AU2017201626A1 - Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting B2 adrenergic receptor agonists and associated methods and systems - Google Patents

Description

COMPOSITIONS FOR PULMONARY DELIVERY OF LONG-ACTING MUSCARINIC ANTAGONISTS AND LONG-ACTING B2 ADRENERGIC RECEPTOR AGONISTS AND

ASSOCIATED METHODS AND SYSTEMS

The present application is a divisional application of Australian Application No. 2015201864, which is incorporated in its entirety herein by reference.

Technical Field [0001] The present disclosure relates generally to pharmaceutical formulations and methods for delivery of active agents via the respiratory tract. In certain aspects, the present disclosure relates to compositions, methods, and systems for pulmonary delivery of long-acting muscarinic antagonists and long-acting β2 adrenergic receptor agonists 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 envirGnmenfaily-frlendly, such as pertluotinaied compounds (RFCs) and hydrofluomalkanes (HFAs).

[0005] The active agent to be delivered; by a suspension MDI is typically provided as a fine particulate dispersed within a propellant or combination of two or more propellants (be., a propellant “system”}, In order to form .the fine particulates, the active agent is typically micronlzed, Fine: particles of active agent: suspended; in a propellant or propellant system tend to aggregate or flocculate rapidly. This is particularly true of active agents present in mforonlzed form, in turn, aggregation or flocculation of these fine particles may complicate the delivery of the active agent. For example, aggregation or flocculation can lead to mechanical failures, such as those that might he caused by obstruction of the valve orifice of the aerosol container, Unwanted aggregation or fioecuiation of drug particles may also lead to rapid sedimentation of 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 W3I forrnulations relates to crystal growth of the drug during storage, resulting in a decrease over time of aerosol properties and delivered dose uniformity of such j^Dls, More recently, solution approaches, such as those disclosed in U.S. Patent No. 8,964,759, have been proposed for MDf formulations containing anticholinergics. [0006| One approach to improve aerosol performance in dry powder inhalers has been to incorporate fine particle carrier particles, such as lactose. Use of such fine excipients has not been Investigated to any great extent for MDIs. A recent report by Young at ah, “The Influence of micronized particulates on the aeifosolization properties of pressurized metered dose inhalers"; Aerosol Science 40, pgs. 324-337 (2009), suggests that the use of such fine particle carriers In fvIDis actually result in a decrease In aerosol performance.

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

Brief Description of the Drawings £80081 FIG. 1 is a graph, which depicts the particle size distribution exhibited by an exemplary co-suspension composition according to the present description, which included giyeopyrnotate, a long-acting muscarinic antagonist, as the active agent, Go-suspension blDls were subjected to temperature cycling conditions (alternating :6h hold time at or 40 °C) for 12 weeks, £00001 FIG. 2 is a graph, which depicts the particle size distribution exhibited by an exemplary co-suspension composition according to the present description, which included giycopyrnoiate, a long-acting muscarinic antagonist, as the active agent Co-suspension MDis were subjected to temperature cycling conditions (alternating Sh hold time at -5 or 40 °C) for 24 weeks, £00101 FIG. 3 provides a micrograph illustrating the morphologies of a variety of suspending particles prepared according to Example 5. £00111 FIG. 4 is a photograph of two vials that allows visualization of a co-suspension formed us^^ agent particles fended using giycopyrnoiate and suspending particles formed using a saccharide.

[0012] FIG. S is a graph, which depicts the serum glycopyrroiate concentration; level achieved oyer a period of 24 hours after s single administration of four different doses of glycopyrroiaie delivered from a co-suspension composition as described herein, £00131 FIG. 8 Is a graph, which depicts the mean change in FEVi from baseline (in iIters) experienced in patients over a;period of 24 hours after receiving a single aim in istfatlon of the indicated dose of giyoopyrroiate formula ted in a co-suspension as described herein, in this study, Splriva (18 pg Tiotropiom) was included as an active control* and the mean change in FEVi from baseline (in liters) experienced1 in patients receiving a single administration of Spiriva is also depicted, [00141 FIG. 7 is a bar graph, which depicts the peak change in FEVi from baseline (in liters) experienced in patients after receiving a single administration of the Indicated dose of glycopyrroiate formulated in a co-suspension as described herein relative to placebo, the area under the curve of the FEVi.oyer 12 hours after dosing, and the ansa under the curve of the FEVi over 24 hours after dosing ...relative to placebo across the four doses evaluated. in this study, Spiriva (18 pg Tiotropium) was Included as an active control and the results following single administration of Spiriva for the above parameters are also depicted in this figure, J001S1 FIG, 8 is a graph, which depicts the proportion of patients which achieved a greater than 12% change in FEVi from baseline and an improvement of 150 ml change from baseline or an absolute improvement of 200 ml from baseline regardless of % change in FEVi from baseline, after receiving a single administration of the indicated doses of a glycopyrrolate co-suspension as described hereto. In this study, Spiriva (18 pg Tiofropium) was included as an active control and the results Mowing single administration of Spiriva for the above parameter are also depicted on this figure, 10016] FIG, 9 is a bar graph, which depicts the peak change to inspiratory capacity experienced in patients after receiving a stogie administration of the indicated doses of a glycopyrroiate co-suspension as described hereto. In this study, Spinva ilB pg TidtropiumJ was included as an active control and the results following single administration of Spiriva for the above parameter are also depicted on this iticmj FIG, 10 is a bar graph providing the change in FEVi AUC achieved inpatients after receiving a single administration of toe indicated doses of a glycopyrroiate co-suspension as described herein. The results achieved by the glycopyrroiate co-suspension according ίο the present description are shown in comparison with the change: in FEVi AUC reported in a published study In patients who received a powder formulation of glycopyrroiate not prepared according to the teachings provided herein, 106181 FIG. 11 is a graph, which depicts toe particle Size distribution of an exemplary giyeopyrrolaie co-suspension prepared according to the present description, containing 4.5 pg/aciuation delivered dose of glycopyrroiate and 6mg/ml. suspending, particles and subjected to temperature cycling conditions (alternating 6h hold time at -5 or 4() °C). 100101 FIG- 12 is a graph, which depicts the particle Size distribution of ah exemplary glycopyrroiate co-suspension prepared according to the present

description, containing 38 pg/actuation delivered dose of glycopyrroiate and 6mg/mL suspending particles and subjected to temperature cycling conditions (alternating 0h: hold time at ~5 or 40 CC).

[0020| FIG. 13 Is a graph, Which depicts the delivered dose through canister life of an exemplary glycopyrroiate co-suspension prepared according to the present description, containing 4.5 pg/actuatlon delivered dose of glycopyrroiate end 6rog/mL suspending particles, [00211 FIG. 14 is a graph, which depicts the delivered dose through canister life of an exemplary glycopyrroiate co-suspension prepared according to the present description, containing 38 pg/actuation delivered dose of glycopyrroiate and 6mg/mL suspending particles, [00221 FIG. 15 Is a graph, which depicts the particle size distribution of an exemplary glycopyrroiate co-suspension prepared according to the present description, containing 36 pg/actuatlon delivered dose of glycopyrroiate and 6mg/mL suspending partides and subjected to 12 months storage at 25^0/60% RH unprotected.

[0023] FIG. 18 is a graph, which depicts the mean delivered dose through canister life of an exemplary glycopyrroiate co-suspension prepared according to the present description, containing 32 pg/actuation delivered dose of glycopyrroiate and Smg/mL suspending particles and subjected to temperature cycling conditions (alternating 6h hold time at -5 or 40 X), [00241 FIG. 17 is a graph, which depicts the particle Size distribution Of an exemplary glycopyrroiate co-suspension prepared according to the present description, containing 32 pg/actuation delivered dose of glycopyrroiate and 6mg/mL suspending particles and subjected to temperature cycling conditions (alternating 8h hold time at -Sor 40 eC) [002SJ FIG, 18 Is a graph, which depicts the particle Size distribution of an exemplary glycopyrroiate co-suspension prepared according to the present

description, containing 24 pg/actuation delivered dose of glycopyrroiate and 6rng/mL suspending partides and subjected to 8 weeks storage at bO^G/ambieht relative humidity and 12 weeks at 4CTC

[00281 FIG, 19 is a photograph that allows visualization of co-suspension compositions prepared according to the present description which include formoterol fymaretc active agent particles.

[0027] FIG. 20 Is a graph, which depicts the delivered dose uniformity achieved by formoteroi fumarate co-suspension compositions prepared according to the present description, [002S] FIG. 21 is a graph, which depicts the aerodynamic particle size distribution determined by cascade impaction of exemplary formoteroi fumarate co-suspension compositions prepared according to the present description and stored for three months at 25 X·/ 75% RH: without protective overwrap, or at 40 °C / 75%RH with protective overwrap, [6029] FIG, 22 is a graph, which depicts the chemical stability of exemplary cosuspension composlsons including formoteroi fumarate as the active agent. The results depicted in this figure allow comparison of the chemical stability of formoteroi fumarate achieved in a co-suspension composition formulated using crystalline formoteroi fumarate with the chemical stability of suspension formulations prepared using spray dried formoteroi fumarate, [0030] F1G< 23 through FIG: 26 areelectron micrographs of suspending particles prepared .from· various different materials, with Figure 23 providing a micrograph of trehalose suspending particles, Figure 24 providing a micrograph of cyciodextnh suspending particles, Figure 25 providing a micrograph of Fiooii MP ?0 suspending particles, and Figure 26 providing a micrograph of inuiin suspending particles, |0031| FIG. 27 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 including glycopyrrolate active agent particles.

[00321 FIG. 28 provides a graph that depicts the aerodynamic pa hide size distribution determined by cascade impaction of exemplary co-suspension compositions prepared according to the present description and including formoteroi fumarate active agent particles: [00331 FIG. 29 provides a graph that depicts the delivered dose uniformity achieved by ultra low-dose formoteroi fumarate co-suspension compositions prepared according to the present description.

[0034] FIG, 30 provides graphs Illustrating the particle size distribution of giyccpyrrolate (top) end formoteroi {bottom} achieved by an exemplary cosuspension compared to particle size distributions achieved by formulations including either glyeopyrrofate or formoterol furnarate alone.

Detailed Description [0035] The present disclosure provides compositions, methods, and systems for respiratory delivery of active agents via an MOI. in particular embodiments, the compositions, methods and systems described herein are adapted for respiratory delivery of active agents selected from a long-acting muscarinic antagonist (“LAMA”) and a long-acting (½ adrenergic receptor agonist (“LABA!. in certain embodiments, the LAMA or LABA active agent may be potent or highly potent and, therefore, formulated at low concentrations and delivered In low doses. The pharmaceutical compositions described herein may be formulated for pulmonary or nasal delivery via an IvlDl. The methods described herein include methods of stabilizing: formulations including LAMA or LABA active agents for respiratory delivery, as well as methods for pulmonary delivery of LAMA and LABA active agents via an MDI. Also described herein are methods for preparing an MDI for delivery of a LAMA or LABA active agent, [0035] In specific embodiments, the methods described herein include methods for treating a pulmonary disease or disorder amenable to treatment by delivery of a LAMA or LABA active agent through an 'MDI. For example, and the compositions, methods end systems described herein can: be used to treat inflammatory or obstructive pulmonary diseases or conditions. In certain embodiments, the compositions, methods and systems described herein can be used to treat patients suffering from a disease or disorder selected from asthma, chronic obstructive pulmonary disease (DORP), 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 a LAMA or LABA, alone or in combination with other therapies, in certain embodiments, the compositions, systems and methods desa'ibed herein dan he used to treat pulmonary inflammation and obstruction associated with cystic fibrosis. As used herein, the terms “CSOPD” and “chronic obstructive pulmonary diseas# encompass chronic obstructive Sung disease (COLD), chronic obstructive airway disease (GOAD)., chronic airflow limitation (CAL) and chronic obstructive respiratory disease (CORD) and inelucte chronic bronchitis, bronchiectasis, and emphysema. As used herein, the term “asthma” refers to asthma of whatever type or genesis, including both intrinsic fnon-silerglc) asthma and extrinsic (allergic) .asthmd,. miid asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced Mowing bacterial infection. Asthma is also to be understood as embracing wheezy-infant |00S7) it will be readily understood that the embodiments described herein are exemplary. The following more detailed: description of various embodiments >s not intended to limit the scope of the present disclosure, but is merely representative of various embodiments. Moreover, the order of the steps or actions of the methods desoribod in eonneetion 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, $00381 Unless specifically defined; otherwise, the technical terms, as used herein, have their norma! meaning as understood In the art. The following terms are specifically defined for the sake of clarity. $0039] The term “active agent" is used herein to include any agent, drug, compound, composition or other substance that may be used on,, or administered to a human Or animal and is a LAMA or LABA. The term; “active agent” may be used interchangeably with the terms, "drug,” "pharmaceutical,” "medicament,* "drug Substance,” or "therapeutic.” $00401 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 Oi another chemical entity, composition, or structure. The association includes, for example, adsorption, adhesion, covalent bonding, hydrogen bonding, ionic bonding and electrostatic-attraction, Ufshitz-van der Waals interactions and poiar interactions. The term hadhere'' or “adhesion” is a form of association and Is used as a generic term tor a!! forces tending to cause a particle or mass to be attracted fee surface. “Adhere” also refers to bringing and keeping particles In contact with each other, such that there is substantially no visible separation between particles due to their different buoyancies in a propellant under normal conditions. In one embodiment, a particle that attaches to or binds to a surface Is encompassed by the term '’adhere." Normal conditions may include storage at room temperature or under an accelerative force due to gravity. As described herein, active agent panicles may associate with suspending particles to form a co-suspension, where there is substantially ho visible separation between the suspending particles and the: active agent particles or flocculates thereof due to differences In buoyancy within a propellant [0041] “Suspending particles” refer to a material or combination of materials that is acceptable for respiratory delivery,: and acts as a vehicle for active agent partides. Suspending particles interact with the active agent particles to facilitate mpeatabie dosing, delivery or transport of active agent to the target site of delivery, te,, the respiratory tract. The suspending partides described herein are dispersed within a suspension medium including a propellant dr 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 partides include particfes that exhibit a particle size that fadilitates respiratory delivery of active agent and have physical configurations suited to formulation arid delivery of the stabilized suspensions as described herein, [0042$ The term “co-suspension” refers to a suspension of two or more types of particles having different compositions within a suspension medium, wherein one type of particle associates at least partially with one or more of the other particle types. The association leads to an observable change In one or more: characteristics of at least one of the individual particle types suspended In the suspension medium . Charactenstics modified by the association may include,: for example, one or more of the rate of aggregation or flocculation, the rate and nature of separation, i.e. sedimentation or creaming,: density of a cream: or sediment layer, adhesion to container wails, adhesion to valve components, and rate and the level of dispersion upon agitation. £0043] Exemplary methods for assessing whether a co-suspension is present can include the following: If one particle type has a pyonometrfc density greater than the propellant and another particle type has a pychdmetrle 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 “pyenornetric 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 via!, typically a glass vial, for visual observation. After initial agitation the vial is let undisturbed for a sufficient time for formation of a sediment or cream layer, typically 24 hours. If the sediment or dream layer is observed to be completely or mostly a uniform single layer, a co-suspension is present; The term foo-suspension” includes partial co-suspensions, where a majority of the at least two particle types associate with each other, however, some separation p.e,, less than a majority) of the at least two particle types may be [00441 The exemplary co-suspension test may be performed at difterint 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, he. all sediment or ail cream, the presence of a co-suspension can be determined by measuring other characteristics of the suspension, such as rate of aggregation or flocculation, rate of separation, density of cream or sediment layer, adhesion to container waiis, adhesion to valve components, and rate and level of dispersion upon agitation, and comparing them to; the respective characteristics of the simliarly suspended indiyidual particle types. Various analytical methods generally known to those skilled in the art can be employed to measure these characteristics. |®04δ| 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 TPO” refers to the dose, either rn total mass or fraction of the nominal dose or metered dose, that is within a respirable range. The dose that is within the respirable range is measured in vitro to be the dose that deposits beyond the throat stage of a cascade impactor, i.e., the sum of dose delivered at stages 3 through filter in a Next Generation jmpactor operated at a flow rate of 30 i/rrtin> [00461 In the context of a composition containing or providing respirabie 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 (ie„ the amount that exits the actuator of a delivery device, such as an MDI) that is within a respirable range. The amount of delivered material within the respirable range is measured in viim as the amount of material that deposits beyond the throat stage of a cascade impactor, e,g„ the sum of the material delivered at stages 3 through filter in a Next Generation Impactor operated at a flow rate of 301/min, [00471 As used herein, the term “inhibif refers to a measurable lessening of the tendency of a phenomenon, symptom or condition to occur or the degree to which that phenomenon,, symptom or condition occurs^ The term 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 like, [0648¾ “Mass median aerodynamic diameter or “MMAD,S as used herein refers to the aerodynamic diameter of an aerosol below which 50% of the mass of the aerosol consists of particles with an aerodynamic diameter smaller than the ivtMAQ, with the MMAD being calculated according to monograph 601 of the United States Pharmacopeia f USP"), [0849! When referred to herein, the term “optical diameter1' 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, Clausihat-Zellerfeld, Germany), [08561 The term solution mediated transformation refers to the phenomenon in which a more soluble form of a solid material (i.e, particles with small radius of curvature (a driving force for Osfwald ripening), or amorphous material) dissolves and recrystaiiizes into the more stable crystal form that can coexist in equilibrium with its saturated propellant solution.

[08511 A “patient” refers to an animal in which LAMA or IAEA active agents will have a therapeutic effect, in one embodiment, the patient is a human being, [80521 “Perforated microstruciures" refer to suspending particles that include a structural matrix that exhibits, defines or comprises voids, poms, defects, hoilows, spaces, Interstitial spaces, apertures, perforations or holes that allow the surrounding suspension medium to permeate, fill or pervade the mierostruetute, such as those materials and preparations described in U S. Patent No, 6,309,623 to Wears, et at The primary form of the perforated microstructure is, generally, not essential, and any overall configuration that provides the desired formulation characteristics is contemplated herein. Accordingly* in one embodiment, the perforated microstfuctures may comprise. approximately spherical shapes, such as hollow, suspending, spray-dried niicrospheres, However, collapsed, corrugated, deformed or fractured partfoolaies of any primary form or aspect ratio may also be compatible. [00§3| As is true of suspending parficies described herein, perforated micfostruetures may be formed of any biocompatibia material that does not substantially degrade or dissolve: in the selected suspension medium. While a wide variety of materials may be used to form the particles, In some embodiments*, the structural matrix is associated with, or inciudes, 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.

[0054| The term "suspension medium" as uses herein refers to a substance providing a continuous phase within which active agent particles and suspending particles can be dispersed to provide a co-suspension formulation. The suspension medium used in co-suspension formulations described herein includes: propellant. As used herein, the term “propellant" refers to one or more pharmacologically inert substances which exert a sufficiently high vapor pressure at normal room temperature to propel a medicament from the canister of an MDI to a patient on actuation of the NIDI'S metering valve. Therefore, the term "propellant refers to both a single propellant and to a combination of two or more different propellants forming a “propellant system." [6056] The term “respirable" generally refers to particles, aggregates, drops, etc. sized such that they cab be inhaled and reach the airways of the lung.

[6066] When used to refer to co-suspension compositions described herein, the terms “physical stability" and “physically stable" refer to a composition: that is resistant to one or more of aggregation, flocculation, and particle size changes due to solution mediated: transformations and is capable of substantially maintaining the MMAD of suspending particles and the fine particle dose, In one embodiment, physical stability may be evaluated through subjecting compositions to accelerated degradation conditions, such as by temperature cycling as described herein, [0057$ When referring to active agents, the term “potent" indicates active agents that are therapeutically effective at or below doses ranging from about 0.01 mg/bg to about 1 nig/kg. Typical doses of potent active agents generally range from about I DO pg to about 100 mg. 10058] When referring to active agents, the term “highly potent” indicates active agents that are therapeuticaily effacfive at or below doses of about 10 pg/kg . Typical doses of highly potent; active agents generally range up to about 100 pg.

