US 20140302147A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0302147 A1 HARTMAN et al. (43) Pub. Date: Oct. 9, 2014

(54) RESPRABLEAGGLOMERATES OF POROUS Publication Classification CARRIER PARTICLES AND MICRONIZED DRUG (51) Int. Cl. A619/16 (2006.01) (71) Applicants: Michael HARTMAN, Millbrae, CA A619/00 (2006.01) (US); Thomas ETARARA, A613 L/40 (2006.01) Burlingame, CA (US); Patrick TEUNG, A613 L/4704 (2006.01) Sunnyvale, CA (US); Jeffry G WEERS, A613 L/58 (2006.01) Belmont, CA (US) (52) U.S. Cl. CPC ...... A61 K9/1617 (2013.01); A61 K3I/4704 (72) Inventors: Michael HARTMAN, Millbrae, CA (2013.01); A61 K3I/58 (2013.01); A61K 31/40 (US); Thomas ETARARA, (2013.01); A61 K9/1682 (2013.01); A61 K Burlingame, CA (US); Patrick TEUNG, 9/0075 (2013.01) Sunnyvale, CA (US); Jeffry G WEERS, USPC ...... 424/489: 514/312: 514/171 Belmont, CA (US) (57) ABSTRACT Embodiments of the present invention provide a dry powder Assignee: composition comprising porous carrier particles associated (73) NOVARTIS AG, Basel (CH) with one, two, three or more micronized drugs or APIs wherein an ordered mixture between the micronized drug or (21) Appl. No.: 14/202,262 drugs and the carrier particle results, such that the micronized drug or drugs adhere strongly to the carrier particles forming a stable ordered mixture of respirable agglomerates. Embodi (22) Filed: Mar 10, 2014 ments of the present invention further comprise a spray-dry ing process to create the respirable agglomerates. Embodi ments of the present invention further relate to the use of the Related U.S. Application Data dry powder formulation comprising respirable agglomerates (60) Provisional application No. 61/784,842, filed on Mar. for the treatment of a patient having a disease or condition 14, 2013. which is treatable thereby. Patent Application Publication Oct. 9, 2014 Sheet 1 of 7 US 2014/0302147 A1

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RESPIRABLEAGGLOMERATES OF POROUS interactions can lead to variability in aerosol performance, CARRIER PARTICLES AND MICRONIZED with differences observed for each drug as a mono-compo DRUG nent or in the fixed dose combination, and with differences in dose strength. The complex interactions between the various FIELD OF THE INVENTION formulation components leads to difficulty in meeting the “combination rule', which relates that the in vitro aerosol 0001. The disclosure relates to physically stable and sub performance of each drug should be equivalent for the drug stantially uniform dry powder medicament formulations of alone and in combination. In order to overcome potential one, two, three, or more active ingredients that are useful for issues with meeting the combination rule with lactose blends, pulmonary administration, and in particular for administering Some groups have turned to Sophisticated devices, where medicaments to treat diseases of the lung. blends of each drug in the fixed dose combination is present in its own receptacle, and the two receptacles are aerosolized BACKGROUND concurrently (see for example, Anderson et al., WO 2003/ 0002 Active pharmaceutical ingredients (APIs) that are 061743). useful for treating respiratory diseases are often formulated for administration pulmonarily, to wit: by inhalation, such as SUMMARY OF THE INVENTION with portable inhalers. Pulmonary drug delivery methods and 0008 Accordingly, embodiments of the present invention compositions that effectively provide the pharmaceutical overcome the complexity observed with standard blends of compound at the specific site of action (the lung) potentially coarse lactose and micronized drug by creating ordered mix serve to minimize toxic side effects, lower dosing require tures of respirable agglomerates comprising Small porous ments, and decrease therapeutic costs. The development of carrier particles and micronized drug. Such systems for pulmonary drug delivery has long been a 0009 Embodiments of the present invention further pro goal of the pharmaceutical industry. vide a method for creating uniform ordered mixtures of respi 0003. Inhalation systems commonly used to deliver drugs rable agglomerates of Small porous particles and micronized locally to the pulmonary air passages are dry powder inhalers drug, comprising preparing a suspension of drug and carrier (DPIs), metered dose inhalers (MDIs), and nebulizers. DPIs in an anti-solvent, followed by removal of the anti-solvent in generally rely entirely on the patients inspiratory efforts to a drying process. introduce a medicament in a dry powder form to the lungs. 00.10 Embodiments of the present invention thus com 0004 To achieve good deposition of aerosolized particles prise a dry powder composition comprising carrier particles in the lungs, the particles should have an aerodynamic diam associated with one, two, three or more micronized drugs or eter in the respirable size range from 1 to 5um. However, fine APIs wherein an ordered mixture between the micronized particles of this size are highly cohesive with poor bulk pow drug or drugs and the carrier particle results, such that the der properties (e.g., poor powder flow, fluidization, and dis micronized drug or drugs adhere strongly to the carrier par persibility). ticles forming stable respirable agglomerates. The carrier 0005 To improve bulk powder properties of dry powder particles are Small and/or porous. aerosols, micronized drug particles are often blended with 0011 Embodiments of the invention comprise a plurality coarse lactose monohydrate carrier particles with a geometric of Small porous carrier particles, together with a plurality of diameter between 50 and 200 um. The blend forms a mixture one or more Small active drug particles which together form with the fine particles adhering to the carrier, and the mixture an ordered mixture of aerodynamically sized, pulmonarily taking on the bulk powder characteristics of the coarse carrier deliverable respirable agglomerates. particles. 