', which Is then removed from the suspension vessel and gently swirled, The slurry is then transferred back to the suspension mixing vessel and diluted with additional HFA~134a to form the final suspension at target concentration stirring gentiy with an impeller. The suspension is then: recirculated via a pump to the filling system for a minimum time prior to initiation of filing. Mixing and recirculation continue thmughoui the filling process. Valves are placed onto MDi canisters and then purged of air either by a vacuum crimping process, or an HFA-134a purging process, followed by valve crimping. The crimped canisters are then filied through-the-valve with the appropriate quantity of suspension, adjusted by the metering cylinder.

Table 14: Giycopyrrolate and Formotero! Fumarate particle size difidhutiens,

[0206J The suspension for pressure filling is prepared by first dispensing the appropriate quantities of micronized giycopyrroiate and formoterol fumarate crystals and suspending particles to· a drug addition vessel (DAVy inside a humidity controlled chamber (RH < 5%), in the current example the suspending particle carrier was added in three equal portions intercalating the addition of GP and FF after the first and second addition respectively. The DAV Is then sealed under a nitrogen atmosphere and connected to the suspension vessel containing 12 kg of HFA~134a. A slurry was then formed by adding 0.5-1 kg of HFA-134a into the DAV, which is then removed from the suspension vessel and gently swirled. The slurry is then transferred back to the suspension mixing vessel and diluted with additional HFA--134a to form the final suspension at target concentration stirring gently with an impeller. The suspension is then recirculated via a pump to the filling system fora minimum time prior to initiation1 of filling. Mixing and recirculation continue throughout the filling process. Valves are placed onto canisters and then purged of air either by a vacuum crimping process, or an HFA-134a purging process followed by valve crimping.. The crimped canisters are then filled t'nrouen-the-vaive with the appropriate quantity of suspension, adjusted by the metering cylinder. 102OTJ MDIs containing the dual co-suspensions described In this Example were prepared to contain two different doses GF and FF. Specifically, a first run of dual co-suspension compositions were prepared to provide IB pg per actuation GP and 4.8 pg per actuation FF (low dose"), and a second run of duai co-suspension compositions were prepared to provide 36 pg per actuation GP and 4.8 M9 Per actuation FF ("high dose"). In addition to the dual co-suspensions coroposif*ons· monotherapy FF and GP co-suspension compositions were prepared- dbe monotherapy co-suspension compositions were prepared as described for the dual co-suspensions, except that they included only one species of active agent particles (either GP or FF). The monotherapy co-suspensions were formulated and monotherapy IMEHs prepared to provide the following targeted delivered doses: 18 pg per actuation of GP, and 0,5, 1.0, 3.8 or 4.8 pg per actuation of FF. The compositions and MQIs providing 0,5 pg FF and 1 pg FF per actuation are referred to as “ultra iow" dose. 10208] The drug specific aerodynamic size disthbyfiohs achieved with IVIDis containing the co-suspension compositions prepared according to this Example were determined as described in Example 1. The proportionality of the aerodynamic size distributions of GP obtained from the iow and high dose dual co-suspensions as well as the equivalency between the duai and monotherapy co-syspensions is demonstrated in Figure 18. In the same manner, the proportionaiity of the aerodynamic size distributions of FF obtained from the dual and monotherapy cosuspensions, including the uitralow, iow, and high dose compositions is demonstrated In Figure 19, |0iO9] The delivered dose uniformity of the ultra low dose FF monotherapy fvIDIs was also measured as described in Example 1..,. The DBU for the 1 pg/actuation and 0J pg/actuation compositions and systems are shown in Figure 20. Desirable dose delivery uniformity is achieved even for ultra iow doses

Claims (58)

1, A pharmaceutical composition deliverable from a metered dose inhaler: comprising: a suspenstdn medium comprising a pharmaceutically acceptable propellant; two or more active agents; one or more species of active agent particles; arm one or more species of respirable suspending particles, wherein the one or mom species of active agent particles comprise at feast one of the two or more active agents and the active agent particles and suspending particles associate to form a co-suspension,

2, A pharmaceutical composition according to claim 1,, wherein the two or mom active agents are selected from short-acting beta agonist, long-acting and ultra long-acting β2 adrenergic receptor agonist (LABA|, corticosteroid, antMhflammaiory, anti-tussive, branchediiator, muscarinic antagonist, and long-acting muscarinic antagonist (LAMA) active agents, including any pharmeceuficaily acceptabie salts, esters, isomers or Solvates thereof.