[00501 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, 10060] The term “sPbstahtially insoluble” means that a composition is either totally insoluble in a .particular solvent or it Is poorly soluble In that particular solvent. The term “substantially insoluble” means that a particular solute has a solubility of less than one part per 100 parts solvent. The term “substantially insoluble·' includes the definitions: of "slightly soluble" (from 100 to 1000 parts solvent per 1 part solute], "Very slightly soluble'' (from 1000 to 10,000 parts solvent per 1 part solute) and “practically insoluble” (mom than 10,000 parts solvent per 1 part solute) as given in Table 10-1 of Remington: The Science: and Practice of Pharmacy, 21st ed, Uppincott, Williams &amp; Wilkins, 2006, p. 212, [0001] The term "surfactant,” as used herein, refers to any agent which preferentially adsorbs to an interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water/air interface or organic solvent/alr interface; Surfactants generally possess a hydrophilic hioiety and a lipophilic moiety, such that, upon adsorbing to· microparticles» they tend to present moieties to the continuous phase that do not attract similarly-coated particles, thus reducing particle agglomeration, in some embodiments, surfactants may also promote adsorption of a drug and increase bioavaliabJlIty of the drug. |0δδ2| 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 prophyiacticaliy inhibiting or preventing the onset of a disease or disorder. A therapeutically effective amount may he an amount: which relieves to some extent one or more symptoms of a disease or disorder In a patient; returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder;; and/or reduces the likelihood of the onset of the disease of disorder, [60631 The terms “chemically stable” and “chemical stability* refer to co-suspension formulations wherein the individual degradation products of active agent remain below the lirhits specified by regulatory requirements during the shelf life of the product for human use (e,g,} 1 % of total chromatographic peak area per ICH guidance Q3B[R2)) and there is acceptable mass balance (e.g., as defined in ICH guidance G1E) between active agent assay and total degradation products.

[0064] The compositions described herein are co-suspensions that include a suspension medium inciuding a propellant, LAMA or LABA active agent particles, and suspending particles. Of course, if desired, the compositions described herein may include one or more additional constituents. Moreover, variations and combinations of components of the compositions described herein may be used. For example, two or more species of suspending particles may be used in compositions for the formulation and delivery of a selected LAMA or LABA active agent. Alternatively, for example, the compositions described herein may include two or more species of active agent particles, in certain such embodiments, the compositions may include LAMA or LABA active agent particles co-suspended with suspending particles, wherein, ih addition to the active agent material included in the active agent particles, at least some of the suspending particles incorporate the selected LAMA or LABA active agent. Even further, if desired, the compositions described herein may include two or more different species of particles containing the selected LAMA or LABA active agent in combination with two or more different species of suspending particles.

[6665] it has been found that, in fcrmutaiions according to the present description, active agent particies exhibit an association with the suspending particles such that separation of the active agent particies from the suspending particles is substantially prevented, resulting In co-location of active: agent particles and suspending particles within the suspension medium,: Generally, due to density differences between distinct species of particles and the medium within which they ere suspended (e.g„ a propellant or propellant system), buoyancy forces cause creaming of particies with Sower density than the propellant and sedimentation of particles with higher density than the propellant. Therefore, in suspensions that include a mixture of particles that vary in their densities, the sedimentation or creaming behavior of each type of particle may vary and may lead to separation of the different particie types within the propellant [0066] However, the combinations of propellant, active agent particles and suspending particles described herein provide co-suspensions wherein the active agent partlotes and Suspendihg particles eoUocaie within the propellant (Le., the active agent particles associate with the suspending particles such that suspending particles and active agent particles do not exhibit substantial separation relative to each other, such as by differentia! sedimentation or creaming, even after a time sufficient for the formation of a cream or sediment 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 and/or centrifugation· at accelerations up to ah over, for example, 1 gf 10 g, 35 g, 60 g, and 100 g However, the co-suspensions described herein need not be defined by or limited to a specific threshold force of association. For example, a co-suspension as contemplated herelh may fee su ccessfu iiy achieved where the active agent particles associate with the suspending particles such that: there is no substantial separation of active agent particles and suspending particies Within the continuous phase formed by the suspension medium under typical patient use conditions, P&amp;6I] Co-suspension compositions according to the present description provide desirable formulation and deiivery charaetensiics for LAMA and LABA active agents. For example, in certain embodiments, when present within an -MDI canister, cosuspensions as described herein can inhibit or reduce one or more of the following·' fioCiCulation of active agent material; differential sedimentation or creaming of active agent particles and 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. In addition, compositions as described herein provide chemical stability for the active agents contained therein. Such qualities work to achieve and preserve aerosol performance as the co-suspension is delivered from an MDI such that desirable fine particle fraction, fine particle dose and delivered dose uniformity characteristics are achieved and substantially maintained throughout emptying of an M0i canister within which the co-suspension composition is contained. Additionally, as illustrated by embodiments detailed herein, co-suspensions according to the present description can provide a stable formulation that provides consistent dosing and respiratory delivery characteristics for LAMA and IAEA 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. 100611 Providing a co-suspension according to the present description may also simplify formulation, delivery and dosing of LAfoA and LABA active agents. Without being bound by a particular theory, it is thought that by achieving a co-suspension of active agent particies and suspending particles, the delivery and dosing of active agent contained within such a dispersion may be substantially controlled through control of the size, composition, morphology and relative amount of the suspending particles, and less dependent upon the size and morphology of the active agent particles. 100691 Accordingly,; foe pharmaceutical compositions disclosed herevi provide for delivery of LAMA and LABA active agents from an MDI. Delivery of the cosuspension compositions described herein provides desirable pharmacokinetic and pharmacodynamic characteristics, and MDI delivery of the pharmaceutical compositions descdbed herein is suitable for treating patients suffering from an inflammatory or obsfo etive pulmonary disease or condition that responds to the administration of a LAMA or LABA active agent. In particular embodiments, the pharmaceutical compositiohs described herein may be used In treating a disease or condition selected from asthma, CORD, exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndroms, pulmonary Hypertension, pulmonary vasoconstriction, emphysema, and any other respiratory disease, condition, trait, genotype or phenotype that can respond to the administration of a LAMIA or IAEA, alone or in combination with other therapies. In certain embodiments, the compositions, systems and methods described herein can be used to treat pulmonary inflammation and obstruction associated with cystic fibrosis. (!) Suspension Medium [0070] 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 propellent gases that can be liquefied under pressure at room temperature, and upon inhalation or topical use, are safe and foxicoiogicaily Innocuous, Additionally, it is desirable that the selected propellant be relatively nomreactive with the suspending particles or active agent particles. Exemplary compatible propellants include hydrofluoroalkanes (HFAs), perfluorinaied compounds |PFCs]} and chlorofluorocarbons (CFGs). £0071J Specific examples of propellants that may be used to form the suspension medium of the co-suspensions disclosed herein include 1,1,1,2-tetrafiuoroethane (CMHT) (HFA-134a), 1,1,1,2,3,3,3-heptafiuoro-n-propane (CF3CHFCF3) (HFA-227), perfiuoroethane, monochloro-ilucrometbsne, 1,1 difluoroethane, and combinations thereof. Even further, suitable propellants include, for example: short chain hydrocarbons; Cm hydrogen-containing chiorofiuoroearhons such as CFLGF, CGbFCHGiF, GF3GHCIF, CHF2CCIF2, CHClFCHFg, CF3CH2Cif and CCSF2CH3; C1.4 hydrogen-containing fluorocarbons (e.g„ HFAs) such as CHF;>CHFs, GF^CH^F, CHFgGHa, and CF^CHFCFs; and perfluorocarbons such as CF3CF3 and OFsCF2GF3. £0072] Specific fluorocarbons, or classes of fiuorinated compounds, that may be used as suspension media include, but are not limited to, fiuoroheptsne, fluorbcycioheptane, fluoromethyicydoheplane; fiuorohexane, fluorocyciohexane, fluoropentane, fluorocyciopentane, fluommetbyicyelopentane, fluorodimefhyl-eyclopenianes, fluoromethylcyclobutane, fluorodimefhyicyclobutane, fiuorolnmeihyi·· cyclobutane, fluorobutane, fluoroeyciobutane, fiuoropropane, fluoroethers. iiuoropolyethers and iiuorotriethylamines. These compounds may be used alone or in combination with more volatile propellants. 1001731 in addition to the aforementioned fluorocarbons and hydrofluoroalkanes, various exemplary chlorofluorocarbons and substituted fluonnaled compounds may also be used as suspension media, in this respect, FG~11 (CCEF), FG-11B1 pBfGl#), FC-11B2 (CBmCiF). FC12B2 (CF2Br2), FC21 {GHCI2F}, FC21B1 (CHBrOiF), FC-2182 (CHBfsF), FC~31B1 (CHgSrF), FCH3A (CChCFs), FC-122 (GCiFgGHaal, FC-123 (CF3GHCI2), FC-132 (CHCIFCHCIF), FC-1-33 (CHCSFCHF2)s FG-141 (CH2ClCHCiF), FC-141B (CCbFCHg), FC-142 (CHFgCHzCi), FC-151 (CHgFGFfsGi), FC-152 (GB2FCH2F)S EC-1112 (GOFCCiF), FC-1121 (CHCI-CFCI) and FC-1131 fCHCNGHF) may also be used, while recognizing the possible attendant environmental concerns. As such, each of these compounds may fee used, alone or in combination with other compounds (le., less volatile fluorocarbons) to form the stabilized suspensions disclosed herein, 10074) In some embodiments, the suspension medium may be formed of a single propellant. In other embodiments, a combination of propellants (a; “propeiiant system") may be used to form the suspension medium, to some embodiments, relatively volatile compounds may be mixed with lower vapor pressure components to provide suspension media having specified physical eharaetefisties selected to improve stability or enhance the bioavaliability of the dispersed active agent. In some embodiments, the Sower vapor pressure compounds wiii comprise fiuorinafed compounds (e,g, fluorocarbons) having a boiling point greater than about 25¾ In some embodiments, lower vapor pressure fluoridated compounds for use in the suspension medium may include perfluorooctyibroroide CsFirBr (PFOB or perfiubron), dlchforoHuomoctane GsF1sGl2, perfiyerooetyiethane Q#i?CgHs. (PFOE), perfiuorodecyibromide CioF21Bf (PFOB) or pedluorobutySetbane G^PsGaHs*· in-certain embodiments, these lower vapor pressure compounds are present in a relatively low level. Such compounds may foe added directly to the suspension medium or may be associated with the suspending particles, (0073) The suspension medium included In compositions as described herein 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. For example, in some embodiments, the suspension medium may be formed of a non-CFC propellant or pmpetlant: system, such as an HFA propellant or propellant system, that Is substantially free of additional materials. Such embodiments simplify the formulation and manufacture of pharmaceutical compositions suited tor respiratory delivery of a LAMA or LA8A active agent. {0070) However, in other embodiments, depending on the selection of propellant, the properties of the suspending particles, or the nature of active agent to be delivered, the suspension medium utilized may include materials in addition to the propellant or propellant system . Such additional materials may include, for example, one or more of an appropriate aniisolvent, solubilizing agent, co-solvent or adjuvant Lo adjust,, for example, the vapor pressure of the formulation: or the stability, or solubility of suspended particles- For example, propane, ethanol, isopropyl alcohol, butane, isobutane, pentane, isopentane of a aralkyl ether, such as dimethyl 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 polyvinylpyrrol idone (“PVP") 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 general, where a volatile cosolvent or adjuvant is used, such an adjuvant or cosoiveot may be selected from known hydrocarbon or fluorocarbon materials and may account for up to about 1% w/w of the suspension medium. For example, where a cosolvent or adjuvant is Incorporated in the suspension medium, the coSolvent or adjuvant may comprise less than about 0.01%, 0.1%, or 0,5% wfw of the suspension medium. Where PVP or PEG are included in the suspension medium, such constituents may be included at up to about 1% wAy, or they may comprise less than about 0.01%, 0.1%, or 0.5% w/w of the suspension medium. (It) Active Agent Particles {00771 The active agent particles included in the co-suspensions described herein are formed to he capable of being dispersed and suspended within the suspension medium and are sized to facilitate delivery of respirable particles from the Φ* suspension, in one embodiment, therefore, the active agent particles are provided as a micronized matenal wherein at least 00% of the active agent particle material by volume exhibits; an optical diameter of about 7 pm or less. In other embodiments, the active agent particles are provided as a micronized materiai wherein at least 9014 of the active agent, particles by volume exhibit an optica! diameter selected from a range of about 6 pm to about 1 pm, about 5 pm to about 2 pm, and about 4 pm to about 3 pm. In further embodiments, the active agent particles are provided as a rnicronized materia! wherein at least 90% of the active agent particles by volume exhibit an optica! diameter selected from 6 pm or less, 5 pm or less, and 4 pm or less. In another embodiment, the active agent particles are provided: as a rnicronized material wherein at least 50% of the active agent particle materia! by volume exhibits an optical diameter of about 5 pm or less, in other embodiments, the active agent particles are provided as a rnicronized material wherein at least 50% of the active agent particles by volume exhibit an optical diameter selected from a range of about 4 pm to about 1 pm, about 3 pm to about 1 pm5 and about 2.5 pm to about 1 pm. In another embodiment, the active agent particles are provided as a rnicronized material wherein at least 50% of the active agent particles by volume exhibit an optica! diameter selected from 4 pm or less, 3 pm or less, and 2 pm or less.

[007SJ in specific embodiments, the active agent material used as or to form the active agent particles may be entirely or substantially crystalline, ie.( a majority of the active agent molecules are arranged In a regularly repeating pattern, over a long range or external face planes. In another embodiment, the active agent particles may be present in both crystal and amorphous states, in yet another embodiment, the active agent particles may be present in substantially an amorphous state, i.e., the active agent particles are overall noncrystalline In nature and do not have a regularly repeating arrangement of molecules maintained over along range. Suitable excipients fee formulation of active agent particles include those described herein in association with the suspending particles, in specific embodiments, tor example, active agent particles may be formulated; with one or more of the lipid, phospholipid, carbohydrate, amino acid, organic salt, peptide, protein, alditols, synthetic or natural polymer, or surfactant materials as described, for example, in association with the suspending particles. In other embodiments, the active agent particles are formed solely from rnicronized active agent material. ίδδ?9| Because the -compositions disclosed; enable the formulation and reproducible delivery-of very low doses of active ^agents, In certain: embodiments* the active agents included in the compositions described herein may be selected from one or more potent: or highly potent active agents* For example* in certain embodiments, the compositions described herein may include a potent active agent that is delivered at a single administration dose Selected torn between about 100 pg and about 100 mg per dose, about 100 pg and about 10 mg per dose, and about 100 pg and 1 mg per dose. In other embodiments, the compositions described herein may include a potent or highly potent active agent that is delivered at a dose selected from up fe about 80 pg per single administration dose, up to about 40 pg per single administration dose, up to about 20 pg per single administration dose, up to about 10 pg per single administration close or between about 10 pg and about i00 pg per single administration dose, Additionally, If*· certain embodiments, the compositions described herein may Include a highly potent active agent delivered at a dose selected from between about 0,1 and about 2 pg per single administration dose, about 0.1 add about 1 pg par single administration dose, and about 0.1 and about 0.5 pg per single administration dose, [0080] In certain embodiments, the active agent included in the compositions described herein is a LAMA active agent, inhere the compositions include a. LAMA active agent, in particular embodiments, the LAMA active agent may be selected from, for example, glycopyrroiafe, dexlpirronium, tidtropium, irospium, adidinium, denatropium, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, [0081] Glycopyrrolate can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as, for example, these described herein. As an anticholinergic, glycopyrrolate acts as a bronchodliator and provides an aniiseeretory effect, which Is: a benefit for use in the therapy of pulmonary diseases and disorders: characterized by increased mucus secretions, Glycopyrrolate is a quaternary ammonium salt. Where appropriate, glycopyrrolate may be used In the form of salts fe.g, alkali metal or amine salts, or as acid addition salts) or as esters or as solvates (hydrates), ..Additionally, the: gSycopyrroiafe may be in arty crystalline form or isomeric form or mixture of Isomeric forms, for example a pure enantiomer, a mixture of enantiomers, a racemate or a mixture thereof: In this regard, the form of glycopyrrolate may be selected te optimize the activity and/or stability of glycopyrrolate and/or to minimize the solubility of glycopyrrolate in the suspension medium. Suitable·' counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifiuoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maieate, succinate, benzoate, p-chiorobenzoate, diphenyl-acetate or triphenyiaeetate, o~hydroxybenzoate, p~hydroxybenzoate, 1-hydroxynaphrhatene-2-earboxyiate, 3 -tryd roxynap hth a I ene-2 -carhoxyia te, methanesulfonate and benzenesultenaie. In particular embodiments of the compositions described herein, the bromide salt of glycopyrrolate, namely 3-[(cydopentyl-hydroxyphenylacetyl)oxy]·· 1,1 -dimethyipyrrolidinlum bromide, is used and can be prepared according to the procedures set out in U S. Pat. No.. 2,956,082. |0082] Where the compositions described herein include glycopyrrolate, in certain embodiments, the compositions may include sufficient giycopyrroiate to provide a target delivered dose selected from between about 10 pg and about 200 pg per actuation of an MDI, about 15 pg and about I SO pg per actuation of an MDI, and about 18 pg and 144 pg per actuation of an MDI. in other such embodiments, the formulations include sufficient glycopyrrolate to provide a dose selected from op te about 200 pg, up to about 150 ug, up to about 75 pg, up to about 40 pg, or up te about 20 pg per actuation, in yet further embodiments, the formulations include sufficient: giycopyrroiate to provide a dose selected from about 18 pg per actuation, 38 pg per actuation, or about 72 pg per actuation, in order to achieve targeted delivered doses as described herein, where cornposlitohs described herein include glycopyrmlate as the active agent, in specific embodiments, the amount of giycopyrroiate Included in the compositions may be selected from, for example, between about 0,04 mg/ml and about 2.25 mg/mf. |8083| In other embodiments, tiotropluni;, 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 fersown, long-action anticholinergic drug suitable for use In treating diseases or disorders associated with pulmonary Inflammation or obstruction, such as those described herein, Tiotropium, including crystal and pharmaceutically acceptable salt forms of tiolroplum, Is described, for example, in O.S. Patent No. 5,610,163, U.S.

Patent; No, RE39820, U.S. Patent No. 6,777,423, and U.S. Patent No, 6,908,926. 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 |jg and about 25 pg, about 2.5 pg and about 20 pg, about 10 pg and about 20 pg, and about 2.5 pg and about 10 pg per actuation of an yoi. In other such embodiments, the formulations include 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 MOl in yet further embodiments, the formulations include sufficient tiotropium to provide a delivered dose selected from about 3 pg, 6 pg, 9 pg. 18 pg, and 38 pg per actuation of the MDS. In order to achieve delivered doses as described herein, where compositions described herein Include tiotropium as the active agent, in specific embodiments, the amount of tiotropium included in the compositions may be selected from, for example, between about 0.01 mg/mi and about 0.5 mg/mi.