0012 Embodiments of the present invention obviate the 0006 Engineered particle blends require a delicate bal need for dispersion of the drug from the carrier during a ance of surface forces. The adhesive force between the drug patients inhalation, and the patient instead inhales the respi and carrier must be strong enough to create an ordered mix rable agglomerates of micronized drug and Small porous car ture that maintains its structure during filling and on storage, rier particles into their lungs. As such, the physicochemical yet weak enough to allow the drug and carrier to separate properties of the drug Substance and its content in the powder during aerosol administration. The adhesive force between become largely irrelevant. This is in contrast to the conven the fine particles and the carrier particles in current marketed tional mixtures of coarse lactose and micronized drug, where products remains high, however, leading to mean lung deliv both the adhesive forces between the drug and carrier, and the ery efficiencies of just 10-30% of the nominal dose, and mean cohesive forces between the micronized drug particles are interpatient variability in lung delivery of approximately critical in the resulting bulk powder properties. Thus, the 30-50%. aerosol performance of the respirable agglomerates of 0007. In practice, the engineered blends of micronized embodiments of the present invention do not depend on a drug adhered to lactose carrier particles do not exist as simple balance of adhesive and cohesive forces between carrier and ordered mixtures. Drug may be stuck to coarse lactose, to fine drug particles, but instead depend only on the cohesive forces lactose, or to itself in large agglomerates. This led some to between the respirable agglomerates. refer to these complex formulations as “multi-particulate 0013 The cohesive forces between small porous carrier nightmares'. The interactions become even more complex for particles are significantly reduced relative to standard fixed dose combinations of two or more drugs. Each drug in micronized drug particles, due to the decreased area of con the combination exhibits a different force of adhesion with tact between particles afforded by the porous particle mor the carrier, and a different dependence of drug dispersion phology, and the hydrophobic nature of the excipients from the carrier with flow rate. In addition, there are addi enriched at the particle Surface. As a result, Small porous tional adhesive forces between the two drugs and between carrier particles have been shown to fluidize and disperse each drug and fine particle excipient. The complexity of the effectively at low peak inspiratory flow rates, reflecting the US 2014/0302147 A1 Oct. 9, 2014 decreased interparticle cohesive forces engineered into these agglomerates leads to Small aerodynamic (respirable) sizes particles. The respirable agglomerates of micronized drugs and as a result, excellent aerosol delivery to the lungs. and Small porous carrier particles exhibit the same powder 0020 Embodiments of respirable agglomerates, methods fluidization and dispersion behavior as the Small porous car of making, methods of using, formulations and doses of the rier particles alone. present invention afford advantages relative to conventional 0014 Embodiments of the present invention accordingly dry powder formulations. Such advantages include one or afford a composition and method to formulate fixed dose more of: (a) a monomodal aerodynamic particle size distri combinations of drugs as a dry powder comprising respirable bution (APSD) vs. a bimodal APSD for conventional blends: agglomerates, wherein the composition and method are (b) an increase in lung targeting, with a resulting total lung largely independent of whether the drug is present as a mono deposition of from 50-70% for the respirable agglomerates component, or in combination with a second or third drug compared to only 10-30% for lactose blends; (c) improve substance. Thus embodiments of the present invention miti ments in dose consistency resulting from reductions in mean gate, reduce or eliminate variations in aerosol performance variability in total lung deposition to 5-20% or less, compared that occur as a result of co-formulation of two or more drugs to a variability of 30-50% for lactose blends; (d) improve in a single formulation. Embodiments of the present invention ments in dose consistency in fixed dose combinations (i.e., afford improved lung targeting (high mean lung delivery effi mono, combo, and triple formulations exhibit comparable ciencies) relative to standard blends with coarse lactose. This APSD); (e) a manufacturing process which enables effective leads to decreases in drug deposition in the mouth-throat and mixing of