AU2015201221A1 - Compositions for respiratory delivery of active agents and associated methods and systems - Google Patents

Abstract

Abstract Compositions, methods and systems are provided for pulmonary or nasal delivery of active agents via a metered dose inhaler. In one embodiment, the compositions include a suspension medium, active agent particles, and suspending particles, in which the active agent particles and suspending particles form a co-suspension within the suspension medium.

Description

COMPOSITIONS FOR RESPIRATORY DELIVERY OF ACTIVE AGENTS AND ASSOCIATED METHODS AND SYSTEMS [0001] The present application is a divisional application of Australian Application No. 2010253770, which is incorporated in its entirety herein by reference. Technical Field [0001a] The present disclosure relates generally to pharmaceutical formulations and methods for delivery of one or more active agents via the respiratory tract. In certain aspects, the present disclosure relates to compositions, methods, and systems for pulmonary delivery of active agents via a metered dose inhaler. Background [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 environmentally friendly, such as perfluohnated compounds (PFCs) and hydrofluoroalkanes (HFAs).

[0005] The active agent to be delivered by an MDI is typically provided as a fine particulate dispersed within a propellant or combination of two or more propellants (ie. a propellant system"), In order to form the fine partculates, the active agent is typicaly micronized. Fine particles of active agent suspended in a propelant or propedant system tend to aggregate or flocculate rapidly This is particularly true of active agents present in ricronized fm in turn, aggregation or flocculation of these fine particles may complicate the delivery of the active agent. For example, aggregation or floc culation can lead to mechanical failures, such as those that might be 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 MDIs. More recently, solution approaches, such as those disclosed in US, Patent No. 6,964,759, have been proposed for MDI fornulations containing anticholinergics [0006] One approach to improve aerosol performance in dry powdeinhalers has been to incorporate fine particle carrier particles, such as lactose, Use of such fine excipients has not been investigated to any great extent for MDIs A recent report by Young et al, "The influence of micronized particulates on the aerosolization properties of pressurized metered dose inhalers"; Aeroso Science 40, pgs 324433 (2009), suggests that the use of such fine particle catersin MDIs actually result in a decrease in aeroso performance. [00071 In traditional CFC systems, when the active agent present in an MD formulation is solubilized within the propellant or propellant system, surfactants are often used to coatthe surfaces of the active agent in order to minimize or prevent the problem of aggregation and maintain a substantially unifom) 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 CFC systems are not effective in HFA and PFC propellant systems because such surfactants exhibit different solubility characteristics in non-CFC propellarts. Brief Description of the Drawings [00081 FIG is a graph, which depicts the partice size distribut on exhibited by an exemplary co-suspension composition according to the present descriptioT which 2 included glycopyrrolate, a longaacting muscarinic antagonist, as the active agent. Co-suspension MDls were subjected to temperature cycling conditions (alternating 6h hold time at -5 or 40 "C) for 12 weeks, [0009] FIG. 2 is a graph vhich depicts the partice size distribution exhibited by an exemplary co-suspension composition according to the present description, which included glycopyrrolate, a long-acting musca rini antagonist, as the active agent, Co-suspension MDis were subjected to temperature cycling conditions (alternating 6h hold time at -5 or 40 :C) for 24 weeks, [0010] FIG. 3 provides a nicrograph illustrating the morphologies of a variety of suspending particles prepared according to Exanple 5. [0011] FIG. 4 is a photograph of two vials that allows visuaization of a co suspension formed using active agent particles formed using glycopyrrolate and suspending particles formed using a saceharide [0012] FIG. 5 is a graph, which depicts the particle size distribution of an exemplary glvcopyrrolate co-suspension prepared according to the present description, containing 4,5 pg per actuation delivered dose of glycopyrrolate and 6mg/mL suspending particles and subjected to temperature cycling conditions (alternating 6h hold time at -5 or 40 *C), [0013] FIG. 6 is a graph, which depicts the particle size distribution of an exemplary glycopyrrolate co-suspension prepared according to the present description, containing 36 pg per actuation delivered dose of glycopyrrolate and 5mg/mL suspending particles and subjected to temperature cycling conditions (alternating 6h hold time at -5 or 40 *C), [0014] FIG. 7is a graph, which depicts the delivered dose through canister life of an exemplary glycopyrrolate co-suspension prepared according to the present description, containing 4.5 pg per auction delivered dose of glycopyrrolate and 6mg/mL suspending particles [0015] FIG. 8 is a graph, which depicts the delivered dose through canister life of an exemplary glycopyrrolate co-suspension prepared according to the present description, containing 36 pg per actuation delivered dose of glycopyrrolate and 6mg/mt suspending particles [0016] FIG. 9 is a graph, which depicts the particle size distribution of an exemplary glycopyrrlate co-suspension prepared according to the present description, containing 36 pg per actuation delivered dose of glycopyrrolate and 3 6mg/mL suspending particles and subjected to 12 months storage at 25C/60% RH unprotected, [0017] RG. 10 is a graph, which depicts the delivered dose through canister life of an exemplary glycopyrrolate cc-suspension prepared according to the present description, containing 32 pg per actuation delivered dose of glycopyrrolate and GSmg/mLt suspending particles and subjected to temperature cycling conditions (alternating 6h hold time at -5 or 40 "C0) [0018] FIG. 11 is a graph, which depicts the particle size distribution of an exemplary glycopyrrolate cc-suspension prepared according to the present description, containing 32 pg per actuation delivered dose of glycopyrrolate and Smg/rnL suspending particles and subjected to temperature cycling conditions (alternating 6h hold time at -5 or 40 "C) [0019] FIG. 12 is a graph, which depicts the parte size distribution of an exemplary glycopyrrolate co-suspension prepared according to the present description, containing 24 pg per actuation delivered dose of glycopyrrolate and 6mg/mL suspending particles and subjected to 6 weeks storage at 50 C/ambient relative humidity and 12 weeks at 40"C [00201 FIG, 13 is a photograph that allows visualization of co-suspension compositions prepared according to the present description which include formoterol funarate active agent particles, [0021] FIG. 14 is a graph, which depicts the derivered dose uniformity achieved by formoterol co-suspension compositions prepared according to the present description. [0022] FIG. 15 is a graph, which depicts the aerodynamic particle size distribution determined by cascade impaction of exemplary formoterol co-suspension compositions prepared according to the present description and stored for three months at 25 Q/ 75% RH, with protective overwrap, or at 40 C I 75%RH with protective overwrap. [0023] FIG. 16 is a graph, which depicts the chemical stability of exemplary co suspension compositions including crystalline formoterol as the active agent The results depicted in this figure allow comparison of the chemical stability of formoterol achieved in a co-suspension composition formulated using crystalline formoterol material with the chemical stability of suspension formulations prepared using spray dried formoterol fumarate. 4 [0024] FIG. 17 through FIG. 20 are electron rmicrographs of suspending particles prepared from various different materials, with Figure 17 providing a micrograph of tehalose suspending particles, Figure 18 providing a micrograph of HP I cyclodextrin suspending parties, Figure 19 providing a micrograph of FicolI MP 70 suspending particles, and Figure 20 provding a mnicrograph of inulin suspending particles. [0025] FIG. 21 provides a graph that depicts the aerodynamic particle size distribution determined by cascade impaction of exemplary cosuspension compositions prepared according to the present description and including glycopyrroiate active agent particles. [0026] FIG. 22 provides a graph that depicts the aerodynamic particle size distribution determined by cascade impaction of exemplary co-suspension compositions prepared according to the present description and inddding formoterol active agent particles. [0027] FIG. 23 provides a graph that depicts the delivered dose uniformity achieved by ulra low-dose formoterol co-suspension compositions prepared according to the present description. [0028 FIG. 24 is a graph which depicts the delivered dose uniformity of a co suspension formulation containing glycopyrrolate and formotero fumarate prepared according to the present description. [0029] FIG. 25 is a graph which depicts the delivered dose ratio of the co suspension formulation described in relation o FIG. 24, [00301 FIG. 26 is a graph which depicts the delivered dose uniformity of a second co-suspension formulation containing formoterol fumarate and glycopyrroate prepared according to the present description. [0031] FIG. 27 is a kph, vhich depicts the delivered dose ratio of the second co-suspension formulation described in relation to FIG 26 [0032] FIG. 28 is a graph, which depicts the dehvered dose uniformity of glycopyrrolate and formotero. fumarate n a co-suspension formulation prepared according to the present description upon storage under different conditions, as indicated. [00331 FIG. 29 is a graph, which depicts the parties size distribution of glycopyrrolate (top) and formoterol (bottom) in exemplary co-suspension 5 formulations prepared according to the present description upon storage under different conditions, as indicated, [0034] FIG. 30 provides graphs illustrating the partice size distribution of glycopyrroiate (top) and formoterol bottomn achieved by an exemplary co suspension upon storage at indicated conditions. [0035] FIG. 31 prides graphs illustrating the particle size distribution of glycopyrroiate (top) and formoterol (bottom) achieved by an exemplary duai co suspension compared to particle size distributions achieved by formulations including either glycopyrrolate or formoterol fumarate alone. [0036] HFK 32 is a graph that depicts the Tormoterol furnarate particle size distribution achieved by a o-susension prepared according to the present description, which included microcrysta I ine formoterol fumarate and glycopyrrolate active agent parties compared to a cosuspenrsion only containing crystaline formoteroi funmarate. [0037] FK. "3 is a graph that depicts the glycopyrrolate particle size distribution achieved by a dual co-suspension prepared according to the present description, which induded microcrystalline glycopyrrolate active agent parties and m icrocrystalline formoterol funa rate active agent particles with two different particle size distributions (denoted "fine" and "coarse") or spray dried formoterol fumarate. [0038] FIG, 34 is a graph that depicts the fornoterol fumarate particle size distribution achieved by a second dua co-suspension prepared according to the present description, which included microcrystal line formoterol turnarate and microcrystalline glycopyrrolate active agent parties cornpared to one that contained microcrystalline glycopyrrolate active agent panicles and spray dried formoterol fumarate particles. [0039] FIG. 35 is a graph, which depicts the de'vfered dose uniformity of glycopyrroate and formaoterol fumarate in an exemplary dual co-suspension formulation prepared according to the present description [0040] FIG. 36 depicts the delivered dose uniformity for each active agent included in an exemplary triple co-suspension composition, which included microcyrstalline gl ycopyrrolate, fornoterol funarate and mometasone furoate active agent particles. [0041] FIG. 37 is a graph depicting the formoterol fumarate aerodynamic partic e size distributions achieved in a triple co-suspension prepared according to the 6 present description, which included microcrystalline glycopyrrolate, formoterol fumarate and mometasone furoate active agent particles, compared to that achieved in a dual co-suspension which included glycopyrrolate and formoterol fumrate, [0042] FIG. 38 is a graph depicting the glycopyrrolate aerodynamic particle size distributions achieved in a triple co-suspension prepared according to the present description, which included n icrocrystalIine gIycopyroiate, formoterol fumarate and mometasone furoate active agent particles compared to that achieved in a dual co suspension which included glycopyrrolate and formoterol funarate. [0043] FIG. 39 is a graph depictng the glycopyrrolate and tiotropium bromide aerodynanic particle size distributions achieved by a triple co-suspension prepared according to the present description, which in addition to either glycopyrrolate or tiotropium bromide included formoterol fu ma rate and mometasone furoate rnicrocrystalliine active agent particles. Detailed Description [00441 The present disclosure provides compositions, methods, and systems for respiratory delivery of one or more active agents. In particular embodiments, the compositions described herein are formulated for pulmonary delivery of one or more active agents via an MDL, In other embodiments, the compositions described herein may be formulated for nasal delivery via an MDI. The methods described herein include methods of stabilizing formulations including one or more active agents for respiratory delivery, as well as methods for pulmonary delivery of active agents. In specific embodiments, the methods described hereininude methods of stabilizing formulations including one or more active agents having specific characteristics, such as potent and highly potent active agents and active agents with particular solubility characteristics In other embodiments, the methods described herein include methods of achieving delivery of such active agents to a patient Also described herein are systems for pulmonary delivery of one or more active agents with specific embodiments of such systems including an MDI system utilizing a composition as described here in. [00451 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 7 embodiments the compositions, methods and systems described herein can be used to treat patients suffering from a disease or disorder selected from asthma, chronic obstructive pulmonary disease (COPD) exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory d stress syndrome, pulmonary hypertension, pulmonary vasoconstriction and any other respiratory disease. condition, trait, genotype or phenotype that can respond to the administration of, for example, a LAMA, LABA corticosteroid, 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 obsb -uction associated with cystic fibrosis, As used herein, the terms 'COPif and "chronic obstructive pulmonary disease" encompass chronic obstructive lung disease (COLD) chronic obstructive airway disease (GOAD), chronic airflow limitation (CAL) and chronic obstructive respiratory disease (CORD) and include chrorcbronchitis bronchiectasis, and emphysema. As used herein, the term "asthma" refers to asthma of whatever type or genesis including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, rild 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 [0046] It will be readily understood that the embodiments, as general described herein, are exemplary, The following more detailed description of various embodiments is not intended to limit the scope of the present disclosure, bt is merely representative of various embodiments 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. Definitions [0047] Unless specifically defined otherwise, the technical terms as used herein, have their normal meaning as understood in the art, The following temis are specific ly defined for the sake of clarity. 8 [0048] 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 huran or animal for any purpose, including therapeutic, pharmaceutical, pharmacological, diagnostic, cosmetic and prophylactic agents and irumunomodulators, The term "active agent" may be used interchangeably with the sterns, . , rutance or "therape utic," temsdrug) "pharmaceuticala" "medicament, "drug subsac rteaetc As used herein the "active agent" may also encompass natural or homeopathic products that are not generally considered therapeutia [0049] The terms "associate," 'associate with" or "association" refers to an interaction or relationship between a chemical entity, composition, or 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, Lfshitz-van der Waals interactions and polar interactions. The term "adhere"or "adhesion" is a form of association and is used as a genere ten 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 condiIons, In one embodiment, a particle that attaches to or binds to a surface is encompassed by the term "adhere) Normal condions 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 fiocculates thereof due to differences in buoyancyithin a propellant [0050] "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 transport of active agent to the target site of delivery, ie 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 to achieving a desired suspension stability or active agent delivery performance. Exemplary suspending particles include particles that exhibit a particle size that facilitates 9 respiratory delivery of active agent and have physical configurations suited to formulation and delivery of the stabilzed suspensions as described herein, [0051] The term "co-suspension" refers to a suspension of two or more types of particles having different composions within a suspension medium, wherein one type of particle associates at least partially with one or more of the other particle types. The association leads to an observable change in one ormore characteristics of at least one of the individual particle types suspended in the suspension medium, Characteristics modified by the association may include, for example, one or more of the rate of aggregation or flocculation, the rate and nature of separation, ise. sedimentation or creaming, density of a cream or sediment layer, adhesin to container walls adhesion to valve components, and rate and the level of dispersion upon agitation, [0052] Exemplary methods for assessing whether a co-suspension is present can include the flowing: if one particle type has a pyonometric density greater than the propellant 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 'pycnometric 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 vil, for visual 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 single layer a co-suspension is present, The term tco-suspension" includes partial co-suspensions, where a majority of the at least two particle types associate with each other, however, some separation (i.e. less than a majority) of the at least two particle types may be observed, [0053] 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, ie. all sediment or all cream, the presence of a co-suspension can be determined by measuring other characterstics of the suspension, such as rate of aggregation or flocculation, rate of separation, density of cream or sediment layer, adhesion to container wals 10 adhesion to valve components, and rate and level of dispersion upon agitation, and comparing them to the respective characteristics of the similarly suspended individual particle types. Various analytical methods generally known to those skilled in the art can be employed to measure these characteristics. [0054] In the context of a composition containing or providing respirable aggregates, particles, drops, etc., such as compositions described herein the term fine particle dose" or "FPD" refers to the dose, either ini 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 vitr to be the dose that deposits beyond the throat stage of a cascade impactor, ie, thesum of dose delivered at stages 3 through filter in a Next Generation lmIpactor operated at a flow rate of 30 1/mmr [00551 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 "FPF" refers to the proportion of the delivered material relative to the delivered dose(e. the amount that exits the actuator of a delivery device, such as an IDI) that is within a respirable range. The amount of 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 eg., the sum of the material delivered at stages 3 through filter in a Next Generation Impactor operated at a flow rate of 30 1/rnin. [0056] 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 temi "inhibit" or any form thereof, is used in its broadest sense and includes minimize, prevent, reduce, repress, suppress, curb, constrain, restrict, slow progress of and the ike. [00571 "Mass median aerodynamic diameter" or "MMAD" as used herein refers to the aerodynamic diameter of an aerosol below which 50% ofthe mass of the aerosol consists of particles with an aerodynamic diameter smaler than the MMAD, with the MMAD being calculated according to monograph 601 of the United States Pharmacopeia CUSP"T [0058] When referred to herein, the term "optical diameter" indicates the size of a particle as measured by the Fraunhofer diffraction mode using a laser diffraction particle size analyzer equipped with a dry powder dispenser (e,g., Sympatec GmbH, Clausthal~ellerfeld. Germany). 11 [0059] "The term solution mediated transformation refers to the phenomenon in which a more soluble form of a sold material (ie. particles with small radius of curvature (a driving force for Ostwald ripening), or amorphous material) dissolves and recrystallizes into the more stable crystal form that can coexist in equilibrium with its saturated propellant solution. [0060] A 'patient" refers to an animal in which one or more active agents as described herein will have a therapeutic effect: In one embodiment the patient is a human being. [0061] "Perforated microstructures" refer to suspending particles that include a structural matrix that exhibits defines or comprises voids, pores, defects, hollows spaces, interstitial spaces, apertures, perforations or holes that allow the surrounding suspension medium to permeate, fill or pervade the microstructure, such as those materials and preparations described in US, Patent No. 6309623 to Weers, et al,, which is incorporated herein by reference in its entirety; The primary form of the perforated microstructure 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 holow porous, spray-dried microspheres However> collapsed, corrugated, deformed or fractured particulates of any primary form or aspect ratio may also be compatible. [0062] As is true of suspending particles described herein, perforated microstructures may be formed of any biocompatible material that does not substantially degrade or dissolve in the selected suspension medium While a wide vaiety of materials may be used to fom the panicles, in so e embodiments, the structural matrix is associated with, or includes, a surfactant such as, a phospholipid or fluorinated 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 preparation of the suspension. [0063] 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 hereinincudes propelant As used herein, the term "propellant" refers to one or more pharmacologically inert 12 substances which exert a sufficiently high vapor pressure at normal room temperature to propel a medicament from the canister of an MDI to a patient on actuation of the MDI's metering valve. Therefore, the term "propellant" refers to both a single propellant and to a combination of twor more different propellants forming a "propellant system," [0004] The term respirablee" generally refers to particles, aggregates, drops, etc sized such that they can be inhaled and reach the airways of the lung, [0065] When used to refer to co-suspension compositions described herein, the terms physicall stability" and "physically stable" refer to a composition that is resistant to one or more of aggregation, floccuation, and particle size changes due to solution mediated transformations and is capable of substantially maintaining the MMAD of suspending particles and the fine partic.e dose, In one embodiment, physical sta bilty may be evacuated through subjecting compositions to accelerated degradation conditions, such as by temperature cycling as described herein. [0066] When referring to active agents, the term potent" indicates active agents that are therapeuticaly 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, [0067] When referring to active agents, the term "highly potent" indicates active agents that are therapeuticallynefective at or below doses of about 10 pg/kg. Typical doses of highly potent active agents generally range up to about 100 pg. [006a] The terms "suspension stability- and "stable suspension" refer to suspension formulations 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. [0069] The term -substantially insoluble" means that a compositions 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 insouble"includes the definitions of "slightly soluble" (from 100 to 1000 parts solvent per I 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 salute) as given in 13 Table 16 1 of Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott, Williams & Wilkins, 2006, p. 212. [0070] The term "surfactant, as used herein, refers to any agent which preferentially adsorbs to an interface between two immiscilIe phases, such as the interface between water and an organic polymer solution a water/ai interface or organic solvent/air interface. Surfactants generllypossess 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 I some embodiments, surfactants may also promote adsorption of a drug and increase boavailability of the drug, [0071] 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 prophylactically inhibiting or 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; retums to normal either partially or completely one or more physiiogical or biochemical parameters associated with or causative of the disease or disorder; and/or reduces thelikelihood of the onset of the disease of disorder. [0072] The terms "chemically stable" and "chemical stability" refer to co suspension formulations where in the individual degradation products of active agent remain below the limits specified by regulatory requirements during the shelflife of the product for human use (e~g, i% of total chromatographc peak area per IOH guidance 03B(R2)) and there is acceptable mass balance (e.g., as defined in ICH guidance Q1E between at ive agent assay and total degradation products. Composiions [0073] The compositions described herein are co-suspensions that include a suspension medium including a propellant, active agent particles, and suspending particles, Of course, if desired, the compositions described herein may include one or more addional constituents Moreover, variations and combinations of components of the compositions described herein may be used. For example, the active agent particles included in the co-suspension formulations may include two or more active agents, or two or more different species of active agent particles may be used, with each different species of active agent particle ndudio one or more different active agents. Alternatively, two or more species of suspending particles 14 may be used in conpositions for the delivery of one or more active agents or active agent particles. Even further, for example, the compositions may include an active agent disposed within the material forming a suspending particle and another active agents) co-suspended as active agent particles with the suspending particles, [0074] It has been found that, in formulations according to the present description, active agent parties exhibit an association with the suspending parties such that separation of the active agent parties from the suspending particles is substa ntiially prevented, resulting in co-location of active agent particles and suspending particles within the suspension medium. Generally, due to density differences between district species of particles and the medium within whch they are suspended (e.g., a propellant or propellant 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 particles with different density or different tendencies to flocculate, sedimentation or creaming behavior is expected to be specific to each of the different particle types anid expected to lead to separation of the different particle types within te suspension medium. [0075 However, the combinations of propellant, active agent parties and suspending particles described herein provide co-suspensions wherein active agent particles and suspending particles co-locate within the propellant (i e., the active agent particles associate with the suspending paricles such that suspending particles and active agent particles do not exhibit substantial separation relative to each other, such as by differential sedimentation or creaming, even after a time sufficient for the formation of a cream or sedment layer). In particular embodiments for 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 andlor centrifugation at accelerations up to an oer, for example, I g, 10 g, 5 g, 50 g and 100g, However, the co-suspensions described herein are not 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 vthin the continuous phase formed by the suspension medium under typical patient use conditions. 15 [0076] Co-suspensions of active agent particles and suspending particles according to the present deseption provide desirable chemical stabiity suspension stabilty, and active agent delivery characteristics. For example, in certain embodiments, when present within an MDi canister, co-suspensions as described herein can inhibit or reduce one or more of the following: flocculation of active agent material: differential sedimentation or creaming of active agent parties an suspending particles; solution mediated transformation of active agent material; 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 formulation is delivered fom an MDI such that desirable fine particle fraction, fine particle dose and delivered dose unifomity characteristics are achieved and substantially 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 stable formulation that provides consistent dosng characteristics, even for potent and highly potent active agents, while utilizing a relatively simple HFA suspension medium that does not require modification by the addition of, for example, cosolvents, antisolvents, solubilizing agents or adjuvants [00771 Providing a co-suspension according to the present description may also simplify formulation, delivery and dosing of the desired active agents. Without being bound by a particular theory, it is thought that by achieving a co-suspension of active agent particles and suspending parades, the delivery, physical stability, and dosing of an active agent contained within such a dispersion may be substantially controled 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, n specific embodiments, the pharmaceutical compositions described herein can be formulated with a non-CFC propellant or propellant system substantially free of antisolvets, solubilizing agents, cosoivents, or adjuvants. [0078] Co)suspension compositions formulated according to the present teachings can inh.ibit physical and chemical degradation of the active agents included therein. For example, in specific embodiments, the compositions described herein nay inhibit one or more of chemical degradation flocculation, aggregation and solution mediated transformation of the active agents included in the 16 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 unitormty throughout emptying of an MDI canister CDDU"), even where the active agents to be delivered are highly potent and delivered at very low doses, [0079] Co-suspension compositions as described herein 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 betters 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 rnore, of the original FPF or FPD performance, even after being subjcted to accelerated degradationconditions [0080] Co-suspension compositions described herein provide the added benefit of achieving such performance while being fomulated using non-CFC propellants. In specific embodiments, the compositions described herein achieve one or more of a targeted DDU, FPF or FPD, while being formulated with suspension medium including only one or more non-CFC propellants and without the need to modify the characteristics of the non-CEO propelant, such as by te addition of, for example, one or more cosolvent, antisolvent, soubilizing agent, adjuvant or other propellant modifying material. Suspension Medium [0081] 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 propellant gases that can be liquefied under pressure at room temperature, and upon inhalation or topical use, are safe and toxicologically innocuous, Additionally, it is desirable that the selected propellant be relatively non-reactive with the suspending particles or active agent particles, Exemplary compatible propellants include hydrofluoroalkanes (HFAs), perfluorinated compounds (PEs) and chlorofuorocarbons (CFCs) 17 [082] Specific examples of propellants that may be used to form the suspension rnedium of the co-suspensions disclosed herein include 1 1 2~ttrafiuoroethane (CCH12F) (HFA-i 34a), 11A1 ,23,3 eptafkuoronropane (CFCHFCFa) (HFA 22, perfluoroethane monochloro-ucromethe, 1 d ifluoroethan&S, and combinations thereof. Even further, suitable propelants include, or example: short chain hydrocarbons; C hydrgen-containing chlorofluorocarbons such as OHg 2 0F CCl: PCHCIF. CP 3 CHCiPF CHP 2 C , CHCIFCHF 2 CPCHaC0 and CCW~CH: Ca hydrogen-containing fluorocarbons (e-g, HFAs) such as CHF 2 CHF2 CF aCHY,