[0084] In certain embodiments, the compositions described herein include a LA8A active sgeni in such embodiments, a LABA active agent can be selected from, for example, bambuterol, clenbuterol, formoteroi.. salmeteroL cemioterob milveteroL indacaterol, and saligenin- or Indole- containlng and adamantyl-denved $z agonists, and any pharmaceutically acceptable salts, esters, Isomers or solvates thereof. In certain such embodiments;, formoteroi is selected as the LABA active agent. Formoteroi can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as, for example, those described herein, Formoteroi has the chemical name {±)“2-hydroxy-5-[f^188)-1 »bydroxy»2:-[[(1 RS|“2-(4~ methoxyphenylpl-meihylethyll-aminolethyl] fdrmanide, and is commonly used in pharmaceutical compositions as the racemic fumarate dihydrate salt. Where appropriate, formoteroi may be used in the form of salts (e.g. alkali metal or amine salts or as acid addition salts) or as esters or as solvates (hydrates). Additionally, the formoteroi may be in any crystalline form or isomeric form or mixture of isomeric forms, for example a pure enantiomer, a mixture of enantiomers, a racemate or a mixture thereof. In this regard, the form of formoteroi may be selected to optimize the activity and/or stability of formoteroi and/or to minimize the solubility of formoteroi in the suspension mediumPharmaceutically acceptable salts of formoteroi include;, for example, sails of inorganic adds such as hydrochloric., hydrobromie, sulfuric and phosphoric adds, and organic adds such as fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, giularie, gluconic, tricarballyNe, oieic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzole, p-chiorobenzoie, methanesuifonic, prtoluenesulfonic and 3~hydroxy~2«naphthalene carboxylic acids. Hydrates of formoterol are described, tor example, in U.S. Pat, No, 3,994,974 and U.S. Pat. No. 5,684,199. Specific crystalline forms of formpterol and other "ft? adrenergic receptor agonists are described, tor example, in WO95/O5805, and specific isomers of formoterol are described in U.S. Patent No. 6,040,344, |0δ85| in specific embodiments, the formoteroi material utilized to form the formoteroi particles is formdtero! fumarate, and in one such embodiment, the formoterol fumarate is present in the dihydrate form. Where the compositions described herein include formpterol, in certain embodiments, the compositions described herein may include 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 1Q pg, about 2 pg and 5 pg, about 2 pg and about 10 pg, about 5 pg and about 10 pg, end 3 pg and about 30 pg per actuation of an MDL in other embodiments, the compositions described herein may include formotero! in an amount sufficient to provide a targeted delivered dose selected from up to about 30 pg, up to about 10 pg, up to abeut 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 formoteroi as the active agent, in specific embodiments, the amount of formoteroi 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/ml and about 0.5 mg/ml, and between about 0.03 mg/mi and about 0.4 mg/mi.

[0O86J Where the pharmaceutical co-suspension compositions described herein Include a LA8A active agent, in certain embodiments, the active agent may be salmeteroi, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. Sairnetero! can be used to treat inflammatory or obstructive pulmonary diseases end disorders such as, for example, those described herein, Salmeteroi, pharmaceutically acceptable salts of salmeteroi, and methods for producing the same are described, tor example, in U.S. Patent No, 4,992,474, U.S. Patent No. 5,128,375, and U.S. patent 5,225,445.

[088?! Where ssimeterol is included as a LABA active agent, in certain embodiments, the compositions described herein may include: saimeterol at a Concentration that achieves a delivered dose selected from between about 2 pg end about 120 pg,: about 4 pg and about 40 pg, about 8 μ| and 20 pg,: about B pg end 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/Ul:e compositions described herein may Include: saimeterol 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 8 pg per actuation of an MDI. In order to achieve targeted delivered closes as described herein, where compositions described herein include saimeterol as the active agent, in specific; embodiments, the amount of saimeterol included in the compositions may be selected from/for example, between about 0.04 mg/mi and about 4 mg/mi, between about 0.04 mg/ml and about 2.0 rng/rnl, and between about 0.12 mg/ml and about 0.8 mg/ml For example, the compositions described herein may include sufficient saimeterol to provide a target delivered dose selected from between about 4 pg and about 120 pg, about 20 pg and about 100 pg, and between about 40 pg and about 120 pg per actuation of an MDI. In still other embodiments, the compositions described herein may include sufficient saimeterol to provide a targeted delivered dose selected from up to about 100 pg, up to about 40 pg, or up to about 15 pg per actuation of an MDI.

[00881 Though the active agent material included in the compositions described herein may be amorphous or substantially amorphous, in specificembodiments, the active agent materlai used as or In the formation of the active agent particles included in the compositions described herein is substantially or entirely crystalline. Active agent material that is substantially or entirely crysialline may be selected to improve the chemical stability of the LAMA or LABA active agent when formulated in the Compositions described herein. Therefore, in specific embodiments, the active agent material included in the compositions described herein is a micronlzed, crystalline LAMA material In one such embodiment, the active agent particles are formed solely of micronlzed, crystalline LAMA materlai, such as a micronlzed crystalline material selected from glycopyrrplaie, dexipirnonium, tioiropium, trospium, aelfofnium, damtropium, and any pharmaceutically acceptable salts, esters or solvates thereof. In other specific embodiments, the active agent material Included in the compositions described herein is a rnicronlzed, crystalline ΙΑΒΑ material in one such embodimenl the active agent particles are formed solely of micronized, crystalline LABA material, such as a micromzed crystalline material selected from bambuiero!, clenbuterol, formoterol salmeterol carmoterol, milveteroi, indacateroi, and sallgensn- or Indole- containing and adamahtyl-derived p2 agonists, and any pharmaceutically acceptable salts, asters or solvates thereof, [00S9| Any suitable process may be employed to achieve micronized active agent material as or in the formulation of the active agent particles included in the cbmpdsitions described herein, A variety of processes may be used to create active agent particles suitable for use in the eo-suspensibn formulations described herein, including, but net limited to micron izatfon by milling: Of grinding processes, crystallization or recrystailizatlon processes, and processes using precipitation from supemfitscaS or near-supercritical solvents, spray drying, spray freeze drying, or lyophilizafion. Patent references teaching suitable methods for obtaining micronized active agent particles are described, for example, in U.S. Patent No, 6,063,138, U.S. Patent No, 5,858,410, U.S, Patent No, 5.851,453, U.S. Patent No. 5,833,891, U.S, Patent No. 5, 701,834, and Internationa! Patent Publication Mo. WO 2007/008184, Where the active agent particles include active agent materia! formuiated with one or more excipient or adjuvant, micronized active agent particles can be formed using one or more of the preceding processes and such processes can be utilized to achieve active agent particles having a desired size distribution and particle configuration, pi) Suspending Particles [0090] The suspending particles included in the co-suspension compositions described herein work to facilitate stabilization and delivery of the active agent included in the compositions. Though various forms of suspending particles may be used, the suspending particles are typically formed from pharmacoicgicaily 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 will not exceed about 10 pm but is not lower than about 500 nm. in an alternative embodiment, the MM:AD of the suspending panicles 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 pm. When used in an embodiment for nasal delivery from an MDI, the MMAD of the suspending particles is between 10 pm and 50 pm.

[00911 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 pm, In one embodiment, the suspending particles exhibit a volume median optical diameter that does not exceed about 25 pm. In another embodiment, the suspending particles exhibit a volume median optical diameter selected from between about 0,5 pm and about 15 pm, between about 1,5 pm: and about 10 pm, and between about 2 pm and about 5 pm, [O092J 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 1 mg/mi to about 15 mg/ml, about 3 mg/mi to about 10 mg/mi, 5 mg/mi to about 8 mg/mi, and about δ mg/mi. 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/mi. [09931 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 partlcies. For example, in specific embodiments, the ratio of the total mass of the suspending particles to the total mass of active agent particles may be between about 3:1 and about 15:1, or alternatively from about 2:1 and 3:1, Alternatively, the ratio of the total mass of the suspending partlcies to the total mass of active agent particles may be above about 1, such as up to about 1.5,/up to about 5, up to about 10, up to about 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 π-atum of the suspending particles and active agent particles used, in further emhodimehts, the mtlo of the total mass of the suspending particles to the iota! 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 16, about 60, and about 170.

[0894] In other embodiments, the amount of suspending particles, as measured by mass, is less than that of the active agent particles. For example, irt particular embodiments, the mass of the suspending particles may be as low as 20% of the total mass of the active agent particles. However, in some embodiments, the total mass of the suspending particles may also approximate or equal the total mass of the active agent particles.

[0095] 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, sorbose, and the like; disaccharides, such as sucrose, lactose, trehalose, celiobiose, and the like; cyclodextrins, such as 2-hydroxypropyl-β-cyciodextrin; and polysaccharides:, such as raffinose, maitodextrins, dextrans, starches, chitin, chitosan, thuiin, and the like; (b) amino acids, such as alanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, leucine, isoleucine, valine, and the like; (c) metal and organic salts prepared from organic acids and bases, such as sodium: citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamin hydrochloride, and the like; (d) peptides and proteins such as aspartame, tnieuone, human serum albumin* collagen! gelatin, and the like; (e) alditols, such, as mannitol, xylitol, and the like; (f] synthetic or natural polymers or combinations thereof, such as poiylactides, polylacfide-glycolldes, cyclodextrins, polyacrylates, methylceliulose, carboxymethyleetibtose, polyyinyt alcohols, polyanhydrides, polylaefams* polyvinyl pyrrolidones, hyaluronic acid, polyethylene glycols; and (g) surfactants including fSuonnated and nonffyorlnated compounds such as saturated and unsaturated lipids, non ionic detergents, non ionic block copolymers, sonic surfactants and combinations thereof. In particular embodiments, suspending particles may include a calcium salt, sued as calcium chloride, as described, for example, in U.S. Patent No. 7,442,388. |OOS$J Additionally, 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 40!'C. Exemplary phospholipids are relatively long chain (i,e„ saturated lipids and may comprise saturated phospholipids, such as saturated phosphatidylcholines haying acyi chain lengths of 18 C or 18 C (palmiloy! and stearoyl), Exemplary phospholipids include phosphoglycerides such as dipaimitoylphospbafidyicholine, d istemylphosphatidyichoilne, diarachidoylphosphafidyicholine, dibehenoyiphosphatidyicholine, diphosphatldyl glycerol, short-chain phosph a tidyi cho! i nes, long-chain saturated phosphatidylethanoiamines, long-chain saturated phosphatidylserihes, long-chain saturated phosphatidylglycerols, and long-chain saturated phosphalidyllnosltols, Additional excipients are disclosed in international Patent Publication No. WO 98/32149 and U.S. Patent Nos, 8,358,530, 8,372,258 and 6,5181239, [0097| in particular embodiments, the suspending particles may be formed using one or more lipids, phospholipids or saccharides, as described herein:, in some embodiments, suspending particles include one or more surfactants. The use of suspending particles formed of or incorporating one or more surfactants may promote absorption of the selected active agent, thereby Increasing hioavalabsiity. The suspending particles described herein, such as, for example, suspending particles formed using one or mote 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 couid be used in forming the suspending particles, as such suspending particles that have the pdfehtlai to reduce opsonization (and thereby reducing phagocytosis by alveolar macrophages), thus providing a longer-lived controlled release particle in the lung.

[08981 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 particles my include pharmaceutically acceptable glass stabilization excipients·: having a Tg of at least 55 CC, at least 75 *C, or at least 100 °C, Glass formers suitable for use in compositions described herein include, but are not limited to, one or more of trlieueine, sodium citrate, sodium phosphate, ascorbic acid, inuiin} cyclodextrim polyvinyl pyrrolidone, mannitol, sucrose, trehalose, lactose, and, proline. Examples of additional glass-forming excipients are disclosed in U. S, Patent Nos. RE 37,872, 5,928,489, 6,258,341, [00991 The suspending particles may be designed, sized and shaped as desired to provide desirable stability and active agent delivery characteristics, In one exemplary embodiment, the suspending particles comprise perforated microstruciures as described herein. Where perforated microstruofures 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, pedorated microstruciures may include at least one of the following: lipids, phosphoiiplcls, nonionic detergents, non ionic block copolymers, ionic Surfactants, biocompafibie fuorinaled surfactants and combinations thereof, particularly those approved for pulmonary use. Specific surfactant that may be used In the preparation of perforated microsiructures include poloxamer 188, poloxamer 407 and poloxamer 338, Other specific surfactants include oleic acid or its alkali salts. !h one embodiment, the perforated: microstruciures include greater than about 10%: w/w surfactant [01881 In some embodimehts, suspending particles may be prepared by forming an oil-in-waier emulsion, using a fluorocarbon oil (e.g., perfluorooctyi bromide, perffoorpdepalin) which may be emulsified using a surfactant, such as a long chain saturated phospholipid. The resyitlng pertiuorocarbon in water emulsion may be then processed using a high pressure homogenizer to reduce the oil droplet size. The pertluofocarboh 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 micrbstructures. As is well known, spray drying is a one-step process that converts a liquid feed to a dried particulate form. Spray drying has been used to provide powdered pharmaceutical material for various administrative routes, including ihhalatibn, 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 producing exemplary perforated microstructures are disclosed In U.S. Patent No. 6,309,823 to Wears ef a!. 101011 Perforated microstructures as described herein may also be formed through iyopbllizstion and subsequent milling or mieronizatlom tyophilization is 3¾ 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 disclosed In U,S, Patent 5,727,333, 10102) Furthermore, suspending particles as described herein may include bulking agents, such as polymeric particles. Polymeric polymers may be termed from biocompatihie and/or biodegradable polymers, copolymers or biends, in one embodiment, polymers capable of forming aerodynamicaily light particles may be used, such as functionalized polyester graft copolymers and bfedegradable polyanhydrides. For example, bulk eroding polymers based on polyesters including po!y(hydroxy acids) can be used. Polyglycolic acid (PGA), polyactlc acid (PLA) or copolymers thereof may be used to form suspending particles. The polyester may include a charged or functionalizahle group, such as an amino acid. For example, suspending particles may be formed of polyfox-lactic add) and/or poly{D,t-iaciic~eo-gjycoiic acid) (FL.GA), which incorporate a surfactant such as DPPC.

[0103) Other potential polymer candidates for use in suspending particles may include polyamides, polycarbonates, polyalkyienes such as polyethylene, polypropylene, polyfethyiene glycol), polyethylene oxide), poiy(eihyiene terephthalate), poly vinyl compounds such as polyvinyl alcohols, polyvinyl ethers, and polyvinyl esters, polymers of acrylic and methacrylic 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.

[01041 The compositions described herein may include two or more species of suspending particles. Even further, compositions according to the present description can include suspending particles that include giycopyrroiete 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.

[01O5J Compositions formulated according to the present teachings can inhibit degradation of active agent included therein. For example, sc specific embodiments, die compositions described herein inhibit one or more of flocculation, aggregation and the solution mediated transformation of active agent material included in the compositions. The pharmaceuticai compositions described herein are suited for respiratory delivery via and MD1 in a manner that achieves desirable delivered dose uniformity fODUw) of LABA and LAMA active agents, including potent and highly potent LABA and LAMA agents throughout emptying of an fvIDi canister. As is described in detail In the Examples Included herein, even when deiivering very iow doses of LAMA or LABA active agents, compositions described herein can achieve a DDU for the active agent of ± 30%, or better throughout emptying of an MDi canister. In one such embodiment, compositions described herein achieve a DDU for the active agent of ± 20%, or better throughout emptying of an MP1 canister, to yet another such embodiment, compositions described herein achieve a DDU for the active agent of ± 20%, or better throughout emptying of an MO! canister.

[0106] Pharmaceuticai compositions described herein also serve to substantially preserve FPF and FPD performance throughout emptying of an MPI canister, even after being subjected to accelerated degradation conditions. For instance, compositions according to the present description maintain as much as 80%, 90%, 95%, or more, of the original FPF and FPD performance throughout emptying of an MDI canister, even after being subjected to accelerated degradation conditions. Compositions described herein provide the added benefit of achieving such performance while being formulated using non-CFC propellants, in specific embodiments, the compositions described herein achieve desired one or ail of a targeted DDU, FPF and FPD performance while being formulated with suspension medium including only one or more non-GFC propellants and without the need to modify the: characteristics of the: nomOFD propellant, such as by the addition of, for example, one or more eosolyent, antisolvent, solubilizing agent, adjuvant or other propellant modifying material [010?! in one embodiment, a co-suspension composition as described herein includes-: a suspension medium comprising a pharmaceutically- acceptable NFA propellant; a: plurality of active agent particles comprising glyeopyrroiate, Including any pharmaceutically acceptable; salts, esters, Isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of glyeopyrroiate of between about 20 pg and about 150 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated microstruciures as described herein exhibiting a volume median optical diameter of between about 1,5 pm and about 10 pm, wherein perforated misrostruetures associate with the plurality of active agent particles to form a od-suspensidn, in one such embodiment, the glyeopyrroiate active agent particles are formed of crystalline glyeopyrroiate material. In another such embodiment, the ratio of the total mass of the suspending particles to the total mass of the active agent perfidies is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1, in yet another such embodiment, the glyeopyrroiate active agent particles are formed of crystalline glyeopyrroiate material 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 3:1 and about 15:1 and between about 2:1 and 8:1. in still another such embodiment, the glyeopyrroiate active agent particles are formed of crystalline glyeopyrroiate material, at least 90% of the glyeopyrroiate active agent particles by volume exhibit an optical diameter of less than ? pm, and the ratio Of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1. PHOBJ In another embodiment, a co-suspension composition as described herein Includes: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising tiotropium, including any pharmaceutically acceptable salts,, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of glyeopyrroiate of between about 5 pg and about 40 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated mierostructures as described herein exhibiting a volume, median optical diameter of between about: 1.5 pm and about 10 pm, wherein perforated mierostructures associate with the plurality of active agent particles to form a co-suspension, in one such embodiment, the tiotropium active agent .particles are farmed of crystalline tiotropium material, in another such embodiment, the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1. In yet another such embodiment, the tiotropium active agent particles are formed of crystalline tiotropium material 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 3:1 and about 15:1 and between about 2:1 and 8:1. In still another such embodiment, the tiotropium active agent particles are formed of crystalline tiotropium: material, at feast 90% of the tioirppibm mctiye agent particles by volume exhibit an optical diameter of less than 7 pm, and the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

[9109] In another embodiment, a co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality ofactive agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration Sufficient to provide a delivered dose of fdrmotenof of between about 0.5 pg and about '10.· pg per actuation of the metered dose Inhaler; and a plurality of respirable suspending particles comprising perforated mierostructures as described herein exhibiting a volume median optical diameter of between about 1.5 pm and about 10 pm, wherein perforated mierostructures associate with the plurality of active agent particles to form a co-suspension, in one such embodiment, the formoterol active agent particles are formed of crystalline formoterol material. In another such embodiment,: the ratio of the total mass of the suspending particles to the; total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1. fn yet another such embodiment* the formoterol active agent particles are formed of crystalline formoterol material 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 3:1 and about 15:1 and between about 2:1 and 8:1. in still another such embodiment, the formoterol active agent particles are formed of crystalline formoterol material, at least 90% of the formoterol active agent particles by volume exhibit an optical diameter of less than 7 pm, and the ratio of the total mass of the suspending particles to the total mass of the active· agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

[91191 In one embodiment, a co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising fomioferol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of fonnoteroi of between about 2 pg and about 10 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated microstructures as described herein exhibiting a volume median optical diameter of between about 1,5 pm and about 10 pm, wherein perforated microstructures associate with the plurality of active agent particles to form a co-suspension In one such embodiment, the formoterol active agent particles are formed of crystalline fontiotefol material In another such embodiment the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1. In yet another such embodiment, the formoterol active agent partlcies are formed of crystalline formoterol material and the ratio of the total mass of the suspending particles to the Mai mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1, In still another such embodiment, the Ibrmoteml active agent particles am formed of crystalline formoterol material, at least 90% of the formoterol active agent particles by volume exhibit an optica! diameter of less than 7 pm, 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 3:1 and about 15:1 and between about 2:1 and 8:1.