3, The pharmaceutical composition according to claim 2, wherein at least one of the at least one species of suspending particles comprises an active agent and the two or more active agents are selected from a LAMA active agent selected from glycopyrrofate, dexipirrolym,itiotroplum:, trosplum, aelidinium, and darntropium, a I..ABA active agent selected fmm bambyteml, clenbuteroi, formoteroL saimeterol, Garmoteroi, milveteroi, indacaferoS,: and safigenin- or Indole- containing and adamantyi-denved S;> agonists, and a corticosteroid active agent selected from beclomethasohe, hudesonide, ciclesonide, fiunisollde, fluticasone, mefhyi-prednisolone, mometasone, prednisone and tnmaelnolone, including any pharmaceptically acceptable salts, esters, isomers or solvates thereof,

4, The· pharmaceutical composition of claim' 2, comprising at least two different species of active agent particles, wherein each of the at least two species of active agent particles comprises a different active agent and the different active agents are selected from a LAMA active agent selected from glycopyrroiate, dexipirmnlpm, tiotropium, trosplum, aelidinium:, and darotropum a IAEA active agent selected from bambuterol, clenbutemi, fomioterol, saimeterol, carrnoterol, milveteroi, indacaterol, and saligenin- or indole- containing and adamantyl-derived β2 agonists, and a corticosteroid active agent selected from' beclomelhasone, budesonide, cidesonide, flunispllde:! fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable sails, esters, isomers or solvates thereof.

5. The pharmaceutical composition of claim 4, comprising at least three different species of active agent particles, wherein each of the at least three species of active agent particles comprises a different active agent and the different active agents are selected from a LAMA active agent selected from glycopyrroiate, dejdplrrpnium, tietropium, trospiurn, aciidiniurn, and darotropom, 3 IAEA active agent selected from bambuteroi, denhuterol, formoteroi, salmeterol, carmoierol, miiveteroi, indacaterol, and saligenin- or indole- containing and adamantyl-derived 82 agonists, and a corticosteroid active agent selected tom beclomelhasone, budesonide, cidesonide., iiunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

6. The pharmaceutical composition of claim 2, comprising at least two different species of active agent particieS: wherein each of the at least two different species of active agent particles cPniprises a different active agent, at least one of the at least one species of suspending particles comprises a third active agent, and the different active agents are selected from a LAMA active agent selected from glycopyrroiate, dexipirronium, tiotropium;, trospiurn, aciidinium, and darotroplum, a LABA active agent selected from hambuteroL clenbuterol, fermoteroi, salmeterbl, carmoteroi, mliveterol, indacaterol, and saligenin- or indole- containing and adamantyt-derived &amp; agonists, and a corticosteroid active agent selected from bedomethasohe, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, Including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

7. The pharmaceutical composition according to claim 2, wherein at least 50% of the active agent particles by volume e&amp;hfbfi an optical diameter of § pm or less.

8. The pharmaceutical composition according to claim 2, wherein at least one species of suspending particles comprise perterated microstructures,

8. The pharmaceutical composition according to claim 8, wherein the pertdrated microstruciures are prepared using a spray drying process. I. 0,: The pharmaceutic#I composition according to ciairn 9, wherein the perforated microstructures comprise a spray dried emulsion of perfluorooctyi bromide, DSPC and calcium chloride in water. II. The pharmaceutical composition according to claim 2, wherein at least one species of suspending particles comprise an excipient selected from at least one of lipids, phospholipids, nonionic detergents, polymers, nonionic block copolymers, surfactants, non-ionic surfacfanis, biocompafible iluorinated surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, and combinations thereof,

12. The pharmaceutical composition according to claim 2, wherein the suspending particles are included in the suspension medium at a concentration selected from between about 1 mg/ml and about 15 mg/ml, between about 3 mg/ml and about TO mg/ml, between about 5 mg/ml and about S mg/ml, and about $ mg/ml.

13. The pharmaceutical composition according to claim 2, wherein each of the at least one species of suspending particles exhibit an fvMAD selected from between about 10 pm and about 500 nm, between about 5 pm and about 750 nm, between about and 1 pm and about 3 pm.

14. The pharmaceutical composition according to claim 2, wherein each of the at least one species of suspending particles exhibit a volume median optical diameter selected from between about 0.2 pm and about 50 pm, bebveeh about 0.5 pm and about 15 pm, between about 1.5 pm and about 10 pm, and between about 2 pm and about 5 pm,

15. The pharmaceutical composition according to claim 2, wherein the propellant comprises a propellant selected torn an HFA propellant, a RFC propellant and combinations thereof, and wherein the propellant is substantially free of additional constituents.

16. The pharmaceuticai composition according to claim 2, wherein a total mass of the at least one species of suspending partitas exceeds a total mass of the at least one species of active agent particles.

17. The pharmaceutical composition according to claim 16, wherein a ratio of the total mass of the at least one species of suspending particles to the total mass of at least one species of agent particles is selected from above 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 ISO. and up to about 200. 18; The:· pharmaceutical composition according to claim 16, wherein a ratio of the total mass of the at least one spades of suspending particles to the total mass of the at least one species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

19. The pharmaceutical; composition according to claim 2, wherein the suspending particles remain associated with the active agent particles even when subjected to buoyancy forces amplified by centrifugation at an acceleration selected from accelerations of at least 1 gf: at least 10 g, at least 50 g, and at least 100 g.