micron-sized particles with low variability in com systemic circulation for drugs that are orally bioavailable. position, and no observed segregation during filling, on Stor Bypassing deposition in the mouth-throat also reduces inter age, and during aerosol administration, (f) an ability to buffer patient variability in total lung delivery. the formulation, thereby enabling more effective control of 00.15 Embodiments of the present invention comprise a chemical stability. One or more of these advantages results process to create the respirable agglomerates. Thus, in some from nearly eliminating the large sized fraction of particles embodiments, a dry powder comprising respirable agglom that deposit in the induction port and pre-separator in an erates is achieved by creating a small and/or porous carrier impactor due to incomplete dispersion of drug from carrier. particle, using a spray-drying process, then preparing a sus This leads to significant reductions in mouth-throat deposi pension of the desired drug or drugs and Small carrier particle tion in vivo, and advantageously decreases un-wanted sys in an anti-solvent (e.g., perfluorooctyl bromide). The anti temic delivery for drugs. solvent is then removed in a solvent removal step, such as by 0021 Embodiments of respirable agglomerates, methods spray-drying, yielding the dry powder comprising respirable of making, methods of using, formulations and doses of the agglomerates. present invention provide compositions and methods which minimize a dissolved fraction of an API resulting in a corre 0016 Embodiments of the dry powder comprising respi sponding minimization of potentially unstable amorphous rable agglomerates, and process, of the present invention API in the final product. maintain a crystallinity of the drug Substance through the 0022. In a first aspect of the present invention, there is manufacturing process and during storage for an extended provided a dry powder composition comprising respirable period. agglomerates comprising engineered carrier particles in an 0017 Adhesion of drug to the porous carrier particles is ordered mixture with one, two, three or more different active driven thermodynamically such that the drug particles favor ingredients. The active ingredients may be present in amor minimal contact with the anti-solvent. The use of a porous phous form but are often present in crystalline form. carrier particle, that is, one with a high Surface area, potenti 0023 The active ingredients can be any active pharmaceu ates strong adhesion of drug to carrier. The strength of the tical ingredients that are useful for treating diseases or con adhesive force between drug and carrier particle is driven ditions. The diseases or conditions may comprise pulmonary primarily by van der Waals forces, which are directly propor diseases or conditions, systemic diseases or conditions, or tional to the diameter of the particles. both. Exemplary diseases or conditions include obstructive or 0018 Removal of drug particles from the porous carrier inflammatory airways disease, such as obstructive pulmonary particles during filling or on administration from a dry pow disease (COPD), asthma, idiopathic pulmonary fibrosis, der inhaler requires that hydrodynamic forces exerted on the bronchiectasis, and cystic fibrosis as well as lung diseases respirable agglomerates exceed the adhesive (primarily van Such as pulmonary arterial hypertension. der Waals) forces. These forces (e.g., drag and lift forces) 0024 Suitable active ingredients include long acting scale with the square of the particle diameter, whereas the Van f-agonists such as salmeterol, formoterol, indacaterol and der Waals forces between drug and carrier scale with the salts thereof, muscarinic antagonists Such as tiotropium and diameter of the particles. For particles in the size range from glycopyrronium and salts thereof, and corticosteroids includ about 1 to 5 microns (Lm), the adhesive forces significantly ing budesonide, ciclesonide, fluticaSone and mometasone and exceed the fluid forces, resulting in poor dispersion of drug salts thereof. Suitable exemplary combinations include (inda from carrier. This is often observed for neat micronized drug caterol maleate and glycopyrronium bromide), (indacaterol crystals or even micronized drug adhered to coarse lactose acetate and glycopyrronium bromide), (indacaterol Xinafoate carrier particles, and was the driving force for blending with and glycopyrronium bromide), (indacaterol maleate and coarse lactose carrierparticles in an effort to improve powder mometasone furoate), (formoterol fumarate and budesonide), flow. (salmeterol Xinafoate and fluticaSone propionate), (salme 0019. In process and composition embodiments of the terol Xinafoate and tiotropium bromide), (formoterol fuma present invention, stable respirable agglomerates are made by rate and tiotropium bromide), (indacaterol maleate, mometa engineering to take advantage of these strong adhesive prop Sone furoate and glycopyrronium bromide), (indacaterol erties. The Small size and porous nature of the resulting stable acetate, mometasone furoate and glycopyrronium bromide), US 2014/0302147 A1 Oct. 9, 2014