[91111 In another embodiment, a co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising ssimeterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in the suspension medium at a concentration sufficient to provide a delivered dose of saimeteroi of between about a pg and about 40 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated microstructures as described herein exhibiting a volume median optical diameter of between about 1,δ pm and about 10 pm, wherein perforated microstructures associate with the plurality of active agent particles to form a co-suspension, in one such embodiment, the saimeteroi active agent particles are formed of crystalline saimeteroi material in another such embodiment, the ratio of the iotai mass of the suspending perfidies to the total mass of the active agent particles is selected from between about 3'1 and about 15:1 and between about 2:1 and 8:1. in yet another such embodiment, the saimeteroi active agent partlcies are formed, of crystalline saimeteroi material 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 3:1 and about 15:1 and between about 2:1 and 8:1. In still another such embodiment, the saimeteroi active agent partlcies are formed of crystalline saimeteroi material, at least 90% of the safmetdroi active agent partlcies by volume exhibit an optica! diameter of less than 7 pm, and the ratio of the total mass of the suspending particles to the total mess of the active agent; particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

Ill Petered Dose inhaler Systems pH 12] As described in relation to the methods provided herein, the compositions disclosed herein may be used in an MDI system, MDis are configured to deliver a specific amount of a medicament in aerosol form, in one embodiment, an MOi system includes a pressurized, liquid phase formulation-flea canister disposed In an actuator formed with a mouthpiece. The MDI system may include the formulations described herein, which include a suspension- medium, giycopyrrolate 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 28: 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. pi13| Inside an exemplary cartridge is a metering valve; Including a metering chamber capable of holding a defined volume of the fomiylatiGn (e.g,, 83 μι or any other suitable volume available in commercially available metering valves), which is released into an expansion chamber at the distal end of the valve stem when actuated. The actuator retains the canister and may also include a port with an actuator nozzle for receiving the 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 high-velocity spray that is drawn into the lungs of a patient. IV. Methods pi 14! Methods for formulating· pharmaceutical compositions for respiratory delivery of LAMA and LAMA active agents ere provided herein. In particular embodiments:, such methods involve the steps of providing a suspension medium, active agent particles selected from active agent particles comprising a LAMA and active agent particles comprising a LABA, and one or more species of suspending particles, as described herein, and combining such constituents to form a formulation wherein the active agent particles associate with the suspending particles and colocate with the suspending particles within the suspension medium such that a co-suspension :tS: formed,: in one such embodiment, the association of the glycopyrrolaie particles and the suspending particles Is such that they do not separate due to their different buoyancies In a propellant. As will fee appreciated, the method may Include providing two or more species of suspending particles in combination with active agent particles, in another embodiment, the method may include providing two or more species of active agent particles and combining the two or more species of active agent particles with one or more species of suspending particles In a manner that results in a co-suspension. In certain embodiments, the active agent panicles consist essentially of a LAMA or LABA active agent as described herein, [0i1S| in specific embodiments of methods for providing a stabilized composition of a LAMA or LABA active agent for pulmonary delivery, the present disclosure provides methods for inhibiting the soiuion mediated transformation of the LAMA or LA8A active agent in a pharmaceutical composition for pulmonary delivery, in one embodiment, a. suspension medium .as. described herein, such as a suspension medium formed by an HFA propellant, is obtained. Suspending particles am also obtained or prepared as described herein. Active agent particles are also obtained, and the suspension medium, suspending particles and active agent particles are combined to form a co-suspension wherein the active agent particles associate with suspending particles and co-locate with the suspending particles within the continuous phase formed by the suspension medium. When compared to active agent particles contained in the same suspension medium in the absence of suspending particles, co-suspensions according to the present description have been found to exhibit a h|gh^''-tDl6rahce:l^:^iui$i^ mediated phase transformation that leads to irreversible crystal aggregation, and thus may lead tb improved stability and dosing uniformity.

In further embodiments, methods for forming stabilized compositions of LAMA and LABA active agents for pulmonary delivery include for preserving the FPF and/or FRO of the composition throughout emptying of an MDI canister, in specific embodiments of methods for preserving the FPF and/or FPD provided by a pharmaceutical composition for pulmonary delivery, a respirable co-· suspension as described herein Is provided which is capable of maintaining the FPD and/or the FPF 10 within ± 20%, ± 10%, or even ± 5% the initial FPD and/or FPF, respectively, throughout emptying of an MSI 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, is obtained. Suspending particles are also obtained or prepared as described herein. Active agent particles are also obtained, and the suspension medium, suspending particles and active agent particles are combined to form a co-suspension wherein the giyoopyrrolate particles associate with suspending particles and co-iocate 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 cycling events. I&amp;1171 Methods for preparing an MD! for pulmonary delivery of LAMA-or LABA active agent are disclosed. The method of preparing the MD! may include loading a canister, as described herein, with active agent particles and -suspending particles. An actuator valve can be attached to an end of the canister and the canister sealed. The actuator valve may be adapted tor dispensing a metered amount of the giycopyoolate pharmaceutical formulation per actuation. The canister can be charged with a pharmaceutically acceptable suspension medium, such as a propellant as described herein. Whereupon the active agent particles and suspending particles yield a stable cotouspenslon in the suspension medium, pi 18] In methods involving pulmonary delivery of a LAMA or LABA active agent using compositions described herein, the compositions may be delivered by an MDL Therefore, in particular embodiments of such methods:, an MDl loaded with a composition described herein is obtained, and a LAMA or LABA active agent is administered to a patient through pulmonary delivery through actuation of the MDL For example, in one embodiment, after shaking the MDl device, the mouthpiece im 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 of the MDl, When actuated, the specified volume of formuiailon travels to the expansion chamber, out the actuator nozzle and into a highweioelty spray that is drawn into the lungs of a patient. In one embodiment the dose of active agent delivered throughout emptying of an MDl canister Is not more than 30% greater than the mbac delivered dose and is not less than 30% less than the mean delivered dose. Therefore, methods of achieving a desired ODD of giyeopyrroiate delivered from an MDl are also provided, in such embodiments, the method may include achieving a DDU for giyeopyrroiate delivered from an MDi selected from, for example, a DDU of ± 30%, or better, a DDU of ± 25%, or belter, and a DOU of ± 20%, or better. |0110] 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 pharmaceutical composition described herein, and in certain such embodiments, pulmonary administration of the pharmaceuticai composition is accomplished by delivering toe composition using an MDL The disease or condition to be treated can be selected from any inflammatory or obstructive pulmonary disease or condition that responds to the administration of a LAMA or LABA agent, in particular embodiments, the pharmaceuticai compositions described herein may be used in treating a disease or disorder selected from asthma, CORD, exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded inspiration,: respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, emphysema, and any other respiratory disease, condition, trait, genotype or phenotype that can respond to the administration of a LAMA or LABA, alone or in combination with other therapies, in certain embodiments, the pharmaceutical compositions described herein may be used in treating pulmonary inflammation and obstruction associated with cystic fibrosis, [01$0| Additionally, pharmaceutical compositions according id the present description delivered from an MDS provide desirable pharmacodynamic (PD) performance, in particular embodiments, pulmonary delivery of the pharmaceutical compositions described herein resuits In rapid, significant improvement in the tong, capacity, which can be characterized by an improvement in the patienfs forced expiratory volume in one second (FEVi}, For example, in particular embodiments, methods for achieving a clinically relevant increase in FE\A are provided, wherein such methods include providing a co-suspension composition comprising a ΙΑΒΑ or LAMA active agent as described herein and administering such composition to a patient experiencing pulmonary inflammation or obstruction via an MO I. For purposes of the present disclosure, a clinically relevant increase in FEVi Is any increase of 100 mi or greater, and in certain embodiments of the methods described herein, admihistratioh of compositidhs according to the present;description to patient results in a otlnscaliy significant increase in FEVi within 1 hour or less, in other such : embodiments, methods for administering a composition as described herein to a patient: via an MDI resuii in a clinically significant increase in FEVI within 0.5 hours or less. The compositions provided and delivered in such embodiments may include a composition Including a LAMA active agent or a composition including a LABA active agent as described herein, |0121] In further embodiments, methods are provided for achieving an increase in FEVi greater than 100 ml. For example, in certain embodiments, the methods described herein include methods for achieving an FEVi of 150 ml or greater within a period of time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less.

in other embodiments, the methods described herein include: methods :fbrachieving an FEV'i of 200 ml of greater within a period of time selected from 0,5 hours or less, 1 hour or less, and 1.5 hours or less, and 2 hours or less, in certain such embodiments, a composition comprising a LABA or LAMA active agent as described herein is provided and administered to a patient experiencing, pulmonary Inflammation or obstruction via an MDL

[0122| in stilt further embodiments, methods for achieving and maintaining a clinically significaniSy increase in FEVi are provided, in particular embodiments, upon administration of a single dose of a LABA or LAMA active agent formulated in a composition as described herein to a patient via an MDi, a clinicaiiy significant increase In F£V< is achieved in a period of time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less, and the clinically significant increase In Ff~% is maintained for up 12 hours or more, in certain such embodiments, the increase in FEV j may be selected from an increase of 150 mi or greater, 200 mi or greater and 25P ml or greater, and the increase in FEVi remains clinically significant for a time period selected from up to 4 houre, up to 6 hours, up to 8 hours, up to 10 hours, and up to 12 hours, or more, in certain such embodiments, a composition comprising a LABA or LAMA active agent as described herein is provided and administered a patient experiencing pulmonary inflammation or obstruction via an MDi.

[0125! Compositions, systems and methods described herein are not only suited to achieving desirable pharmacodynamic performance in short periods of time, but will achieve such results In a high percentage of patients. For example, methods are provided herein for achieving a 10% or greater increase in FEV j in 50% or more of patients experiencing pulmonary inflammation or obstruction. For example, in particular embodiments, methods for achieving a 10% or greater Increase in FEVj in a patient include providing a co-suspension composition comprising a LABA or LAMA active agent as described herein and administering such composition via an : MDI to a patient experiencing pulmonary Inflammation or obstruction- in certain such embodiments, idmihistratson of the composition results in 10% or greater increase in FEVj within a period of time selected from 0,5 hours or less, 1 hour or less, 15 hours or less, end 2 hours in 50% or more of patients. In other such embodiments, administration of the composition results in 10% or greater increase in FEVi within a period of time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 or less hours in 60% or more: of patients. In still other such embodiments, edmioistmtion of the composition results in 10% or greater increase in F£V< within a period of time selected from 0.5 hours or iess, 1 hour or less, 1.6 hours or less, and 2 hours or less in 70% or more of patients. In yet other such embodiments, administration of the composition results in 10% or greater increase in FEVi within a period of time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 or less hours in 80% or more of patients [0124] in specific embodiments, the methods described herein facilitate treatment; of patients experiencing pulmonary inflammation or obstruction, wherein such methods include providing a co-suspension composition comprising a LA BA or LAMA active agent as described herein and administering such composition to a patient experiencing pulmonary inflammation or obstruetieo via an MDi and result in a high proportion of such patients experiencing either an increase from baseline in FEV1 of at least 200 mi or a 12%f or greater, increase from baseline in FEVi coupied with total increase in .FEV1 of at least 150 ml. In certain such embodiments, administration #F the composition results in either an Increase from baseline in FEVi of at least 200 mi or a 12%, or greater, increase from baseline in FEV1 coupled with iota! increase in FEVi of at least 150 mi within a period of time selected from 1 hour or iess, 1.5 hours or less, 2 hours or less, and 2,5 hours or iess in §0% or more of patients. In other such embodiments, administration of the composition; results in an increase from baseline in FEVi of at least 200 ml or a 12%, or greater, increase from baseline in FEVi coupied with total increase in FEV·: of at least: 150 ml within a period of time selected from 1 hour or less, 1,5 hours or less, 2 hours or less, and 2.5 hours or less .In 60% or more of patients, !h still other such embodiments, administration of the composition results in either an increase from baseline in FEV, of at least 200 ml or a 12%, or greater, increase from baseline in FEVi coupled with total increase in FEVi of at least 150 ml within a period of time selected from 1.5 hours or less, 2 hours or less, 2.5 hours or less, arid 3 hours or less In 70% or more of patients. In yet other such embodiments, administration of the composition results In either an increase from baseline in FEVi of at least 200 ml or a 12%, or greater, Increase from baseline in FEVi coupled with total increase in FEVi of at least 150 ml within a period of time selected from 1.5 hours or iess, 2 hours or less, 2.5 hours or less, and 0 hours or less In 60% or more of patients. £01261 in some embodiments, pharmaceutical compositions according to the ^msentdascriptiondaihrerad'tit>m an MO! provide improvement''in the lung capacity, which can be characterized by an improvement inspiratory capacity (f€), which is defined as the maximal volume of gas that can be taken into the lungs in a full inhalation following a normal expiration. For example, in particular embodiments, methods for achieving a clinically relevant Increase in SC are provided, wherein such methods include providing a co-suspension composition comprising a LABA or LAMA active agent as described herein and administering such composition to a patient experiencing pulmonary inflammation or obstruction via an MDf. For purposes of the present disclosure, a clinically relevant increase in !G is any increase of:70 mi or greater, and in certain embodiments of the methods described herein, administration of compositions according to the present description to patient results in a clinically significant increase in 1C within 2 hours or less. In other such embodiments, methods for administering a composition as described herein to a patient via an MDI resuit in a clinically significant increase in 1C within 1 hour or less, in other such embodiments, administration of compositions according to the present description to patient results in an increase in iC of 100 m! or greater within a period of time selected from 1 hour or less and 2 hours or less, in still other Such embodiments, administration of compositions according to the present description to patient results in an Increase in IC of 150 ml or greater within a period of time selected from 1 hour or less and 2 hours or iess. In even further such embodiments, administration of compositions according to the present description to patient results in an increase in IC of 300 mi or greater within a period of time selected from 1 hour or less and 2 hours or: less. The, compositiohs provided: and delivered in such embodiments may indude a composition including a LAMA active agent or a composition including a IAEA active agent as described herein, |O12if in particular embodiments of the methods described herein, the compositions provided include a LAMA active agent; in such embodiments, the LAMA active agent can be selected from, for example, glycopyrrolate, dexipirronium, tiotropium, trospium, aclldihium, and darotropium, including any pharmaeeufieaiiy acceptable salts, esters, isomers dr solvates thereof. in specific embodiments of the methods described herein, the composition is a co-suspension composition as described herein that includes glycopyrrolate or any pharmaceuticsliy acceptable salt, ester, isomer or solvate thereof, ίο other specific embodiments of the methods described herein, the composition! is a co-suspension composition as described herein that includes tiotropium or any pharmaceutically acceptable salt, ester, isomer or solvate thereof. Where giycopyrnolaie or tiotropium is selected as the active agent for use in the compositions produced or administered as part of the methods described herein, the amount of giycopyrroiate or tiotropium included in the composition may be selected Irony for example, those amounts specifically d isclosed with respect to the pharmaceutical compositions described herein.

[0127J in further embodiments of the methods described herein, the compositions provided include a L.ABA active agent. In such embodiments, the LABA active agent can be selected from, for example, bam bate rol, ci en bu terol, forme teroi, salmeteroi, carmoferoL milveteroi, indacateroi, and sailgenin- or indole- containing and adamantyl-derived (¾ agonists, including any pharmaceutically acceptable salts, esters, Isomers or solvates thereof, in specific embodiments of the methods described herein, the composition is a co-suspension composition as described herein that inciudes fonmotefoi or any pharmaceutically acceptable salt, ester, isomer or solvate thereof. In other specific embodiments of the methods described herein, the composition is a cx>-suspens|oh composition as described herein that includes saimeteroi or any pharmaceuticaily acceptable salt, ester, Isomer or solvate thereof. Where formotefoi or salmeteroi is selected as the active agent for use in the compositibhs produced or administered as pari of the methods described herein, the amount of formotero! or salrntero! included in the composition may be selected from, for example, those amounts specifically disclosed with ms pact to the pharmaceutical compositions described herein.

[01281 Compositions, methods and systems described herein provide desirable dose efficiency and dose response for LAMA or LABA active agents formulated for pulmonary delivery, For example, pulmonary delivery of 'giycopyrroiate. for treatment of conditions such as CORD has been previously suggested or reported by Schroeckenstein eta!., J, Allergy Clin. Immunol., 198S; 82(1}* 115-119, Leckie et aL, Exp, Opln, Invest. Drugs, 2000; 9(1): 3-23, Skorodln, Arch, Intern, Med,, 1993: 153: 814-828, Walker et a!., Chest; 198?; 91(1): 49-51, and International Patent Publication WO/1997/039758, These references report a minimum effective dose for giycopyrroiate of 200 pg - 1,000 pg. Such dosing regyirements are in line with human clinical results reported by Bannister et M, id U,S, Patent No, 7,229,607, wherein subjects were givers a 480 pg dose of giycopyrmiate. As &amp; described in Example 6 pspvided hereiili, compositions of glycopyrrolate prepared according to the present description and delivered to human subjects via an MDI achieved guick onset of action end clinically relevant improvements In FEVi and 1C T accordance with the methods detailed Herein, even when delivering significantly smaller doses of glpopyrrolate |the largest single dose delivered in the study was 144 pc). 101291 Singh et ai. p Singh, P A Corns, and S D Snape. “NVA237, a once-dsily inhaled antimuscarinic, provides 24~hour bronchodiiator efheacy in patients with moderate to-severe COPD55 Poster presented at the American Thoracic Society international Conference, San Diego, California, May 19 -24, 2006] reported clinical work wherein glycopyrrolate was administered to human subjects via pulmonary delivery at doses of 20 pg, 125 pg, 250 pg, and 400 pg. Though such doses ranged below the 200 pg threshold previously reported, as Is also detailed in Example 6, Compositions of glycopyrrolate formulated and delivered as described herein still achieved a relatively improved dose efficiency. For example, changes in FEVi AUC achieved by glycopyrrolate co^suspensions as described and evaluated in the clinical trial described in Example 6 are compared to those achieved by the compositions of Singh et ak in Figure 10. The 18 pg glycopyrrolate dose from Example 6 provided significantly better bronchodilator response than the 20 pg dose reported by Singh et #1,, and the 36 pg and 144 pg glycopyrrolate doses from Example 6 providing comparable bronchodilator response to the 125 pg and 250 pg doses, respectively, reported by Singh et ai. |913Q1 In particular embodiments, methods for achieving desired phamiaeodynarnle effects are provided, wherein the methods include administering a co-suspension composition as described herein to a patient via a metered dose inhaler, wherein the co-suspension includes glycopyrrolate active agent particles as described herein to a patient via a metered dose inhaler such that a delivered dose of no more than 150 pg giycopyrrolate is administered to the patient. In one embodiment, a method for achieving a clinically significant Increase In FEVi is provided, wherein the method includes administering a co-suspensidh as described herein comprising glycopyrrolate active agent particles to a patient via a metered close inhaler such that a delivered dose of no more than T50 pg glycopyrrolate is administered to the patient. In one such embodiment, a delivered dose of no more than 100 pg giycopyrroiate is administered to the patient, and in another embodiment, a delivered dose of no more than 80 ug giycopyrroiate is administered to the patient. Even where doses of no more than 80 pg, no more than 100 ug giycopyrroiate, or no more than 150 ug giycopyrroiate are administered to the patient, in particular embodiments, the clinically significant increase in FEV1 is achieved in 1 hour or less. In some such embodiments, the clinically .significant increase in FEV1 is achieved in 0.5 hours or less.

[01 31] In further embodiments, methods are provided for achieving an increase in FEVS greater than 100 ml, wherein the methods Include administering a cosuspension as described herein comprising glycopyrroSate active agent particles to a patient via a metered dose inhaler such that a delivered dose of no more than 150 MO giycopyrroiate is administered to the; patient. For example, in certain embodiments, methods for achieving an PEVi of 150 mi or greater within a period of time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less, are provided, wherein the methods include administering a co-suspension as described herein comprising giycopyrroiate active agent particles to a patient via a metered dose inhaler such that a delivered dose of no more than 150 pg giycopyrroiate is administered to the patient In other embodiments, the methods described herein include methods for achieving an FEV'f of 200 ml or greater within a period of time selected from 0.5 Hours or less, 1 hour or less, and 1.5 hours or less, and 2 hours or less, wherein the methods include administering a co-suspension as described herein comprising giycopyrroiate active agent particles to a patient via a metered dose inhaler such that a delivered dose of no more than 150 pg giycopyrroiate is administered to the patient.