20. A method for treating a pulmonary disease or disorder in a patient the method comprising:: providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension comprising: a suspension medium comprising a pharmaceutical!^ acceptable propellant; two or more active agents; one or more species of active agent particles: and one or more species of respirable suspending particles, wherein the one or more species of active agent particles comprise at least one of the two or more active agents and the active agent particles and suspending particles associate; and administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition: comprises delivering a therapeutically effective amount of the two or more active agents to the patient,

21. The method of claim 20, wherein providing a pharmaceutically acceptable: co-suspension comprises providing: a co-suspension comprising two or more active agents selected from short-acting beta agonist, long-acting and ultra long-acting p2 adrenergic receptor agonist (IAEA), corticosteroid, anti-inflammatory, antidussive, bronchodiiator, muscarinic antagonist, and long-acting muscarinic antagonist (LAMA) active agents, including any pharmaceutically acceptable salts, esters, isomers or solvates tbereot 22. : The method of Claim 21, wherein the pulmonary disease or disorder is selected froi at least one of asthma, CORD, chronic bronchitis, emphysema, bronchiectasis, allergic rhinitis,* sinusitis, pulmonary· vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis,

23, The method of claim 22, wherein providing a pharmaceuticaily -acceptable co-suspension comprises providing a co-suspension wherein at least one of the at least one species of suspending particles comprises an active agent and the two or more active agents are selected from a LAMA active agent selected from gtycopyrroiate, dexipirronium, tiotropium, trospium, aclidinium, and darotroplum, a LABA active agent selected from bambuteroi, cienbuieroh formoteroi, salmeteroL earmoterob miiveterol, indacateroS, and sallgenin- or Indole- containing and adamantyl-derived p2 agonists, and a corticosteroid active agent selected from beclbmithasohe, budesonide, cicfesonide, flunisollde, fluticasone, methyl-prednisolone,, morneiasone, prednisone and thmacinolbne, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof,

24, The method of claim 22, wherein providing a pharmaceuticaily acceptable co-suspension comprises .providing a co-suspension comprising at ieast two different species of active agent particles, each of the at least two species of active agent particles comprises a different active agent, and the different active agents are selected from a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium:, and daretroplum, a IAEA active agent selected from bambuteroi, elenbuteroi, formoteroi, saimeterol, carrnoteroi, roiiveterol, indacaterol, and sailgenin· or indole- containing and adamantyl-derived 1¾ agonists, and a corticosteroid active agent selected tom beciomethasene, budesonide, cicfesohide, flunisoiide, fluticasone, methyl - pred n isolone, mometasone, prednisone and ihrhaeinolone, including any pharmaceutically acceptable sails, esters, isomers or solvates thereof.

25. The method of claim 24, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising at ieast three different species of active agent particles, each of the at least three species of active agent particles comprises a different active agent, and the different active agents are selected from a LAMA active agent selected from glycopyrroiate, de^plmonium^. tsotropium, trospium, aclidinium, arid darotropsum, a LABA active agent selected fern bambuteroi, clenbuteroi, formoteroi, salmeterol, carmoterol, milveteroi, indaeaterol, and saligeoin-or indole-containing and adamantyl-derived fa agonists, and a corticosteroid active agent selected fern beciomefhasone, budesonide, ciciesonide, flunisollde, fluticasone> methyl-prednisolone:, mdmetasdne, prednisone and trimaeinolone, including any pharmaceutically acceptabie salts, esters, isomers or solvates thereof,

26. The method of claim 22, wherein providing a pharmaceutically acceptabie co-suspension comprises providing a eo suspension comprising at Seast two different species of active agent particles, each of the at least two species of active agent particles comprises a diffesrent active agent, at least one of the at least one species of suspending particles comprises a third active agent, and the different active agents are selected from a LAMA active agent: selected from giycopyrrolate, dexipirronium, tlotropium, fespium, aclidimum, and darotropium, a LABA active agent selected from bambuteroi, clenbuteroi, formoteroi, salmeterol, carmoterol, milveteroi, indaeaterol, and salfgeoin- or indole- containing and adamantyl-derived fa agonists; and a corticosteroid active agent selected fern beciomethasone, budesonide, ciciesonide, flunisolide, fluticasone, methyl-prednisolone, momeiasone, prednisone and tnmacinQlone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof,

27. The method of claim 22, wherein delivering a therapeutically effective amount of the two or more active agents to the patient comprises slmultaneousSy delivering therapeutically effective amounts of a LAMA active agent selected fern giycopyrrolate, dexipirronium, fiofepium, frospium, aclldinium, and darotropium, and a LABA active agent selected from bambuterol, clenbuteroi, formoteroi, salmeterol, carmoterol, mliveteroi, indaeaieroi, and sailgenin- or indole- containing and adamantyt-derlyed "fa agonists, including any pharhiaceutiealiy acceptable salts, esters, isomers or solvates thereof,

28. The method of claim; 22, wherein delivering a therapeutically effective amount of the two or more active agents to the patient comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent selected from giycopyrrolate, dexipirronium, tiotropium, trospium, aeiidinium, and darofepium, and a corticosteroid active agent selected from beeioroefhasdne, budesonide, cieiesonide, Bunisollde, fluticasone, methyl-prednisolone, mometasone, prednisone and trimaclnolone». including any phanmaeeuticaliy acceptable sails, esters, isomers or solvates thereof,

29. The method of claim 22, wherein delivering a therapeutically effective amount of the two or more active agents to the patient comprises simultaneously delivering therapeutically effective amounts of a LABA active agent selected from bambuteroi, elenbuterol, formoteroi, salmeteroi, earmoteroi, mllveterol, indacateroi, and saligenin- or indole* containing and adamantybdehved :β2·" agonists, and a corticosteroid active agent selected from beciomethasone, budesonide, ciciesonide, fiunisoiide, fluticasone, methyl-prednisolone, mometaspne, prednisone and trimscinotone, including any pharmaceutically acceptable salts, esters, isomers or soivates thereof.