CHF

2

CH

3 , and CF 3 CHFCF; and perfluorocarbons such as CFCF and CFCF 2

CF

3 . [008$] Specii fluorocarbons, or classes of fluornated compounds, that may be used as suspension media include, but are not limited to, fluoroheptane, fluorocycloheptane, flioromethylcycloheptane, fluorohexa ne, fluorocyclohexane, fluoropentane, fluorocyclopentane, fluoromethylcycopentane, fluorodimethy cyclopentanes, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorotrirnethyl cycdobuta n e fluorobuta ne, fiuorocyclobutane I uoropropane, fluoroethers, fluoropolyetters and fluorotriethylaniines These compounds may be used alone or in combination with more volatile propellants. [00841 In addition to the aforementioned fluorocarbons and hydrofluoroalkanes, various exemplary chloroffuorocarbons and substituted fluorinated compounds may also be used as suspension media. In this respect, FC- I1 (CCI 3 F), FC8I 1 (CBrCGiP) FC-11B2 (CBr2 F FC12B2 (C'Cr4 P021 (CHOLF), FC21B1 (CHBrCIF), FC21B2 (CHBr 2 F), F-31B1 (CH 2 BrF), FC13A (CCCF) FC-122 (CCIFCHCI), FC-123 (CFCHC14 FC-132 (CHCIFCHCPF) FC133 (CHCIFCHP4) FC-141 (CHuCICHCiF PC-141B (CCLFCH) FC442 (CHFFCH 2 ) FP$151 (CH FCHCI} FC12 (CH 2