[0132] In stl further embodiments, methods for achieving and maintaining a clinically significantly increase in EE¥? am provided, wherein the methods include administering a co-suspension as described herein comprising giycopyrroiate active agent pirticles to a patieht via a metered dose inhaler such that a delivered dose of no more than 150 pg giycopyrroiate is administered to the patient, in certain such embodiments, upon administration of a single: delivered dose of giycopyrroiate of no more than 150 pg, a clinically significant increase In FE¥i is achieved In a period of time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less, and the clinically -.significant increase m FEVi is maintained for up 12 Poors or more, For example, in particular embodiments, the increase in FEVi may be selected from an increase of 150 mf or greater, 200 ml or greater and 250 mi or greater, and foe increase in FEVi remains clinically significant: for a time period selected from up to 4 hours, up to 6 hours, up to 8 hours, up to 10 hours, and Up to 12 hours, or more, pi 33| Methods for achieving an increase from baseline in FEV< of at least 200 ml or a 12%, or greater, increase from baseline In FEVi coupled with total increase in FEVi of at least 150 ml are also provided, wherein the methods include administering a co-suspension as described herein comprising glycopyrrolate active agent particles to a patient via a metered dose inhaler such that a delivered dose of no more than 150 pg glycopyrrolate: is administered to the: patient. In certain such embodiments, administration of a delivered dose of no more than 150 pg glycopyrrolate from a co-suspension as described herein via a metered dose inhaler results In elfoer an increase from baseline in FEVi of at least 200 mi or a 12%, or greater, increase from baseline in FEVi coupled with total Increase in FEVi of at least 150 ml within a period of time selected from 1 hour or less, 1,5 hours or less, 2 hours or less, and 2.5 hours or less In 50% or more of patients. In other such embodiments, administration of a delivered dose of no more than 150 pg glycopyrrolate from a co-suspension as described herein via a metered dose Inhaler results in an increase from baseline in FEVi of at least 200 ml or a 12%, or greater, increase from baseline in REV? coupled with total increase In FEVi of at least 150 ml within a period of time selected from 1 hour or less, 1.5 hours or less, 2 hours or less, and 2.5 hours or less in 60% or more of patients, In still other such embodiments, administration of a delivered dose of no more than 150 pg glycopyrroiate from: a co-suspension as described: herein via a: metered dose inhaler results in either: an increase from baseline in FEVi of at least 200 ml or a 12%, or greater, increase from baseline in FEVi coupled with total increase In FEVi of at least 150 mi within a period of time selected from 1,5 hours or less, 2 hours or less, 2.5 hours or less, and 3 hours or less In 70% or more of patients. In yet other such embodiments, administration of a delivered dose of no more than 150 pg glycopyrrolate from a co-suspension as described herein via a metered dose inhaler results In either an increase from baseline in FEVi of at least 200 mi or a 12%, or greater, increase from baseline in FEVi coupled with total Increase in FEVi of at least ISO ml within a period of time selected from 1.5 hours or less, 2 hours or less, 2.5 hours or less, and 3 hours or less in 80% or more of patients, J®134| Methods for achieving a eilnieaiiy significant Increase in iC are provided, wherein the methods include administering a co-suspension as described herein comprising giycopyrroiate active agent particles to a patient via a metered dose inhaler such that a delivered dose of no more than 150 pg giycopyrroiate is administered to the patient In certain such embodiments, administration of a delivered dose of no more than 150 pg giycopyrroiate from a co-suspension as described herein via a metered dose inhaier results in a clinically significant Increase in iG within 1 hour or less. In other such embodiments, administration of a delivered dose of no more than 150 pg giycopyrroiate from a co-suspension as described herein via a metered dose inhaler results in an increase In 10 of 100 ml or greater within a period of time selected from 1 hour or less and 2 hours or less, in still other such embodiments, administration of a delivered dose of no more than 150 pg giycopyrroiate from a co-suspension as described herein via a metered dose inhaler results in an increase in 1C of 150 ml Or greater within a period of time selected from 1 hour or less and 2 hours or less. In even further such embodiments, administration of a delivered dose of no more than 150 pg giycopyrroiate from a co-suspension as described herein via a metered dose ihhaier resuits in an increase In 1C of 300 ml or greater within a period of time selected from 1 hour or less and 2 hours or less, |0135| The specific examples included herein are for illustrative purposes only and are not to be considered as limiting to this disclosure. Moreover, the compositions, systems and methods disclosed heroin have been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration, it will fee apparent to those skilled in the art that the invention is susceptible to addiiionai embodiments and that certain of the details described herein may be varied without departing from the basic principles of the invention. Any active: agents and reagents used in the .following examples are either commercially available or can be prepared accordirig to standard literature procedures by those skilled in the art of organic synthesis. The entire contents of ail publications, patents, and patent applications referenced heroin are hereby incorporated herein by reference.

Example 1 |01361 Active agent particles formed of gfycopyrrolate (Pyrroiidinium, 3-{{cycipgentyihydmxyphenyi^^ bromide) were formed by micmniziog gSycopyrrotate using a jet: mill. The particle size distribution of the micronizedi glycopyrroiafe (GP) was determined by laser diffraction, 5:0% by volume of the mlcfonlzed particles exhibited an optical diameter smaller than 2,1 pm, §0% by volume were sriiailer than 5 prn, [0137J Suspending particles were manufactured as follows: 500 ml of a fluorocarbon-in water emulsion of PFOB (perfiuoroctyi bromide) stabilized by a phospholipid was prepared, 18.7 g of the phospholipid, DSPC (1,2-Distearoyl-sn·· GSycero-3-PhosphoehoSine), and 1.3 g of calcium chloride were homogenized in 400 ml of hot water (75 X) 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 C3; Avestln, Ottawa, CA) at pressures of up to 170 MPa for 5 passes.

[01361 The emulsion was spray dried in nitrogen using the following spray drying conditions: Inlet temperature 95 X, outlet temperature 72 CC, emulsion feed rate 2.4 ml/iiiln, total gas flow 525 t/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, [61301 Metered dose inhalers were prepared by weighing the target masses of micmnized GP particles and suspending particles into fluorinated ethylene polymer (PEP) coated aluminum canisters (Presspart Blackburn, UK) with 19 ml volume. The target masses and the target delivered dose assuming 20% actuator deposition are: given in Table 1 for five d if fere n t conflgurations (configurations 1A through 1C representing different suspensions of GP particles and suspending particles; configuration ID representing GP particles alone; configuration IE representing suspending particles alone). The canisters were; crimp sealed with 63 μ!waives (# 8K 357, Bespak, King's Lynn, UK) and: filled with 12,4 g of UFA 134a (1,1,1,2-tetrafluproethane) (Inaos Fluor, Lyndhurst, UK) by overpressure through the valve stem, After injecting the propellant, the canisters were sonicated for I S seconds and agitated on a wrist action Shaffer for 30 minutes. The canisters were fitted with polypropylene actuators with a 0.3 ram orifice (# BK 838, Bespak, King's Lynn, UK), Additional Inhalers for visual observation of suspension quality were prepared using: glass vials,

Table 1: Results for Glycopyrroiste Co-suspensions of Example 1

|01401 Aerosol performance was assessed shortly after manufacturing in accordance with USP «601 > (United States Pharmacopeia Monograph 601). A Next Generation impactor (NG!) operated at a flow rate of 30 L/min was used for determination of particle size distribution. Sample canisters were seated into an actuator with two waste actuations and two additional waste priming actuations. Rive actuations were collected In the NG1 with a USP throat attached. The valve, actuator, throat, NGI cups, stages, and filter were rinsed with volurnetricaily dispensed solvent. The sample solutions were assayed using a drug specific chromatographic method. The fine particle fraction was defined using the sum of stages 3 through filter. Delivered dose uniformity through use testing was performed using a Dose Uniformity Sampling Apparatus as described In USP <601 >, Inhalers were seated and primed as described before. Two actuations were collected and assayed at beginning, middle and end of use, [01411 Visual observation of the co-suspended configurations (1A, 18, 1C) showed no sedimentation of drug crystals. The suspension flocculated slowly and formed a homogeneous, single cream layer similar to the comparator configuration 1E, which included suspending particles suspended alone. In contrast, the micronized CP particles alone (configuration ID) flocculated and sedimented quickly. Configuration 1B showed no indication of separation of GP particles from the suspending particles even after centrifugation at 35g for 20 minutes. The same ([.©>, lack, of GP particle separation) when centrfuged up to 2000. Configuration 1C (low suspending concentration) showed a small amount of GP crystals settling out after centrifugation at 3Sg for 20 minutes.

[0142] While the co-suspended eonfigu rations achieved a delivered dose within 10 % of target, the GP particles suspended alone showed much higher variability in delivered dose in a range slgnificahtly below target. The fine particle taction relative to configuration 1D 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 16 and TO, 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 co-suspension was formed, and the aerosol pertormance of the co-suspension was mostly determined by the suspending particles.

[01431 The association between GP crysfais and suspending particles 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 is inhibited.

Example 2 [01441 Giycopyrrolate (GP) particles were formed by micmnizatfon using a jet mill. Suspending particles were manufSctMred as described in Example 1, The particle size distribution of the micronized GP was determined by laser diffraction. 50% by volume of the rnicronised particles exhibited an optical diameter smaller than 1,7 pm, 90% by volume exhibited an optical diameter smaller than 4,1 pm. Five different lots of metered dose inhalers were different lots were made. For configurafions 2A, 28 and 2C the total concentration of DSPC, CaCb, and GP in the feedstock was 40 mg/ml, for configuration 20 and 2E this concentration was doubled, [0145] Metered dose inhalers were prepared by weighing the target masses of GP particles and suspending particles info canisters as described in Example 1. No further excipients were used. The target masses were 4 mg / canister for GP particles and 60 mg/ 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 in a suspending particle to GP particle rat© of 10 for configuration 2B, The target masses were δ mg / canister for GP particles and 60 mg / canister for the suspending particles, resulting tn a suspending particle to GP particle ratio of 7,5 for configurations 20 and 2E, Propellant and container closure system were as described In Example 1. J&amp;140J The GP crystals were placed in HFA 134a in a canister under pressure and were eguilibrated for 3 weeks at room temperature to determine their solubility 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 chromatographieaily analyzed, A solubility of 0.17 ± 0,07 ug/g was 'found. Using this value it was determined that: 2:^1 pg or 0,05% of GP present in the canister dissolved. In the propellant, Previous articles teach that microcrystalline materia! with a measurable solubility in the propellant will not be physically stable due to solution mediated transformation [N. C. Miller, Hie Effects of Water in Inhalation Suspension Aerosol Formulations, in; P. A. Byron, Ed. Respiratory Drug Delivery, CRC Press, 1990, p 250], or that actives with solubility's above 0.1 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 Gpih, Drug Dellv, 2,626-638,2005], [0147j The Tiled metered dose inhalers were stored valve down without overwrap at two different conditions; 1) refrigerated at 5*C; and 2} room temperature at 26*G / 60% RH, Aerosol performance and delivered dose uniformity tests as described in Example 1 were carried out at different time points. The results, which are summarized in Tabie 2, show a stable fine particle fraction at refngerated and room temperature conditions.

Table 21 Fine particle fraction of configurations in Example 2

P14SI Configurations 20 and 2E were subjected to a temperature cycling test. The canisters were subjected to -5 *C and 40 aC alternating between temperatures every 5 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% tor configuration 2C and at 53% for configuration 2E, [01491 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 ί and 2 show the aerosol particle size distributions as measured by the NCI for configurations 2A and 2B, 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, 3 and 12 weeks and at 8,12 and 24 week for configuration 28. Though there Is a measureable fraction of the suspended GP dissolved in the propellant, there is no evidence of a coarsening of the size distributions, Moreover, as evidenced by these Exampiesi the aerosol performance of a cosuspension at suitable suspending particle to GP ratios is determined largely by the suspending particles, [01 §0f Several' similar batches of suspending particles were made as described in Example 1, The suspending particles were combined with glycopyrrojate (GP) particles that were micron:zed to different extents, using two different types of jet mis with various milling parameters. The optical diameter and particle size distribution of the micfohized GP particles was determined by laser diffraction. Table 3 lists the dso and dfo values for the different lots of mlicronized materia! used, dso and dso denote the particle size at which the cumulative volume distHbufloh reported by the particle sizing instrument reaches 50% and 90% respectively. J0151] Twelve different lots of metered dose inhalers were prepared as described in Example 1, In all cases foe suspension concentration of GP particles in HFA 134a 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 configurations were deemed similar enough to pool· the date for a meta-analysis presented in this Example.

[0152] The filled metered dose inhalers were stored valve down without overwrap at two different conditions' refrigerated at 5*0 and controlled mom temperature at 25 °Q / 60% RH, Aerosol performance tests as described in Example 1 were carried out at different time points. The results did not show any statistically 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 from -different stress conditions and time points were pooled to determine how the particle size distribution of the micron ized material affects aerosol performance.

[01531 Table 3 summarizes the ΜΜΑΟ results of the meta-analysis. The first column describes the six different configurations. The second column Identifies now many individual lots were used in the compilation of the data for the respective configuration. The third column lists the number of indivlduai MMAD determinations Used to calculate the average MMAD for the respective configuration. Columns four and five show the dgo and dso of the micronlzed materia! used to manufacture the cosuspensions. The results are sorted by 0¾ value from coarse to fine. The Iasi two columns display the average MMAp and standard deviation.

Table 3: Pooled MIViAD results for 12 giycopyrroiate co-suspensions, sorted by the d§o of the micronized glycopyrroiete particles.

[01..54} These results show a weak dependence of MtvIAD on the dso of the micronized material. A similar analysis for the dsa showed no statistically significant trend. It can be concluded that changes in the size distribution of the micronized material |e.g<f different micronized materia! Sots, or induced by solution mediated transformetionsl lead to only minor differences in the size distribution of the aerosol emitted from the metered dose inhaler.

Example 4 [0155J Micronized glycopyrroiate (GP) particles were formed tested as described in Example 1, The optical diameter of the micronized GP particles was determined and 50% by volume of the micronized GP particles were smaller than 1.7 pm, 90% by volume were smaller than 3 J pm.

[0155] Five batches of suspending particles were made as described in Example 1, The batches differed in concentration, Cf, and volume fraction of PFOB, Vpr-os: bf the feed emulsion prior to spray drying, ranging from 20 mg/ml to 160 mg/ml and 20% to 40%, respectively. The different configurations are described in Table 4. [015?| Petered dose inhalers were prepares} by weighing the target masses of micronized GP and suspending pedicles into coated glass vials with TS 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 pi valves (Valois, Les Vaudreull, France) and filled with 10 g or 12 g of HFA 134a (1,1 UlSrtefmttuoroethane) ffneos Fluor, byndhurst, 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 3Q minutes.

[61501 As described in Example I, micronized GP particles formulated alone flocculated and sedimented quickly. The glass vials ini this example were left to settle for at least 24 h without: agitation and then it was tested by visual observation whether the crystal, GP particles were ca~suspended completely.. For the vials marked with “Yes” in Table 4, no GP particles were observed at the bottom of the vlais, except for very few foreign particulates in some vials. Occasional foreign particles were also visible in a similar very low amount in yiais fled with suspending particles only. For the vials marked <sFartlal,N a fraction of the GF particles was visible at the bottom of the vial

Table 4: Co-suspension observations for glycopyrrolate configurations with various suspending partide to giycopyrroiate particle ratios.

10159J Glycopyrrolate £QF) particles were mioropized with a jefmiii and tested as described in Example 1, 50% by volume of the micron ized particles exhibited' so optical diameter smaller than 1.7 μη% 90% by volume exhibited an optical diameter smaller than 4.4 pm. J01501 Six batches of suspending particles were made by spray drying as described in Examnie 1. Configuration 5A was spray dried from an emulsion-;

Configuration 6B was manufactured in a similar fashion but using dipalmitoylphosphatldylchollne (DPPC) instead of DSPC, Configuration 5C was spray dried from an ethanolic solution. For configurations 50, 5E, and 5FS saccharides were spray dried from aqueous solution. The spray drying parameters for ail configurations are given in Table 5a,

Table 5a: Suspending particle configurations used In Example 5,

[0161] The particle size distribution of the suspending particles was determined by laser diffraction. The volume median optical diameter, VIVID, and geometric-standard deviation, GSD, for the different configurations are given in Table 5b.

Table 5b: Characteristics of suspending particle configurations used in Example 5.

|01S2J Electron micrographs of the suspending particles showed a variety of morphologies, summarized in Figure 3. The particles that were spray dried from emulsion, SA and 58, had high porosity and low density. The DSPC particle spray dried from an ethanoiie solution, 5C, showed a much smaller particle size with no noticeable porosity., Indicating, a high density. Ail saccharides produced smooth particles with no visible porosity. Configuration 5E had the smallest particles, as expected due to Its low feed concentration.

[0163] Petered dose inhalers were prepared by weighing the 4 mg of mictonized GP particles and 60 mg; of suspending particles into coated glass vials with 15 ml volume. The canisters were crimp sealed with 63 pi valves (Valois DF30/83 RCU. Les Vaudreuil, France) and filled with 9.5 ml 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 ag itated on a wrist action shaker lor 30 minutes:. Additional inhalers with suspending particles only were manufactured as control for each configuration, [0164] The suspending particles in Examples 5A, 58, and 5C, have true densities lower than the propellant They formed a cream layer and were tested for foe presence of a co-suspension as described In Example 4, No GP particles were visible at the bottom of the vials for configuration SA and 58. Configuration SC formed a partial co-suspension. 10465] The saccharide particles sediment because they have a higher true density than the propellant. However, all control vials for the saccharide configurations showed a significant faster sedimentation rate than mieronized GP particles alone. In configurations 50, 5E, and 5F, the sedimentation rate was similar to that of the control vials with the suspending particles alone and faster than the micronized GP particles alone, demonstrating the association of the GP 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 via! was observed one nlinute 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 inihe propellant. piSSl Pharmaceutical compositions according to the preserrt description were evaluated in a multi-center clinical trial. MDI devices containing a pharmaceutical composition of glyeopyrrolste prepared according to the; present description were provided.

[9187] Suspending particles used were prepared in a similar manner described in Example 1. MDI manufacturing was accomplished using a drug addition vessel pVA| by first adding half of Suspending particle quantity, next filling the microcrystalline GP, and lastly adding the remaining half of suspending particles to the top. Materials were added to the vessel In a humidify controlled environment of <10% RH. The DAM was then connected to a 4 L suspension vessel and flushed with BPA 134a propellent and then mixed. The temperature inside the vessel was maintained at 21-23 °G throughout the entire batch production. After reciroulation of the hatch for 30 min canisters were filled with the suspension mixture through 50 pi EFObf valves. Sample canisters were then selected at random for total canister assay to ensure correct formulation quantities. The freshly manufactured co-suspension MDI batch was then placed oh one week quarantine before initial product performance analysis.