30. The method of claim 22, wherein delivering a therapeutically effective amount of the two or more active agents to the patient comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent selected from qlycopyrrolafe, dexipirronium, tiotropium, trospium, aciidinium, and darotroplum, a LABA active agent selected from bambuteroi, elenbuteroi, formoteroi, salmeteroi, cprmptsrbl, miiveteroi, indacateroi, and saligenin- or indoie- containing and adamantyi-derived Pa agonists* and a corticosteroid active agent selected from beciomethasone, budesonide:,: eieleseoide, fiunisoiide, fluticasone, methyl-· prednisolone, momeiasdns, prednisone and trimadnolone, Including any pharmaceutically acceptable salts, esters, isomers or solvates thereof,

31. A method for respiratory delivery of two or more active agerits to a patient, the method com prising: providing metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium comprising a pharmaceutically acceptable: propellant; two or more active agents: one or more species of active agent particles;: and one or more species of respirable suspending particles, wherein the one or more species of active agent particles comprise at least one of the two or more active agents and the active agent particles and suspending particles associate; and actuating the metered dose inhaler to provide respiratory delivery of the two of more active agents to the patient.

32. The method of claim 31» wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising two or more active agents selected from short-acting beta agonist, Song-acting and ultra long-acting β:3 adrenergic receptor agonist {LABA}, coiilcosterold,. anti-inflammatory, antiTussive,, bfonehbdlafor, muscarinic antagonist,: and long-acting muscarinic: antagonist (LAMA) active agents, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

33. The method of claim 32,, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension: wherein at least one of the at least one species of suspending particles comprises an active agent and the two or more active agents are seiected from a LAMA active agent seiected tom glyeopyrrolaie, dexiplrronium, thiropiuro, trospium, aeNdinium, and darotropium, a LABA active agent seiected from bambuteroi, clenbuteroL formoteroi, salmeterol, carmoterol, miiveterol, indacaterob and saligenin- or indole- containing and adamantyl-dehved β2 agonists, and a corticosteroid active agent selected from beclomethesone., budesonide, ciclesonide, fiunisofide, fluticasone, methyl· prednisolone, mometasone, prednisone and trimacinoione, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof,

34. The method: of claim 32, wherein providing a pharmaceutically acceptable co-suspension comprisesproviding a co-suspension comprising at least two different species of active agent particles, each of the at least two species of active agent particles comprises a different active agent, and the different active agents are selected from a LAMA active agent seiected from giycopyrroiate, dexiplrronium, tiotropium,. trospium, adidshlum, and darotrepium, a LABA active agent selected from bambuteroi, clenbutero!, formoteroi, salmeterol, eafmoteroi, miiveterol, indacaterol, and saligenin-Or indole- containing and adamantyi-derived p2 agonists, and a eortieostefoid active agent seiected from beciomelhasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinoione, including any .pharmaceutically -acceptable salts, esters, isomers or solvates thereof.

35. The method of claim 34, wherein providing a pharmaceutically acceptable co-suspension comprises providing s co-suspension comprising at least thme different species of active agent particles, each of the at least three species of active agent particles comprises a different active agent, and the different active agents are selected from a LAMA active agent selected from giycopyrrolate, dajdpirfomum, tieiropiunii; tmspium, aclidlnlurn, and damtropfum, a ΙΑΒΑ active agent selected from bambuterol, cfenbyterof formoterol, salmeterol, carmotarol, miiJVeterol, indacateroi, and saligenin- or indole- containing and adamantyl-derived p2: agonists, and a corticosteroid active agent selected from beelomeihasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, momeiasone, pmdnisone and trimacinolone, including any pharmaceutically acceptabie salts, esters, isomers or solvates thereof.

38. The method of claim 32, wherein providing a pharmacedtieaiiy acceptable co-suspension comprises providing a co-suspension comprising at least two different species of active agent particles, each of the at least two species of active agent particles comprises a different active agent, at least one of the at least one species of suspending particles: comprises a third active agent, and the different active agents are selected from and the two or more active agents are selected from a LAMA active agent selected from giycopyrrolate, dexipirronium, tiotropium, trospium, acSidinium, and ddfotropium·, a LABA ^active agent selected from hambutenol, clenbuierpi, forrooteroi, salmeteroi, earmoterel, mliveterol, indacateroi, and saligenin- or Indole- containing and adamantyl-derived β2 agonists, and a corticosteroid active agent selected from beciomethasone, budesonide, ciclesonide, fiunisolide, fluticasone, methyl-prednisolone, momeiasone, prednisone and trimacinoione, ineluding any pharmaceutically acceptabie salts, esters, Isomers or solvates thereof.