FCH

2 F), PCI112 (CCIF*CCIF), FCi 121 (CHCl=CFCI) and FC-1131 (HCI=CHP) 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. [00851 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 physical characteristics selected to improve stability or enhance the 18 bioavailability of the dispersed active agent. In some embodiments, the lower vapor pressure compounds will comprise fluoinated compounds (eug., fluorocarbons) having a boiling point greater than about 25T, In some embodiments, lower vapor pressure fluorinated compounds for use in the suspension medium may include perfluorooctylbromide CFiBr (PFOB or perflubron, dichlorofluorooctane CsFiP perfluorooctylethane OFtCH (PFOE, perfluorodecylbroride CNFBr (PFDB) or perfluorobutylethane C 4 FK~tH In certain embodiments, these lower vapor pressure compounds are present in a relatively low levels Such compounds may be added directly to the suspension medium or may be associated with the suspending particles, [0086] In some embodiments, the suspension medium may be formed of a propellant or propellant system that is substantially free of additional materials, including, for example, antisolvents, solubilizing agents, cosolvents or adjuvants. 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, additional materials such as, fr example, one or more of an appropriate antisolvent, solubilizing agents, cosolvent or adjuvant may be added, for example, to adjust vapor pressure stability; or solubility of suspended particles. For example, propane, ethanol, isopropyl alcohol butane, isobutane, pentane, isopentane or a dialkyl ether, such as dirnethyl ether may be incorporated with the propellant in the suspension medium, Similarly, the suspension medium may contain a volatile fluorocarbon, In other embodiments, one or both of polyvinyipyrrolidone ( PVPr) or polyethylene glycol ("PEG") 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 generalwhere used, up to about 1% wvw of the propellant may comprise a volatile cosolvent or adjuvant such as a hydrocarbon or fluorocarbon. In other embodiments, the suspension medium may comprise less than about 0.01%, 0.1%, or 0.5% w/w cosovent or adjuvant. Where PVP or PEG are included in the suspension medium, such constituents may be included atup to about 1% w/w, or they may comprise less than about 001 %, 0. 1%, or 0.5% w/w of the suspension medium. Active anent particles 19 [0087] 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 respite 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 acted agent particles by volume exhibit an optical diameter of about 7 pm or less. ln other embodiments the active agent particles are provided as a micronized material wherein at east 90% of the active agent particles by volume exhibit an optical diameter selected from a range of about 7 pm to about 1 pm, about 5 pm to about 2 pm, and about 3 pm to about 2 pm In further embodiments, the active agent particles are provided as a micronized material wherein at least 90% of fthe 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 m or less. r another embodiment, the active agent particles are provided as a micronized material 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 micronized material wherein at least 50% of the active agent particle material by volume exhibits an optical diameter selected from about 3 pm or lessabout 2 pm or less, about 1.5 pm or less. and about 1 pm or less, In still further embodiments, the active agent particles are provided as a rrcronized material wherein at least 50% of the active agent parties by volume exhibit an optical diameter selected from a range of about 4pm to about 1 pm, about 3pm to about I pm, about 2 pm to about 1 pm, about 1.3 pm , and about 1..9 pm, [00881 The active agent particles may be formed entirely of active agent or they may be formulated to include one or more active agents irNcombination wth one or more excipients or adjuvants. In specific embodiments, an active agent present in the active agent present in the active agent particles may be entirely or substantially crystalline, In another embodiment the acive agent partcles may include an active agent present in both crystal and amorphous states, In yet another embodiment, the active agent particles may include an ative agent present in substantially an amorphous state. In yet a further embodiment, where two or more active agents are present in active agent particles, at least one such active agent may be present in crystalline or substantial crystalline form and at least another active agent may be present in an amorphous state. In still another embodiment, where two or more active agents are present in active agent particles, each such active agent may be 20 present in crystalline or substantially crystafline form. Where the active agent particles described herein include one or more active agents in combination with one or more excipients or adjuvants, the excipients and adjuvants can be selected based on the chemical and physical properties of the active agent used. Moreover, suitable excipients for formulation of active agent partcles include those described here in association with the suspending particles, I specific embodiments, for example the active agent particles may be formulated with one or more of the lipid, phospholipid carbohydrate, amino acid, organic salt, pept ide, protein, a:lditols, synthetic or natural polymer, or surfactant materials as described for example, in association with the suspending particles. [0089] In other embodiments including two or more active agents, at least one of the active agents is included in active agent particles co-suspended with suspending particles, while at least one other active agent may be included in suspending particles utilized in the co-suspension. For example, one or more active agents may be added to a solion of one or more of the lipidphospholipit carbhydrate, amino acid, organic salt, peptide, protein alditols, synthetic or natural polyme, or surfactant materials and spray-dried to form one or more different species of suspending particle that contain the active agent within the material forming the suspending particle, [0090] Any suitable process may be employed to achieve micron ized active agent material for inclusion in the compositions described herein A variety of processes may be used to create active agent particles suitable for use in the co-suspension formulations described herein, including, but not limited to, micronization by milling or grinding processes, crystallization or recrystallization pocesses, and processes using precipitation from supercriticai or near-supercritical solvents, spray drying, spray freeze drying or lyophilization. Patent references teaching suitable methods for obtaining micronized active agent partcles include, for example, in U.S Patent No 6,063,138, US. Patent No. 5,858,410, U.S Patent No, 525453 US Patent No. 5,833,91, US, Patent No. 5, 707634, and International Patent Publication No, WO 2007/009164. Where the active agent particles include active agent material formrulated with one or more excipient or adjuvant, micronized active agenf particles can be formed using one or more of the preceding processes and such processes can be utilized to achieve active agent particles having a desired size distribution and particle configuration. 21 [0091 Trhe active agent particles may be provided in any suitable concentration within the suspension medium. The active agent included in the active agent particles is substantially insoluble in the suspension medium, in some embodiments the active agent, despite being substantially insoluble, exhibits measurable solubility in the suspension medium. However, even where the active agent exhibits measurable solubility in the suspension medium, the compositions described herein work to preserve the physical stabibty of such active agents. In particular, in specific embodiments, an active agent included in the compositions descnbed herein may exhibit sufficient solubility in the suspension medium such that as much as 5% of the total active agent mass dissoles in the suspension medium. Alternatively the solubility of an active agent may result in dissolution of as much as 1% of the total active agent mass in the suspension rnedium. In another embodiment. the of an active agent may result in dissolution of as much as 0,5% of the total active agent mass in the suspension medium. In yet another embodiment, the solubility of an active agent may result in dissolution of as much as 005% of the total active agentmass in the suspension medium. in still another embodiment, the solubility of an active agent may result in dissolution of as much as 0.025% of the total active agent mass in the suspension medium, [0092] A variety of therapeutic or prophylactic agents can be incorporated into the co-suspension compositions disclosed herein. Exernplary 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 (eg. is substantially insoluble or exhibits a solubilty in the suspension medium that substantially maintains a co-suspension formulation), is capable of forming a co-suspension with the suspending particles, and is subjeto respirable uptake in physiologically effective amounts. The active agents that May be utilized in forming the active agent particles described herein canhave a variety of biological activities. [0093] 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., bitolterol carbuterol. fenoterol. hexoprenalinel isoprenalne (isoproterenol), levosalbutamol, orciprenalne (metaproterenoi pirbuterol, procaterol, rimitero, salbutamol (albuterol) terbutaline, tulobuterol, reproterol, ipratropium and 22 epinephrine, longBactng2 adrenergic receptor agonist (LABA"), eig., bambuterol, clenbutero, formoterol, and salmeterol; ultra long-acting O adrenergic receptor agonists, e g, carmoterol, milveterol, indacaterol and saligenin- or indole containing and adamantyl-derived ?agonists; corticostero ide, e g., beclomethasone budesonide ciclide, de, flunisobde fluticasone, methylprednisolonermometasone, prednisone and trimacinolone; antinflammatories, e.g. fluticasone proponate, beclomethasone dipropionate, fiunisoflide, budesonide, tripedane, cortisone, predenisone, prednisilone, dexamethasone. betamethasone, or triamcinolone acetonide; antitussives, e.g, noscapine bronchodilators, e.g,, ephedrine, adrenaline, fenoterol. formoteroisoprenaline, metaproterenol, salbutamol. albuterol, salmeterol, terbutaline; and muscarinic antagonists, including long-acting muscariric antagonists (IAMA"), eg., glycopyrrolate. dexipirronium. scopolmine tropical ide, pirenzepine, dimenhydrinate, tiotropium, darotropium, acidinium, trospium, ipatropium, atropin, benzatropin, or oxitropium. [0094] Where appropriate, the active agents provided in the composition including but not limited to those specifically described hereinmay be used in the form of salts (e g., alkali metal or amine salts or as acid addition salts) or as esters solvates (hydrates), derivatives, or a free base thereof. Additionally, the active agents may be in any crystalline 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 stability of the active agent and/or to minimize the solubility of the active agent in the suspension medium. [0095] Because the compositions disclosed enable the reproducible delivery of very low doses of active agents, in certain embodiments, the active agent included in the compositions described herein may be selected from one or more potent or highly potent active agents, For example, in certain embodiments, the compositions described herein may include one or more potent active agents that are to be delivered at a (lose seated frorn between about 100 pg and about 100 mg, about 100 pg and about 10 mg, and about 100 pg and I mg per actuation of an MDL In other embodiments, the compositions described herein may include one or more potent or highly potent active agents that are to be delivered at a dose selected from up to about 60 pg, up to about 40 pgup to about 20 pg, or between about 10 pg and about 100 pg per actuation of an MDI Additionally, in certain embodiments, the 23 compositions described herein may include one or more highly potent active agents ftat are to be delivered at a dose selected from between about 0.1 and about 2 pg, about 01 and about I pg, and about 0, and about 0 5 pg per actuation of an MDI [0096] A composition as described herein may. if desiredcontain a combination of two or more active agents. For example, a combination of two or more species of active agent particles may be co.suspended with a single species of suspending particles. Alternatively, a composition nay include two or more species of active agent particles co-suspended with two or more different species of suspending particles. Even further, a composition as described herein may include two or more active agents combined within a single species of active agent partice. 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 incIde individual particles that include two or more different active agents. [0097] In certain embodiments the active agent included in the compositions described herein is a LAMA active agent. Where the compositions include a LAMA active agent, in particular embodiments, the LAMA active agent may be selected from, for example, glycopyrrolate dexipirrortium tiotropium trospium, alidinium darotropium, including any pharmaceutical acceptable salts, esters, isomers or solvates thereof. [0098] Glycopyrrolate can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as, for example, those described herein. As an anticholinergic, glycopyrrolate acts as a bronchodilator and provides an antisecretory effect, which is a beneft for use in the therapy of pulmonary diseases and disorders characterized by increased mucus secretions. Glycopyrrolate is a quaternary arnmoniu salt. Where appropriate, glycopyrrolate 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) Additionaly, the glycopyrrolate may be in any crystalline form or isomeric form or mixture of isomernic forms, for example a pue enantiomer a mixture of enantiorners a racemate or a mixture thereof. In this regard. the form of glycopyrrolate may be selected to optimize the activity and/or stability of glycopyrrolate and/or to minimize the solubility of g ycopyrrolate in the suspension medium. Suitable counter ions are phamaceuticay acceptable counter ions including, for example, fluohde, chloride, bromide, iodide, nitrate, sulfate, phosphate, 24 formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hyd roxybenzoate, p-hyd roxybenzoate, Ihydroxynaphthalenet carboxylate, 3-hydroxynaphthalene%.carboxylate, methanesuifonate and benzenesulfonate. In particular embodiments of the compositlons described herein, the bromide salt of glycopyrrolate namely 3-[(cycopentyl.-hyd roxyp henylacetyI)oxy' 1dimethylpyrro idintium bromide, is used and can be prepared according to the procedukres set out in U.S, Pat, No. 2,956,062 [0O99] Where the compositions described herein include glycopyrrolate, in certain embodiments. the compositions rnay include sufcient glycopyrrolate to provide a target delivered dose selected from between about 10 pg and about 200 pg per actuation of an MIDI, about 15 pg and about 150 pg per actuation of an MDI, and about 18 pg and 144 pg per actuation of an MD In other such embodiments, the formulations include sufficient glycopyrrolate to provide a dose selected from up to about 200 pg, up to about 150 pg up to about 75 pg, up to about 40 pg, or up to about 20 pg per actuation. In yet further embodiments, the forrulations include sufficient glycopyrrolate to provide a dose selected from about 18 pg per actuation, 36 pg per actuation or about 72 pg per actuation. In order to achieve targeted delivered doses as described herein, where compositions described herein include glycopyrrolate as the active agent, in specific embodiments, the amount of glycopyrotate included in the compositions may be selected from, for example, between about 04 mg/mL and about 2.25 mg/mL [01001 In other embodiments, tiotropium. including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, may be selected as a LAMA active agent for inclusion in a composition as described herein. Tiotropium is a known, long acting anticholinergic drug suitable for use in treating diseases or disorders associated with pulmonary inflammation or obstruction such as those described herein. Tiotropiumincluding crystal and pharmaceutical acceptable salt forms of tiotropium, is described, to example, in US. Patent No. 5,610,163, US. Patent No. RE39820 U.S. Patent No. 6,777423, and U.S. Patent No. 6.908,928 Where the compositions described herein include tiotropium, in certain embodiments, the compositions may include sufficient tiotropium to provide a delivered dose selected from between about 2.5 pg and about 50 pg, about 4 pg and about 25 pg per actuation, and about 2.5 pg and about 20 pg, about 10 pg and about 25 20 pg and about 2.5 pg and about 10 pg per actuation of an MDL In other such embodiments, the formulations ndude sufficient tiotropium to provide a delivered dose selected from up to about 50 pg, up to about 20 pg, up to about 10 pg, up to about 5 pg, or up to about 2.5 pg per actuation of an MDL In yet further embodiments, the formulations olude sufficient tiotropium to provide a delivered dose selected from about 3 pg, 6 pg9pg, 18 pq, and 36 pg per actuation of the MD In order to achieve delivered doses as described hereia, where compositions described herein include lotropium as the active agent, in specific embodimeras, the amount of tiotropium included in the compositions may be selected from, for example between about 001 mg/mL and about 05 mg/mL. [0101] In certain embodiments, the compositions described herein include a LABA active agent, In such embodiments, a LABA active agent can be selected from, for example barmbuteroi cenbuterol, formoterol, salmeterol, carmoterol milveterol, indacaterol, and saligenin- or indole- containing and adamantykderived p agonists, and any pharmaceutical acceptable salts esters, isomers or solvates thereof In certain such embodiments, formoterol is selected as the LABA active agent. Forrnoterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as. for exampIe, hose described herein Formoterol has the chemical name (±)hydroxy 5 1RS1 -hydroxy2[[(1 RS)-2(4 methoxyph enylrnethyethyl] arminoethyi] formanilide, and is commonly used in pharmaceutical compositions as the racemic fumarate dehydrate salt Where appropriate, formoterol 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 fornioterol may be in any crystalline form or isomeric form or mixture of isomeric fonms, for example a pure enantiomer, a mixture of enantiomers, a racemate or a mixture thereof, In this regard, the form of formoterol may be selected to optiniize the activity and/or stability of formoterol and/or to minimize the solubility offormoterol in the suspension medium. Pharmaceutically acceptable salts of formoteroi include, for example, salts ofinorganic acids such as hydrochloric hydrobromic sulfuric and phosphoric acids, and organic acids such as funaric, maleic. acetic lactic, citric tartaric, ascorbic, succinia, glutaic, gluconic, tricarballylic, oleic, benzoic, p methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic. p-toluenesufonic and 3 hyoxy-naphthaene carboxylic acids Hydrates of formoterol are described, for example, in U.S. Pat, No, 3,994,974 and 26 U.S, Pat: No. 5643199 Specific crystaline forms of formoterol and other % adrenergic receptor agonists are described, for example, in WO9/05805, and specific isomers of formoterolare described in U.S Patent No. 6,040,344. [0102] In specific embodiments, the fomaoterol material uti zed to torm the formioterol particles is formoterol fumarate, and in one such embodiment, the formoterol fumarate is present in the dehydrate form Where the compositions described herein include formoterol, in certain embodiments the compositions described herein may ndlude formoterol at a concentration that achieves a targeted delivered dose selected from between about 1 pg and about 30 pg, about 1 pg and about 10 pg. about 2 pg and 5 pg, about 2 pg and about 10 pg, about 5 pg and about 10 pg, and 3 pg and about 30 pg per actuation of an MDL In other embodiments, the compositions described herein may include formoterol in an amount sufficient to provide a targeted delivered dose selected from up to about 30 pg; up to about 10 pg. 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. In order to achieve targeted delivered doses as described herein, where compositions described herein include fornoterol as the active agent, in specific errmbodiments, the amount of formoterol included in the compositions may be selected from, for example, between about 0.01 mg/mL and about 1 mg/mL, between about 0.01 mg/nt and about 0.5 mg/mL, and between about 0,03 mg/mL and about 0.4 mg/nt [0103] Where the pharmaceutical co-suspension compositions described herein include a LABA active agent, in certain embodiments, the active agent may be salmeterol, including any pharmaceutically acceptable salts, esters isomers or solvates thereof, Salmeterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as, for example, those described herein. Salmeterol phan-naceutically acceptable salts of salmeterol, and methods for producing the same are described, for example, in U.S. Patent No. 4,992,474, U.S. Patent No. 5,126,375, and U.S. patent 5,225,4 4 5 [0104] Where salmeterol is included as a LABA active agent, in certain embodiments, the compositions described herein may include salmeterol 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 pg and 20 pg about 8 pg and about 40 pg, about 20 pg and about 40 pg. and 12 pg and about 120 pg per actuation of an MDI. In other embodiments, the compositions described herein may 27 include salmeterol in an amount sufficient to provide a delivered dose selected from up to about 120 pg up to 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 MDL In order to achieve targeted delivered doses as described herein, where compositions described herein include salmeterol as the active agent in specific embodiments, the amount of salmeterol included in the compositions may be selected from, for example, between about 0.04 mg/mL and about 4 mg/mL, between about 0.04 mg/mL and about 2,0 mg/iL, and between about 0,12 mg/mL and about 0,8 mght For example, the compositions described herein may include sufficient salmeterol to provide a target delivered dose selected from between about 4 pg and about 120 pgabout 20 pg and about 100 pg, and between about 40 pg and about 120 pg per actuation of an MDL In still other embodiments, the compositons described herein may include sufficient saflmeterol to provide a targeted devered dose selected from up to about 100 pg, up to about 40 pg, or up to about 15 pg per actuation of an MDI. [0105] in still other embodiments; the compositions described herein indude a cort-icosteroid. Such active agents may be selected from, for example, beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methy prednisolone, nometasone, prednisone and trimacinolone Where the compositions include a corticosteroid active agent, in particular embodiments, mometasone may be selected. Mometasone, pharmaceutically acceptable salts of rnometasone, such as mometasone furoate and preparation of suct materials are known and described for example, in US, Pat No. 4,472,393, US. Pat, No. 5,86 200 and U.S. Pat. No. 6,177,560, Mometasone is suitable for use in treating diseases or disorders associated with pulmonary infIammation or obstruction, such as those described herein (see, e g., U.S, Pat No. 5,89,015, U.S. Pat No. 6,057,307, U.S. Pat. No. 6,057581, U.S Pat. No. 63677:322, US Pat. No ,677323 and U.S. Pat No. 6, 35,581) [0106] Where the compositions described herein include mometasone, in particular embodinents the compositions include mometasone, 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 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 00 pg. and about 50 pg and about 100 pg per actuation of an MDI. In still other embodiments, the compositions 28 described herein may ncdude mometasone indlding any pharmaceutica y acceptable saits, esters, isomers or solvates thereof, in an amount sufficient to provide a targeted delivered dose selected from up to about 400 pg, up to about 200 pg or up to about 100 pg per actuation of an MDL [0107] In other embodiments, the compositions described herein include a cortcosteroid elected from ft!uticasone and budesonidea Both fluticasonea aid budesonide are suitable for use in treatment of conditions associated with pulmonary inflammation or obstruction, such as those described herein. FIuticasone, pharmaceutically acceptable salts of fluticasone, such as fluticasone propionate, and preparation of such materials are known. and described for example in US. Pat No. 4,335,121, U.S,. Pat, No. 4,187,01, and US, Pat. Pub, No. US2008125407 Budesonide is also well known and described, for example, in U.S, Pat. No, 3.929,768 In certain embodiments, compositions described herein may include fluilcasone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, in an amount sufficient to provide a target delvered dose selected from between about 20 pg and about 200 pg, about 50 pg and about 17$ pg, and between about 80 pg and about 160 pg per actuation of an MDL In other embodimentshe compositions described herein may include fluticasone, including any pharmaceutical 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 include 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 MDL In still other embodiments, the compositions described herein may include budesonide, including any pharmaceutically acceptable seats, esters, isomers or solvates thereof in an amount sufficient to provide a targeted alive ad dose selected from up to about 240 pg, up to about 120 pg, or up to about 50 pg per actuation of an MDL [0108] The co-suspension compositions described herein can be formulated to include (and deliver) a single active agent Alematively, the co-suspension compositions descred herein may include two or more active agents, In particular embodiments, where two or more active agents are included, the compositions 29 described herein may include a combinaton of active agents selected from a combination of a LAMA and LABA active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA and corticosteroid active agents, In other embodiments, the cosuspension compositions described herein may include three or more active agents. In certain such embodiments, the composition includes a combination of actie agents selected from a combination of a LAMA, LABA and corticosteroid active agents. For example, a consuspension composition as described herein may include a combination of active agents selected from a combination of formoterol and budesonide, a combination of glycopyrrolate and forroteroK a combinaion of ciclesonide and formoterol a combination of budesonide and mometasone, a comibination of saimetero and fluticasone a conbination of glycopyrrolate, formoterol, and budesonide, and a combination of glycopyrroiste, formoterol, and mornmetasone [01091 With the aid of the present disclosure, it will be appreciated by those having skill in the art that a wide variety of active agents may be incorporated into the suspensions discosed herein. The above list of active agents is by way of example and not limitation. Susoendino particles [0110] 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 parties 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 respirable range. In particular embodiments, therefore, the MMAD of the suspending particles wil not exceed about 10 pm but is not lower than about 500 nm. In an alternative embodiment, the MMAD of the suspending particles is between about 5 pm and about 750 nm, In yet another embodiment, the MMAD of the suspending particles is between about 1 pm and about 3 urn When used in an embodiment for nasal delivery from an MDI, the MMAD of the suspending particles is between 10 pm and 50 pm [0111] In order to achieve respirable suspending particles within the MMAD ranges described, the suspending particles will typically exhibit a volume median optical diameter between about 0.2 pm and about 50 ,p. m In one embodiment, the 30 suspending particles exhibit a volume median optical diameter that does not exceed about 25 pm. In another embodiment, the suspending parties exhibit a volume median optical diameter selected from between about 0,5 pm and about 15 pm, between about I,5 pm and about 10 pm, and between about 2 pm and about 5 pm, [0112] 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 particles are included in the suspension medium at a concentration selected from about I mg/mL to about 15 mg/mb, about 3 mg/mL to about 10 mg/nib, 5 mg/mL to about 8 mgLand about 6 mg/mL, In another embodiment the suspending particles are included in the suspension medium at a concentration of up to about 30 mg/mL. In yet another embodiment, the suspending particles are included in the suspension medium at a concentration of up to about .25 mg/mL. [0113] The relative amount of suspending particles to active agent particles is selected to achieve a co-suspension as contemplated 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 suspend ing particles to the total mass of active agent particles may be between about 31 and about 15:1, or alternatively from about 2:1 and 8.1 Altematively, 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 15, up to about 5, up to about 10, up to about 15, up to about 17, up to about 20, up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150, and up to about 200, depending on the nature of the 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 particles may be selected from between about 10 and about 200, between about 60 and about 200, between about 15 and about 60, between about 15 and about 170, between about 15 and about 60, about 1 6 about 60, and about 170. [0114) In other embodiments, the amount of suspending partcles, as measured by mass, is less than that of the active agent particles. For example, in particular embodiments, the mass of the suspending parties may be as low as 20% of the total mass of the active agent particles, However, in some embodiments, the total 31 mass of the suspending particles may also approximate or equal the total mass of the active agent particles; [0115] 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 or dissolve 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 (a) carbohydrates, e-g, monosaccharides such as fructose, galactose, glucose, D-mannose, soroseand the hke; disaccharides such as sucrose lactose trehalose, cellobiose, and the like; cyclodextins, such as 2hydroxypropyl4 cyclodextrin; and polvsaccharides, such as raffinose, maltodextrins, dextrans, starches, chitin, chitosan, inulin, and the like; (b) amino acids, such as alanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine leucine, isoleucine valne, and the ike; (c) metal and organic salts prepared from organic acids and bases, such as sodium citiate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamin hydrochloride, and the like; (d) peptides and proteins such as aspartame, thleucine, human serum albumin, collagen gelatirand the like; (e) alditols, such as mannitol. xylitoL and he Uke; (f) synthetic or natural polymers or combinations thereof, such as polylactides, pilactideglycolies, cyclodextrins, polyarylates methylceliose, carboxymethyiceillse polyvinyl alcohols, polyanhydrides, polylactams polyvinyl pyrroiidones hyauronic acid, polyethylene g alycols and (g) surfactants including fluorinated and nonfluorinated compounds such as saturated and unsaturatedlpids, nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof, [01161 Additionaly, phospholipids from both natural and synthetic sources may be used in preparing suspending particles suitable for 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 40k> Exemplary phospholipids are relatively long chain (i.e., GwC) saturated lipids and may comprise saturated phospholi ids, such as saturated phosphatidycholines having acyl chain lengths of 16 C or 18 C (paimitoyl and stearoyl). Exemplary phospholipids include phosphoglycenides such as dipamitoylphosphatidylcholine, disteroylphosphatidylcholine, darachidoylphosphatidcholine 32 d ibehenoylphosphatidychoIine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatdylethanolam ines, long-chain saturated phosphaidyiseines, long-chain saturated phosphatidylgaycero s, nd long chain saturated phosphatdylinositols. Additional excipients are disclosed in International Patent Publication No,, WO 96/32149 and U.S, Patent Nos, 6358530' 6,372,258 and 6,518,239, [0117] In particular embodiments, the suspending particles may be formed using one or more lipids, phospholipids or saccharides, as described herein. In sorne embodiments, suspending particles include one or more surfactants. The use of suspending particles forrned of or incorporating one or more surffctants may promote absorotion of the seected active agent, thereby increasing biavailabity The suspending particles descflbed herein, such as, for example, suspending particles 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 opsoniation (and thereby reducing phagocytosis by aleolar macrophages), thus providing a longer-lived controlled release particle in the lung. [0118] 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 2005/000267, For example, in one embodiment, the suspending parties my cndude pharmaceutically acceptable glass stabilization recipients having a Tg of at least 55 "C, at least 75 :C, or at least 100 -C, Glass formers suitable for use in compositions described herein incude, but are not limited to, one or more of trileucine, sodium sodium phosphate, ascorbic acid, inulin, cycodextrin, polyvinyl pyrrolidone, mannitol, sucrose, trehalose, lactose, and, proline. Examples of additional glass-forming excipients are disclosed in U. S. Patent Nos. RE 37,872, 5,928,469, 6,258341 and 6309,671 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, [0119] The suspending particles may be designedsized and shaped as desired to provide desirable stability and active agent delivery characteristics. In one 33 exemplary embodiment, the suspending particles comprise perforated microstructures as described herein. Where perforated microstructures are used as suspending particles in the compositions described herein, they may be formed using one or more excipients as described herein. For example, in particular embodiments, perforated microstructures mayinclude at least one of the following lipids, phospholhpids, nonionic detergents nonionic block Copolymers, ionic surfactants, biocompatible fluorinated surfactants aid combinations thereof particularly those approved for pulmonary use, Specific surfactants thait any be used in the preparation of perforated microstructures include poloxamer 188, poloxamer 40T and poloamner 338. Other specific surfactants indude oleic acid or its alkali salts. In one embodiment, the perforated microstructures include greater than about 10% w/w surfactant, [0120J In sor.e embodiments, suspending particles may be prepared by forming an oii-in-water emulsion, using a fluorocarbon oil (e g, perfluoroocty bromide. perfluorodecalin) which may be emulsified using a surfactant such as a long chain saturated phospholipid, The resulting perfluorocarbon in water emulsion may be then processed using a high pressure homogenizer to reduce the oil droplet size. The perfuorocarbon emulsion 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 know 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 pharmaceutcal material for various administrative routes, including inhalation. Operating 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 microstructures. Such methods of poducing exemplary perforated microstructures are disclosed in US. Patent No. 6,309,623 to Weers et al. [0121] Perforated microstructures as described herein may also be formed through lyophilization and subsequent mailing or micronization. Lyophilization is a freeze-drying process in which water 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 discosed in U.S. Patent722333 34 [0122] Furthermore, suspending particles as described herein may include bulking agents, such as polymeric particles. Polymeric polymers may be formed from biocompatible and/or biodegradable polymers, copoyers or blends, In one embodiment, polymers capable of forming aerodynamically light particles may be used, such as functionalized polyester graft copolymers and biodegradable polyanhyddes For example, bukeroding polymers based on polyesters including poly(hydroxy acids) can be used. Polyglycolic acid (PGA), polyactic acid (PLA) or copolymers thereof may be used to form suspending particles. The polyester may include a charged or functionalizable group, such as an amino acid, For example, suspending particles may be formed of poly DJrxactic acid) and/or poiy(nDxIactic-co glycolic acid) (PLGA), hih incorporate a surfactant such as DPPC [0123] Other potential polymer candidates for use in suspending particles may include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly vinyl compounds such as polyvinyl alcohols, polyvinyl ethers, and polyvinyl esters, polymers of acrylic and methacle acids, 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, [0124] In an embodiment of a composition as described herein that includes one or more of g lycopyrrolate, fluticasone, mometasone, and budesonide as an active agent, the ratio of the total mass of the suspending parties to the total mass of the active agent particles may be selected from between about I and about 20, between about 2.5 and about 15, and about 2.5 and about 10 In an embodiment of a composition as described herein that includes one or more of fluticasone, mometasone, and budesonide as an active agent, the ratio of the total mass of the suspending particles to the total mass of the active agent parties may be selected from between about I and about 15, between about 1,5 and about 10, and between about 25 and about 8, In another embodiment of a composition as described where the composition includes salmeterol as an active agent, the ratio of the total mass of the suspending particles to the total mass of the active agent particles may be selected from between about 10 and about 30, between about 15 and about 25, and about 20. In yet afurther embodiment where a composition as described herein includes formoterol as an active agent, the ratio of the total mass of the 35 suspending particles to the total mass of the active agent particles may be selected from between about 10 and about 200, between about 50 and about 12$, about 5 and about 50, between about I and abou 15, between about 1 5 and about 10, and between about 2.5 and about 8, [0125] The compositions described herein may include two or more species of suspending particles, For example; the compositions described herein may include a single species of active agent particle and two or more species of suspending particles. Alternatively, in other embodiments, the compositions described herein may include tvo or more species of active agent particles combined with two or more species of suspending parties. 