(indacaterol Xinafoate, mometaSone furoate and glycopyrro molar ratio of 2:1 dispersed in an aqueous liquid phase and nium bromide) and (formoterol fumarate, fluticasone propi spray-drying said first feedstock to provide a plurality of onate and tiotropium bromide). Small porous carrier particles; 0025. In a second aspect of the present invention, there is 0035 (b) preparing at least a first, a second, and optionally, provided a powder composition comprising respirable a third or more active drug ingredient by micronizing each agglomerates comprising Small porous engineered carrier drug to provide particles having a size of less than about 4 particles, having one or more of a MMD of about 1-10 microns; microns, an MMAD of about 2-4 microns and a tapped den 0036 (c) preparing a second feedstock comprising the sity of about 0.03 to 0.5 g/cm; a first micronized active drug carrier particles of step (a) and the micronized drug particles particle comprising indacaterol, a second micronized active of step (b) in a non-aqueous anti-solvent; and; drug particle comprising mometasone, and a third micronized 0037 (d) subjecting the second feedstock to a solvent active drug particle comprising glycopyrrolate as an ordered removal process to yield a dry powder comprising a plurality mixture with the carrier particle. Each of the micronized drug of respirable aggregate particles comprising an inhalable dry particles comprise an MMD of less than about 4 microns, powder formulation. In a further version of this aspect, the such as about 0.1-3 microns. The active ingredients are pref first active comprises a beta adrenoreceptor agonist, such as erably present in substantially (i.e., at least about 95%) in indacaterol, the second active comprises an anti-inflamma crystalline form. tory Such as mometasone and the third active comprises an 0026. In a third aspect of the present invention, there is anti-muscarinic Such as glycopyrrolate. provided a powder composition comprising respirable 0038. In a seventh aspect, the present invention relates to a agglomerates comprising a f-agonist, a corticosteroid, Small method for the treatment of a patient, and/or the use of the dry porous carrierparticles, and optionally, an anti-muscarinic. In powder formulation comprising respirable agglomerates a further variation of this aspect, the actives are each present according to any embodiments herein, which method and/or in an amount of from about 0.5-3% by weight, and the small use comprises administering to a patient (or Subject) having a porous carrier particles comprise a 2:1 molar ratio of DSPC: disease or condition an effective amount of the dry powder CaCl. formulation comprising respirable agglomerates according to any embodiments herein. Exemplary diseases or conditions 0027. In a fourth aspect of the present invention, there is include obstructive or inflammatory airways disease, such as provided a powder composition comprising respirable obstructive pulmonary disease (COPD), asthma, idiopathic agglomerates comprising at least one relatively water soluble pulmonary fibrosis, bronchiectasis, and cystic fibrosis as well drug active, at least one relatively water in-soluble drug as lung diseases such as pulmonary arterial hypertension. active, and Small porous carrier particles. In a further varia 0039. In a further aspect, a method of treatment comprises tion of this aspect, the actives are each present in an amount of administering to a subject a dry powderformulation compris from about 0.5-3% by weight, and the small porous carrier ing respirable agglomerates comprising about 0.5-3% w/w particles comprise a 2:1 molar ratio of DSPC:CaCl. indacaterol acetate, about 0.5-3% w/w mometasone furoate, 0028. In a fifth aspect, the present invention relates to a about 0.5-3% w/w glycopyrronium bromide, and about process for preparing a respirable dry powder formulation of 91-99% small porous carrier particles comprising about a 2:1 agglomerate particles, the process comprising the steps of: molar ratio of DSPC:CaCl. 0029 (a) preparing a first feedstock comprising a hydro 0040. In a further aspect, a method of treatment comprises phobic excipient dispersed in an aqueous liquid phase and administering to a subject a dry powderformulation compris spray-drying said first feedstock to provide a bulk powder ing respirable agglomerates comprising about 0.5-3% w/w composition comprisingaporous dry powder carrier particle: indacaterol acetate and about 0.5-3% w/w mometasone 0030 (b) preparing at least a first active drug ingredient by furoate, and about 94-99% small porous carrier particles micronizing the drug to provide particles having a mass comprising about a 2:1 molar ratio of DSPC:CaCl. median diameter (MMD) of less than about 4 microns: 0041. In a further aspect, a method of treatment comprises 0031 (c) preparing a second feedstock comprising a sus administering to a subject a dry powderformulation compris pension of the carrier particles of step (a) and the micronized ing respirable agglomerates comprising about 0.5-3% w/w drug particles of step (b) in a non-aqueous anti-solvent; and indacaterol acetate and about 0.5-3% w/w glycopyrronium bromide, and about 94-99% small porous carrier particles 0032 (d) subjecting the second feedstock to a solvent comprising about a 2:1 molar ratio of DSPC:CaCl. removal process to yield a bulk powderformulation compris 0042. In a further aspect, the present invention relates to ing a plurality of respirable aggregate particles, wherein the the aforementioned dry powder