37. The method of ciairn 32, wherein actuating the metered dose Inhaier to provide respiratory delivery of the two or more active agents comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent and a LABA active agent to the patient, wherein each of the LAMA active agent and the LABA active agent are delivered to the patient at a ODU selected from a DDU of ± 25%, or better, a DDU of ± 20%, or better, and a DDU of ± 15%, or better, throughout emptying of the canister,

38. The method of claim 37, wSierein the LAMA active agent is selected from giycopyrrolate, dexipirronium, tiotroplum, trosplurn, aciidinium, and darotropiurh, and the LABA active agent is selected from bambuterol, clenbuteroi, formoteroi, salmeteroi,: oarmoterob rfiilvetero!, jndaesierol, and saiigenin- or indole- containing and adamant-derived (¾ agonists, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

39. The method of claim 38. wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA and LABA active agents comprises delivering the LAMA and LABA active agents at an Initial fine particle fraction, and the initial fine particle' fraction delivered from the metered dose inhaler is substantially maintained such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initiai fine particle fraction.

40. The method of claim 39, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initiai fine particle fraction.

41. The method of claim 40, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler Is maintained within 95% of the initial fine particle fraction.

42. The method of claim 32, wherein actuating the metered dose inhaler to provide respiratory delivery of the two or more active agents comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent and a corticosteroid active agent to the patient, wherein each of the LAMA active agent and the corticosteroid active agent are delivered to the patient at a DDU selected from a DDU of ± 25%,. or better, a DDU of ± 20%, or better, and a ODU of ± i 5%. or better, throughout emptying of the canister.

43. The method of claim 42, wherein the LAMA active agent is selected from glycopyrrolate, dexspirronlum, tiotroplum, trospium, aelidiniuro, and darotropium, and the corticosteroid active agent is selected from heelomethasone, budesonide, ciclesonlde, ffunlsolide, fluticasone, methyl-prednisolone, mometasone, prednisone add trimacinoione, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof,

44. The method of ciaim 4.3, wherein actuating the metered dose Inhaler to provide respiratory delivery of the LAMA and corticosteroid active agents comprises delivering the LAMA and corticosteroid active agents at an initial fine particle fraction, and the initial fine particle fraction delivered from the metered dose inhaler Is substantially maintained such that, throughout emptying of the canister, the fine: particie fraction delivered tom the metered dose Inhaler is maintained within 00¾ of the initial fine particle fraction. 4§v The method of claim 44, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler Is maintained within :90% Of the initial fine particle fraction,

40. The method of claim: 45, wherein, throughout emptying of the canister, the fine particle fraction delivered from: the metered dose inhaler Is maintained within 95% of the initial fin© particle fraction,

47. The method of daim 02,. wherein actuating the metered dose inhaler to provide respiratory delivery of the two or more active agents comprises simultaneously delivering therapeutically effective amounts of a LABA active agent and a corticosteroid active agent to the: patient, wherein each of the LABA active agent and the corticosteroid active agent are delivered to the patient at a DDU selected from a ODU of ± 25%, or better, a DDU of ± 2;0%, or better, and a DDU oft 15%, or better, throughout emptying of the canister.

48. The method of claim 4T„ wherein the LABA active agent is selected from bambuteroi, clenbuterol, formoterol, saimeterol, carmoterol, miiveterol, ihdacateroi, and saligenin* or Indole* containing and adamantyi-dehved agonists, and the corticosteroid active agent is selected from beclomethasone, budesonide, ciclesonide, flunisOlide, fluticasone, methyl-predhlsoione, roometasona, prednisone and inmacinoione, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

49. The method of claim 48, wherein actuating the metered dose Inhaier to provide respiratory delivery of the LABA and corticosteroid active agents comprises delivering the LABA and corticosteroid active agents at an initial fme particle fraction, and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 89% of the initial fine particle fraction.

50. The method of ciaIm 49, wherein, throughout emplying of the canister, the fine particle fraction delivered from the metered dose inhaler Is maintained within 90% of the initial fine particle fraction. 51 > The method of claim 50, wfierein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.

52. The method of ciaim 32; wherein actuating the metered dose inhaler te provide respiratory delivery of the two or more active agents comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent, a LABA active agent and a corticosteroid active agent to the patient, wherein each of the LAMA active agent, the LABA actwe agent and the corticosteroid active agent are delivered to the patient at a DDU selected from a DDU of ± 25%, or better, a DDU of ± 20%, or better, and a DDU of ± 15%, or better, throughout emptying of the canister.

53. The method of claim 52, wherein the LAMA active agent is selected from gtycopyrrolate, tioifopiurm irospium, sciidinium:, and darotropium, the LABA active agent Is selected from barhbuterol, denbuteroi, formoterol, saSmeferol, carmdterol, msiveterpl, indacatero!, and sallgenin- or Indole- containing a no adamantyl-derived ,¾ agonists, and the corticosteroid active agent is selected from beclomethasone, budesonsde, cidesonitie, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and ifirnacinoione, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

54. The method of claim 53, wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA, LABA and corticosteroid active agents comprises delivering the LAMA, IAEA and corticosteroid active agents at an initial fine particle fraction, and the initial fine particle fraction delivered from the meterep dose inhaler is substantially maintained such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose Inhaler is maintained within 80% of the initial fine particle fraction.

55. The method of claim 54, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler Is maintained within 99% of the Initial fine particle fraction.