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 into suspending particles, the suspending particles will be of a respirable size and can be formulated and produced using, for example, the methods and materials described herein in association with the active agent particles, the suspending particles and the experimental Examples provided. [01261 Compositions formulated according to the present teadhings 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 ("DDU") of each active agent included in a combination of two or more active agents, even with combinations including potent and highly potent active. 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 DDU of ± 30%, or better, for each active agent throughout emptying of an MD1 canister In one such embodiment, compositions described herein achieve a DDU of S25%, or better, for each actie agent throughout emptying of an MDI canister in yet another such embodiment, compositions described herein achieve a DDU for the active agent of t 20%, or better, for each active agent throughout emptying of an MDI canister. [0127] Pharmaceutical compositions described herein also serve to substantially preserve FPF and FPD performance throughout emptying of an MDI canister, even 36 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 performance throughout emptying of an MDI canister, even after being subjected to accelerated degradation condition. Compositions described herein provide the added benefit of achieving such performance while being formulated using nronCFC propellants and eliminating or substantially avoiding combination effects often experienced with compositions incorporating multiple active agents, In specific embodiments, the compositions described herein achieve one or all of a targeted DDU, FPF and FPD performance while being formuated with suspes ion medium including only one or more non-tF propellants and without the need to modify the characteristics of the non-FC propellant, such as by the addition of, for example, one or more cosolvent, antisovent, solubiiizing g adjuvant orother propellant modifying material Methods [0128] Compositions formuated according to the present teachings can inhibit degradation of the active agent included therein. For example, in specific embodiments, the compositions described herein nhibit one or more offnlocculation, aggregation and Ostwald ripening of the active agent(s) included in the compositions. The stability provided by the compositions described herein allows the compositions to be dispensed in a manner that achieves desirable delivered dose uniformity throughout emptying of an MO canister (DDUt even where the active agent to be defiNvered is highly potent and the delivered dose of the actve agent is selected from, for example, less than one of 100 pg , 80 pg, 40 pg. 20 pg, 10 pg 9 _g, pg, 2 pg 1 pg, and 01 pg per actuation of the MDI. As is described in detail in the Examples included herein, even at low doses of highly potent active agents, compositions described herei Ican achieve a DDU of ± 30% or better, for each of the active agents included in the composition. In an alternative embodiment. compositions described herein achieve a DDU of ± 25% or better, for each of the active agents included in the composition In yet another embodiment, compositions described herein achieve a DDU of 20%, or better, for each of the active agents included in the composition. [0129] Moreover, 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 37 instance, composaions according to the present description maintain as much as 80%, 90%, 95%, or more, of the original FPF and FPD performance, even when they incorporate multiple actve agents, Compositions described here provide the added benefit of achieving such performance while being formulated using non-CFC propellants. In specific embodiments, the compOsitiOns described herein achieve desired one or all of a targeted DDU, FPF and FPD performance while being ornmulated with suspension medium induding only one or more non-CFC propellants and without the need to modify the characterstics of the nontFC propelant; such as by the addition of, for example, one or more cosolvent, antisolvent., solubilizing agent, adjuvant or other propellant modifying materiaL [0130] The stability and physical characteristics of the compositions described herein support several methods, For example, in one embodiment, a method of formulating a pharnaceutcal composition for respiratory delivery of an active agent is provided herein. 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 as described herein, and combining such constituents to form a composition wherein active agent particles associate with the suspending particles and co-locate with the suspending prticles within the suspension medium such that a co-suspension as described herein is formed. In one such embodiment, the association of the active agent parties and the suspending particles is such that they do not separate due to their different buoyancies in a propellant, As vill 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 spedes of suspending particles Atematively the method may include providing two or more suspending particles in combination with one or more spedes of active agent particles. [0131i In further embodiments the compositions described herein support, for exarnpemethods for forming stabilized formulations of active agents for pulmonary delivery, -ethods for preserving the FPF and/or FPD throughout emptying of an MDI canister. methods for pulmonary delivery of potent or highly potent active agents, and methods of achieving a DDU selected from ± 30%, or better, ± 25%, or better, and ± 20%, or better, for potent and highly potent drugs administered through pulmonary delvery, 38 [0132] In methods involving pulmonary delivery of active agents using compositions described herein, the compositions may be delivered by an MDI. Therefore, in particular embodiments of such methods, an MDI loaded vwith a composition described herein is obtained, and the desired active agent is administered to a patient through pUlmonary delivery through actuation of the MDL For example in one embodiment, after shaking the MDI device, the mouthpiece is inserted into a patients mouth between the lips and teeth. The patient typical exhales deeply to empty the lungs and then takes a slow deep breath while actuating the cartridge of the MDLI When actuated, the specified volume of formulation travels to the expansion chamber out the actuator nozzle and into a highvelocity spray that is drawn into the lungs of a patient. In one embodiment the dose of active agent delivered throughout emptying of an MDI canister is not more than 20% greater than the mean delivered dose and is not less than 20% less than the mean delivered dose, [0133] in specific embodiments of methods for providing a stabilized formulaton of active agent for pulmonary deliey the present disclosure provides methods for inhibiting solution mediated transformation of an active agent in a pharmaceutical formulation for pulmonary delivery In one embodiment, a suspension medium as described herein, such as a suspension medium formed by an HFA propellant, is obtained, Suspending particles are also obtained or prepared as described herein. One or more species of active agentparticles as described herein are also obtained, and the suspension medium, suspending particles and active agent particles are combined to form a cosuspension wherein the active agent particlesassociate with suspending parties and co-locate with the suspending particles within the continuous phase formed by the suspension medium. When compared to the active agent contained in the same suspension medium in the absence of suspending particles, cosuspensions according to the present description have been found to exhibit a higher tolerance to solution mediated transformation and irreversible crystal aggregation, and thus can lead to improved stability and dosig uniformity, allowing the formulation of active agents that are somewhat physicay unstable in the suspension medium alone. [0134] In specific embodiments of methods for preserving the FPF and/or FPD provided by a pharmaceutical formulation for pulmonary delivery a respirable oo suspension as described herein is provided which is capable of maintaining the FPD 39 and/or the FPF to within ± 20% 10%, or even 2 5% the initial FPD and/or EFF respectively, throughout emptying of an MIDI canister. Such performance can be achieved 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 s obtained. Suspending particles are also obtained or prepared as descrbed herein One or more species of active agent particles as described herein are also obtained, and the suspension medium, suspending particles and active agent particles are combined to fom a co suspension wherein the active agent particles associate with suspending particles and colocate with the suspending particles within the suspension medium Even after exposure of such composition to one or more temperature cycling events, the co-suspension maintains an FPD or FPF within ± 20%, 10%, or even ± 5% of the respective values measured prior to exposure of the composition to the one or more temperature cycaing events. [0135] Methods for treating patients suffering from an inflammatory or obstructive pulmonary disease or condition are provided herein. In specific embodiments, such methods include pulmonary delivery of a therapeuticaHy effective amount 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 MDL 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, COPD, 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, and any other respiratory disease, condition, trait, genotype or phenotype that can respond to the administration of, or example, a LAMA, LABA, corticosteroid, or other active agent as described herein, whether alone or combination with other therapies In certain embodiments, the compositeins, systems and methods described herein can be used to treat pulmonary inflammation and obstruction associated with cystic fibrosis. In specific embodiments of methods for treating patients suffering from an inflammatory or obstructive pulmonary disease or condition, the pulmonary disease of condition is selected fom those especially described heren and the method includes pulmonary delivery of a co-suspension composition according to the 40 present description to the patient via an MDI, wherein the pulmonary delivery of such composition includes administering one or more active agents at a dose or dose range as described in association with the cosuspension compositions disclosed herein. Metered Dose Inhaler Systems [0136] As described in relation to the methods provided hereinthe compositions disclosed herein may be used in an MDI system, MDIs are configured to deliver a specific amount of a medicament ir aerosol form, in one embodiment an MDI system includes a pressurized, liquid phase formulationtiled canister disposed in an actuator fbmed with a mouthpiece. The MDI system may include the formations 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 be any of any suitable configuration and in one exemplary embodiment, the canister may have a volume ranging from about 5 mL to about 25 mL, such as, 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, [01T37 Inside an exemplary carridge is a metering valve including a metering chamber capable of holding a defined volume of the forrmlation (e.g., 63 pl or any other suitable volume available in commercially available metering valves), vhich 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 valve stem of the metering valve. When actuated, the specified volume of formulation travels to the expansion chamber, out the actuator nozzle and into a highvelocity spay that is drawn into the lungs of a patient. [013a] The specific examples included herein are for illustrative purposes only and are not to be considered as bmiting to this disclosure. Moreover, the compositions, systems and methods disclosed herein have been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the 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. 41 Any active agents and reagents used in the following examples are ether commercially available or; with the benefit of the teachings provided herein can be prepared according to standard literature procedures by those skied in the at The entire contents of all publications, patents and patent applications referenced herein are hereby incorporated herein by reference Example 1 [0139] Active agent particles formed of glycopyrrolate (Pyrrolidinium, 3 ((cyclopentyhydroxyphenylacetyi oxyfri ,l dimethyL, bromide) were formed by nicronizing glycopyrrolate using a jet mill. The partide size distribktion of the micronized glycopyrrolate (GP) was determined by laser diffraction. 50% by volume of the micronized particles exhibited an optical diameter smaller than 2A1 pm, 90% by volume were smaller than 5 pm. [0140] Suspending particles were manufactured as follows: 500 mL of a fluorocarbon-in water emulsion of PFOB (perfluoroctyl bromide) stabilized by a phospholipid was prepared. 18,7 g of the phospholipid, DSPC (1,2~Distearoyksn Glycero-3-Phosphocholine), and 13 g of calcium chloride were homogenized in 400 mL of hot water (75 *C) using a high shear mixer, 100 mL of PFOB were added slowly during homogenization, The resulting coarse emulsion was then further homogenized using a high pressure homogenizer (Model 03, Avestin, Ottawa, CA) at pressures of up to 170 MPa for 5 passes, [01411 The emuIsion was spray dried in nitrogen using the following spray drying conditions, Inlet temperature 95 *C, outlet temperature 72 *C.emulsion feed rate 24 mLi'in, total gas flow 525 1/min The particle size distribution of the suspending particles was determined by laser diffraction. 50% by volume of the suspending particles were smaller than 2.9 pm, the Geometric Standard Deviation of the distribution was 1.8, [0142] Metered dose inhalers were prepared by weighing the target masses of micronized OP particles and suspending particles into fluorinated ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) with 19 mL volume. The target masses and the target delivered dose Pssuming 20% actuator deposition are given in Table 1 for five different configurations (configurations 1A through IC representing different suspensions of GP particles and suspending particles configuration 1D representing GP particles alone; configuration 1E representing 42 suspending particles aloneY The canisters were crimp sealed with 63 p1 valves (# BK 357, Bespak, King's Lynn, UK) and filled with 124 g of HFA i34a ( 11 2 terafiuoroethane) (Ineos Fluor, Lyndhurst, UK) by overpressure through the valve stern. After injecting the propelant; 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 03 mm orifice ( BK 636Bespa King's Lynn UK), Additional inhalers for visualobservation of suspension quality were prepared using glass vials Table 1: Results for Glycopyrrolate o-uspensions of ExampleI 0nf gu rn io n G P- Suspend:'~ J Target Delivece U FPF IMADQ D (mg/can) part c es delvered Dose (W) (%) { m) __________ ___ ____ %q'a~u dose g) _ _____ _ _ _ _ _ _ _ _ IA3,4 Cl16.5 17, 41.3 -141 12 9.4 42,0 .9 D 4.1 0 20 11A1-53 2 70 1 3 IF0 61 ________53$* 6 3 Base or~c assay. [0143] Aeosol performance was assessed shortly after manufacturing in accordance with USP 601 > (United States Pharmacopeia Monograph 601). A Next Generation lmpactor (NGI) operated at a flow rate of 30 Umin was used for determination of particle size distribution. Sample canisters were seated into an actuator with two waste actuations and two additionalwaste priming actuations Five actuations were collected in the NO with a UJSP throat attached The valves actuator, throat, NGI cups, stages, and filter were rinsed with volumetrically dispensed solvent. The sample solutions vere assayed using a drug specific chromatographic method The fine particle fraction was defined using the sum of stages 3 through filter Deiered dose uniformity through use testing was performed using a Dose Uniformity Sampling Apparatus as described in USP <601> Inalers were seated and primed as described before. Two actuations were collected and assayed at beginning, middle and end of use, [0144] Visual observation of the co-suspended configurations (1A, 1B, 10) showed no sedimentation of drug crystals. The suspension flocculated slowly and formed a homogeneous, single cream layer similar to the comparator configurtion 43 1E, which included suspending parties suspended alone, In contrast, the micronized GP particles alone (configuration I D) flocculated and sedimented quickly, Configuration 18 showed no indication of separation of GP particles from the suspending particles even after centrifugation at 35g for 20 minutes. The same rest was observed (i.e, lack of OP particle separation) where centrifuged up to 200g, Configuration 10 (low suspending concentration) showed a smal amount of GP crystals settling out after centrifugation at 35q for 20 minutes [0145] While the co-suspended coifigurations achieved a delivered dose within 10 % of target, the GP particles suspended alone showed much higher variability in delivered dose in a range significant below target. The fine particle fraction relative to configuration ID was improved by more than 50%. The MMADs of the co suspended configurations were acceptable and depended on the suspension concentration of the suspending particles. The delivered dose uniformity through use was tested for configurations I B and IC All individual delivered doses were within 20% of mean The results showed that the drug crystals forming the GP particles associate to the suspending particles, a cosuspension was formed, and the aerosol performance of the cosuspension was mostly determined by the suspending particles. [0146] The association between GP crystals and suspending parties was strong enough to overcome buoyancy forces, as it was observed that GP crystals do not separate from the perforated microstructures and settling of the crystals s inhibited Example 2 [0147] Glycopyrroiate (GP) particles were formed by micronization using a jet mill. Suspending particles were manufactured as described in Example 1, The particle size distribution of the rnicronized GP was determined by laser diifraction. 50% by volume of the micronized particles exhibited an optical diameter smaller than 1. pm, 90% by volume exhibited an optical diameter smaller than 41 pm. Five different lots of metered dose inhalers weedifferent lots were made, For corfgurations 2A, 2 and 2C the total concentration of DSPC, CaC3,, and OP in the feedstock was 40 mg/mW for configuration 20 and 2E this concentration was doubled, [0148] Metered dose inhalers were prepared by weighing the target masses of GP particles and suspending particles into canisters as described i E example 1, No further excipients were used. The target masses were 4 mg / canister for GP 44 particles and 60 mg I canister for the suspending particles, resulting in a suspending particle to GP particle ratio of 15 for configurations 2A and 2D, The target masses were 5.1 mg / canister for GP particles and 51 mg canister for the suspending particles, resulting irn a suspending particle to GP particle rato o 10 for configuration 21, The target masses were 8 mg / canister for GP particles and 60 mg / canister for the suspending particles, resulting in a suspending particle to OP particle ratio of 1S for configurations 20 and 2E. Propellant and container closure system were as described in Exarmple 1 [0149] The OP crystals were placed in HFA 134a in a canister under pressure and were equilibrated for 2 weeks at room temperature to determine their soubility in the propellant, The samples were filtered under pressure at ambient temperature through filters with a pore width of 0,22 pm, The filtrate was evaporated and the GP dissolved in methanol and chromatographicaly analyzed. A solubility of 01 ± 0,07 pgg was found. Using this value it was determined that 21 pg or 005% of GP present in the canister dissolved in the propellant Previous artides teach that microcrystalline material with a measurable solubility in the propelwat will not be physically stable due to solution mediated transformation [N C.ller The Effects of Water in Inhalation Suspension Aerosol Fomlatios in P. A. Byron, Ed Respiratory Drug Delivery, CRC Press 1990 p 250, or that actives with solubility's above 01 pg/g should be formulated with an adjuvant to prevent a solution mediated transformation [P, Rogueda, Novel Hydrofluoroalkane Suspension Formulations for Respiratory Drug Delivery, Expert Opin Drug Deliv. 2, 625-638, 2005] [01501 The filled metered dose inhalers were stored valve down without overwrap at two different conditions: 1) refigerated at 5C; and 2 room temperature at 25cc 60% RH. Aerosol performance and delivered dose uniformity tests as described in Example I were carried out at different time points The results which are summarized in Table 2, show a stable fine particle fraction at refrigerated and room temperature conditions. Table 2: Fine particle fraction of configurations in Example 2 4 Store ___FPFPi % ___ 5nial 2 months months 6 months 2A 49 -25*/60%RH 48 5 2B 25 0 C/60 % RH 50 46 49 48 45 2D7 51 5 ~25 C/60 %RI 14 49 9 [0151] Configurations 2C and 2E were subjected to a temperature cycling test. The canisters were subected to ~-5 *C and 40 * alternating between temperatures every 6 hours for a total duration of twelve weeks. Fine particle fraction was 53% for both configurations at the beginning of the study, After twelve weeks of cycling the FPF was unchanged, i.e, at 55% for configuration 2C and at 53% for configuration 2E. [0152] The delivered dose uniformity through use was tested at the 1, 2 and 6 month time points. All individual delivered doses were within ±20% of mean Figures 1 and 2 show the aerosol particle size distributions as measured by the NGl for configurations 2A and 28, respectively. Also shown are the amounts of drug recovered from actuator, and from the induction port (throat) and its mouth piece adaptor, Recovered masses are expressed as percent of nominal dose, For configuration 2A, aerodynamic particle size distribution individual replicates are shown at 4, 8 and 12weeks and at 8, 12 and 24 week for configuration 28. Though there is a neasureable fracion of the suspended GP dissolved irn the propellant, there is no evidence of a coarsening of the size distributions, Moreover, as evidenced by these Examples, the aerosol performance of a co-suspension at suitable suspending particle to GPratios is determined largely by the suspending particles, Example 3 [0153] Several similar batches cf suspending parties were made as described in Example 1 The suspending particles were combined with glycopyrrolate (G) particles that were micronized to different extends, using two different types of jet mills with various milling parameters. The optical diameter and particle size distribution of the micronized GP particles was determined by laser diffracton. Table 3 lists the d, and d, 1 values for the different lots of micron ized material used. d and de denote the particle se at which the cumulative volume distribution reported by the parole sizing instrument eaches 50% and 90% respectively. [0154] Twelve different lots of metered dose inhalers were prepared as described in Example 1. In all cases the suspension concentration of GP particles in HFA 134a 46 was in the range of 0.32 - 0,45 mg/mL and the suspension concentration of the suspending particles was in the range of 5,8 - 6.1 mg/mL. The configuration were deemed similar enough to pool the data for a metaenalysis presented in this Example. [01551 The filled metered dose inhalers were stored valve down without overwrap at two different conditions refigerated at 5 *C and controled room temperature at 25 5C 60% RH. Aerosol performance tests as described in Example 1 were carried out at different time points. The results did not show any staistically significant trend as a function of time up to twelve weeks of storage.No difference between room temperature storage and refrigerated storage was discernible Hence results fror differed stress conditions and tine points were pooled to determine how the particle size distribution of the micronized maternal affects aerosol performance [0156] Table 3 summarizes the MMAD results of the metaanalysis The first column describes the six different configurations. The second column identifies how many individual ots were used in the compilation of the data for the respective configuration. The third column lists the number of individual MMAD determinations used to calculate the average MMAD for the respective configuration. Columns four and five show the de 3 and d of the micronized material used to manufacture the Co suspensions. The results are sorted by do 3 value from coarse to fine, The last two columns display the average MMAD and standard deviation. Table 3: Pooled MMAD results for 12 glycopyrrolate co-suspensions, sorted by the d 00 of the micronized glycopyrrolate particles. nniNumbdr od Average Lot ID MMAD MMAD SD ots ym) (p ot measurements pm) rn 3A 3 21 50 18 40 028 B2 9 49 2 4.1 0.37 30 1 6 4,8 18 3.6 012 3D 1 4 43 17 3 0.22 3 21 1 3.7 0.28 Y210 35 173.601 A47 [01571 These results show a weak dependence of MMAD on the d of the micronized material A similar analysis for the ds showed no statistically significant trend, It can be concluded that changes in the size distribution of the micronized material (eog different micronized material lots, or induced by solution mediated transformations) lead to only minor differences in the size distribution of the aerosol emitted from the rmetered dose inhaler, E'xam~ple 4 [0168] Micronized glycopyrrolate (GP) particles were formed tested as described in Example 1, The optical diameter of the micronized OP parties was determined and 50% by volume of the micronized GP particles were smaller than 1. pm, 90% by volume were smaller than 38 pm. [0159] Five batches of suspending parties were made as described in Example I The batches differed in concentration, C, and volume fraction of PFF, % gof the feed emulsion prior to spray drying, ranging from 20 mgmL to 160 mgirmL and 20% to 40%, respecvely The different configurations are described in Table 4, [01601 Metered dose inhalers were prepared by weighing the target masses of micronized GP and suspending particles into coated glass vials with 15 mL volume. The target suspension concentrations and suspending particle to GP ratios are given in Table 4 for the 26 different vials tested The canisters were crimp sealed with 63 p1 valves (Valois, Lee Vaudruilt France) and filled with 10 g or 12 g of HFA 134a (1 ,2detrafluoroethane) (Ineos Fluor, Lyndhurst, UK) by overpressure through the valve stem. After injecting the propelant the canisters were sonicated for 15 seconds and agitated on a wrist action shaker for 30 minutes [01611 As described in Example 1, micronized OP parties formulated alone flocculated and sedimented quickly. The glass vials in this example were left to setle for at least 24 h without agitation and then it was tested by visual observation whether the crystal GP particles were co-suspended completely. For the vials marked with "Yes" in Table 4, no GP parties were observed at the bottom of the vials, except for very few foreign particulates in some vials. Occasional foreign particles were also visible in a similar very low amount in vials filled with suspending particles only. For the vials marked "Partial? a fraction of the GP parties was visible at the bottom of the vial 48 Table 4: Co-suspension observations for g lycopyrrolate configurations with various suspending particle to gycopyrrolate particle ratios. Suspending C in partide to Co mgbmL glycopyrrolate suspension particle ratio Suspend ng # 4A j 20 40 1.8 3,8 Part .20 40 72 15 Yes 4B 40 40 3.0 1.9 Partial 40 40 1.8 3,8 Parial 40 40 3.0 18 Yes 45 40 60 38 )es 140 40 9 0 56 Yes 40 40 30 75 Yes le 40 40 6 0 7.5 Yes 40 40 9,0 11.3 Yes 40 40 6,0 15 Yes 40 0 72 15 Yes 404G 9,0 22,5 Yes 4C 80 20 3 0 1.9 Partial 80 20 3.0 3.8 Partial 1 80 20 6.0 3.8 Yes 20 9 0 5.6 Yes 80 20 ;0 7.5 Yes 80 20 6.0 7-5 Yes 80 20 9.0 113 Yes ____D_ 8 20 6. 15 f es _ 80 20 9.0 225 Yes 4D 80 40 18 8 Partia 80 j 40 7.2 15 Yes 4E 160 40 1.8 38 [ Partial 1 0 2Yes Example 5 [0162] Glycopyrrolate (GP) particles were micronized with a jetriti and tested as described in Example 150% by volume of the micronized particles exhibited an optical diameter smaller than 1,7 pm, 90% by volume exhibited an optical diameter smaller than 4.4 pm. [0163] Six batches of suspending particles were made by spray drying as described in Example 1, Configuration 5A was spray dHed from ran emulson. 49 Configuration 5B was manufactured in a similar fashion but using dipalmitoylphosphatidyicholine (DPPC) instead of DSPC. Configuration 50 was spray dried from an ethanolic solution, For configurations 5D: 5E, and 5F, saccharides were spray dried from aqueous solution, The spray drying parameters for all configurations are given in Table Sc Table 5a: Suspending particle configurations used in Example 5. Spray Dryng Parameters Lot Powder Feed comompositio n position F Fee Tota mg/mL TM~ # (% wiw)e Gas Flow 915 DSPC 8 5A 40 2A 95 72 526 6.5 1al 20 % PR0.13 92,9 % DPPC 70 % H 0 5B60 2A 95 67 525 71%al 30% PFO 95 % Ethanol 5 100 % DSPC 100 5 95 70 520 5 % PFOB SD 100 % Lactose 100 % H 0 100 4 95 70 668 5E 100 % Trehalose 100 % H20 10 100 68 527 SF 100 % Trehaose 100 % H,0 89 4 100 1 670 [0164] The particle size distribution of the suspending particles was determined by laser diffraction. The volume median optical diameter, VMD, and geometric standard deviation, GSD, for the different configurations are given in Table 5b, TA Characteristics of suspending particle configurations used in Example 5. VMD Co Lot # GSD Separation Comment {pm suspension CA 36 1.8 Creams Yes No or few 583 rasYes cstsviil on bottanm of 50 Lot # GSD Separation Comment (pm) suspension 5C 1,2 1,9 Creams Partial vials 5D 1 7 23 SedP ients Yes Causes GP - - - - 4 - - - - - - - - - - - - - - - - - - - - - - - - - - - crystals to SE 0 9 1 Sediments Yes the 5F 1 24 Sediments Yes suspending [0165] Electron micrographs of the suspending partiAes showed a variety of morphologies, summarized in Figure 3. The particles that were spray dried from emulsion; "A and SB, had high porosity and low density. The DSPO partice spray dried from an ethanoic solution, 5C, showed a much smaller particle size with no noticeable porosity, indicating a high density All saccharides produced smooth parties with no visible porosity. Configuration 5E had the smallest particles, as expected due to its Ilow feed concentration. [01661 Metered dose inhalers were prepared by weighing the 4 mg of micronized GP particles and 60 mg of suspending parties into coated glass vials with 15 mL volume. The canisters were crimp sealed with 63 pi valves (Valois DF30/63 RCU, Les Vaudreuil, France) and filled with 95 mLA of HFA 134a (ineos Fluor, Lyndhurst, UK) 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. Additional inhalers with suspending particles only were manufactred as control for each configuration, [0167] The suspending particles in Examples &A 5B, and 5O, have true densties lower than the propellant. They formed a cream layer and were tested for the presence of a co-suspension as described in Example 4. No GP partices were visible at the bottom of the vials for configuration SA and 5B. Configuration 5C formed a partial co-suspension. [0168] The saccharide particles sediment because they have a higher true density than the propelant; However, all control viais for the saccharide cornigurations showed a significantly faster sedimentation rate than micronized GP parties alone, i configurations SD, 5E and 5F the sedimentation rate was siiiar to that of the control vials with the suspending particles alone and faster than the 51 micronized GP particles alone, demonstrating the association of the OP crystals with the suspending particles, A co-suspension was formed in these cases, Figure 4 shows an example of this behavior for configuration 5D. The glass vial was observed one minute after agitation. The co-suspension has already settled leaving a clear propellant layer, while in the control containing GP particles alone, most of the crystals are still suspended in the propellant [0169] GlycopyrroIate (GP) was micronized using a jet mill to a volume median optical diameter (d,) of 1 4prn with 90% of the cumuative distribution (d< having a volume optical diameter below 3.0pm Suspending parties were manufactured simiarly to those in Example I. MDI canisters were manufactured using FEP coated canisters (Presspart Biackburn, UK) to provide products with metered dose of 5.5 pg per actuation GP and 44 pg per actuation GP which correlates to approximately 4,5 pg per actuation and 36 pg per actuphon OP delivered dose from a 50 p1 EPDM valves (Bespak, King's Lynn, UK), The formulations contained 6mgkinL of suspending particles, MDI manufacturing was accomplished using a drug addition vessel (DAV) by first adding half of suspending particle quantity, next filling the rnicmcrystalline GP, and lastly adding the remaining half of suspending particles to the top. Materials were added to the vessel in a humidity controlled environment of <10% RH. The DAV was then connected to a 4 L suspension vessel and flushed with HFA 134a propellant and then mixed. The temperature nside the vessel was maintained at 21~23 *C throughout the entire batch production. After recirculation of the batch for 30 min canisters were filled with the suspension mixture through the valve, Sample canisters were then selected at random for total canister assay to ensure correct formulation quantities. The freshly manufactured cosuspension MD batch was then placed on one week quarantine before initial product performance analysis. In addition, canisters from each lot were subjected to a temperature cycling stability study, The canisters were subjected to -5 *C and 40 '" alternating between temperatures every 6 hours for a total duration of 84 cycles (3 weeks) and 168 cycles (6 weeks). [0170] Each lot was tested for delivered dose uniformity through can life and aerodynarinc particle size distribution by Next Generation Impactor (NGI) in accordance to USP <601>, The initial and temperature cycled aerodynamic particle 52 size distributions as measured by the NGI are shown in Figures 5 and 6, Also shown are the amounts of drug recovered from valve stem and actuator (denoted as actuator), and from the induction port (throat) and its mouth piece adaptor, Recovered masses are expressed as percent of nominal dose, After 168 cycles, the % FF (eactuator) is not significantly different from initial, A summary of the stabliity of the e parties reaction is shown in Table 6. The fine particle fraction remained unchanged over 168 cycles lustrating the stability of the GP co suspensions disclosed herein across a GP dose range. Table e 6. Temperature Cycling Stabfity of the Fine ParticQe Fraction of crystalline OP co suspended with suspending particles at two doses in MD containing HFA 134a Time 4.5 pg per actuation 36 pg per actuation (%FPF ex-actuator) (%FPF ex-actuator) Initi a 60.9 574 3 Weeks (4 cyles) 619 58,0 6 Weeks (168 cyces 60.6 59.0 [0171] The delivered dose through life of the MDI canisters i shown in Figures 7 and 8 No change in delivered dose from beginning to middle of can is observed and a -10% increase from middle to end of canister The change from middle to end is anticipated based upon evaporative losses of propellant as the can is emptied. Figures 7 and 8 demonstrate desirable delivered dose uniformity for MDI for doses as low as 4.5 pg per actuation. Exaole [0172] MDI Canisters were manufactured to contain 6mg/mL suspending particle concentration and to provide a metered dose of 36 pg per actuation with a 5Opl valve volume according to Example 6. Micronized GP had a de, and d.