The composition was formulated and the MDI devices configured to provide a dose of 18 pg glycopyrrolate per MDI actuation, pi¢91 The study was a randomized, double-blind, four-period, six-treatment, placebo and active-controlled crossover study which evaluated single administration of 4 ascending doses of glycopyrrolate in patients with mild: to moderate CGPD compared to placebo and open label tlotrapium (18 qg via the Gplriva Handihaler) as an active control The six study treatments were Giycopyrroiate MDf ait doses of 18, 38,72 and 144 ug were achieved by one, two, four or eight consecutive actuations of the 18 Mg per actuation Giycopyrroiate MDf, Tiotropium Handihaler at 18 pg, and Placebo Ml, which was identical to the Giycopyrroiate MDi but without giycopyrroiate, Each patient was randomized to one of six possible seciuences that included lour of the study treatments. Each sequence included two or three Giycopyrroiate MDi doses, which were administered in ascending order to each patient, Giycopyrroiate MD1 and Placebo MDi treatments were blinded and tiotropium was open label. Thirty-three patients were enrolled and analyzed for safely; thirty patients were analyzed for efficacy. Peak Improvement in FEVl relative to: test day baseline (FEVi is the maximum volume of air exhaled during the first second of maximum effort from a maximum inhalation), time to onset of action, time to peak FEVi, FEVi AUGo-iz, FEV< AUC(,24, FEV< AUC^24? 12 and 24-hour trough; FEVt, and similar analyses for peak expirator flow rate (PEFR) and FVCi as wen as peak improvement in inspiratory capacity (IG) were evaluated, Blood samples were ediiected pre-dose and 2, 6, 20 minutes*, and 1, 2, 4, 8, 12, and 24 hours post-dose for determining plasms concentrations used to calculate PK parameters. The ratios of clinical spirometry outcomes (FEV1) to glycopymolafe PK outcomes (AUGO-12 and CWG were determined. P178J Alt doses of Giycopyrroiate MDt were safe and well toieratec·, and the mean piasrha glyttopyrroiafe concentration-time profiles were well characterized with rapidly occurring peak plasma concentrations, generally within 20 minutes. Piasma giycopyrroiate increased with dose level. Figure 5 shows the serum giycopyrroiate concentration (in pg/rhL) compared to placebo over a 24 hour period experienced in [01711 Giycopyrroiate MDf showed statistically significant and clinically relevant superior efficacy compared to Placebo tvlDI fpO.GOI for ail tour giycopyrroiate doses) with a dear dose response relationship. The efficacy of Giycopyrroiate MDf 144 pg and Giycopyrroiate 72 pg bracketed that of tiotropium 18 ug in terms of peak improvement in FEVi over time. For improvement in secondary FEVi endpoints relative to test day baseline, including trough FEVt at 12 hours, FEVi AUGsua, FEVi ΑϋΟο..24, FEVi AUC12-24. and 12 and 24-hour trough FEVi, ail doses of Giycopyrroiate MDi demonstrated: clinically relevant and statistical supertority compared to Placebo MDi (p < 0.049 tor si! four dose levels), with the exception of improvement in trough FEV-, at 24 hours following aciministration of Giyeopyrroiate MDi 36 pg (difference compared to placebo - 0 073L; p~O,069). Similar to the clear dose-response relationship observed for improvement in peak FEVi, dose ordering across all four doses of Giyeopyrroiate MO! evaluated was also observed for improvements in FEV-j AUC0.12, FEV'i AUCa,2o and FEVi AUCta^..

[91721 The Giyeopyrroiate MO! 144 pg and 72 pg doses were shown to be sistisficaliy non inferior to tiotropiurn 18 ug In terms of peak change in FEV;, FEVi .AUC^ia, and FEVi AUGa.24, with the a pood defined non~inferlorify bound of 100 mi. The Giyeopyrroiate 144 pg dose was also noounfenor to tlotropium for 12-hour trough and FEVi .AUCis-m- Point-estimates for the majority of the FEV; parameters for the 72 and 144 pg doses were within ± 50 mi compared to tlotropium.. In general, the secondary endpoints (time to onset of effect, peak and trough FEVi. FVCi PEER, and peak 1C) confirmed the findings of the primary endpoint Giyeopyrroiate MDi demonstrated a more rapid onset of action compared to tiOtropiumviB pg, with mean time to M0% improvement in FEVi of 1 hour or less for all doses of Giyeopyrroiate MDI evaluated, compared to approximately 3 hours for tiotropiym 18 pg.

[017¾ Figure 8 plots the mean change in FEVi from baseline (in liters) experienced by the study subjects over a period of 24 hours. Figure 7 depicts the change in FEVi from baseline (In liters) for patients at different giyeopyrroiate desing levels compared to the results obtained for tlotropium. Specifically, Figure 7 compares the peak change from baseline oyer the placebo value for different giyeopyrroiate concentrations and the area under the curve over a 12 hour and 24 hour period. Figure 8 depicts the proportion of patients which experienced either 1.). an increase from baseline in FEVi of at least 200 ml or 2) a 12%, or greater, increase from baseline in FEVi coupled with total increase in FEVi of at least 150 mi or greater. Figure 0 shows the peak improvement in IG experienced by patients administered the venous doses of Giyeopyrroiate;, as well as the peak improvement: sh IG for patients receiving iiotropium, Figure: 10 shows change in FEVi cumulatively over a 24 hour period in patients receiving giyeopyrroiate, compared with the results obtained from another clinical study where NVA237 (a powder formulation of giyeopyrroiate) was given at various doses by Singh et a! (D Singh, PA Corns, and S 0 Snap. ^VA237, a once-daily inhaled antimuscarinic, provides 24-hour bronchodilator efficacy in patients with moderate to-severe CORD" Poster presented at the American Thoracic Society internationai Conference, San Diego, California, May 19-24.2006).

Examoie 7 [0174J Glycopyrroiste (GP) was mieronized using a jet mill to a volume median optical diameter (dso) of 1.4pm with 90% of the cumulative distribution (dgo) having a volume optical diameter below 3T)pm, Suspending particles were manufactured similarly to those in Example 1. MDI canisters were manufactured using FEP coated Presspart cans to provide products with metered dose of 5.5pgtectuation GP and 44pg/actuation GP which correlates to approximately 4,Spg/aetU8tion and 36pg/actuation GP delivered dose from a 50pi volume metering chamber from commercially available Bsspak valves* The formulations contained 6mg/mt of suspending, particles. The MDS canisters were manufactured using standard pressure filling process where drug substance and the suspending were mixed with HFA 134a in a suspension vessel and tied into canisters through a commercially available filling head, p1?6| Each lot was tested for delivered dose uniformity through can life and aerodynamic particle size distribution by Next Generation Impacter after manufacture. The aerodynamic particle size distributions as measured by the NGI are shown in Figures 11 and 12. Also shown are the amounts of drug recovered from valve stem and actuator, and from the Induction port {throat) and its mouth piece adaptor. Recovered masses are expressed as percent of nominal dose. The fine particle fraction remained unchanged over 168 cycles, illustrating the stability of the GP co-suspensions disclosed herein across a GP dose range. The delivered dose through life of the MDI canisters is shown in Figures 13 and 14. 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 fosses of propellant as the can Is emptied. The compositions described in this example demonstrate desirable delivered dose uniformity for MOI for doses as low as 4.5ug/3Ctu8tlon. Ρ17δ| in addition, canisters from each lot were subjected to a temperature cyciing stability study. The canisters were subjected to -5 eC and 40 *C alternating between temperatures every 6: hours for a total duration of 84 cycles (3 weeks) and 1§8 cycles p weeks). After 184 cycles, the % FRF f ex-actuator) is not significantly different from initial, A summary of the stability of tile fine particle fraction is shown in Tabie 6.

Table 6. Temperature Cycling Stability of the Fine Particle Fraction of Crystalline Q P eo suspended with suspending particles at two doses in MDi containing PFA 134a

Example 8 [0177] MDS Canisters were manufactured to contain 6mg/mL suspending particle concentration and to provide a metered dose of 38 pg/aetuaiion with a SOpf valve volume according to Example 7, Micronlaed GP had a dso and dso of 1.8pm and 4.1 pm respectiveiy and suspending particles were manufactured similarly to the process described in Example 1. The canisters were placed on stability without protective packaging at 25X/80% RH and stored for duration of 12 months. Aerodynamic particle size distribution was determined by next generation impaction at 2 weeks, 1, 2, 3, 6 or 12 months. The fine particle fraction, as a percentage of GF ex-actuator, at initial sampling was 50,2%, No significant change in the fine particle fraction was noted at any of the tsmepoints out to 12 months, with FRF of 47.7% after 12 months, Figure IS provides a view of the entire aerodynamic size distribution for each of the timepoints demonstrating desirable consistency on aerosoi delivery. A summary of the fine particle fraction is shown in Table 7.

Example 9 [017SJ MDi Canisters were mamfctu-red to contain 8mg/mL-suspending particle concentration and to provide a motored dose of 38 pg/actuation as described in Example 7. These canisters were packaged in a heat seated aluminum foil overwrap containing desiccant, and cycled for 6 weeks (8 Pours atTS *G and 6 hours at 40 CC). The delivered dose uniformity through use was tested at the 0, 2: 4 and 8 weeks time points. The mean giycopyrrolate delivered dose of each lot each time period was within ±15% of the mean, with one exception, as demonstrated in Figure 18. The aerodynamic particle size distribution as measured by MG! remain unchanged after 188 temperature cycles as shown in Figure 17. 101791 MDi Canisters were manufactured to contain gmg/mL suspending particle concentration and to provide a metered dose of 24 ug per actuation according to Example 7. These canisters were stored for six weeks at SO *€ under ambient humidity. Another lot was stored for 8 weeks at 48 °C and 75% relative humidity^ Yet another lot was stored for 12 weeks at 49 *C and 75% relative humidity, the fine particle fraction was 58,3% initially. The canister stored for 8 weeks at 50 °C had an FRF that was unchanged compared to the initial lot, La at 53,4 %, The lot stored at 49 ”G tor 8 and 12 weeks had an FPF that was also unchanged compared to the initial, j.e. at 58,8 % and 57,6% respectively. The aerodyna?nic particle size distributions as measured by the NO! m shown in Figure 18. The MMAD remains relatively unchanged after 6 weeks at 50 °G, 3,94 pm, and up to 12 weeks at 40 C. 3.84 pm, compared to the initial at 3,54 pm. in addition, the FRF ond the amounts of giyeopyrrolale recovered from valve stem and actuator, and from the Induction port (throat) and its mouth pied© adaptor* remained relatively unchanged over 3 months at ©ievsted temperatures, |Θ1Βδ1 Metered dose inhalers including pharmaceutical compositions of form otero I fume rate as described herein were prepared, Formotero! fumarate, (±)-2-h'ydrc^^[(1RSH^yd!!ip^y-2^(tF^^2^4-m0ihoxyphehyl)-1“^etHy!0thyl}-aminojethyli formantSide fumarate, aiso known as (±)-2hhydtoxy-5F|(RS)~1-hydroxy-2“i[(RS)^“methoxy“0"niBthylphe:heihyil“amine]ethy!l formanliide fumarate, dihydrate was micronized to form active agent particles. The particle size distribution of the micronized tofmoiterp! fumarate (FF) was determined by laser diffraction. 50% by volume of toe micronized particles exhibited an optical diameter smaller than i ,:6 pm, and 90% by volume exhibited an optical diameter smaller than,3M pm, [01811 Suspending particles were manufactured as follows: 503 mi of a fiuorocarbon»in»water emulsion of PFOB (perfluorooctyl bromide) stabilized by a phospholipid was prepared, 20,6 g of the phospholipid, DSPG (1,2ml!Steroyl~sn-glyoerO“3“phosphocholtoe)| and 1.9 g of calcium chloride were homogenized in 403 ml of hot water (75%>) using a high shear mixer. 100 ml of PFOB were added slowly during homogenization. The resulting coarse emulsion was then furtoer homogenized using a high pressure homogenszer (Model C3: Avestin, Ottawa, CA) at pressures of up to 170 MPa for $ passes. $01821 The emulsion was spray dried in nitrogen using the following spray drying conditions: Inlet temperature 9S°C, outlet temperature 71SCS emulsion feed rate 2.4 ml/min, total gas flow 498 L/min. The particle size distribution of the suspending 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. (01331: 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 configuratioh,: additional glass bottles were tilled with the respective amount of FF active agent particles without any suspending particles. The canisters were crimp sealed with 63 μί valves (Valois, Les Vaudreui!, France) and filled with 11 g (9.1 ml at 25 Th of HFA 134a {1,1,1;2'ietrafluoroethane} (Ineos Fluor, Lyndhurst, UK) by overpressure through the valve stem* Alter injecting the propellant, the: canisters were sonicated for 16 seconds and agitated on a wrist acfon shaker for 30 minutes.

Table 6; Target doses for formoterGl fumarate co-suspensions of Example 10

$01184] Visual observation of the co-suspended configurations (6A, 6B, 6C) showed no sedimentation of the crystalline FF forming the active agent panicles. The suspension flocculated slowly land formed a homogeneous, single cream layer. For ail concanirations tested the mioronlaed active agent particles alone sedimented guickly. Pictures of the co-suspension and the traditionai comparator Suspensions, indicated by an asterisk, are shown in Figure T9. 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. J013SI The results showed that the FF crystals associated with the suspending particles. The association between FF particles and suspending panicles was strong enough to overcome buoyancy forces, as FF particles did not separate from the suspending particles and settling of the active agent particles was successfully inhibited in each of the three different formulation configurations.

Example 12 [0180] Forrnoterol fumarate MDi compositions were prepared according to foe present invention:. Micnahiaed formoterpi fumarate was commercially obtained and its particle sice distribution measured as described in Example 1 was Characterized by a diO: dso, d?a of D,6: 1 9 and 4.4 pm respectively and a Span of 2.0, Suspending particles used were prepared in a similar manner described In Example 1. MDi manufacturing was accomplished using a drug addition vessel (OVA) by first adding; Naif of suspending particle quantity, next filling the microerystaliine FF, and lastly adding the remaining half of suspending particles to the top, Materials were added to the DAY in a humidity controlled environment of «10% RH. The DAY was then ePhnecfed 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 DAV, which is then removed from the suspension vessel and gently swirled. The slurry is then transferred back to the suspension mixing vessel and diluted with additional HFA-1348 to form the final suspension at target concentration stirring gently with an impeller. The temperature inside the vessel was maintained at 21-23 X throughout the entire batch production. After recirculation of the batch for 30 min, 14-mL fluorinated ethylene polymer (FEP) coated aiumlnum canisters (Presspart, Blackburn, UK) were filled with the suspension mixture through 50 pt EPDM valves (Bespak, Ring’s Lynn, UK), Sample canisters were then selected at random for total canister assay to ensure correct formuiation guantities.

[0187] The freshly manufactured co-suspension MDS batch was then placed on one week quarantine before initial performance analysis. Aerosol performance was assessed In accordance with USF <601 > [United States Pharmacopeia monograph 601). A Next Generation impacior (MGI) operated at a flow rate of 30 L/min was used for determination of particle size distribution. Sample canisters were seated into an actuator with two waste actuations and two additional waste priming actuations. Five actuations were collected in the NGl with a USP throat attached. The valve, actuator, throat, MGI .cups* stages, and filter were rinsed with volumetricaliy dispensed solvent. The sample solutions were assayed using a drug; specific: chromatographic method. The fine particle fraction; was defined using the sum of: stages 3 through filter. Delivered dose uniformity through use testing was performed using a Dose Uniformity Sampling Apparatus as described by USP <601 >. Two actuations were collected and assayed at beginning, middle and end of use. pi8S| Figure 20 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.

Example 13 [01891 Formoterol Fumarate MDI compositions were prepared according to the present invention, yieronized forrooterol fumarate was coromercialiy obtained and its particle size distribution measured as described in Example 1 was characterized by a dto, dgr;, d~x; of 0.6« 19 and 4,4 urn respectively and a Span of 2,0. Suspending particles Used were prepared in a similar manner described In Exampie 1, MDI manufacturing was accomplished as described in Example 12.

Mroso! performance was assessed in accordance with USP <801 >, A Next Generation Impacior (NGI) operated at a flew rate of 30 t/min was used for determination of particle- size distribution. Sample canisters were seated into an actuator with two waste actuations and two additional waste priming actuations. Five actuations were collected in the NGI with a USP throat attached. The valve, actuator, throat, NGI cups, stages, and filter were rinsed with voiumetricaliy 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 particle size distribution of a FF co-suspension formulation was evaluated after manufacture and after three months of Storage at 25 °C and 75%RH {unprotected canisters) and 40 X and 75 %RH Iprotected canisters wrapped in aluminum foil pouch). The aerodynamic particle size distributions shown in Figure 21 demonstrate that the compositions described in the present '..invention display desirable stability charactensiics even at accelerated conditions1. · [01901 The chemical stability of formoterol: fumarate |FF) included In a cosuspension formulation prepared according Example 11 was evaluated, FF MDI canisters containing HFA 134s were overwrapped with an aluminum foil pouch and stored at 25 X and 80% relative humidity and 40 X and 75% relative humidity for thirteen and six months, respectively, Likewise FF MDI canisters containing HFA 227ea were overwrapped with an aluminum foil pouch and stored at 25 *C and 80% relative humidity and 40 °0 and 75% relative humidity for six months. The amount of impurity F, a characteristic degradation product of FF( and total Impurities were determined by reverse phase HPLC assay as follows: each canister is chilled, cut open, and the can contents are transferred to a centrifuge tube; the contents were dissolved in organic solvent, followed by the addition of an aqueous solvent to precipitate excipient (DSPC) from the solution; the solution was centrifuged to produce a clear supernatant solution; and each sample solution was analyzed using a CI S column, 4,6 x 150 mm and 3.0 pm particle size. The column temperature was kept at 30 *C. The injection volume was 20 pi, and flow rate was sot at 1 ml/min and detected by determining the UV absorption at: 214 nm. A gradient was used mixing pH 3,1 aqueous phosphate buffer and acetonitrile, 17% acetonitrile first 27 minutes, then 50% acetonitrile for 30 seconds followed by 6,5 minutes at 75% acetonitrile and 17% acetonitrile for 8 minutes. Impurities were reported as area percent of formoterol peak area (corrected for relative response factors, where available^ As shown in Figure 22 (or Table 9 and 10), a co-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 25eC and 80% relative humidify, in contrast a spray dried, non co-suspended fermoterel formulation showed a faster degradation rate under the same storage conditions. Likewise crystaliine FF active agent particles fornied a chemically stable co-suspension imHFA 227a, as shown in Table 11.

Table 9. Chemical Stability of Spray Dried FF Suspending Partides in FF Mpl

Containing HFA 134a at 25XAi0%RHs Overwrapped in Aluminum Foil Pouches

Table 10. Chemical Stability of Crystalline FF Qe-saspendeb vi?th Suspehdlng Partlclea In FF MDI Containing HFA 134a at 26"C/E0%RH, Overlapped in Aluminum Foil Pouches

Table 11. Chemical Stability of Crystalline FF Cb-suspended with Suspending Particles in F? MO! Containing HFA 227ea at 2^0/00%^, Overwrapped in Aluminum Foil Pouches

Example 1S |0191] Micro nixed formoterof furoarate dihydrate (FF) (IdHe, SA... Barcelona,

Spain) used in the present example had with particle si26 distribution by laser diffraction of 50% by volume of the micromzed particles exhibited an optical diameter smaller than 1,9 pm, 90% by volume exhibited an diameter smaller than 4.1 pm. Four batches of suspending particles were rnenufactured by spray drying as described in Example 1. Ail four batches were sprey'dned from aqueous solution; solution concentration and spray drying parameters af® 9*VBf! in Table 12.

Table 12: Suspending particle configurations used in Example 15

[0192) Electron micrographs of the suspending particles showed a variety of morphologies, and are shown in Figure 23 through Figure 26, with Figure 23 providing a micrograph of trehalose suspending particles, Figure 24 providing a micrograph of HP-proyclodoxrnrr suspending particles, Figure 25 providing a micrograph of Ficoil MR 70 suspending particles, and Figure 26 providing a micrograph of inulirr suspending particles:. Trehalose particles appear to he spherical, with a smooth surface, HP-proyclodextrtn particles show extensive wrinkling of the surface, suggesting a partially buckled exterior with a hollow core. Ficoil MP 70 and fnylin particles display some surface rugosity but are generally spheroidal.