56. The method of claim 55, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particie fraction,

57. A pharmaceutical composition deliverable from a metered dose inhaler; comprising: a suspension medium comprising a pharmaceutically adaptable HFA propellant; a first species of active agent particles comprising glycopyrrolatei inciudlng any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrroiate of between about 1b pg and about 80 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising formoterol, including any ghanmaceeticaliy acceptable salts, esfers, isomers or so!vales thereof suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated microstructures exhibiting a volume median optical diameter # between about 1.5 pm and about 10 pm, wherein the first and second species of active agent particles associate with the plurality of suspending particles to form a co-suspension. SO. The pharmaceutical composition according to claim 5?, wherein a ratio of the:. total mass of the suspending particles to the total mass of the first and second species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

59. A pharmaceutical composition deliverable from a metered dose inhaler, comprising: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising giycopyrrolate,, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium at a concentration sufficient to provide a delivered dose of giycopyrrolate of between about 15 pg and about 80 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising formoterol, including any pharmaceutically acceptable salts* esters, isomers or solvates thereof, wherein the plurality of suspending particles exhibit a volume median optical diameter of between about 1.5 pm and about 10 pm, are included In the suspension medium at a concentration sufficient to provide a delivered dose of iormoieroi of between about 2 Mg and about 10 pg per actuation of the metered dose inhaler, add associate with the plurality of active agent particles to form a co-suspension.

60, The pharmaceutical composition according to claim 59, wherein a ratio of the total mass of the suspending particles to the total mess of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1. 61 A phannaceutical compcsitlon deliverable from a metered dose inhaler, comprising; a suspension medium comprising a phsfrnaeeuticaiiy acceptabie HFA propellant; a first species of active agent particles composing giycopyrrolate, Ineiuding any pharmaceutically acceptabie salts, esters, isomers or solvates thereof, wherein at least 90% of the active agent pedicles by volume exhibit an optical diameter of 7 pm suspended in the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrroiate of between about 15 pg and about 80 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising formoterol, including any pharmaceutically acceptabie salts, esters, isomers or solvates thereof suspended in the suspension medium at a concentration sufficieht: to provide a delivered dose .of formoterol of between about 2 ug and about 10 pg per actuation of the metered dose inhaler; a third species of active agent particles comprising a corticosteroid selected from beciOmeihaspne, hudesonlde, ciciesonide, flunisolide, fluticasone, methyl” prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof; and a plurality of respirable suspending particles comprising perforated mierostructures exhibiting a volume median optical diameter of between about 1J prn and about 10 phi, wherein the first, second and third species of active agent particles associate with the plurality of suspending particles to form a co-suspension.

62. The pharmaceutical composition according to claim 61, wherein a ratio of the total mass of the suspending particles to the total mass of the first, second and third species of active agent particles Is selected from between about 3:1 and about 16:1 and between about 2:1 and 8:1. 83> A; pharmaceutical composition deliverable tom a metered dose Inhaler, comprising; a suspension medium: comprising a pharmaceutically acceptable HFA ;p.fppe|iant; a first species of active agent pahides comprising giycopyrroiaie: including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in She suspension medium at a concentration sufficient to provide a delivered dose of glycopyrroiafe of between about 15 μρ and about 80 pg per actuation of the metered dose inhaler; a second species of active agent particles comprising formotero!, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension: medium at a concentration sufficient to provide a delivered dose of fermoteroi of between about 2 ug and about 10 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated microsfrueiures and a corticosteroid selected -from beelometbasone, budesonide, ciclesonide, Ifunisolide; fluticasone, methyl-prednisolone, niometasone, prednisone and tfimacinoione, including; any pharmaceutically acceptable salts, esters, Isomers or solvates thereof, wherein the suspending particles exhibit a volume median optical diameter of between about 1.5 pm and about TO pm and associate with the first and second species of active agent particles to form a co-suspension.

84. The pharmaceuticai composition according to ctalrn 83, wherein a ratio of the total mass of the suspending particles to the tofai mass of the first and second species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

65. A method for respiratory delivery of a combination of LAMA and LABA active agents to a patient, the method comprising; providing a metered dose inhaler comprising a canister containing a phami seeuticaily acceptable co-suspension comprising; a suspension medium comprising a pharmaceutically acceptable HFA propellant; a first species of active agent particles comprising giycopyrrolate, including pharmaceutically aceepiabie salts, esters, isomers or solvates thereof; a second species of active agent particles comprising fermoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and a plurality of respirable suspending particles, wherein the first and second species of active agent particles associate with the suspending particles; and actuating the metered dose inhaler to provide respiratory delivery of glycopyrroSate and formoterol to the patient at a DO0 of &amp; 20%, or better, throughout emptying of the canister.