0 of 16pm and 4. pm respectively and suspending particles were manufactured similarly to the process described in Exampie 1, The canisters were stored without protective packaging at 25 C and 60% RH and stored for duration of 12 months. Each lot was tested for delivered dose uniformity through can life and aerodynamic particle size distribution by Next Generation impactor (NO in accordance to USP <60 Aerodynamic particle size distribution was determined by next generation impaction 53 at2 weeks, 1 2, 36 or 12 months The fine partie traction, as a percentage of GP ex-actuator, at initial sampling was 50,2%, No signif4cant change in the fine particle fraction was noted at any of the throughout 12 months of storage at 25 "C and 60% RH without aluminum fa overwrap, with FPF of 477% after 12 months. Figure 9 provides a view of the entire aerodynamic size distribution for each of the stability samples demonstrating desirable consistency on aerosol delivery, A summary of the fine particle fraction is shown in Tabe '7 Table 7, Stalhity of the Fine Particle Fraction of crystalline GP co suspended with suspending particles in MDI containing HFA 134a stored at 25t0 and 60%RH with no protective packaging % FPF TimePoint _______________ ex actator) n tial 50.2 2 Week 461 I Month 42.0 2 Month 46.0 3 Month 48 9 6 Month 47 12 Month 47 7 ExamoLe8 [0173] Glycopyrrolate MDI canisters containing 36 pg per actuation were prepared as described in Exampie 6, packaged in a heat sealed aluminum foil overwrap containing desiccant, and cycled for 6 weeks (6 hours at -5 C and 6 hours at 40 C) The delivered dose uniformity of glycopyrrolate through use was tested at the 0, 2, 4 and 6 weeks time points. The mean glycopyrrolate delivered dose of each lot each time period was within ±15% of the mean, with one exception, as demonstrated in Figure 10, The aerodynamic particle size distribution as measured by NGI remain unchanged after 163 temperature cycles as shown in Figure 11, Example 9 [0174) Glycopyrrolate MDI canisters containing 24 pg per actuation were prepared as described in Example 6 were stored for six weeks at 50 "C under ambient humidity. Another lot was stored for 8 weeks at 40 *O and 75% reaive 54 humidity, Yet another lot was stored for 12 weeks at 40 *C and 75% relative humidity. The initial fine particle fraction (FPP) was 59.3%, The FPF, 584%, of the canster stored for 6 weeks at 50 0C was unchanged compared to the initiaL The initial FPF of a lot stored at 40 *C remained unchanged after 8 and 12 weeks, FPF 56.8 and 576% respectively. The aerodynamic particle size distributions as measured by the N0t are show in Figure 12. The MMAD remains relatively unchanged after 6 weeks at 50 OG 3.94 pm, and up to 12 weeks at 40 4C, 3,84 pm compared to the initial at 354 pm. In addition, the FPF and the amounts of glycopyrroiate recovered from valve stem and actuator, and from the induction port (throat) and its rnouth piece adaptor rema ned relatively unchanged over 3 months at elevated temperatures as shown in Figure 12. [0175] Metered dose inhalers including pharmaceutical compositions of formoterol furnarate as described herein were prepared Formotero fumarate()2 hydroxy5-[( I RS)~I -hyd roxyr2d[ RS)~244nmethoxyphenyl)4-.ethylethyl aminolethyl] formanide fumarate, also known as (22hydroxy-5'(RSY1Aydroxy 24[(RSppmethoxyamnethiphenethyl~amineethyg formanilide funiarate, dihydrate was micronized to form active agent particles The particle size distribution of the micronized formoteroi fumarate (FF) was determined by laser diffraction. 50% by volume of the micronized particles exhibited an optical diameter smaller than 1.6 pm, and 90% by volume exhibited an optical diameter smaller than 3.9 pm, [01I6] Suspending particles were manufactured as follows: 503 mL of a fIuorocarbon in-water emulsion of PFOB (perfluoctyl bromide) stabilized by a phospholipid was prepared. 20.6 g of the phospholipid, DSPC (1,2-disteroylsn glycero-3phosphocholine), and 19 g of calcium chloride were homogenized in 403 mL of hot water (75QC) using a hgh shear mixer 100 nL of PFOB weradded slowly during homogenization. The resting coarse emnlsion was then further homogenized using a high pressure homogenizer (Model 03,Avestin, Ottawa, CA) at pressures of up to 170 MPa for 6 passes [0177] The emulsion . was spray dried in nitrogen using the following spray drying conditions: Inlet temperature 950C, outlet temperature 710emulsion feed rate 2A mL'min, total gas flow 498 Lrmin. The partice size distribution of the suspending 55 particles was determined by laser diffraction. 50% by volume of the suspending particles were smaller than 3 pm, the geometric standard deviation of the distribution was 1.9 [0178J Metered dose inhalers were prepared by weighing the target masses of micronized active agent particles and suspending particles into coated glass vials with 15 ML volume. The target masses and the target delivered dose assuming 20% actuator deposition are given in Table 8 for three different configurations, For each configuration, additional ass bottles were filled with the respective amount of FF active agent particles without any suspending particles, The canisters were crimp sealed with 63 p1 valves (Valois, Les Vaudreuil, France) and filled with 11 g (91 mL at 25 *C) of HFA 134a (112tetrafluoroethane) (ineos Fluot Lyndhurst, UK) by overpressure through the valve stem. After injecting the propellant, the canisters were sonicated for 15 seconds and agtated on a wrist action shaker for 30 minutes, Table: Target doses for formoterol fumarate co-suspensions of Examnpie 10 FF Acive Target Suspendin I Configuration Agent delivered Particle to # Particles dose active particle _U3_1_n_.....pg/can.g.can pg ratio 6A 300 1 167 6B 860 50 4.6 58 3_010 16_ _ 1El [0179J Visual observation of the co-suspended configurations (6A 6B, 6C) showed no sedimentation of the crystal ne FF forming the active agent particles The suspension flocculated slowly and formed a homogeneous single cream layer For all concentrations tested the micronized actve agent particles alone sedimented quickly. Pictures of the co-suspensionand the traditional comparator suspensions, indicated by an asterisk, are shown in Figure 13. The vials were left to settle for 24 h without agitation. No FF crystals were visible at the bottom of any of the co suspension vials. [0180] The results showed that the FF crystals associated wih the suspending particles. The association between FF particles and suspending particles was strong enough to overcome buoyancy forces, as FF particles did not separate fom the suspending particles and settling of the active agent particles was successfully inhibited in each of the three different formulation configurations. 56 Example 11 [01811 Formoterol fumarate MDI compositons were prepared according to the present invention, Micron ized fornoterol fumarate was conmercialy obtained and its particle size distribution measured as described in Example I was charaderized by a di, dz d oo or 0.6, 1,9 and 4A pm respectively and a Span of 2.0 Suspending particles used were prepared in a similar manner described in Example 1, MD! manufacturing was accomplished using a drug addition vessel (DVA) by first adding half of suspending particle quantity, next filling the microcrystalhne FE, and latIly adding the remaining half of suspending particles to the top. Materials were added to the DAV in a humidity controlled environment of <10% RH. The DAV was then connected to a 4 L suspension vesseL A slurry was then formed by adding a known amount of HFA-134a propellant (Ineos Fluor, Lyndhurst, UK) into the DAY which is then removed from the suspension vessel and gently swiped The slurry is then transferred back to the suspension mixing vesse and diluted with additional HFA I34a to form the final suspension at target concentration stirring gently with an impeller, The temperature inside the vessel was maintained at 2-23 OC throughout the entire batch production. After recirculation of the batch for 30 min, 14-mL fluorinated ethylene polymer (FEP) coated aluminum canisters (Presspart Blackburn, UK) were filled iVh the suspension mixture through 50 pL EPDM valves (Bespak, King's Lynn, UK). Sample canisters were then selected at random for total canister assay to ensure correct formulation quantities. [0182] The freshly manufactured co-suspension MDI batch was then placed on one week quarantine before initial performance analysis. Aerosol performance was assessed in accordance with USP 60i> (United States Pharmacopeia monograph 601), A Next Generation impactor (NGI operated at aflow rate of 30 L/min was used for determination of particle size distribution. Sample can sters 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, NGi cups, stages, and filter were rinsed with volumetrically 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 57 performed using a Dose Unifomity Sampling Apparatus as described by USP <601> Two actuations were collected and assayed at beginning middle and end of use, [01&3 Figure 14 shows the delivered dose uniformity for a co*suspension of FF at a 4.8 pg target dose per actuation. The individual delivered dose per actuation for beginning, middle and end of actuations was within ±25% of the mean delivered dose, as demonstrated in Figure 14, Example 12 [01841 Formoterol Fumarate MDI compositions were prepared according to the present invention. Micron ized frmoterol fumarate was commercially obtained and its particle size distribution measured as described in Example 1 was characterized by a d d d0 or 0,6, 1,9 and 44 pm respectively and a Span of 2.0. Suspending particles used were prepared in a similar manner described in Example 1, MD1 manufacturing was accomplished as described in Example !1, [0185] Aerosol performance was assessed in accordance with USP <601>. A Next Generation Impactor (NGI) operated at a flow rate of 30 Ltmin 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 NG1 with a USP throat attached. The valve, actuator, throat, Mel cups, stages, and filter were nnsed with volumetrically 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, The aerodynamic parties size distribution of a FF co suspension formulation was evaluated after manufacture and after three months of storage at 25 *t and 75%RH (unprotected canisters) and 40 *C and 75 %RH (protected canisters wrapped in aluminum foil pouch) The aerodynamic particle size distributions shown in Figure 15 demonstrate that the compositions described displayed desirable stability characteristics even at accelerated conditions E' xam1 11P le_13i [0186] The chemical stability of formoterol fumarate (FF) included in a co suspension formulation prepared according Exarnple 11 was evaluated. F MDI canisters containing HFA 134a were overwrapped with an aluminum foil pouch and 58 stored at 25 *C and 60% relative humidity and 40 'C and 75% relative humidity for thrteen and six months, respectively. Likewise FF MDI canisters containing HFA 227ea were overwrapped with n alurninum foil pouch and stored at 25 "C and 60% relative humidity and 40 'C and 75% relative humidity for six months, The amount of impurity F, a characteristic degradation product of Fr, and total impurities were determined by reverse phase HPLO assay as follows each canister is chilled, cut open, and the can contents aretransferred to a centrifuge tube; the contents were dissolved in orga io solvent, followed by the addition of an aqueous solvent to precipitate excipient (DSPC) from the solution; the solution was centrifuged to produce a clear supematanr solution; and each sample solution was analyzed using a C1 column, 4,6 x 150 mm and 30 pm particle size. The column temperature was kept at 30 Q The injection volume was 20 pl, and flow rate was set at I mnmin and deeteced by determining the UV absorption at 214 nrrt A gradient was used mixing pH 3. aqueous phosphate buffer and acetontrile, 17% acetonitrile first 27 minutes, then 50% acetonitrile for 30 seconds followed by 65 minutes at 75% acetonitrile and 17% acetonitrile for 8 minutes, Impurities were reported as area percent of fornoterol peak area (corrected for relative response factors, where available). As shown in Figure 16 (or Table 9 and 10), a suspension prepared using crystalline FF active agent particles suspended in HFA 134a with suspending particles was chemically stable for 18 months at a temperature of 25'C and 60% relative humidity, in contrast a spray dried, non cosuspended formoterol formulation, showed a faster degradation rate under the same storage conditions, Likewise, crystalline FF active agent particles formed a chemically stable co-suspension in HFA 227a as shown in Table 11, T-abteChemical Staility of Spray Dred FF Suspending Particles in FE MDI Containing HFA 134a at 2'C60%RH, Overwrapped in Aluminum Foil Pouches Tien (months) 0 2 3 12 1s NmpurityIF(%) ND 0..2% 004% 15% 2.77% Total Impurities 0.62% 44,% 9% 3%% ND= Not detected 59 Tabe 10. Chemial Stability of Crystaline FF Co-suspeded with Suspending Pardcles in FF MDl Contanrng HFA 134a at 2,5C/60%RH, Cverwrapped in Aluminum Foil Pouches Time (months) 0 1 2 3 6 10 13 lmpufity F (%) 0.05% 0.08% 0.08% 0,14% 0.06% 0.22% 0.35% Total impurities (%) 0.44% 0 32% 0,32% 0.37% 0.18% 0.45% 0.64% at 40C/75% RH, Overwrapped in Aluminum Foil Pouches Time (months) 0 1 2 3 6 Impurity F (%) 005% 0 11% 031%1 18% 174% Total Impuriies (%) 044% 0.41% 05% 1.58% 2.54% Table 11, Chemical Stablity of Crystalline FF Co-suspended with Suspending Partices in FF MDi Containing HFA 227a at 25 C/60%RH Cvervrapped n Aluminum Foil Pouches Time (months) 0 1 2 3 6 Impunity F (%) 0,04 036 0.07 0.13 0.05 Total Impurities (%) 0.4 03 0.3 04 0.1 at 40*C75%RH, Overwrapped in aluminum foil pouches Time (months) 0 1 2 3 6 Impurity F (%) 0.04 0.08 0.18 0.80 1.14 Total Impurities (%) 0.40 0.39 053 1,13 1.56 Exaple14 [0187] Micronized formoteroI fumarate dihydrate (FF) (Inke, SA, Barcelona. Spain) used in the present example had with paticle size distribution by laser diffraction of 50% by volume of the micronized parties exhibited an optical diameter smaller than 1.9 pm, 90% by volume exhibited an optical diameter smaller than 4. pm, Four batches of suspending particles were manufactured by spray drying as described in Example 1. All four batches were spray-dried from aqueous solution; solution concentration and spray drying parameters are given in Table 12.e Table 12: Suspending particle configurations used in Example 14 P In S ii Drying^ParIN ie5i C60 Composition m /t _______ ___ ____________ Dsrbto ----- T--------ai