[0193) Metered dose inhalers were prepared by weighing 0.9 mg of the micronlzed FF active agent particles and 60 mg of suspending particles into coated glass vials with 15 ml volume. FF was combined with each type of the four suspending particle species of Table 11. The canisters were crimp sealed with 50 pi valves (Valois DF31/S0 PtCU, Les Vaudreuil, 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 sonicated for 30 seconds and agitated on a wrist action shaker for 30 minutes. Additional inhalers containing suspending partides only and active agent particles oniy were filled as a control for each configuration, [0194) Crystalline FF has a greater density than propellant 134a at room temperature, as do ail four species of suspending particles in the present example. Consequently both FF and suspending particles settled to the bottom of the inhalers at room temperature, To test these inhalers for active-suspendihg agent particle interactions indicating a oo-suspension, the inhalers were immersed in an ethanol bath at ^ -IQ * C (resulting In increased' propellant density) and allowed to equilibrate for a minimum of 30 minutes. At this temperature, the FF active agent particles are less dense than the propellant and consequently cream to the top of the propellant volume, while all four species of suspending agent particles remain settled at the bottom: of the propeliant volume.

[01-951 The tested configurations and the results of the observations are presented in Table 13 FF active agent particles alone formed a cream layer atop the propellant volume, and trehalose, HP- 3-cydodextrin, iiiuiiri:, and Flcoil PM 70 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 layer, with no particles creamed or afloat in the propellant, indicating that the FF particles interact with the trehalose suspending particles, and a co-suspension Is formed. In the case of FF particles in combination with ΗΡ-β-cyclodextnn suspending particles, some turbidity was present in the propellent, similar to that observed in the suspending particle only confroi vial. Additionally, some floating flops were observed, which may have been FF particles; however, such floes 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. Thus, this configuration is an example of a partial co-suspension, FF particles in combination with inufih suspending particles formed a single sediment layer, indicating a co-suspension was formed. Though some turbidity was present in this configuration, similar cloudiness was observed in the inuiin-oniy control via!. FF active agent particles in combination with Flcoil PM7Q suspending particies formed a sediment iayer at the bottom of the vial. Indicating that a co-suspension was formed. While some turbidity and floating floes were observed in this configuration, similar turbidity, and ffoc frequency were observed in the FicolTOnly control vial.

Table 13: Summary of tested configurations and results of observations

Example 1 β J0196| Co-suspension compositions including glycopyrrolate (GP) and formoterof fumarate (FF) active agent particles were produced and MDfs incorporating the co-suspension compositions were prepared. The co-suspension compositions produced included GP active agent particles, FF active agent particles or a combination of both GP and FF active agent particles, The GP and FF materia! was supplied as mlcronized:, crystalline materia! with particle size distribution as shown in Table 14.

PIITJ Suspending particles were manufactured via spray dried emulsion at a feed stock concentration of 80 rng/ml with a compositfon of 93.44% DSPC (1,2-Dislearoyl-sn-Glycero-S-Phosphocholina) and 6,56% anhydrous caiciuni chloride (equivalent to a 2:1 DSPC:C8Cu mole/mofe ratio). During the emulsion preparation, DSPC and CaGfe was dispersed with a high shear mixer at 8000-10000 rpm in a vessel containing heated water (80 ± 3 *€·} with PFOB slowly added during the process. The emulsion was then processed with 8 passes in a high pressure homogenize?' (10000-25000 psi). The emulsion was then spray dried via a spray drver fitted with a 0.42" atomizer nozzle with a set atomizer gas flow of 18 SCFML

The drying gas How rate was set to 72 SCFM with an inlet temperature of 135 T, outlet temperature 70 Ta and an emulsion flow rate of 58 msl/min, P1881 The co-suspensions were prepared by first dispensing the appropriate quantities of micronized GP and FF active agent particles end 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 udder &amp; nitrogen atmosphere end connected to the suspension vessel containing 12 kg of HFA-134a (fneos Fluor, Lyndhurst, UK). A slurry was then formed by adding 0.5-1 kg of HFA-134a into the DAV) which is then removed from the suspension vessel and gently swirled.. The slurry is than transferred back to the suspension mixing vessel and diluted with additional HFA-134a to form the final suspension at target concentration stirring gently with an impeller. The suspension is then recirculated via a pump to the .tilting system fora minimum time prior to Initiation of'filling, Mixing and recirculation continue throughout the fiiifhg process. 50 pi valves ( Sespak, King's Lynn, UK) are placed onto 14-mL. fluohnated ethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn, UK) canisters and thin purged of air either by a vacuum crimping process, or an Hi- A-134a purging process followed by vaive crimping. The crimped canisters are then tilted through4he-valve with the appropriate quantity of suspension, adjusted by the metering cylinder.

Table 14: Glvcopyrrolate and Formoterol Fumarate particle size distributions,

J0199I MOts containing the dual co-suspenSions described In this Example were prepared to contain two different doses GP and FF, Speciflcaliy, a first run of dual co-suspenston compositions were prepared to provide 18 pg per actuation GP and 4.8 pg per actuation FF flow dose”), and a second run of dual co-suspension compositions were prepared to provide 36 pg per actuation GP and 4,8 pg per ssrhfaenn cp Ahinh rinse"), in addition to the dual co-suspensions compositions, cosuspensions 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" oh “monotherapy** co-suspensions. The monotherapy co-suspension compositions were prepared as described for the dual co-suspensions, except that they included only one species Of active agent particles (either GP or FF). The monotherapy eO-suspenslons were formulated and monotherapy fdDts prepared to provide the following targeted delivered doses: 18 pg per actuation of GP, and Oitt 3,6 or 4.8 pg per actuation of FF. The compositions and tVIDIs providing 6.S pg FP and 1 pg FF per actuation are referred to as “ultra low” dose and were manufactured in a similar manner at a 41 scale. [020S1 The drug specific aerodynamic size distributions achieved with MDfs 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 27. in the same: manner, the proportionality of the aerodynamic size distributions of FF obtained from the dual and monotherapy cosuspensions, including the ultra low, low, and high dose compositions is demonstrated in figure 28, (02011 The delivered dose uniformity of the ultra low dose FF monotherapy MDIs was aiso measured as described in Example 1. The DDU for the FF MDI containing 0.5 pg per actuation and 1.0 pg per actuation are shown in Figure 29. Desirable dose delivery uniformity is achieved demonstrating the utility of the present invention to consistently deliver ultra low closes, in order to evaluate whether the combination of GP and FF within a single formulation would result in the degradation Of the aerosol properties relative to compositions including a single active agent, the aerosol properties of co-suspension compositions were assessed relative to suspension compositions including only a single active agent As can be seen in Figure 30, 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 suspension compositions including either GP or FF alone. Therefore, there were no combination effects observed.

Example 17 [02021 Micronized saimeieroi xinafoate (4-hydroxy tol 4116^4- phenyibutoxyfeexyijamino] methyi]-1,3-benzenedimethanoi, 1 -hydroxy-2~ naphthalenecarboxylate) was received by the manufacturer (inke SA, Germany) and used as active agent particles. The particle size distribution of the salmetero! xinafoate fSX) 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 dptieaf diameter smaller than 3.9 urn.

[0203J Suspending particles were manufactured as fellows' 150 ml of a fiuosxjcarbon in water emulsion of PFOB {perfluorocly! bromide! stabilized by a phospholipid was prepared. 12.3 g of the phospholipid, DSPC (1;2-Distearoyi"Sn~ GiyeerortTPhosphocholine), and 1.2 g of -calcium chloride were homogenized in 100 ml of hoi water (70 °C) using a high shear mixer. 65 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 140 MPa for 3 passes [0204] The emulsion was spray dried in nitrogen using the following spray drying conditions: inlet tempefatufe 00 °C, outlet temperature 89 Ό. emulsion feed rate 2.4 mUmin, total gas flow 4981/rmn. The particle size distribution of the suspending particles, VMD, was determined by iaser diffraction, 50% by volume of the suspending particies were smaller than 2.7 pm, the Geometric Standard Deviation of the distribution was 2,0. Additionally, the aerodynamic particle size distribution of the suspending particies was determined with a iime-of-fiight particle sizer. 50% by volume of the suspending particies had an aerodynamic particle diameter smaller than 1,8 pm. The large difference between aerodynamic particle diameter and optica! particle diameter indicafes that the suspending particies had a low particle density < 0.5 kg/L.

[020$! Metered dose inhalers were prepared by weighing 2 mg of SX active agent particles and 60 mg of suspending particies intoJuohhated ethylene polymer (FEE) coated aluminum canisters (Presspart, Blackburn, UK) with 18 ml volume. The suspending particle to active particle ratio was 30, The target delivered dose assuming 20% actuator deposition was 10 pg, The canisters were crimp sealed with 63 pi valves (# BK 357, Bespak, King's Lynn, UK) and filled with 10 mL ofTIFA 134a (1»i; 1 .S-tetraf!uoroethane) by overpressure through the valve stem,: After injecting the pmpeiiant, the canisters were sonicated for 1$ seconds and agitated on a wrist action shaker for 30 minutes. The canisters were fitted with polypropylene actuators with: a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK). Additional inhalers for visual observation of suspension quality were prepared using 15 ml glass viais inciuding a comparator filled with mieronized SX only. Aerosol performance was assessed as described in Example 1. The WyAD was 3,7 pirti 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 *C - 20 °C, the visual observation was condycted on glass vials that were: heated up to 30 f:C · 36 *C sn a water bath. Under these conditidns the SX active agent particies termulafed alone sedimented rapidly, but no SX crystals were visible at the bottom of the co-suspenston vial.

[02061 Mieronized sairneierol xinafoate active agent particles were co-suspended through association with suspending particles of lew density that were formulated according to the disclosure provided herein. The association between sairneterol crystals and the suspending particles was strong enough to overtime buoyancy forces as it was observed that settling of the crystals is inhibited.

Claims (101)

1. A pharmaceutical compositiondeliverable from a metered dose inhaler, comprising: a suspension medium comprising a pharmaceutically acceptable propellant; a plurality of active agent padicies comprising an active agent selected from a long-acting muscarinic antagonist (LAMA) active agent and a long-acting J32 adrenergic receptor agonist (LABA) active agent; and a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles to form a co-suspension.

2. A pbarmaceuticai composition according to claim t, wherein the active agent included in the active agent particles is a LAMA active agent selected from giycopyrrolate, dexipirnonium, tiotrop;um; trosplum, aclldinium, darotropium, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof,

3. The pharmaceutical composition according to claim 2, wherein the active agent particles comprise giycopyrrolate, Including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

4. The pharmaceutical composition according to claim 3, wherein the active agent particles comprise crystalline glycopyrrolafe.

5. The pharmaceutical composition according to claim 3, wherein the §lyeppyrmiate active agent particles are Included in the suspension medium at a concentration "sufficient to provide s delivered dose of giycopyrrolate per actuation of the metered dose inhaler selected from between about 2 pg and about 200 pg per actuation, between about 10 pg and about 150 pg per actuation, and between about 15 pg and about SO pg per actuation, S,: The pharmaceutical composition according: to claim 3i: wherein the concentration of giycopyrrolate included In the co-suspension is between about 0,04 mg/mi and about 2,25 mg/ml

7. The pharmaceutical composition according to claim 3, wherein at least 90¾ of the giycopyrrolate active agent particles by volume exhibit an optical diameter of 7 pm or less.

8. The pharmaceutical composition according to claims, wherein at least 50% of the glycopyrrolate active agent particles by volume exhibit an optica! diameter of 5 pm or less,

9. The pharmaceutical composition according to claim 2: wherein the suspending particles comprise perforated microstructures.

10. The phirmeceytiesi composition according to claim 9, wherein the perforated microstructures are prepared using a spray drying process. IT - The pharmaceuticai composition according to claim 10, wherein the perforated microstructures comprise a spray dried emulsion of perfluoroociyi bromide, BSRO and calcium chloride in water.

12, The pharmaceytiesi composition according to claim 2, wherein the suspending particles comprise an excipient selected from at least one of lipids, phospholipids, nonionic detergents, polymers, nonionic block copolymers, surfactants, non-ionic surfactants, hiocompatlbie fluorinated surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, and combinations thereof,

13, The pharmaceutical composition according to claim 2, wherein the suspending particles exhibit an IVUVtAD selected from between about 10 pm and about 500 nm, between about 5 pm and about 750 nm, between about and 1 pm

14, The pharmaceutical composition according to claim 2, wherein the suspending particles, exhibit a volume median optica! diameter selected from between about 0,2 pm and about 50 pm; between about 0.5 gfn and about 15 pm, between about 1,5 pm and about 10 pm. and between about 2 pm and about 5 pm.

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

16, The pharmaceutical composition according to claim 2, wherein a total mass of the suspending particles exceeds a total mass of the active agent particles.

17, The pharmaceutical composition according to claim 16,. wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is seiepteb from above: about 1.5, up to about 5, up to about 10, up to about 15, up to about T7>· u.p to -about 20, up to about 3Q, 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.

18, The pharmaceutical composition according to claim 16, whereto a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about i5;1 end between about 2:1 and 8:1.

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

20. A method for treating a pulmonary disease or disorder In a patient, the method comprising: providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension comprising: a suspension medium comprising a pharmaceutically acceptable propellant': a plurality of active agent particles comprising an active agent selected from s LAIVIA active agent and a LA8A active agent; and a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a therapeutically effective amount of the LAMA or LABA active agent to the patient,

21, The method of claim 20, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising a LAIMiA active agent.

22. The method of claim 21, wherein the ΙΑΜΑ active agent is selected from giycopyrrolate, dexipirroniuni, tiotropium, irospium, a cl id in ium, da rotrop iu m, and any pharmaceutically acceptable salts, esters, Isomers or solvates thereof.

23, The method Of claim 22, wherein the pulmonary disease or disorder is selected from at least one of asthma, CORD, allergic rhinitis, sinusitis, pulmonary vasoconstriction:, inflammation, allergies, impeded respiration, respiratory distress syndrome, .pulmonary hypertension, pulmonary vasoconstriction, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis. M, The method of claim 23, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising giycopyrrolate, including any pharmaceuticaiiy acceptabie salts, esters, isomers or solvates thereof.

25, The method of claim 24, wherein providing a pharmaceuticaiiy acceptable co-suspension comprises providing a co-suspension composing a plurality of active agent particles comprising giycopyrrolate, including any pharmaceuticaiiy acceptable salts, esters, isomers or solvates thereof, and the concentration of giycopyrrolate included in the co-suspension is between about 0.04 mg/ml and about 2;25 mg/ml

28. The method of claim 22, wherein administering the pharmaceutically acceptabie co-suspension comprises administering the pharmaceutical composition in an amount resuiting in a clinically significant increase in FEV< in the patient within 1 hour, or less,

27. The method of claim 22, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composite in an amount resulting in a Clinically significant inerease in FEVi in the patient within 0.5 hours, or less.

28. The method of claim 22, wherein administering the pharmaceuticaiiy acceptable co-suspension comprises administering the pharmaceutical composite in an amount resulting in an increase of FEV^ of 150 ml or greater within a period of time selected from 0.5 hours, or less, 1 hour, or less, and 1,5 hours, or less.

29. The method of claim 22, wherein administering the phanmaoeyticaily acceptable co-suspension comprises administering the pharmaceutical composite in an amount msuiting in a eilmcaliy significant inerease in FEVi in the patient within 0.5 hours, or less, and providing a cliolcsSiy significant increase in F£V\ for a time period selected from up to 4 hours, up to 8 hours, up to 8 hours, up to 10 hours, and up to 12 hours, or more.

30. The method of claim 23, wherein administering the pharmaceutically acceptabie co-suspension comprises administering to the patient a dose of LAMA: active agent selected from 20Θ pg, or less, 150 pg, or less, 100 pg, or less, 75 pg, or less, 50 pg, or less, and 25 pgf of less, per actuation of the metered dose inhaler,

31, The method of claim 23, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of glyeopyrmlate or a pharmaceutieslfy acceptable salt, ester, isomer or solvate thereof, selected from about 150 pg* or less·; about 30 pg, or less, about 40 pg, about 20 pg, or less, and about 10 pg, or less, per actuation of the metered dose Inhaler,

32, The method of claim 28, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of LAMA: active agent selected from 200 pg, or less, 150 pg, or less, 100 pg, or less, 75 pg, or less, 50 pg, or less, and 25 pg, or iess, per actuation of the metered dose inhaler.

33, The method of claim 26, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of glycopyrrolate or a pharmaceutically acceptable salt, ester, Isomer or solvate thereof, selected ϊΙόγη about 150 pg, or less, about 80 pg, or less, about 40 pg, about 20 pg, or less, and about 10 pg, or less, per actuation of the metered dose inhaler.

34, The method of claim 22, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmace utlcal corn position in an amount resulting in a clinically significant increase In inspiratory capacity,

35, A method for respiratory1 delivery of a LAMA or SLABA active agent to a patient, the method comprising; providing metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium comprising a pharmaceutically acceptable propellant; a plurality of active agent particles comprising an active agent selected from a LAMA active agent and a LABA active agent; and a plurality· of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and actuating the metered dose inhaler to provide respiratory delivery of the LAMA or LABA active agent to the patient.

36. The method of claim 35, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising a LASVIA active agent.

37. The method of claim 36, wherein the LAIV1A active agent is selected from glycopyrroiate, dexipsrroniurn, tiotropium, trospium, aelidinium, darotropium, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

38. The method of claim 37, wherein the LAMA active agent is glycopyrrolate, including pharmaceutically aeeeptable salts, esters, isomers or solvates thereof.

39. The method of claim 36, wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA active agent comprises delivering the LAMA active agent to the patient at a DDU selected from a DDU of ± 30%, or better, a DDU of ± 25%, of better, and a DDU of ± 20%, or better, throughout emptying of the canister.

40. The method of claim .36, wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA active agent comprises delivering the LAMA active agent at an initial fine particle fraction and the initial fine particle fraction delivered from the metered dose Inhaler Is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the Initial fine particle fraction.

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

42. The method of claim :40, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 96% of the initial fine particle fraction,

43. A pharmaceutical composition according to claim 1, wherein the active agent included in the active agent particles is a LABA active agent selected from bambuterol, cienbuterol, formotefol, saSmeteroi, carmPterol, milveteroi, indacateroi, and saligenin- or indole- containing and adamaniyS-denved pa agonists, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

44. The pharmaceutical composition according to claim 43, wherein the active agent particles comprise formoterol: including any pharmaceutically acceptable salts, esters. Isomers or solvates thereof

45. The pharmaceutical composition according to claim 44, wherein the active agent particles comprise cf^tailine tormoterol

46. The pharmaceutical composition according to claim 44, wherein the formoteroi active agent particles are included in the composition at a concentration sufficient to provide a delivered dose of formoteroi selected from between about 1 pg and about 30 pg, between about 0.5 pg and about 10 pg, between about 2 pg and 5 pg, between about 2 pg and about 10 pg, between about 5 pg and about 10 pg, and between 3: pg and about 30 pg per actuation of the metered dose inhaler,

47. The pharmaceutics! composition according to claim 44, wherein the formoteroi active agent particles are included in the composition at a Concentration sufficient to provide a delivered dose of formoteroi selected from up to about 30 pg, up to about 10ipg, Up to about 5 pg, up to about 2.5 ug, up to about 2 pg, or up to about 1.5 pg per actuation of the metered dose inhaler.

48. The pharmaceutical composition according to claim 44, wherein foe concentration of formoteroi included in the co-suspension is selected from between about 0.01 mg/ml and about 1 mg/ml, between about 0.01 mg/m! and about 0.5 mg/mi, and between about 0,03 mg/ml and about 0.4 mg/ml,

49. The pharmaceutical composition according to claim 44, wherein at least 90% of foe formoteroi active agent particles by volume exhibit an optica! diameter of 5 pm or less.

50. The pharmaceufica! composition according to claim 44, wherein at least 50% of the formoteroi active agent particles Py volume exhibit an optical diameter of 2 pm or less,

51. The pharmaceutical composition according to claim 43, wherein the suspending parades comprise perforated microstrucfures.