66. The: method of claim 65, wherein actuating; the metered: dose Inhaler to provide respiratory delivery of giyeopyrfolate and fdrmoteroi to the patient comprises delivering the gtycopyrmlate .and formoterol at an initial fine particle fraction, and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle1 fraction,

67. The method of claim 66, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction,

68. The method of claim 87, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction,

69. A method for respiratory delivery of a combination of LABA and LAMA active agents to a patient, the method comprising; providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising; a suspension medium comprising; a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and a plurality of respirable suspending particles comprising formoterol, including pharmaceuticaily acceptable silts, esters, isomers or solvates thereof, wherein the plurality of active agent panicles associate with the plurality of suspending particles; and actuating the metered dose inhaler to provide respiratory delivery of giycopyrtoSais and formetersl to the patient at a DDU of ± 20%, or better, throughout emptying of the canister,

70, The method of claim SO, wherein actuating the metered dose inhaler to provide respiratory delivery of giycopyrrolaie and fermoteroi to the patient comprises delivering the giycopyrrolate and formoieroi at an initial fine particle fraction, and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained such that, throughout emptying of the canister, the fine particle fraction delivered from the metered1 dose inhaler is maintained within 80% of the initial fine particle fraction.

71. The method of claim 70, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler Is maintained within 90% of the inifiai fine particle fraction.

72, The method of claim 71, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose Inhaler Is maintained within 95% of the initial fine particle fraction,

73. A method for respiratory delivery of a combination of LAMA, LABA and corticosteroid active agents to a patient, the method composing; providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium: comprising a pharmaceutically acceptable HFA propellant; a first species of active agent particles comprising giycopyrroiate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; a second species of active agent particles comprising formoteroi, (deluding pharmaceutically acceptable salts, esters, isomers or solvates thereof; a third species of active agent particles comprising a corticosteroid selected from beclomethasone, budesonide, detesonide, flunisoiide, fluticasone* methyl-prednisolone, mometasone, prednisone and trimacinolpne, Including any pharmaceutically acceptable salts, esters, isomers or solvates thereof; and •a plurality of respirable suspending particles, wherein the first, second arid third species of active agent particles associate with the suspending particles; and actuating the metered dose inhaler to provide respiratory delivery of giyeopyrrolate, formoteroi and the coreticosterold active agent to the patient at a DDU of ± 20%, or better, throughout emptying of the canister.

74. The method of claim 78, wherein actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate, formoteroi and the corticosteroid active agent to tie patient comprises delivering the glycopyrrolate, formoteroi and corticosteroid active agent at an initial fine particle fraction, and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained such that, throughout emptying of the canister, the fine particle traction delivered from the metered dose inhaler is maintained within 80% of the initial fine particie fraction.

75. The method of claim 74, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particie fraction.

76. The method of claim 75, wherein, throughout emptying of the canister, the fine particie fraction delivered from the metered dose inhaler is maintained within 85% of the initial fine particie fraction,

77. A method for respiratory delivery of a combination of LAMA, LABA and corticosteroid active agents to a patient, the method comprising; providing a metered dose inhaler comprising a; canister containing a pharmaceutically acceptable co-suspension oomphsing: a suspension medium comprising a pharmaseuticaliy acceptable HFA propellant; a first species of active agent particles comprising glycopyrrolate, Including pharmaceutically acceptable salts, esters, isomers or solvates thereof; a second species of active agent particles comprising formoteroi, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and a plurality of respirable suspending particles comprising a corticosteroid selected from beclomethasone, budesonide, ciciesonide, fiunssoiide, fluticasone, methyl-prednisolone* momeiasone, prednisone and frimaciridione, including any pharmaceutically·' acceptable salts, esters, isomers or solvates thereof, wherein the plurality of active agent particles associate with the first and second species of suspending particies; and actuating the metered dose inhaler to provide respiratory delivery of giycopyrrolate, formoterol and the coroticosferoid active agent to the patient at a DDU of ± 20%, or better, throyghout emptying of the canister.

78. The method of claim 77, wherein actuating the metered dose inhaler to provide respiratorydelivery of giycopyrrolate, formoterol and the corticosteroid active agent to the patient comprises delivering trie giycopyrrolate, formoterol arid corticosteroid active agent at an initial fine particiefraciion^and trie Initial fine particle fraction delivered from the metered dose inhaler is substantially maintained such that, throughout emptying of the canister, the fine particle fraction delivered 'from trie metered dose inhaler Is maintained within 80% of the initial fine particle fraction. 79. trie method of claim 78, wherein, throughout emptying of the canister, the fine particle fraction delivetid from trie metered dose inhaler is maintained within 90% of the initial fine particle fraction.

80. Trie method of Claim 79, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine parade fraction.

81. A method for preparing a composition suitable for respiratory deiivery of a combination of .LAMA and IAEA active agents to a patient via an metered dose inhaler, the method comprising; providing a suspension medium comprising a pharmaceuticaiiy acceptable HFA propellant; providing a first species of active agent particles comprising glycopyrroiate, including pharmaceuticaiiy acceptable seifs, esters, isomers or solvates thereof; providing a second species of active agent particles comprising formoteroi, including pharmaceutically acceptable salts, esters, Isomers or solvates thereof; providing a plurality of respirable suspending particles; and cbm hiding the suspension medium, trie first and second species of active agent particies, and the plurality of respirable suspending particles such that the first and second species of active agent particles associate with the suspending particies to form a co-suspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle side distribution characteristics, the- delivered dose uniformity, end the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose Inhaler are within ± 20% of those achieved by a comparable formulation including only one of glyeopyrroiate or fosTnoteroi.