-----------

Feed rate T iT n T Tm Flow n std p in mt-.min C C XA 100 % trehalose 80 10 | 150 82 385 1.62 220 100 % HP-P X 1 80 10 100 68 885 y iod xM 1_ 100% F P 80 10 100 70 8852 7D 100% frulin 80 10 100 70 885 12 20 [0188] The partice size distribution of the suspending particles was determined by laser diffraction The volume median optical diameter (VMD) and geometric standard deviataon (GSD) are given in Table 12. [0189] Electron micrographe of the suspending parties showed a variety of morphologies, and are shown in Figure 17 through Figure 20, with Figure 17 providing a micrograph of trehalose suspending particles, Figure 18 providing a micrograph of HP-4%cyclodextin suspending particles Figure 19 providing a micrograph of Ficoli MP 70 suspending particles, and Figue 20 providing a micrograph of inulin suspending particles. Trehalose particles appear to be spherical, with a smooth surface. HP-cycderin particles show extensive wrinkling of the surface, suggesting a partially buckled exterior with a hollow core. Fkoil IMP 70 and Inulin particles display some surface rugosity but are generally spheroidal. [01901 Metered dose inhalers were prepared by weighing 0.9 mg of the micronized FF active agent particles and 60 mg of suspending parties into coated glass vials with 15 mL volume. FF was combined with each type of the four suspending particle species of Table 12. The canisters were crimp sealed with 50 pt valves (Valois DF31/50 RCU, Les Vaudreuii, France) and filled with 10 mL of HFA propellant 134a (Ineos Fluor, Lyndhurst, UK) by overpressure through the valve stem, After injecting the propellant, the canisters were son icated for 30 seconds and agitated on a wrist action shaker for 30 minutes. Additional inhalers containing suspending particles only and active agent particles only were filled as a control for each configuration. [01911 Crystalline FF has a greater density than propellant 134a at room temperatures do all four species of suspending particles in the present example. 61 Consequently both FF and suspending particles settled to the bottom of the inhalers at room temperature, To test these inhalers for active-suspending agent particle interactions indicaing a co-suspension, the inhalers were inmmersed in an ethanol bath at -10' C (resulting in increased propellant density) and allowed to equilibrate for a minimum of 30 minutes, At this temperature, the FF active agent parties are less dense than the prooellant and consequently cream to tphe op oN the propellant volume, while all four species of suspending agent particles remain settled at the bottom of the propellant volume, [0192] The tested configurations and the results of the observations are presented in Table 13. FF acte agent parties alone formed a cream layer atop the propellant volume, and trehalose, HP- frcycdodextrin, inulin, and Flooll PMI0 particles alone all settled to the bottom of the glass vial FF active agent particles in combination with trehalose suspending particles formed a single sediment layerwith no particles creamed or afloat in the propellant, indicating that the FF particles interact with the trehalose suspending parties, and a couspension is formed In the case of FF particles in combination with H4cydodextrin suspending parties some turbidity was present in the propellant, similar to that observed in the suspending particle only control vial. Additionally, some floating floes were observed, which may have been FF particles; however, such flocs accounted for a small amount of solid mass relative to the control vial, indicating that some if not all FF particles were interacting with the suspending agent particles, FF particles in combination with inulin suspending particles formed a single sediment layer, indicating a coususpension was formed, Though soie turbidity was present in this configuration, similar cloudiness was observed in the inulinvonly control vial. FF active agent particles in combination with Ficoil PM70 suspending particles formed a sediment layer at the bottom of the vial, indicating that a co-suspension was formed. While some turbidity and floating flocs were observed in this configuration, similar turbidity, and fioc frequency w. ere observed in the Ficolkonly control vial, Table 13 Summary of tested configurations and results of observations Conainer Contents in pendi Us Io Notes, Co ID 10 mL o134a Partide t 10 C suspension Particle Ratio 62 Container Contents in Suspending Gbservational Notes, Go ID 10 mL p134a Particle to - 10 C suspension Active Particle Ratio 0-FF K9 m 2 FF n/a Creamed to top n 60 nmg na Setted to bottom na trehainse T FF60 mg 67 Sed ment layer: no particdes Yes treadose. OS creamed C 60 mg HP4% rua Settled to bottom; some n/a C FE 60 mg HRIf 67 Solis mostly in sediment layer partial cyclodextrn [at bottom; some turbidity; sonic 1 60 nig nin nra Settled to bottom; some n/a ik_ _turbidity 6 nip nui paen y F 60 mg Fico na Setted to bottomith some n/a _______ P M70 ______ foatngjflocs ______ FF 60 mg Pico Sedinent layer; very few Yes PM70. O> mg floating floes FF Example 15 [01931 (o suspension compositions including glycopyrrolate (GP) and formoterol furnarate (FE) active agent particles were produced and MDis incorporating the co suspension compositions were prepared. The co-suspension compositions produced included GP active agent particles, FE active agent particles or a combination of both GB and FE active agent particles. The GP and FE material was suppled as miicronized, crystalline material with particle size distribution as shown irn Table 14 [0194] Suspending particles were manufactured via spray dried emulsion at a teed stock concentration of 80 mg/mL with a composition of 93 44% DSPC (1 2 Distearoyl-sn -Glycero-3Phosphocholine) and 6,56% anhydrous calcium chloride (equivalent to a 21 DSPC:CaC mole/mole ratio). During the emulsion preparation DSPC and Ga was dispersed with a high shear mixer at 8000-10000 rpm in a vessel containing heated water (80 ±3 C) with PEGB slowly added during the process. The emulsion was then processed with 6 passes in a high pressure homogenizer (10000-25000 psi) The emulsion was then spray dried via a spray dryer fitted with a 042 atomizer nozzle with a set atomizer gas flow of 18 SCEM 63 The drying gas flow rate was set to 72 SCEM with an inlet temperature of 135 'G, outlet temperature 70 *C, and an emulsion flow rate of 58 mb/nin [0195] The co-suspensions were prepared by first dispensing the appropriate quantities of micronized GP and FF active agent particles and suspending particles into a drug addition vessel (DAV) inside a humidity controlled chamber (RH < 5%). In the present Example, the suspending particles were 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 (Ineos Fluor, Lyndhurst, UK) A slurry was then formed by adding 05bi kg of HFA.i 4,3 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 add itional HFA 134a to form the final suspension at target concentration stirring gently with an impeller, The suspension is then recircuiated via a pump to the filling system for a minimum time prior to initiation of filling. Mixing and recirculation continue throughout the filling process. 50 pL vales ( Bespak, King's Lynn UK) are placed onto 14mL fluorinated ethylene polymer (PEP) coated aluminum canisters (Presspart, Blackburn, UK) canisters and then purged of air either by a vacuum crimping process, or an HFA4 3a purging process followed by valve crimping. The crimped canisters are then filled throughdthe-valve with the appropriate quantity of suspension adjusted by the metering cylinder. Table 14: Glycopyrrolate and Formoterol Fumarate particle size distibutions. Designation d 10 pm . (pm) d pm Span FAPI t6 { 1.9 41 1.8 GP API 05 1. o, 1.9 [0196) MDIs containing the dual coasusoensions described in this Exarmple were prepared to contain two different doses GP and FF Specifically, a first run of dual co-suspension compositons were prepared to provide 18 pg per actuation GP and 4.8 pg per actuation FF ("low dose"), and a second run of dual co-suspension compositions were prepared to provide 36 pg per actuation OP and 4,8 pg per actuation FF ('high dose"). In addition to the dual cosuspensions compositions, co 64 suspensions including a single species of active agent particle were prepared. These compositions included either GP active agent particles or FF active agent particles and were referred to as 'mono" or >monotherapy" co-suspensions. The monotherapy co-suspension compositons were prepared as described for the dual co-suspensions, except that they induded only one species of active agent particles (either GP or FF). The monotherapy co-uspensions were formulated and monotherapy MDIs prepared to provide the foiowing targeted delivered doses 18 pg per actuation of GP, and 05, 1.0, 3.6 or 4.8 pg per actuation of FF. The compositions and MDIs providing 0.5 pg FF and 1 pg FF per actuation are referred to as ultra iow dose and were manufactured in a similar manner at a 4L scale [0197] The drug specific aerodynamic size distributions acnieved with Mls 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 low and high dose dual co-suspensions as well as the equivalency between the dual and monotherapy co-suspensions is demonstrated in Figure 21, In the same manner the proportionally of the aerodynamic size distributions of FF obtained from the dual and monotherapy co suspensions, including the ultralow, low, and high dose compositions is demonstrated in Figure 22 [0198] The delivered dose uniformity of the ultra low dose FF monotherapy MI11s was also measured as described in Exampe I, The DDU for the FF MDI containing 0,5 pg per actuation and 1,0 pg per actuation are shown in Figure 23. Desirable dose delivery uniformity is achieved even at ultra low doses. Example 16 [0199] Micronized salmetero an afoate (4 -hydroxy-o -[[[64 phenylbutoxy)hexyllamino] methyl] -1, 3-ben zene di methanol, I -hydrox2 naphthalenecarboxylate) was received by the Sanufacturer (Inke SA Germany) and used as active agent particles. The particK size distribution of the salmeterol xinafoate (SX) was determined by laser diffraction. 50% by volume of the micronized particles exhibited an optical diameter smaller than 2 pm, 90% by volume exhibited an optical diameter smaller than 3.9 pm. [0200] Suspending particles were manufactured as follows: 150 mL of a fluorocarbon-in water emulsion of PFOB (perfluoroctyl bromide) stabilized by a 65 phospholipid was prepared. 12.3 g of the phospholipid, DSPC (I .2-Distearoyl-sn Glycero&3Phosphcholine), and 12 g of calcium chloride were homogenized in 100 mL of hot water (70 "C) using a high shear mixer, 65 mL of PFOB were added slowly during homogenizabon. The resulting coarse emulsion was then further homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA) at pressures of up to 140 MPa for 3 passes [0201] The emulsion was spray dried in nitrogen using the following spray drying conditions: Inlet temperature 90 *C, outlet temperature 69 *Cemulsion feed rate 2.4 mL/min, total gas flow 498 Imn, The partide size distribution of the suspending particles, VMD, was determined by laser diffractin 50% by vome of the suspending particles were smaller than 2pm the Geometric Standard Deviation of the distribution was 2.0. Additionally, the aerodynamic partide size distribution of the suspending particles was determined wth a time-ofilight particle sizer. 50% by volume of the suspending particles had an aerodynamic particle diameter smaller than 1.6 prm. The large difference between aerodynamic pericle diameter and optical particle diameter indicates that the suspending particles had a low particle density < 0.5 kg/L [02021 Metered dose inhalers were prepared by weighing 2 mg of SX active agent particles and 60 mg of suspending particles into fluorinated ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) with 19 mL volume. The suspending particle to actie particle ratio was 30 The target delivered dose assuming 20% actuator deposition was 10 pg. The canisters were crimp sealed with 63 p valves (i BK 357, Bespak, King's Lynn, UK) and filled with 10 mL of HFA. 134a (144 /2-etrafluoroethane) 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. mm orifice (4 BK 636, Bespak, King's Lynn, UK). Additionalinhalers for visual observation of suspension quality were prepared using 15 rnt glass vials including a comparator filled with mieronized SX only Aerosol performance was assessed as described in Example 1, The MMAD was 37 pm and the fine particle fraction was 48%. Because the SX crystals forming the active agent particles and the propellant were nearly density matched at 15 0 - 20 C, the visual observation was conducted on glass vials that were heated up to 30 3$ *'C in a water bath. 66 Under these conditons the SX active agent particles formulated alone sedimented rapidly, but no SX crystals were visibLe at the bottom of the co-suspension vial [0203] Micronized salmeterol xinafoate active agent padres were co-suspended through association with suspending particles of low density that were formulated according to the disclosure provided herein, The association between salmetero crystals and the suspending particles was strong enough to overcome buoyancy forces as it was observed that settling of the crystals is inhibited. Example 17 [02041 Micronized fluticasone propionate (S fluoromethyl)69-ifuoro -1 7 d ihyd roxy 6%ethyPoxoandrosta~4edene47carbothioatea I propionate) was received as micronized by the manufacturer (Hovione FarmaCiencia SA, Loures Portugal) ard used as active agent particles. The particle size distribution of the kitcasone propionate (FP) was determined by laser diffraction. 50% by volume of the micronized particles exhibited an optical diameter smaller than 2. pm, 90% by volume exhibited an optical diameter smaller than 6.6 pm, [0205) The suspending particles were the same lot that was used in Example 16, and the manufacture and characteristics of the suspending particles are described there. [0206] Metered dose inhalers were prepared as described in Example 16. Propellant typefill weights; suspending particle tO active particle ratio, and target ex actuator dose for six configurations are listed in Table 15 Additional inhalers for visual observation of suspension quality were prepared using 15 mL glass vials. Two comparator glass vials were filled wi micronized FP only in either HFA 134a or HFA 227ea Table 15: Configurations Example 17 and aerosol performance FPfillj Susp-endinq Targe ex EPE in MI lAD HFA weight in particle to actuator % n pm mg active dose in pg 67 partde rato 9A 134a 34 4n - 8 7.5 40 -- 9B 227ea 31 4,6 9C 134 33 4 S 16 375 80 9D 227ta 36 4 5 E 34a, 3049 30 2 150 9a 31 49 [0207 Aerosol performance was assessed as described in Example The results are shown in Table 15, These co-suspensions were made with micronized FP that had a relatively coarse partice size distribution. The MMAD is comparatively large and trends upward with increasing FP concentration, but is still in a range usable for respwiatory drug delivery, No significant differences were observed between propellant types. [0208 Visual observation of the co-suspe.nded configuratins in HFA 134a PA. 9C, and 9E, showed no sedimentation of drug crystals fuming the active agent parties. The suspension flocculated slowly and formed a homogeneous, single cream layer. In contrast, microrized FP in HFA 134a sedimented. The test for the configurations in HFA 227ea was conducted at 35-40 C as described in Example 16, because FP is nearly density matched with this propellant at room temperature. At the elevated temperature, micronized FP active agent particles sedirnented in HFA 227ea, but no sedimentation of active agent particles was seen in configurations 9B, 9D and 9F. The results show that fluticasone propionate forms co-suspensions with suspending particles in both tested propellants when formulated according to the disclosure provided herein. [0209] The formulation of a combination product of salmeterol xinafoate (SX) active agent particles and fluticasone propionate (FP) active agent particles in a co suspension format is described, Both FP and SX are present in the propellant as a micronized, crystalline parties. The two species of micron sized active agent particles are co-suspended with spray dried suspending particles. 68 [0210] The ftuticasone propionate and salmeterol xinafoate used were as described in Examples 16 and 17, respectively. [0211] The suspending particles were the same lot that was used in Example 16, and the manufacture and characteristics of the suspending particles are described there. [0212] Metered dose inhalers were prepared by weighing the target masses of miaronized fluticasone propionate and salmeterol xinafoate and suspending particles into fluorinated ethylene polymer (FEP) coated aluninur canisters (PresSpart, Blackburn, UK) with 19 mL volume, The canisters were crimp sealed with 63 pI valves (# BtK 35 Bespak, King's Lyin, UK) and filed with 10 mL of FFA 34a (1;112,letrafluoroethane) (Ineos FluoLyndhurst UK) by overpressure through the valve stern After injecting the propelant 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 03 mm orifice (# BK 636, BespaR, King's Lynn, UK). Aerosol performance was assessed shorty after manufacturing in accordance with USP 601 as previously described in Example 1. Results are reported below in Table 16. Table 16. Results for a co suspension of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) of Example 18 Suspending Target Targe t FP FP SX FP SX particle Delivered IDeivered DDDU DU F F MMAD MMAD conc Dose FP Dose SX 5 9 mg.ntP n 12 pg 25 pg 61% 6 i 27% -49% 4.1 pm 3.4 pm *no trend observed [0213] The MMADs of fluticasone propionate 6Ltive egent parties and salmeterol xinafoate active agent particles were acceptable and similar to the aerosol performance of the respective monotherapy co-suspensions, described in Examples 16 and 17, respectively. The delivered dose uniformity through use was tested and all individual delivered doses were within ±20 % of meant 6. 1% relative standard deviation. 69 [0214] Visual' observation of the co-suspension was conducted in glass vials as described in Exarm ple 16, No sedimentation of active agent patices was observed, The suspension flocculated slowly and formed a homogeneous, single cream ayer, xanmpe 19 [02151 The formulation of a combination product of salmeterol xinafoate (SX) active agent particles and fluticasone propionate (FP) suspending patties in a co suspension format is described. SX is present in the propellant as micronized, crystalline active agent particles. It is co-suspended with spray dried suspending particles that incorporate micronized FP To achieve IhisEP crystals are suspended in the feedstock used to manufacture the lpid-based suspending particles, [0216] The fluticasone propionate and salmeterol xinafoate used to form the active agent particles and suspending particles referenced in this example were as described in Examples 16 and 17 respectively. [0217] Fluticasone propionate containing suspending particles were manufactured as follows: 200 mL of a fluorocarbonin-water emuision of PFOB stabiized by a phospholipid was prepared, 3y3g of the phospholipid (DSPC) and 0.8g of micronized fluticasone propionate were dispersed and 03g of calcium chloride dihydrate was dissolved |in i OmL of warm water (70"C) using ahigh shear mixer, 44mL of PFOB was added slowly during dispersion, This resulting coarse emulsion was then further homogenized using a high pressure homogenizer at 140 MPa for 3 passes, The homogienization-r reduced the particle size of the suspended FP crystals, The emulsion was spray dried in nitrogen using the following spray drying conditions inlet temperature 95 *C:outlet temperature 72 -C; emulsion feed rate 2.4 m Jmin and total gas flow 525 Lmin [0218] Metered dose inhalers were prepared by weighing the target masses of rnicromized salmeterol xinafoate active agent particles and futicasone propionate containing suspending particles into fliuornated ethylene polymer (FEP) oated aluminum canisters (Presspart, Blackburn, UK) with 19 mL volume, The canisters were crimp sealed with 63 p1 valves (# BK 357, Bespak, King's Lynn, UK) and filled with 10 mL of HFA 134a (IV-tetluoroethane) (Ineos Fluor, Lyndhurst UK) by overpressure through the valve stem, Aftrinjecting the propellant, the canters were sonicated for 15 seconds and agitated on a wrist action shaker for 30 minutes. The canisters were fitted with polypropylene actuators with a 03 mm orifice (# BK 70 636, 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 17. Table 17: Results for a Co-suspension of Sarneterol Xinafoate (SX) Active Agent Particles with Fluticasone Propionate Containing Suspending Particles. FP- Target Target FP SX FP SX FP SX Suspending Delivered De ivered DDU DDU FPF FPF MMAD MMAD concs_ Dose FP_ Dose SX 4.2 mg/nL 60 pg 13 pg 9,0% 13% 55% 151% 2.8 pm 3.0 pm