formulation comprising respirable agglomerate particles comprise an ordered mixture respirable agglomerates for use in the treatment of a disease of carrier particles and micronized drug particles. In this or condition. aspect, the hydrophobic excipient may further comprise 0043. In a further aspect, the present invention relates to a DSPC and calcium chloride. In a still further version of this delivery system that comprises an inhaler that contains one or aspect, the micronized drug particles may have a size range of more embodiments of the dry powder formulation compris 1-3 microns. In a still further version of this aspect, the respi ing respirable agglomerates. rable agglomerates are characterized by an MMAD of about 0044. In a further aspect, the present invention relates to a 2-4 microns and a tapped density of about 0.03 to 0.5 g/cm. unit dose that comprises a receptacle that contains one or 0033. In a sixth aspect, the present invention relates to a more embodiments of the dry powder formulation compris process for preparing a respirable dry powder formulation of ing respirable agglomerates. agglomerate particles, the process comprising the steps of: 0045. A still further aspect of the present invention com 0034 (a) preparing a first feedstock comprising a hydro prises any two or more of the herein described aspects, phobic excipient such as DSPC and calcium chloride in a embodiments or features. US 2014/0302147 A1 Oct. 9, 2014

TERMS oropharynx and systemic circulation. In one or more embodi 0046 Terms used in the specification have the following ments, the rugosity S is from 3 to 20, e.g., from 5 to 10. meanings: 0057 “Emitted Dose' or “ED as used herein refers to an 0047 Active ingredient”,99 “therapeutically&g active ingredi indication of the delivery of dry powder from an inhaler ent”, “active agent”, “drug or “drug substance' as used device after an actuation or dispersion event from a powder herein means the active ingredient of a pharmaceutical, also unit. ED is defined as the ratio of the dose delivered by an known as an active pharmaceutical ingredient (API). inhaler device to the nominal or metered dose. The ED is an 0.048 "Fixed dose combination” as used herein refers to a experimentally determined parameter, and may be deter pharmaceutical product that contains two or more active mined using an in vitro device set up which mimics patient ingredients that are formulated together in a single dosage dosing. It is sometimes also referred to as the Delivered Dose form available in certain fixed doses. (DD). The ED is determined using a drug specific method 0049 Amorphous” as used herein refers to a state in Such as high pressure liquid chromatography. which the material lacks long range order at the molecular 0058 “Emitted Powder Mass' or “EPM as used herein level and, depending upon temperature, may exhibit the refers to the mass of a powder that is delivered from an inhaler physical properties of a solid or a liquid. Typically Such device after an actuation or dispersion event from a powder materials do not give distinctive X-ray diffraction patterns unit. The EPM is measured gravimetrically. and, while exhibiting the properties of a solid, are more for 0059) “Mass medianaerodynamic diameter” or “MMAD” mally described as a liquid. Upon heating, a change from as used herein refer to the median aerodynamic size of a Solid to liquid properties occurs which is characterised by a plurality of particles, typically in a polydisperse population. change of State, typically second order ("glass transition'). The “aerodynamic diameter' is the diameter of a unit density 0050 “Crystalline' as used herein refers to a solid phase in sphere having the same settling Velocity, generally in air, as a which the material has a regular ordered internal structure at powder and is therefore a useful way to characterize an aero the molecular level and gives a distinctive X-ray diffraction solized powder or other dispersed particle or particle formu pattern with defined peaks. Such materials when heated suf lation in terms of its settling behaviour. The aerodynamic ficiently will also exhibit the properties of a liquid, but the particle size distributions (APSD) and MMAD are deter change from Solid to liquid is characterised by a phase mined herein by cascade impaction, using a NEXT GEN change, typically first order ("melting point). In the context ERATION IMPACTORTM (as described by United States of the present invention, a crystalline active ingredient means Pharmacopeia <601 > Appartutus 6). In general, if the par an active ingredient with crystallinity of greater than 85%. In ticles are aerodynamically too large, fewer particles will certain embodiments the crystallinity is Suitably greater than reach the deep lung. If the particles are too small, a larger 90%. In other embodiments the crystallinity is suitably percentage of the particles may be exhaled. greater than 95%. 