82, The method of claim 81, wherein the method comprises combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the first and second species of active agent particles associate with the suspending particles·, to form a co-suspension and for each of the active agents Included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ± 15% of those achieved by a comparable formulation including only one of glyeopyrroiate or formoterol.

83, The method of claim 81, wherein the method comprises combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the first and second species of active agent particles associate with the suspending particles to form a cosuspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within &amp; 1p% of those achieved by a comparable formulation including only one of glyeopyrroiate or formoterol.

84, A method for preparing a composition: suitable for respiratory delivery of a combination of LAMA and IAEA active agents to a patient via an metered dose inhaler, the method Comprising;: providing a suspension medium: comprising a pharmaceutically acceptable HFA propeilant; providing a plurality of active agent particles comprising glyeopyrroiate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; providing a plurality of respirable suspending particles comprising formoterol, including pharmaceutically acceptabie salts, esters, isomers or solvates thereof; and combining the suspension medium,, the: active agent particles, and; the plurality of respirable suspending partldes such that the active agent particles associate with the suspending particles to form a co-suspension and lor each of the active agents included in the co^suspensiohi one or more of the aerosol properties, the pa.rtici:e,:$:itev'distribuiidri characteristics:, the delivered dose uniformity, and the plasnw concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ± 20% of those achieved by a comparable formulation including only one of glycopyrroiate or forrnoteroL

85, The method of claim 84, wherein the method comprises combining the suspension medium, tie active agent particles, and the plurality of respirable suspending particles such that the active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the co^suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±15% of those achieved by a comparable formulation including only one of glycopyrroiate or formoteroi.

86, The method of Claim 84, wherein the method comprises combining the suspension medium, the active agent particles, and; the plurality of respirable suspending particles such that the active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±10% of those achieved by a comparable formulation including only one of glycopyrroiate or formoteroi.

87, A method for preparing a composition suitable for respiratory delivery of a combination of LAMA, LABA and corticosteroid active agents to a patient via an metered dose inhaler, the method comprising; providing a suspension medium comprising a phafmaceutlcaiiy acceptable HFA propellant; providing a first species of active agent particles comprising glycopyrroiate, including pharmaceuficaliy acceptable saits, esters, isomers or solvates thereof; pmysding a second species of active agent particles comprising formoteroi, including pharmaceuticsliy acceptable sails, esters, isomers or solvates thereof; providing a third species of active agent particles comprising a corticosteroid selected from; beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, imethyl-prednisolone, momeiasone, prednisone and tnmaeinofone, including any pharmaceutically acceptable salts; esters, isomers or solvatestherebf; providing a plurality of respirable Suspending particles; and combining the suspension medium, the first, second and third species of active agent particles, land the plurality of respirable suspending particles such that the first, second and third species of active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ± 20% of those achieved by a comparable formulation including only one of giycopyrrolate, formoteroi, or the corticosteroid,

88, The method of claim 87, wherein the method comprises combining the suspension medium, the first, second and third species of active agent particles, end the plurality of respirable suspending particles such that the first, second and third species of active agent particles associate with the suspending particles to farm a co-suspension end for each of active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within * 15% of those achieved by a comparable formulation including only one of glycdpyrroiate or formoteroi,

89, The method of ciaira 87, wherein the method comprises combining the suspension medium:, the first, second and third species of active agent particles, and the plurality of respirable suspending particles such that the first, second and third species of active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery Io the patient from the metered dose inhaler are within ± 10% df those achieved by a comparable formulation including only one of gfycopyrnolate, formoterol, erihe corticosteroid.

90. A method for preparing a composition suitable for respiratory delivery of a combination of LAMA, LA8A and corticosteroid active agents to a patient via an metered dose inhaler, the method comprising; providing a suspension medium comprising a pharmaceutlcaliy acceptable HFA propellant; providing a first species of active agent particles comprising: glycopyrroiate. including pharmaceutically acceptable salts, esters, isomers or solvates thereof; providing; a second species of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; providing a plurality of respirable suspending particles comprising a corticosteroid selected from bedomothasone,, budesonlde, cidesonide, fiunisoilde, fluticasone, methyl-predhisolone, mometssohe, prednisone and frimadnolone, including any pharmaceutically acceptable salts, esters. Isomers or solvates thereof; and combining the suspension medium* the first and second species of active agent particles, and the plurality of respirable suspending particles such that the first and second species of active agent particlesassociate with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the piasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler ana within ± 20% of those achieved by a comparable formuiahon including only one of glycopymolate, formoterol, the corticosteroid.

91. The method of claim 90s wherein the method comprises combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the active agent particles associaie with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, end the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose Inhaler are within ± 15% Of those achieved by a comparable formulation ineiuoing .only on© or glycopyrroiate, tormotero! or the corticosteroid. 92 The method of claim 80, wherein the method comprises combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the active agent particles associate with the suspending particles to form a co-suspension and tor each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, end the plasma concentration over time achieved by the eo-suspension upon delivery to the patient from the metered dose Inhaler are within ± 10% of those achieved by a comparable formulation including only one of giycopyrrolate, formoterol or fhb corticosteroid.