RSD

t RSD *with a slight upward trend [0219] The delivered dose uiformity through use was tested and all individual delivered doses were within 25% of mean, at 9 0% RSD for FP and 13% RSD for SX. 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, showing no indication of separation of SX and suspending particles Example 20 [02201 Budesonide, I6,17-(butylidenebis(oxy))4-11,21 -dihydroxy-, (1 1 -6 pregna-1 4-diene-3,20-dione. was received micronized by the manufacturer (AARTI. Murnbai, India) and used as active agent particles The particle size distribution of the budesonide was determined by laser diffraction, 50% by volume of the nicronized particles exhibited an optical diameter smaller than 1.9 pm, 90% by volume exhibited an optical diameter smaller than 4 3 pm [0221] Mometasone furoate, c21-Dichloro-1113,17-dihydroxy-16a-methylpregna I,4-dien e-3,20-dione 17-(2-furoate) was received micronized by the manufacturer (AARTI, Mumbai, India) and used as active agent particles The particle size distribution of the budesonide was determined by laser diffraction 50% by volume of the micronized particles exhibited an optical diameter smaller than 1,6 pm, 90% by volume exhibited an optical diameter smaller than 3.5 pm, 71 [0222] Suspending particles were manufactured as described in Example1 The emulsion was spray dried in nitrogen using the following spray drying conditions: Inlet temperature 95 *C, outlet temperature 72 'C, emulsion feed rate 2,4 mL/min, total gas flow 498 Limin. [0223] Metered dose inhalers were prepared by weighing the target masses of micronized active and suspending particles into oaOted glass vials with 15 mL volume, The canisters were crimp sealed with 63 p1 valves (Valois, Les Vaudreui, France) and filled with 9.2 g of HFA 134a (1*2tetrafluooethane) (Ineos Fluor, Lyndhurst, UK) 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 orifice (# BK 636, Bespak. King's Lynn, UK) Aerosol performance was assessed shortly after manufacturing in accordance with USP <60l> as previously described in Example 1, The suspension concentrations were o.8 mg/mL for budesonide active agent particles, 1I mgi/mL for mometasore furoate active agent particles, and 6 mgrnkL for the suspending parties. The suspending particle to active agent particle ratio was 7.5 for budesonide and 5,5 for mometasone furoate Target ex actuator doses were 40 pg for budesonide and 55 pg for mometasone furoate. [0224] Visual observation of the co-suspended configurations showed no sedimentation of active agent particles. The suspensions flocculated and formed a cream layer The vials were left to settle for 16 h without agitation. No active agent particles were visible at the bottom of the co-suspension vials, The association between active agent particles and suspending particles was s t rong enough to overcome buoyancy forces as settling, of the active agent particles was successfully inhibited. Example 21 [0225] An exemplary co-suspension composition as described herein was prepared and evaluated. The composition included a combination of glycopyrrolate (GP) and formoterol fumarate (FF) active agents GP vas present in the propellant as micronized, crystalline active agent particles. It was co-suspended with spray dried suspending particles that included FF disposed within the mateal forming the 72 suspending particle. To achieve this, FF was dissolved in the feedstock used to manufacture the lipidbased suspending particles. [0226] GP active agent particles were formed by mironizing glycopyrrolate using a jet mill The partie size distribution of the glycopyrrolate active agent particles was determined by laser diffraction 50% by volume of the active agent particles exhibited an optical diameter smaller than 1 7 pm, and 90% by volume exhibied an optical diameter smaller than 35 pm. [0227] FF-containing suspending particles were manufactured as follows: 654 mL of a fluorocarbon in-water emulsion of PFOB (perfluorooctyl bromide) stabilized by a phospholipid was prepared 265 g of the phosphoipid SP (2 disteroy -sn glycero-&phosphocholine),and 24 g of calcium chloride were homogenized in 276 mL of hot water (S0*G) 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, CA) at pressures of up to I0 M a for 5 passes. 552 mg FF was dissolved in 273 mLof waarm water (50"C) and most of the solution was combined with the emulsion using a high shear mixer. The emulsion was spray dried in nitrogen using the following spray drying conditions; inlet temperature 95"C; outlet temperature 680; emulsion feed rate 24 mL/min; and total gas flow 498 /min, The final mass fraction of formnoterol in the spray dried powder was 2%' [0228) A second lot of FF-containing suspending particleswas 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 parties was manufactured without FF [0229] The particde size distribution of the suspending parties (VMD) was determined by laser diffraction. For both lots of FE containing suspending particles, 50% by volume were smaller than 3.5 pm 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 vas 1.8. [0230] MDIs were prepared by weighing the target masses of active agent partices and suspending parties into fluorinated ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) with a 19 mL volume, The canisters were crimp sealed with 63 p1 ales (# BK 357, Bespak King Lynn, UK) and filled with 12.4 g of HFA 134a (1,1 1 2derafluoroethane) (Ineos Euor, Lyndhurst, UK) by 73 overpressure through the valve stern. The resulting suspension concentrations and the target delivered dose assuming 20% actuator deposition are given in Table 18a for three different configurations (configurations IA through 1) After injecting the propellant the canisters were sonicatad for 15 seconds and agitated on a wrist action shaker for 30 minutes. The canisters were fitted with polypropylene actuators with a 0.3 nm orifice (# BK 63& Bespa Kings Lynn, UK). Tabie 18,: Configurations of the glycopyrrolate - formoterol fumarate combination co-suspensions of Example 21 Suspending Suspending Suspending Ex actuator GP Particle 1 Particle 2 Particie to dose Active Cs FF Cs GP # Cs [mgmL Particde FF [pg] [cnig mLJ content [ipg] IA 19% 32 6 I 0,48 1.0% 64 133 240 3 IC 19% 32 3.2 133 [0231J The filled MDis were stored valve down at two different conditions refrigerated at 5*C without overwrap and controled room temperature at 25 C!60% RH with a foil overwrap. Aerosol performance and delvered dose uniformity tests were carried out at different time points Aerosol performance was assessed shorty after manufacturing in accordance with USP <601>. A Next Generation lrnpactor (NG) operated at a flow rate of 30 L/min was used for determination of parties size distribution. Sample canisters were seated into an actuator with two waste actuations and two additional waste pricing actu nations. Five actuations were collected in the NG with a USP throat attached The valve, actuator throat, NGI cups, stages, and filter were rinsed with volumetrically dispensed solvent. The sample solutions were assayed using a drug-specific chromatogrphic method, The fine particle fraction was defined using the sum of stages 3 throughfilter Delivered dose uniformity through use testing was performed using a Dose Uniformity Sarnplng Apparatus as described by USP <601>. whalers were seated and primed '74 as described before. Two actuations were collected and assayed at beginning, middle and end of use. [0232] No trends in aerosol performance or delivered dose uniformity were observed for the duration of the study (3 months) or as a function 0f storage temperature Hence, all aerosol performance test results were pooled Table 18b lists the average performance of the different configuration The fine oaricle dose is the sum of collected mass on stages 3 to filter of the impactor normalized by the metered dose. The average aerosol performance for all three configurations was equivalent. Tabl I1b: Average aerosol performance for combination co-suspensions in Example 21 !,'M IAD0 in m FPD in % # FF OP FF GP IA 2.3 34 52 44 1B 2.9 3.6 51 45 IC 2,9 6 51 45 [0233] Dose content uniformity was tested through canister life for both actives of the combination product, Figures 24 and 26 show the ex-actuator dose for configuration IA and 1B, respective, 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 GP doses are represented by dots and triangles, respectively. The closed line denotes the mean of the formoterol doses, and the broken line denotes the mean of the glycopyrrolate doses. Figures 25 and 27 show the ratio of the normalized ex actuator doses for configuration 1A and 1B respectively. 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 co-uspension with a consistent carrier to active ratio was formed and maintained through container life. [0234] The resul t s show that; when fon1iulated according to the discosue provided herein, combination product co-sus tensions ae formed with suspending particles containing one of the active pharmaceutical ingredients, in this case FF 75 Suspending particle to acive agent partcle ratios can be adjusted to achieve targeted dose content uniformity while maintaining similar aerosol performance Exame 2 [02351 MDIs containing FF and GP were prepared to provided target delivered doses of 2,4 and 18 pg per actuation FF and GP, respectively. GP active agent was micronized and had a do, d, dan and span of 06, 1 36 and 1 9 pm respectively as measured by laser diffraction as described Example 21FF was incorporated into spray dried suspending particles and prepared as described in Example 21, with a composition of 2% FF 91 5% DSPO and 6.5% Pa he OP, FF and OP + F MDIs were prepared by weighing the target masses of active agent parties and suspending particles into fluorinated ethylene polymer (FEP) coated aluminum canister (Press.art Blackburn, UK) with a 19 mL volume. The canisters were crimp sealed with 50 p valves (# BK 357, BespaK Kings Lynn, UK) and filled with 10.2 g of HFA 134a (11 tetrafluoroethane) (ness Fluor, lyndhurst UK) by overpressure through the valve stem. After injecting the propellant, he 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 03r mm orifice (# BK 636, Bespak. King's Lynn, UK), [0236] Long term stability and delivery characteristics of these 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 <601> as described in Example 21, under various conditions and, in some instances, for periods of time extending up to 12 months For example, as is shown in Figure 28, the delivered dose uniformity provided by the compositions prepared according to Example 21 was substantially preserved, even after 12 months storage of such compositions at 15C or after 4.5 months at 25 "C and 60 %relative humidity (RH)for samples stored inside aluminum foil pouches to minimize water ingress into the MD canister (i.e., 'protected storage') [0237] 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 months, As is shown in. Figure 29, the GP and FF particle size distributions provided by this co-suspenson composition were substantially preserved after 12 months of protected storage at SC and six months 76 of unprotected storage conditions at 2OC and 60% RH. As is shown in Figure 30, even under stressed conditions (40"C 75% RH), the compositions showed no noticeable degradation in the particle size distribution of GP and FE delivered from the metered dose inha'ers after six months. [0238] As can be seen in Figure 31 the aerosol performance of the combination co-suspension composition including both GP and FF active agent was no different than the aerosol performance achieved by a suspension compositin including FF alone or a co-suspension composition containing GP alone, demonstrating that the aerosol properties of the individual active agents are substantially the same when achieved fom the single component or dual combination co-uspensions. Exam ple 23 [0239] An exemplary dual co-suspensicn crnposition according to the present description was produced and metered dose inhalers incorporating the composition were prepared. The composition included a combination of glycopyrrolate (GP) and formoterol fumarate (F) with each being provided as a micronized, crystalline material. A combination crystalline co-suspension MDI was manufactured by semi automated suspension filling, The dual co-suspension consisted of a combination of two microcrystalline active pharmaceutical ingredients (also referred to as }:AP1s or "API" in the singular), GP and FF, co-suspended with suspending particles in HFA 134a propellant. The dual co-suspension was formulated to provide a delered dose of 18 pg GP per actuation and 438 pg FF per actation, 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 fine] Whether the co-suspension conpositions incorporated coarse or fine FF the compositions were formulated to provide a delivered FF dose of 42 pg per actuation. The particle size characteristics for the coarse FE, fine FF and GP API materials used in formulation the co-suspension compositions described in this Example are detaied in Table 19, In addition to the dual o-suspension compositions, a monotherapy co-suspension composition incorporating only FF active agent niaterial was formulated. The FE 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 4,8 pg FF per actuation. 77 [0240] Suspending particles were manufactured via spray dried emulsion at a feed stock concentration of 80 mg/mL with a composition of 93 44% DSPC (1 2 Distearoyn -Glycero-Phosphocholine) and .56% anhydous calcium chloride (equivalent to a 2,1 DSPC:CaC, mole/mole ratio). During the emulsion prep DSPC and CaOC 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 6 passes in a high pressure hormogenizer (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 SCFR The drying gas flow rate was set to 72 SCFM with an inlet temperature of 135 'G outlet temperature 70 'G, and an emulsion flow rate of 58 mL/min [0241] For the MDI manufacturing drug addition vessel (DAY') was prepared for suspension filling in the following manner: first adding half of suspending particle quantity, next filing microcrystalline materials, and lastly adding the remaining half of suspending particles to the top, Materiais were added to the vessel in a humidity controlled 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 back to the suspension mixing vessel and diuted with additional HFA-134a to form the final suspension at target concerration stirring gently with an impeller. The temperature inside the vessel was maintained at 21-23 *C throughout the entire batch production After recirculation for 30 min the suspension was filled into 14 mL fluorinated ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) through 50 p 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 micronized formoterol partcdes was determined by laser diffraction as described in Example 1, Table 19 lists the d d and d 9 x values for the different lots of micronized material used. d, d&, and d: denote the parties size at which the cumulative volume distribution reported by the particle sizing instrument reaches 10% 50% and 90% respectively. [0242] The parties size distributions provided by both dual co-suspension formulations prepared in accordance with this Example were compared to the parties size distribution provided by co-suspension compositions prepared according to Example 21, The results of this comparison are provided in Table 20, where e 78 %FPF FF" and "%FPF GP' represent the fine particle mass of the specified ctive agent on Stages 3 through filer of an NGl. divided by actuator mass, and multiplied by 100. Tabie 19: Particle Size Distributions for micronized Formoterol Fumarate and Oycopyrrolate used to prepare Dual Co-Suspensions Designation dt (pm) dc (pm) dw (pm) Span Coarse FF AP1 0.6 1.9 44 2,0 F ne FF AP 01 2.3 1,5 GP AP 0. 13 359 Table 20: Particle Size D strnbutions for Different, Exemplary GP/FF Co-suspensions MMAD MMAD %FPF MMAD %FPF FFP GP GP DSPC DSPC Dual Co FOPP DPGSO Suspension 1 34 59% 2.9 65% 29 64% (FF coarse) D ual Co- Suspension 2 27 62% 62% 3.1 62% FF fine) Spray-dred FF 23 66% 2,9 65% iot tested not tested [0243] The aerosol performance of the dual co-suspension compositions prepared according to this Example was evaluated and compared to the cou suspension composition prepared according to Example 21 with aerosol performance being determined in accordance with USP <601> as described Example 1. The results of such comparisons are provided in Figure 32 through Figure 34, As is easily appreciated by reference to these figures, regardless of whether the crystalline fornoterol mateia used in providing the dual co-suspension was fine or coarse, the FE and GP particle size distributions for the dual co suspension compositions were substantially the same as those achieved by the co 79 suspension composition prepared according to Example 21 where FE is incorporated into the suspending particles via spray drying, [0244] In addition, the delivered dose uniformity for GP and FF provided by the dual co-suspension compositions as described in this Example was assessed determined in accordance with USP <601> as described Example 1, The results of this assessment ae lustrated in Figure 35, The dual co-suspension formulations provided desirable DDU characteristics for both GP and FF as al actuations delivered the expected dose within 25% of the mean. E example 24 [0245] Dual co-suspension compositions were prepared with suspending particles including either mometasone furoate (MF) or budesonide (BD) and MDIs incorporating the composition were prepared The tdple co-suspension composition included a combination of crystalline glycopyrrolate (GP) and forrmoterol fumarate (PF) active agent particles cosuspended th suspending particles including either MF or BD, Each of the APIs were provided as a micronized crystalline material [02461 Suspending particles containing 50% (w/w) of either BD or MF were manufactured as follows: high shear homogenization of a dispersion containing 2,8 g of DSPC Q ,2-DistearoyksneGlycero-3-Phosphocholine), and 020 g of calciurn chloride in 400 mL of hot water (75 'C) using a high shear mixer was performed while 56,6 g of PFOB were added slowly. Mirnized MF or ED (in 1:1 weight proportion to DSPC) was added to the resulting coarse emulsion, which was further homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA) 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 C outlet temperature 95-72 *C emulsion feed rate 2-8 mtirn total dry nitrogen flow 525 850 LImin. The particle size distribution of the resulting powders was determined by laser diffraction, 50% by volume of the suspending particles were smaller than 1 8 pm, the span of the distribution was I pm. MDI canisters containing either 50% (w/w) MF or BD containing suspending particles were prepared, targeting a 50 or 100 pg per actuation of ME or BD, respectively, Metered dose inhalers were prepared by weighing the target masses of active agent containing suspending particles and in sonc cases additional suspending particles, to reach a total suspension concentration of 5.5 mg/mL into fluorinated ethylene 80 polymer (FEP) coated auminum canisters (Presspa, Blackbum, UK) with 14 mL volume, The canisters were crimp sealed with 50 p valves (Bespak, King's Lynn, UK) and filled with 10 mL of FEA 13i4a (1 1,2tetrafluoroethane) (Ineos Fluor, Lyndhurst. UK) by overpressure through the valve stem. After injecting the propellant, the canisters were sonicated for 1$ seconds and agitated on a wrist action shaker for 30 minutes, The canisters were fitted with polypropylene actuators with a 0.3 mm orifice (Bespak, King's Lynn, UK). [0247] The aerosol particle size distributions of the above MDIs were determined in accordance with USF <601> as described in Example and results are shown in Table 21. A comparable series of canisters containing MF or BD containing suspending particles in combination with GP and FF active agent particles were produced. Sufficient micronized GP and FE API material was added to such canisters in amounts sufficient to provide targeted delivered doses of 36 pg per actuation and 6 pg per actuation for GP and FF, respectively In some cases, additional suspending part cles prepared as described in Example 1 were added to reach a total suspension concentration of 5.5 mg/mL [0248] The aerosol particle size distributions of the above triple co-suspension MDIs were determined in accordance with USP <601> as described in Example 1, with the results are shown in Table 22. Comparison of results in Table 21 and Table 22 demonstrate that the mass mean aerodynamic diameter of the corticosteroid in the single component suspensions is equivalent to the one obtained in the corresponding triple combination compositions As was true 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, In addition the fine partcle fractions of the microcrystalline active agents are mostly independent of the type of the corticosteroid in monotherapy or triple combination compositions, even though the doses per actuation of MF or BD are substantialy different. Table 21. Suspension MDIs in FEA 134a propellant containing cortcosteroid suspending particles, Aerosol properties mass aerodynamic diamete and fine particle fraction determined by drug specific cascade impaction Suspension. MMAD FPF 81 1 (my/m) 552,88 61 0 Furoate Budesormde I32 1 3-&20 61.7 Table 22: Tr pIe combination suspension MDIs in HFA 134a prope:antincuding corticosteroid containing suspending particles (Mometasone Furoate or Budesonide), a LAMA (Glycopyrrolate) and a LABA (Forrnoterol Fumarate), Mass mean aerodynamic diameter and fine partcle fraction determined by drug specific cascade impaction. MMAD FPF Concentration Drug (pm) (%) 44A Formoterc 3.96 Triple A 2. Gycopyrrolate 3.71 249, 0Momeitaso Z-S01-0290 44A4 Formoterc 352 Triple B* 5,6 3,yopyroate 344 (-with added suspending suspending parties) Moetasne 2.54 616 Formotero ~ 33 47 Trip e C lyopyrrolate 374 50 0 Budesonide Example 25 [0249] Metered dose nhalers containing a triple co-suspension composition were prepared according to the present description. The composition included a combination of glycopyrrolate (P, formnoteul fumerate (FF.), and momnetasone furoate (MF) active agent particles, with each being provided as a micronized, crystalline AP material 82 [0250] A triple co-suspension MDI was manufactured by semiautomated suspension filling. The triple co-suspension consisted of a combination of three microcrystalnfie active pharmaceutical ingredients forming three different species of active agent particles: MF (corticosteroid) GP (LAMA) and 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 pg per actuation GP; and 4.8 pg per actuation FP. In addition to the triple co-suspension, a nonotherapy co-suspension including only MF was produced. The monotherapy MF co suspension included MF active agent particles co-suspended in the propellant with suspending particles as described in this Example, and was formulated to provide a target delivered dose of 50 pg per actuation MF [02511 Suspending particles were manufactured via spray dried emulsion at a feed stock concentration of 80 mg/mL with a composition of 9344% DSPC (12 Distearopi-sn-Glycero-3-Phosphocholine) and 6 s6% anhydrous calcim chloride (equivalent to a 21 DSPC:CaCl loe/mole ratio) During the emulsion prep, DSPC and CaOl 2 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 5 passes in a high pressure homogenizer (1000025000 psi), The emulsion was then spray dried via a spray dryer fitted with a 0A2" atomizer nozzle with a set atomizer gas flow of 18 SCM, The drying gas flow rate was set to 72 SCFM with an inlet temperature of 135 *C, outlet temperature 70 *C; and an emulsion flow rate of 58 mL/min. 0252] For MDI manufacturing, a drug addition vessel (DAV) was used for suspension filing in the following 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 vesselin a humidity controlled environment of <10% R. The DAV was then connected to a 4 L suspension vessel and flushed with HFA 134a propenand then mixed with a magnetic stir bar. The temperature inside the vessel was maintained at 21 -23 QC throughout the entire batch production. After recirculation of the batch for 30 min canisters were filled with the suspension mixture through 50 pL EPDM valves. Sample canisters were the selected at random for Total Canister Analysis to ensure correct formulation quantities, The freshly manufactured triple co-suspension MDI 83 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, Fluorinated ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) with 14 mL volume. The canisters were crimp sealed with 50 pI valves (Bespak, King's Lynn, UK) and filled with 10 mL of HFA 134a (I1 2 etatluoroethane) (Ineos Fluor, Lyndhurst UK) by overpressure through the valve stem. The canisters were fitted with polypropylene actuators with a 0.3 mm orifice (Bespak, Kingr's LynnUK), [0253] The primary particle size distribution of all microcrystalline APIs was determined by laser diffraction as described in Example 1 results are shown in Table 23. Aerodynamic particle size distribution and rmass mean aerodynamic diameter of al components upon actuation of the suspension MDIs was determined by drug specific cascade impaction in accordance with USP <601> as described in Example I and are shown in Table 24, Table 23: Triple microcrystalline Co~Suspension in HFA 134a propellant MDI. Primary particle size distribution determined by aser difracuin (Sympatec) Materials Spans p) ~ m ____ Micronized Mometasone 0422 22 Furoate (MF) Micronized Glycopyrrolate (GP) M icronized Formoterol 0,6 19 41 1.8 Fumarate Dihydrate (FF) Table 24: Triple co-suspension MDIs in HA 34a propellant containing microcrystalline Gorticosteroid (Mometasone Furoate) LABA (Formoterol Fumarate) and a LAMA (Glycopyrroate). Aerosol properties mass mean aerodynamic diameter and fine particle fraction were determined by drug specfi cascade impaction (NI). Suspension MA P Concentration Drug L Metasone 62 Triple M3.18 34 (Crtcoteoi, Formoterol 160A 59,5 LABA, LAMA 2.9 64A0 Glycopyrrolate Mono (Corticosteroid) Mometasone 3,36 58,9 [02541 Delivered dose uniformity and the aeroso performance achieved by the triple cosuspensions prepared according to this Example was evaluated in accordance with USP <601> as described in Example I. Figure 36 illustrates the DDU of GP, FF and MF achieved from two canisters contairng MF only and two canisters containing MF, GP and FE prepared according to this Example, The DDU of MF delivered from the MV rnonotherapy configuration Is equivalent to the one achieved with the triple co-suspension compostion, The aerosol particde size distributions achieved for FF and GP from the triple co-suspension comnposition of this Example was compared to the one achieved from a co-suspension containing two active agents, FF and GP prepared according Example 15. The aerodynamic particle size distribution of FE and GP are equivalent whether delivered from the compositions containing two active agents or three active agents as shown in Figures 37 and 38, respectively, thus the triple co-suspension compositions prepared according to the present description avoided a combination effect, Example 26 [0255) Exemplary triple co-suspension compositions according to the present description were produced and metered dose inhalers incorporated in the composition were prepared. The triple co-suspensions incuded glycopyrrolate (GP or tiotropiur bromide (TB) in combination with formotel fumarate (FE), and mometasone furoate (MF) active agents, with each API being used as micronized, crystalline material. [0256] Two separate suspension MDI batches containing three active pharmaceutical ingredients (APIs) a corticosteroid a LAMA and a ABA were prepared. The APIs were provided as miccrystalline materials that served as the active agent particles co-suspended with suspending particles prepared as described herein, The triple co-suspens ion compositions prepared as described in 85 this Example were prepared by adding the active agent particles and suspending particles to an HFA 134a propellant. [0257] The triple co-suspension containing glycopyrrolate (Triple GFM) was formulated to deliver 40 pg per actuaon ME; 13 pg ctuation GP; and 48 pg per actuation FF, The active agent particles were co-suspended with suspending particles manuactured using an emliOn composed of 93A6% DSPC 2 Distearoyk-sn-Glycero-Phosphocholine) and 6.54% anhydrous calcium chloride spray dried with an 80 mgmL tfeed concentration. The DSPCGCaCl molar ratio of the suspending particles was 21, The suspending particles were combined with the active agent particles in propellant for a formulation target suspending particle concentration of 6 mg/mL. The primary particle sizes of the microcrystalline ative agent parties, determined by Sympatec laser diffraction measurements as described in Example 1, are displayed below in Table 25. [0258] The triple co-suspension containing tiotropium bromide (Triple TFM) was prepared using anhydrous tiotropium bromide JB). The TFM triple co-suspension was formulated to deliver 50 pg per actuation ME; 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 co-suspension, and the active agent particles were co-suspended with the suspending particles at a targeted suspending particle concentration of 6 mg/mb. The primary particle sizes of the microcrystalline active agent particles, determined by Sympatec laser diffraction measurements as described in Exarnple 1, are displayed below in Table 26. [02591 The aerosol particle size distribution fine parties fraction, and mass rnedian aerodynamic diameter were determined for the triple co-suspension compositions described in this Examplein accordance with USP <601> as described in Example 1 Tab 27 sets out the MMAD and FPF performance for Tiple GFM and Triple TEM, while the desirable aerosol properties achieved by the Triple GEM and Triple TFM co-suspensions are shown in Figure 39 (showing the aerodynamic particle size distribution of GE and TB obtained fomn Triple GEM and Triple TFM, respectively). The fine particle fractions of the individual microcrystalline active agents, achieved in the triple formulations are remarkably similar in spite of differences in the size of the active agent particles, demonstrating the benefits of the compositions described in the present invention. 86 Table 25: Triple GFM priary particle size distribution of mironized crystalline drugs determined by laser diffraction (Sympatec). Materials do (pm) dw (pm) d(p Span Micronized Mometasone 04 10 2 9 Furoate ate 1A 3A 2.1 Glycopyrrolate051434 21 Micronized Formotero1 Pumarate Dihydrate Tabe 26: Triple TEM primary partice size distribution determined by laser diffraction Sympatec). IMaterials d 10 (pm) dso (pm) dgo (pm) ]Sa Micronized Mometasone 0.4 1 8 22 Furoate Micronized Tiotropium 3.9 2 Bromide Anhydrous Micronized Formoterol 19 41 1.9 Fumarate Dihydrate Tabe 27: Triple GFM and Triple TEM aerosol properties, mass mean aerodynamic diameter and fine partice traction deternined by drug specific cascade mpaction Suspension Concentration Drug MMAD FFP ___ __ ___ _ m~ p g Form oterol2 8 65.3 Triple GEM 6 Glycopyrrolate 2.90 49.5 Mometasone 3 10 49 2 Formoterol 3.82 42.4 Triple TFM 6 Tiotropium 379 42 0 Mometasone 4.00 436 87