0051. “Solids Concentration” refers to the concentration 0060 “Fine particle fraction” or “FPF as used herein of active ingredient(s) and excipients dissolved or dispersed means the mass of an active ingredient below a specified in the liquid solution or dispersion to be spray-dried. minimum aerodynamic size relative to the nominal dose. For 0052 “Drug Loading refers to the percentage of active example, FPF-sis, refers to the percentage of the nominal ingredient(s) on a mass basis in the total mass of the formu dose which has an aerodynamic particle size less than 3.3 Lum. lation. FPF values are determined using cascade impaction, either on an ANDERSENTM cascade impactor (as described by United 0053 “% Dissolved” refers to percentage of a crystalline States Pharmacopeia <601 > Appartutus 6), or a NEXTGEN active ingredient which dissolves in the liquid feedstock to be ERATION IMPACTORTM cascade impactor. FPF values may spray-dried. also be expressed relative to an impactor device stage and/or 0054 “Mass median diameter or “MMD' or “x50 as the impactor device filter, meaning that the percentage of used herein means the median diameter of a plurality of particles that remain in the designated Stage. Thus FPFs, particles, typically in a polydisperse particle population, i.e., refers to that fraction of the nominal dose that remains on the consisting of a range of particle sizes. MMD values as stage 3 through the filter of the impactor device. reported herein are determined by laser diffraction (Sympatec Helos, Clausthal-Zellerfeld, Germany), unless the context 0061 “Fine Particle Dose” or “FPD as used herein indicates otherwise. means the dose (mass) of an active ingredient below a speci 0055 “Rugous' as used herein means having numerous fied minimum aerodynamic size. wrinkles or creases, i.e., being ridged or wrinkled. 0062. Throughout this specification and in the claims that 0056 “Rugosity’ as used herein is a measure of the sur follow, unless the context requires otherwise, the word “com face roughness of an engineered particle. For the purposes of prise', or variations such as "comprises' or “comprising. this invention, rugosity is calculated from the specific Surface should be understood to imply the inclusion of a stated integer area obtained from BET measurements, true density obtained or step or group of integers or steps but not the exclusion of from helium pycnometry, and the Surface to Volume ratio any other integer or step or group of integers or steps. obtained by laser diffraction (Sympatec), viz: 0063. The use of the term “about to qualify a numerical Rugosity=(SSA'p)/S, range, qualifies all numbers within the range, unless the con where S-6/D, where D is the average diameter based on text indicates otherwise. unit Surface area. Increases in Surface roughness are expected 0064. The entire disclosure of each United States and to reduce interparticle cohesive forces, and improve targeting International patent or patent application mentioned in this of aerosol to the lungs. Improved lung targeting is expected to patent specification is fully incorporated by reference herein reduce interpatient variability, and levels of drug in the for all purposes. US 2014/0302147 A1 Oct. 9, 2014

DETAILED DESCRIPTION OF THE DRAWINGS nary delivery, especially from an active or passive dry powder inhaler device. Embodiments of the present invention com 0065. The dry powderformulation of the present invention prise a process to create the respirable agglomerates. Thus, in may be described with reference to the accompanying draw Some embodiments, a dry powder comprising respirable ings. In those drawings: agglomerates is achieved by creating a small and/or porous 0066 FIG. 1 is an SEM photomicrograph of the respirable carrier particle, using a spray-drying process, then preparing agglomerates comprising indacaterol and mometasone drug a suspension of the desired drug or drugs and Small carrier Substances with porous carrier particles, as described in particle in an anti-solvent (e.g., perfluorooctyl bromide). The Example 1 (Lot 11015A-6-7). The porous carrier particles are anti-solventis then removed in a solvent removal step, such as depicted in greyscale and drug crystals are shown in white. by spray-drying, yielding the stable dry powder comprising 0067 FIG. 2 is a graph showing dose content uniformity respirable agglomerates. of a dry powder formulation comprising respirable agglom 0074 Embodiments of the present invention comprise a erates of indacaterol acetate, mometasone furoate, and gly dry powderformulation comprising respirable agglomerates, copyrronium bromide and Small porous carrier particles comprising an ordered mixture of carrier particles and one or made according to Example 1 (Lot 11015A-7-6). more micronized drug particles. The physical form of the 0068 FIG.3 is a graph showing delivered dose uniformity drug may be wholly or substantially crystalline or wholly or for a dry powder formulation comprising respirable agglom Substantially amorphous. In embodiments of the present erates of indacaterol acetate, mometasone furoate, glycopyr invention the drug is wholly or Substantially crystalline, and ronium bromide and Small porous carrier particles made amorphous content is minimal. Such as less than 5%. In according to Example 1 (Lot 11015A-6-7). Filled capsules embodiments of the present invention the drug is wholly or are assayed across the batch (i.e., at the beginning (B), middle Substantially amorphous, and crystalline content is minimal, (M), and end (E) of the filling process). Each drug is assayed such as less than 0.1%. In embodiments of the invention the by a drug specific method, and this is compared with the carrier particles have an MMD less than 10 microns, such as delivered dose determined gravimetrically. less