52. The pharmaceutical composition according to claim 51, wherein the perforated microstructures are prepared using a spray drying process,

53. The pharmaceuticai composition according to claim 52, wherein the perforated microstrucfores comprise a spray dried emulsion of periluorooctyl bromide, DSRG and caiciam chioride In water.

54. The pharmaceutics! composition according to claim 43, wherein the suspending particles comprise an excipient selected from at least one of lipids, phospholipids, nonionie detergents, polymers, nonionic block copolymers, surfactants, non-ionic surfactants, biocompatible fluorinated surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, and combinations thereof,

55. The pharmaceutical composition according to claim 43, wherein the suspending particles exhibit an MfVIAD 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,

56. The pharmaceuticai com according to claim 43, 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 about 1.5 pm and about 10 pm, and between about 2 pm and about 5 pm,

57. The pharmaceutical composition according to claim 43, wherein the propellant comprises a propellant selected from an HFA propellant, a PFO propellant and combinations thereof, and wherein the propellant is substantially free of additional constituents.

58. The pharmaceuticai composition according to claim 43, wherein a total mass of the suspending particles exceeds a total mass of the active agent particles.

59. The pharmaceutical composition according to claim 58, wherein a ratio of the total mass of the suspending particles to the total mass of the active agent panicles Is selected from above about 1,5, up to about 5, up to about 19, up to about 15, up ip about 17, up to about 20, up to about. 30, up to about 40, up to about 59, up to about 60, up to about 75, up to about 100, up to about 150, and up to about 200.

60. The pharmaceutical composition according to claim 58, wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1,

61. The pharmaceutical composition according to claim 43, wherein the suspending particles remain associated with the active agent particles even when subjected to buoyancy forces amplified by centrifugation at an acceleration selected from accelerations of at least 1 g, at least 10 g, at least 50: g, and at least 100 g,

82, The method of claim 20, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising a LABA active agent,

63. The method of claim 62, wherein the LABA active agent is selected from bambuferoL clenbuteroi, iormoterol, saimeterol, carmoteroL milveterol, indaeaterol, and saligenin- or indole- containing and adanisniyTderived 1¾ agonists, and any phanmaceuticaliy acceptable salts, esters, Isomers or solvates thereof,

64. The method of claim 63, wherein; the pulmonary disease or disorder is selected from at least one of asthma, COPD, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension* pulmonary: vasoconstriction, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis,

65. The method of claim 63, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising fomioterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

66. The method of claim 65, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a 'plurality1· of active agent particles comprising iormoterol, including any pharmaceuticaliy acceptable salts, esters, isomers or solvates thereof, and the concentration of formoteroi included in the co-suspension Is selected from between about O.Oi mg/ml and about 1 rng/mi, between about 0.01 mg/mi and about 0.5 mg/ml, and between about 0.03 rng/mi and about 0.4 mg/ml,

67. The method of claim 83, wherein administering the pharmaceutica! compositioh comprises administering: the pharmaceutical composition in an amount resulting in a clinically significant Increase in FEVi in the patient within 1 hour, or less.

68. The method of claim 63, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FE% in the patient within 0.5 hours, or less.

69. The .method of claim 83, wherein administering the pharmaceutleaiiy acceptabie co-suspension comprises administering the pharmaceutical composition in an amount resuiting in an increase of FEVt of 150 m! or greater within a period of time selected from 0.5 hours, or less, 1 hour, or iess, and 1.5 hours, or less.

70. The method of claim 63, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV; in the patient within 0.5 hours, or iess, and providing a clinicaily significant increase in FEVi for a time period selected from up to 4 hours, up to 8 hours, and up to 8 hours, or more,

71. The method of claim 67, wherein administering the pharmaceutically acceptable oo-suspenslon comprises administering to the patient a dose of IAEA active agent selected from between about 1 pg and about 50 pg, between about 1 pg and about 30 pg, between about 2 pg and 5 pg, between about 2 pg and about 10 pg, between about 5 pg and about 10 pg, and between 3 pg and about 30 pgper actuation.

72. The method of claim 87, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of formotero! or a pharmaceutically acceptable salt, ester, isomer or soivate thereof, 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 abdut:;2: pg, and up to about 1,5 pg per actuation,

73. The method of claim 63, wherein administering the pharmaceutical composition comprises administering the pharmaceutical composition in an amount respiting in a clinically significant increase in inspiratory capacity.

74. The method of claim 35, wherein providing a pharmaceutically acceptabie co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising a LABA active agent.

75. The method of claim 74, wherein the IAEA active agent is selected from bambuterol, cienbuterol, termoterpi, saimeteroi,. carmoterol, milveteroi, indacatenoi, and saiigenin- or indole- containing and adamantyl-derived pg agonists, and any pharmaceutically acceptable salts, asters, isomers or solvates thereof.

76. The method of claim 75, wherein the IAEA active agent is formoteroi, including pharmaceutically acceptable salts, asters, isomers or solvates thereof.

77, The method of claim 75, wherein actuating the metered dose inhaler to provide respiratory delivery of the LABA active agent comprises delivering the LABA active agent to the patient at a DDL! 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,

78, The method Of claim 75, wherein actuatihg the metered dose inhaler to provide respiratory delivery of the ΤΑΒΑ active agent comprises delivering the LABA active agent at arr initial fine particle fraction and the Initial fine particle fraction delivered from the metered dose Inhaler is substantially maintained, such that, throughout emptying of the: canister, the; fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the Initial fine particle fraction,

79, The method of claim 78, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction.

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

81, A metered dose inhaler for delivery of a LAMA or a LABA active agent, the metered dose inhaler comprising: a canister containing a pharmaceutically acceptable co-suspension Comprising: a suspension medium comprising 3: pharmaceutically acceptable propellant; a plurality of active agent particles comprising an active agent selected from a LAMA active agent and a LABA active agent; and a plurality of respirable Suspending particles, wherein the plurality or active agent particles associate with the plurality of suspending particles; wherein the LAMA or LABA active agent Included |n the pharmaceutically acceptable co-suspension is chemically stable over a period of at least 18 months when stored at 5°C.

82, The metered dose inhaler according to claim 81, wherein the LAMA of LABA active agent included in the pharmaceutically acceptable co-suspension is chemically stable over a period of at least 18 months when stored at 26aC,

83. The metered dose inhaler according to claim 81, wherein the LAMA or LABA active agent included in the pharmaceutically aeeeptabie co-suspension is a LABA active agent selected from bamteuieroi, clenbutero;, formoterol, saimeteroi, earmoieroi, milveterol, indacateroi, and saligenin- or indole- containing and adarcardyl-derived agonists, and any pharmaceutically aeeeptabie salts, esters, isomers or sol vales thereof.

84. The metered dose inhaler according to claim 83 wherein the LABA active agent is fdrmoiero!, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

85. The metered dose Inhaler according to claim 84, wherein a rate of formation of N-{2~hydroxy~5-(1 -(2~hydraxy~5-{1 -hydroxy-2-(1 -(4- mefhoxyphenyi}propan-2“yiamino}ethyi}pbemyiamino)-2-(1-(4-methoxyphenyi)proparv2-ylsmino}eihyi)phenyi}acetamide within the pharmaceuticaily acceptable co-suspension is not greater than about 0.15%, after the Canister is subjected to a temperature of 40°C and a relative humidity of 75% for a period of one month.

88. The metered dose inhaler according to claim 84, wherein a rate of formation of N~{2~hydroxy-5-{1 ~(2-hydroxy-5~{1 -hydroxy--2-(1 -(4- methoxyphenyl )propan-2'y^mino)ethyi)phenyi3m!no}-2~(1-(4-methpxyphenyi )propan-2~ylamino)ethyf)pheny!)8cet8rnide within the phaiTnaceuticaIly acceptable co^suspensioh is hoi greater than about 0.5%, alter the canister is subjected to a temperature of 4CTC and a relative humidity of 75% for"a period of ope month.

87. A pharmaceutical composition deliverable tom a metered dose inhaler comprising: a suspension medium comprising a pharmaceutically acceptable HFA propellant: a plurality of active agent particles comprising giycopyrrolate, Including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, said active agent particles are included in the suspension medium at a concentration sufficient to provide a delivered dose of giycopyrrolate of between about 15 pg and about 80 pg per actuation of the metered dose inhaler; and a plurality of respirable suspending particles comprising perforated microstruetures exhibiting a volume median optical diameter of between about 1 .6 pm and about 10 pm, said perforated microstructures associate with the plurality of active agent particles to form a co-suspension. 88; The pharmaceutical composition according to claim 87, wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and' 8:1.

89. A pharmaceutical composition deliverable tom a metered dose inhaler, comprising: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising formoterol. Including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, said active agent particles are included in the suspension medium at a concentration sufficient to provide a delivered dose of fermoienof of between about 2 pg and about 10 pg per actuation of the metered dose Inhaler; end; a plurality of respirable suspending particles comprising perforated rriicrostructures exhibiting a volume median optical diameter of between about 1,5 pm and about 10 pm , said perforated microstructures associate with the plurality of active agent particles to form a co-suspension.

90. The pharmaeeutieai composition according to ciaim 89, wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 8:1 and about 15:1 and between 2:1 and 8:1.

91. A method for respiratory delivery ©f::LAMA active agent to a patient, the method comprising; providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality Of active agent particles comprising giycopyrroSate, including pharmaceutically acceptabie salts, esters, isomers or solvates thereof; and a. plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles: and actuating the metered dose inhaler to provide respiratory delivery of giycopyrmiate to the patient at a DDU of ± 20%, or better, throughout emptying of the canister,:

02, The method of claim 91, wherein actuating the metered dose inhaler to provide respiratory delivery of giycopyrroiate to the patient comprises delivering the glyeopynoisfe at an initial; fine particle fraction; and the initial fine particle fraction delivered from the metered dose inhaler Is substantially maintained, such that, throughout emptying: of the canister, the fine particle fraction delivered from the metered dose ihhaler is maintained: within 80% Of the initial fine particle fraction,

93, The method of claim 92, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90%; of the: Initial fine particle fraction .

94. The method of claim 93, wherein, throughout emptying of the canister, the fine partible fraction delivered from the metered dose Ihhaler is maintained within 95% of the initial fine pa rticie fraction-

95. A method; for respiratory delivery of ΙΆΒΑ active agent to a patient, the method comprising; providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable eotouspehsion comprising: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising iormoterol, Including pharmaceutically acceptable salts, esters, isomers or solvates thereof: and a plurality of respirable Suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and actuating: the metered dose inhaler to provide respiratory delivery of fdrmoterdi to the patient at a DDU of ± 20%, or better, throughout emptying of the canister,

96, The method of claim 85, wherein actuating the metereddese inhaler to provide respiratory delivery of formoterol to the patient comprises delivering the iormoterol at an initial fine particle fraction and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained 'within 80% of the Initial tine particle fraction,

97, The method of claim 98, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particie fraction.

98, The method of claim 97, wherein, throughout emptying of the canister, the fine particie fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particie fraction,

99, A method for treating a pulmonary disease or disorder in a patient, the method Comprising; providing metered dose inhaier comprising a pharmaeeuticaiiy acceptable co-suspension, the co-suspension comprising: a suspension medium comprising a pharmaceutically acceptable HFA propellant; a plurality of active agent particles comprising gtycopyrroiate, including pharmaeeuticaiiy acceptable sails, esters, isomers or solvates thereof; and a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of 'suspending particles; and administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose of 150 pg, or less, of glycopyrrolate per actuation of the metered dose inhaler and results in a clinically significant increase in FEVt In the patient,

100, The method of ciaim 99, wherein the puimonary disease or disorder is selected from at least one of asthma, CORD, allergic rhinitis, sinusitis, puimonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, puimonary inflammation associated with cystic fibrosis, and puimonary obstruction associated with cystic fibrosis.

101, A method lor treating a puimonary disease or disorder in a patient, the method comprising: providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension comprising; a suspension medium comprising a pharmaceutically acceptable HFA propellant: a plurality of active agent particles comprising forrooteroi, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose of 10 pg, or less, of formoterol per actuation of the metered dose inhaler and results in a cilnicaliy significant increase in FE¥i in the patient.

102. The method Of claim 101., wherein the pulmonary disease or disorder is selected from at least one of asthma, COPD, allergic rhinitis, sinusitis, pulmonary yasoconstrictioh, inflammation, allergies, Impeded respiratioh, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, pulmonary inflammation associated wild cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis,

103. The method of date 99, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no mere than I SO pg.

104. The method of claim 99, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 pg.

105. The method of claim 99, wherein said administering of the cosuspension composition comprises administering a delivered dose of giyeopyrrolate of no more than 80 pg.

106. The method of claim 99, wherein said administering of the co-suspension composition comprises administering a delivered dose of giyeopyrrolate of no more than 150 pg, and sold administration results in an "increase in FEVi of at least 150 mi within 0.5 hours, or less,

107. The method df claim 99, wherein said administering of the cosuspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 pg, and said administration resuits in an increase in FB/i of at least 150 mL within 0.5 hours, or less.

108. The method of claim 98, wherein said administering of the co~ suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 pg, and said adminisiration results In an increase in FEVi of at least 160 ml within 0.5 hours, or less

109. The method of cialm 99, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrroiate erf no more than ISO pg, and said administration results in an increase in FEVi of at least 200 mL within 1.0 hour, or less.

110. The method of cialm 99, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrroiate of no more than 1001 pg, and said: administration results in an increase in FEVi of at least 200 ml within 1.0 hour, or less.

111. The method of claim 99, wherein said administering of the cosuspension composition comprises administering a delivered dose of glycopyrroiate of ho more than 80 pg, and said administration results in an increase in FEVi of at least 200 ml within 1,0 hour, or less.

112. A method for treating a pulmonary disease or disorder in a patient, the method comprising: providing metered dose inhaler comprising a pharmaceutically acceptable cosuspension, the co-suspension comprising: a suspension medium comprising a pharmaceutically acceptabl© HFA propellant;. a plurality of active agent particles comprising glycopyrroiate, Including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and a plurality· of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and administering the co-suspension to the patient by actuating the metered dose Inhsier, wherein said administering of the co-suspension composition comprises delivering a dose of 150 pg, or less, of glycopyrroiate per actuation of the metered dose inhaler and results clinically, significant increase in FEVI in 0.5 hours, or less, and a clinically significant increase in FEVr is maintained tor up to 12 hours. US, The method of claim 112, wherein said administering of the cosuspension composition comprises administeringta delivered dose of glycopyrroiate Of no more than I SO pg,

114. The method of claim 112, wherein said administering of the cosuspension composition comprises administering a delivered dose of glycopyrroiate of no more than 100 pg.

115. The method of claim 112, wherein said administering of the co-suspension composition comprises administering a delivered dose of giyoopyrrolate of no more than 80 pg, 1T8, The method of claim 112, wherein said administering of the co-suspension composition eompfises administering a delivered dose of glycopyrroiate of no more than 150 pg, and said administration results in an increase in FEY, of at least ISO ml within 0.5 hours, or less, and a clinically significant increase in FEVi is maintained for at least 12 hours,

117, The method; of claim 112, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrroiate of no more than 100 pg, and said administration results in an increase in FEV; of at least ISO ml within 0.5 hours, or less, and a .clinically significant increase in FEYi is maintained for at least 10 hours.

110. The method of claim 112s wherein said administering of the do-suspension composition comprises administering a delivered dose of giyoopyrrolate of no more than 80 pg, and said administration results in an increase in FEVi of at ieast 110 ml within 0.5 hours, or less, and a clinically significant increase in FEV; is maintained for at least 8 hours,

110. The method of claim ill, wherein said administering of the co-suspension composition comprises administering a delivered dose of giycopyrrolate of no more than 150 pg, and said administration results in an increase in FEVi of at least 200 rat within 1.0 hour, or less, and a clinically significant increase in FEV'i is maintained for at ieast 12 hours.

120. The method of ciaim ill, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrroiate of no more than 100 pg, and said administration results in an increase in FEV< of at least 200 mL within 1,0 hour, or less, and a clinically Significant increase in FE\A is maintained for at least 10; hours,

121. The method of claim 112, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrroSate of no more than 80 pg, and said administration results in an increase In FEV1 of at least 200 rht within 1,0 hour, or less, and a:: clinically significant increase in FE^ is maintained for at least 8 hours,

122. A method for treating a pulmonary disease or disorder in a patient population, the method comprising: providing metered dose inhalers comprising a pharmaceutically acceptable cd-suspension, the co-suspension comprising:; a suspension medium comprising a pharmaceutically acceptable MFA propellant; a plurality of active agent particias comprising giycopyrroiate, including pharmaceu tioaily acbepfable salts, esters, isomers or solvates thereof; and a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and administering the co-suspension to the patient population by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose of 150 pg, or less, of giycopyrroiate per actuation of the metered dose inhaler and, In at least 50% of the patient population, results in an increase from baseline in FEV> selected from (ITan increase in baseline FEV< of at least 200 mi and p) a 12%, or greater, increase from baseline in f EV| coupled with total Increase in i'FEVi of at least 150 ml,

123. The method of claim 122, wherein said administering of the co-suspension composition comprises administering a delivered dose of giycopyrroiate of no more than 150 pg,

124. The method of claim 122, wherein said administering of the co-suspension composition comprises administering a delivered dose of giycopyrroiate Of no more than 100 pg,

125. The method of claim 122,. wherein said administering of the co-suspension composition comprises administering a delivered dose of giycopyrroiate Of no more than 80 pg. 126! The method of claim 122, wherein, for at least 60% of the patient: population, said administering of the co-suspension composition results in an increase from baseline in FEVi selected from either (i) an increase In baseline FEVi of at least 200 mi and (ii) a 12%, or greater, increase from baseiine in FEVi coupled wit) total increase in FEV5 of at least 160 mi,

127, The method of claim 122, wherein, for at least 80% of the patient population, said administering of the co-suspension composition results in an increase from baseline in FEVi selected from either (i) an increase in baseline FEVi of at least 200 ml and (H) a 12%, or greater, increase from baseiine in FEVi coupled With total increase in FEVi of at least 160 ml,

128. A method for treating a pulmonary disease or disorder In a patient, the method comprising: providing metered dose inhaler comprising a pharmaceutically acceptable co* suspension, the co^suspension comprising: a suspension medium comprising a pharmaceutically acceptable HFA propellant: a plurality of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and a plurality of respirable suspending particles, wherein the plurality of active agent pedicles associate with the: plurality of Suspending particles; and administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose Of ISO pg, or less, of giycopyrrOlate per actuation of the metered dose inhaler and results in a clinically significant increase in Inspiratory capacity (IQ) in the patient

129, The method of claim 128, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycdpyrrolate of do more than 160 pg,

130. The meihod of claim 128, wherein said administering of the cosuspension composition comprises administering a delivered dose of glycopyrrolate of no more than TOO pg.

131. The method of claim 128, wherein said ad m in istering of the eo-suspension composition comprises administering a delivered dose of glycopyrroiate of no mom than 80 pg.

132. The method of claim 128, wherein said administering of the co-suspension composition comprises administering a delivered dose of giyoopyrroiafe of no more than 15D pg, and said administration resuits in an increase in 1C of at least 300 mi within a period of time selected from 1 hour or iess and 2 hours or less,

133. The method of claim 128, wherein said administehnq of the co-suspension composition comprises administering a delivered dose of glycopyrroiate of no more than 150 pg. and said adrn inistration results in ah increase in 1C of at least ISO mi within i period of time selected from 1 hour or less and 2 hours or less.

134. The method of claim 123, wherein said administering of the co~ suspension composition comprises administering a delivered dose of glycopyrroiate of no more than 150 pg, and said administration results in an increase in 1C of at least 100 mi with in a period of time seiected from 1 hour or less and 2 hours or less.