Claims (24)

1. 5. A co-suspenson according to any of claims I through 3, wherein the active agent parties compose particles of active agent in amorphous form. 6, A co-suspension according to any preceding claim, wherein the active agent exhibits measurable solubility that results in dissolution selected from as much as I % of the total actve agen rnass i the suspension medium, as much as 0:5% of the total active agent mass in the suspension Medium, as much as 0,05% of the total active agent mass in the suspension medium, and as much as 0,025% of the total active agent mass in the suspension medium, 7, A co-suspension according to any of claims I through 5, wherein the total mass of the active agent that dissolves in the suspension medium is less than 5% of the total active agent mass in the suspension medium, 8, A co-suspension according to any preceding claim, wherein the plurality of active agent particles includes two or more different active agents,
2. 9. A co-suspension according to any preceding daim, wherein the active agent particles comprise an active agentselected from short-acting beta agonists, such as bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenolJ levosalbutamol, orciprenalne (metaproterenol, pirbuterol, procatero, rimiterol, saibutainol (albuterol terbutalIne, tulobuterol reproterol and epinephrine long acting beta agonists, such as bambuterod, cienbutero forrmoteroland salmeterol, 88' ultra long-acting beta agonistsi such as carmoterol, milveterol indacaterol, and saligenin~ or indole~ containing and adamantylkderived % agonists, corticosteroids' such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl prednisolone, mornetasone, prednisone and trimacinolone, anti-nflammatories, such as fluticasone propionate, bec:omethasone dipropionate flun isol ide, budesonide trpedane cortisone, prednisone dnisilone, dexamethasone, betamethasone, or triamcinolone acetonide antitussives such as noscapine, bronchodiators such as ephedrine, adrenaline, fenoterol, formoterol. isoprenaline, metaproterenol, salbutarmol, albuterol, sanetero. terbutaline, antichobnergics, such as glycopyrroiate, dexipirronium scopoamine, tropicaide pirenzepne, dimenhydrinate, tiotropium, darotropium.aclidiniurn, traspiurr ipatropiurn, atropine, benzatropin, or oxitropium, including any pharmaceutically acceptable saIts, esters, isomers or solvates thereof. 10, A cosuspension according to any preceding claim, wherein two or more active agents are included in the active agent particles and the two or rore active agents are selected from a combination of formoterol and budesonide, a combination of glycopyrrolate and formoterol, a combination of ciciesonide and formoterol, a combination of salmeterol and fluticasone, a combination of glycopyrrolate, fornoterol, and budesonide, and a combination of glycopyrrolate formoteroi, and mometasone, including any pharmaceutically acceptable salts, esters, isomes or solvates thereof. 11, A suspension according to any preceding claim, wherein the active agent is selected from potent and highly potent active agents. 12, A cosuspension according to any preceding claim, wherein the target delivered dose of active agent is selected from between about100 pg and about 100 mg per dose, between about 100 pg and about 10 mg per dose, and between about 100 pg and I mg per dose. 13, A co-suspension according to any of claims 1 through 11, wherenthe target delivered dose of active agent is selected from up to about 80 pg per dose, up to about 40 pg per dose, up to about 20 pg per dose, or between about 10 pg and about 100 pg per dose.
3. 14. A co-suspension according to any of claims 1 through 11, wherein the target delivered dose of active agent is selected from between about 0. and about 2 89 pg per dose, about 0.1 and about 1 pg per dose, and about 0 1 and about 0,5 pg per dose, 15, A co-suspension according to any preceding claim, wherein the suspending particles exhibit an MMAD selected from between about 10 pm and about 500 nm, between about 5 pm and about 750 nm, and 1 pm and about 3 pm. 16 A co-suspension according to any preceding claim, wherein the suspending particles exhibit a volume median optical diameter selected from between about 0.2 pm and about 50 pm, between about 0.5 pm and about 15 pm, between about15 m and about 10 pm, and between about 2 pm and about 5 pm
4. 17. A co-suspension according to any precedig clain, wherein the suspending particles are included in the suspension medium at a concentration selected from to about 30 mg/mL and up to about 25 mg/mL. 18 A co-suspension according to claim 17, wherein the suspending particles are included in the suspension medium at a concentration selected from between about 1 mg/nt to about 15 ng/n abo ut 3 mg/m L to about 10 mg/t, about 1.5 mq/mL to about 10 mg/mLI
5. 19. A co-suspension according to claim 17, wherein the active agent parties comprise glycopyrrolate, and the suspending parties are included in the suspension medium at a concentration selected from about 6 mg/mL, between about 3 mg/mL and about 10 mg/mt. and between about 1 mg/mt. and about 15 mg/mL
6. 20. A co-suspension according to claim 17, wherein the active agent particles comprise formotero and the suspending particles are invaded in the suspension medium at a concentration selected from about 3 mg/mL between about 1. mg/mL and about 5 mg/mt , and between about 05mg/nL and about 7 mglmL 21, A co-suspension according to claim 1 wherein the active agent particles comprise formotero and the suspending particles are included in the suspension medium at concentration selected from about 6 mg/tnL, between about 3 mg/mL and about 10 mgntLand between about 1 mg/mL and about 15 ig/mit.
7. 22. A co-suspension according to claim 17, wherein the active agent particles comprise salmeterol, and the suspending particles are included in the suspension medium at a concentration selected from about 5 mg/L between about 3 mg/nL and about 10 mg/mt. ,and between about I mng/nmL and about 15 mga/mt 90
8. 23. A co-suspension according to daim 17, wherein the active agent particles comprise budesonide, and the suspending particles are included i the suspension medium at a concentration selected from about 8 mg/mL between about 5 mg/mL and about 20 mg/m and between about 0.5 mg/mL and abou 30 rngmL,
9. 24. A co-suspension according to claim 17, wherein the active agent particles comprise fliuticasone, and the suspending particles are included in the suspension medium at a concentration selected from about 6 mg/mL, between about 3 mg/mL and about 10 mg/mL and between about 1 mg/mL and about 15 mg/mL
10. 25. A co-suspension according to any preceding claim, wherein the total mass of the suspending particles exceeds the total mass of the active agent particles, 26, A co-suspension according to claim 25, wherein the ratio of the total mass of the suspending particles to the totalmass of the active agent particles is selected from above about 1,5, upo about 5, up to about 10, up to about 15, up to about 20.p to about 30 up to about 50 up to about 7( p to about 100, up to about 150, and up to about 200.
11. 27. A co-suspension according to claim 25, wherein at least one of the active agents included in the active agent particles is a highly potent active agent and the ratio of the totali mass of the suspending particles to the total mass of the active agent particles is selected from between about 5 and about 175, between about 10 and about 150, between about 15 and about 125, and between about 25 and about 75. 23. A co-suspension according to claim 25, wherein the active agent particles include one or more of glycopyrrolate, fluti casone, mometasone and budesonide, and the ratio of the total mass of the suspending parties to the total mass of the active agent particles is selected from between about I and about 20, between about 5 and about 15, and about 10, 29, A co-suspension according to claim 25, wherein the active agent particles include one or more of fiuticasone mometasone, and budesonide, and the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about I and about 15, between about 1.5 and about 10, and between about 2.5 and about 5. 30 A co-uspension according to claim 25, wherein the active agent particles include salmeterol, and the ratio of the total mass of the suspending 91 particles to the total mass of the active agent parties is selected from between about 10 and about 30, between about 15 and about 25, and about 20, 31, A co-suspension according to claim 25, wherein the active agent particles include formoterol, and the ratio of the total mass of the suspending particles to the total mass of the active agent parties is selected from between about 10 and about 200, between about 50 and about 125, and about 75
12. 32. A cosuspension according to any preceding claim, wherein the suspending particles remain associated wih active agent particles even when subjected to buoyancy -forces amplified by centrifugation at an acceleration selected from acelerations of at .east I g, at least 10 g, at 50 g and at least '100 g. 33 A suspension according to any preceding claim, wherein the suspending particles comprise an excipient selected from the group consisting of lipids phospholipids, nonionic detergents, polymers, such as nonionic block copolymers, su rfactants, such as non-ionic surfactants and biocompatible fluorinated surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, and combinations thereof. 34, A co-suspension according to any preceding claim, wherein the suspending particles comprise active agent particles composing an excipient selected from the group consisting of lipids, phospholipids, nonionic detergents, polymers, such as nonionic block copolymers, surfactants, such as non-onic surfactants and biocompatible fluorinated surfactants carbohydrates, amino acids, organic salts, peptides, proteins, aditos, and combinations thereof.
13. 35. A co-suspension according to any preceding claim, wherein one or more of said plurality of suspending particles comprises an active agent. 36, A co-suspension according to any preceding claim, wherein the suspension medium comprises propellant substantially free of additional constituents.
14. 37. The co-suspension according to claim 36, wherein the propellant comprises a propellant selected from an H.FA opellanta PFC propellant and combinations thereof. 38, A co-suspension according to any of claims I through 35, wherein the suspension medium comprises propellant in combination with one or more constituents selected from a ntisolvents solubiliing cents, cosolents, adjuvants, PVP and PEG. 92
15. 39. A cosuspension according to any preceding claim, wherein the active agent particles are prepared by a micronization process selected from milling, grinding, crystaIiization, recrystal[izationand superritical or nea r-supercritica precipitaion processes, and the suspending particles are prepared using a spray drying process. 40, A metered dose inhaler comprising a canister with an outlet valve including an actuator for dispensing a metered volume said canister containing a cO suspension as defined in any of claims I through 39, wherein the metered dose inhaler exhibits a delivered dose uniformity CDDU") for the co-suspension formulation selected from a 0o ,r a DDU of :t 25%or better, and a DDU of 20%, or better, throughout emptying of the canister
16. 41. A metered dose inhaer according to claim 40, wherein the metered dose inhaler dispenses the co-suspension at an initial fine particle fraction and the initial fine particle fraction dispensed from the metered dose inhaler is substantially rmtaintainedsuch that; throughout emptying of the canister; the fine parties fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle fraction
17. 42. A metered dose inhaler according to claim 41, wherein the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction
18. 43. A metered dose inhaler according to claim 41, wherein the fine parties fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine partide fraction
19. 44. A metered dose inhaler according to any of caims 40 through 43, wherein the co-suspension formulation contained within the canister of the metered dose inhaler is storage stable for atleast six months 45, A metered dose inhaler according to claim 40, wherein the metered dose inhaler exhibits a delivered dose uniformity (CDLU") for the co-suspension formnulation selected from a DDU of ± 30% better, a DDU of t 25%, or better, and a DDU of ± 20%, or better, throughout emptying of the canister, after said canister is subjected to temperatures alternating between -5 *C and 40 *C every 6 hours for a period of six weeks.
20. 46. A metered dose inhaler according to any of caims 41 through 43, wherein the fine particle fraction is substantially maintained throughout emptying of 93 the canister, after said canister is subjected to temperatures alternating between -5 OC and 40 "C every 6 hours for a period of six weeks. 47, A method of preparing a metered dose inhaler containing a stable co suspension formulation, the method comprising: loading a canister with suspending particles and active agent particles containing at least one active agent; attaching an actuator valve to an end of said canister and sealing said canisteu said actuator valve adapted for dispensing a metered amount of the co-suspension formulation per actuation; and charging the canister wth a pharmaceuticalyacceptable suspension medium composing a propellant,wherein the active agent particles suspending particles and suspension medium are selected such that said loading of the active agent particles and suspending particles and said charging of the canister with a pharmaceutically acceptable suspension medium provides a cosusension formulation as defined in any of claims 1 through 39, 4.89 A method of preparing a metered dose inhaler containing a stable co suspension formulation, the method comprising loading a canister with active agent particles containing at least one active agent and suspending particles attaching an actuatorvale to an end of said container and sealing said canister, said actuator valve adapted for dispensing a metered amountof the co-suspension formulation per actuation; and charging the canister with a pharmaceutiaIy acceptable suspension medium comprising a propellant, wherein the active agent particles, suspending particles and suspension medium are selected such that said loading of the active agent particles and suspending particles and said charging of the canister with a pharmaceutically acceptable suspension medium provides a metered dose inhaler as defined in any of claims 40 through 46,
21. 49. A method of respiratory delivery of an active agent to a patient, the method comprising: providing a metered dose inhaler comprising a canister containing a co-suspension as defined in any of claims I through 39; and 94 delivering the co-suspension to the patient using the metered dose inhaler,
22. 50. The method of daim 49, wherein delving the co-suspension formulation to the patient comprises delivering the co-suspension formulation at a DDU selected from a DDU of ± 30%, or better, a DDU of ± 25%, or better, and a DDU of 20%,or better, throughout emptying of the canister 51 A method of respiratory delivery of an active agent to a patientthe method comprising: providing a metered dose inhaler as defined in any of claims 40 through 46; and deliering the co-suspension to the patient using the metered dose inhaler.
23. 52. A method for treating a patient suffering from an inflammatory or obstructive pulmonary disease or condition, the method comprising administering to the patient via an MDI a therapeutically effective amount of co-susoension as defined in alny of claims 1 through 39.
24. 53. The method of claim 52, wherein the disease or condition is selected fr asthma, COPD exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hyperension, pulmonary vasoconstriction, and pulmonary inflammation and obstruction associated with cystic fibrosis. 54, The method of claim 53, wherein administering the therapeutically effective amount of the co-suspension comprises providing a metered dose inhaler comprising a canister containing the co suspensior and delivering the co-suspension to the patient using the metered dose inhaler such that a DDU selected from a DDU of i 30%, or better, a DDU of ± 25%, or better, and a DDU of 20%, or better, throughout emptying of the canister 95