than 5 microns, or less than 3 microns. In embodiments of 0069 FIG. 4 is a graph comparing aerodynamic particle the invention the drug particles have a mass median diameter size distributions for respirable agglomerate dry powder for (MMD) less than 3 microns, such as less than 2 microns, or mulation comprising indacaterol maleate made according to less than 1.5 microns. In embodiments of the invention the Example 1 (Lot 11015A-6-7) and manufactured by three respirable agglomerates comprise a size range Substantially discrete processes. The processes comprise a lactose blend as as that of the carrier particles. a commercial lot of OnBrez (Novartis); a standard Pulmo SphereTM lot made using the suspension-based PulmoSphere Carrier Particle manufacturing process, where the micronized indacaterol maleate is suspended in the emulsion-based feedstock and 0075. The carrier particles comprise porous and/or perfo spray-dried; and the respirable agglomerates of Example 1. rated microstructures. In some embodiments the carrier par 0070 FIG. 5 is a graph of aerodynamic particle size dis ticles comprise one or more of a rugous, a wrinkled and/or a tributions of dry powder respirable agglomerate formulations raisin-like Surface morphology. In embodiments of the comprising mometasone furoate in comparison with the mar present invention, the carrierparticles comprise a sponge-like keted ASmaneXR drug product (200 microgram strength). porous particle structure. In some embodiments the carrier The respirable agglomerate formulations were made accord particles are Small, and comprise a geometric diameterofless ing to Example 1. Thus, Lot #11015A-7-1 is the “mono'; Lot than about 10 microns, such as less than 5 microns or less than #11015A-7-5 is the “combo' formulated with indacaterol: 3 microns. In some embodiments the carrier particles com and Lot #11015A-7-6 is the “trombo” (or triple combination) prise a geometric diameter of about 2 to 3 microns. In some formulated with indacaterol and glycopyrrolate. embodiments a bulk, or dry, powder comprising the carrier (0071 FIG. 6 illustrates three X-ray powder diffraction particles has a tapped density of less than 0.5 g/cm, such as patterns for indacaterol drug Substance as indacaterol free less than 0.2 g/cm of less than 0.1 g/cm. In some embodi base in water (upper curve); as indacaterol acetate dispersed ments, the carrier particles comprise combinations of these in PFOB (middle curve); and neatindacaterol acetate. characteristics or attributes. 0072 FIG. 7 illustrates X-ray powder diffraction patterns 0076 A porous particle morphology aids in making the for indacaterol acetate formulated as dry powder respirable agglomerate particles aerodynamic, and in facilitating disper agglomerates (middle curve) in accordance with Example(s) sion of the powder agglomerates from a dry powder inhaler. 1—Lot 227-74-2. Also shown are the corresponding diffrac The porous nature of the particles may also be important in tion patterns for the near drug Substance (upper curve) and the achieving a strong adhesion with the micronized drug par PulmoSphere placebo (lower curve). The diffraction pattern ticles via interlocking forces between particles. A mass for the 6% QAB acetate formulation contains peaks charac median diameter of the porous carrier particles is between 1 teristic of crystalline QAB acetate. No evidence of QAB free and 10 microns, such as between 1 and 5 microns or between base is observed. These results confirm that the physical form 2 and 3 microns. Such small MMDs confers upon the small of indacaterol acetate is maintained through the manufactur porous carrier particles a high Surface to Volume ratio, facili ing process to prepare the respirable agglomerates. tating strong adhesion with the micronized drug particles. In embodiments of the invention, the carrier particles and drug DETAILED DESCRIPTION OF THE INVENTION particles Substantially adhere during the powder manufactur ing process. In embodiments of the invention, the carrier 0073 Embodiments of the present invention comprise a particles and drug particles Substantially adhere during the bulk powder composition comprising carrier particles asso powder manufacturing process and the process of filling the ciated with one, two, three or more micronized drugs or APIs powder into unit doses. In embodiments of the invention, the forming stable respirable agglomerates Suitable for pulmo carrier particles and drug particles Substantially adhere dur US 2014/0302147 A1 Oct. 9, 2014 ing the powder making process and the process of filling the ids are present, the amount is typically sufficient to provide a powder into unit doses, and during dispensing of the powder porous coating matrix of phospholipids. If present, phospho from an inhaler device. lipid content generally ranges from about 40-99% w/w of the 0077. In some embodiments of the invention, a tapped medicament, for example 70% to 90% w/w of the medica density of the small porous particles is less than about 0.5 ment. The high percentage of excipient is also driven by the g/cm, such as less than about 0.4 g/cm, or less than about 0.3 high potency and therefore typically small doses of the active g/cm or less than about 0.2 g/cm, or less than about 0.1 agents. The excipients also serve as bulking agents in the g/cm, or less than about 0.05 g/cm. In some embodiments of formulation, enabling effective delivery of low dose thera the invention, a tapped density of the Small porous particles is peutics. between about 0.03-0.5 g/cm, with tapped densities less than I0086 Generally compatible phospholipids comprise about 0.3 g/cm or less than about 0.1 g/cm, often preferred. those having a gel to liquid crystal phase transition greater The tapped density is a reasonable approximation of the par than about 40°C., such as greater than 60°C., or greater than ticle density, typically being about 20% less than particle about 80° C. The incorporated phospholipids may be rela density. tively long chain (e.g., C-C) saturated phospholipids. 0078. In some embodiments of the present invention a Exemplary phospholipids useful in the disclosed stabilized MMAD of the small porous carrier particles is between 1 and preparations include, but are not limited to, phosphatidylcho 5 microns, such as between 1 and 4 microns, or 2 and 4 lines, such as dipalmitoylphosphatidylcholine (DPPC), dis microns. In some embodiments the carrier particles have tearoylphosphatidylcholine (DSPC), and hydrogenated egg MMAD values between 2 and 4 microns or between 2 and 3 or soy phosphatidylcholines (e.g., E-100-3, S-100-3, avail microns. able from Lipoid KG, Ludwigshafen, Germany). Natural 0079. In some embodiments the porous carrier particles phospholipids are preferably hydrogenated, with a low iodine comprise one or more excipients. Particularly preferred are value (<10). excipients with a history of use in pharmaceutical aerosols. I0087. The phospholipids may optionally be combined Suitable excipients comprise carbohydrates, for example lac with cholesterol to modify the fluidity of the phospholipid tose, glucose, mannitol, phospholipids, for example, dipalmi acyl chains. toylphosphatidylcholine (DPPC), and distearoylphosphati I0088. The long-chain phospholipids may optionally be dylcholine (DSPC), and hydrophobic amino acids or combined with a divalent metal ion (e.g., calcium, magne peptides, for example, leucine or trileucine. In some embodi sium). Such a divalent metal ion acts to decrease headgroup ments the excipients are those that enable the desired porous hydration, thereby increasing the phospholipid gel to liquid particle morphology. crystal phase transition, and the wettability of the powders on 0080. In some embodiments, the small porous carrier par lung lining fluid. The molar ratio of polyvalent cation to ticles of the present invention contain a pharmaceutically phospholipid may be at least about 0.05:1, such as about acceptable hydrophobic excipient. 0.05:1 to 0.5:1. In one or more embodiments, a molar ratio of 0081. In some embodiments, the hydrophobic excipient polyvalent cation:phospholipid is 0.5:1. While not intending facilitates development of a rugous particle morphology. This to be bound by theory, it is believed that the divalent metalion means the particle morphology is wrinkled and creased rather binds to the phosphate groups on the Zwitterionic phosphati than Smooth. This means the interior and/or the exterior Sur dylcholine headgroup, displacing water molecules in the pro face of the inhalable medicament particles are at least in part cess. Molar ratios of metal ion to phospholipid in excess of rugous. This rugosity is useful for providing dose consistency 0.5 may result in free metal ion not bound to the phosphate and drug targeting by improving powder fluidization and groups. This can significantly increase the hygroscopicity of dispersibility. Increases in particle rugosity result in the resulting dry powder, and is not preferred. When the decreases in inter-particle cohesive forces as a result of an polyvalent metal ion is calcium, it may be in the form of inability of the particles to approach to within van der Waals calcium chloride. Although metal ions, such, as calcium, are contact. The decreases in cohesive forces are sufficient to often included with phospholipids, none is required, and their dramatically improve powder fluidization and dispersion in use can be problematic when other ions are present in the ensembles of rugous particles, and in the respirable agglom formulation (e.g., phosphate, which may precipitate the cal erates comprising rugous carrier particles as well. cium ions as calcium phosphate). When compatibility issues 0082. The rugosity of the small porous carrier particles occur, there may be benefit in using Mg" salts, as they may be increased by using a pore-forming agent, Such as typically have K values which are three to four orders of perflubron, during their manufacture, or by controlling the magnitude higher than Ca" Salts. formulation and/or process to produce rugous particles. I0089. The hydrophobic excipient may also comprise long 0083. In some embodiments the porous carrier particles of chain fatty acid soaps. The alkyl chain length is generally the dry powder formulation of the invention suitably have a 14-22 carbons in length with saturated alkyl chains preferred. rugosity of greater than 1.5, for example from 1.5 to 20, 3 to The fatty acid soaps may utilize monovalent (e.g., Na', K') or 15, or 5 to 10. divalent counterions (e.g., Ca", Mg"). Particularly pre 0084. The hydrophobic excipient may take various forms ferred fatty acid soaps are sodium Stearate and magnesium that will depend at least to some extent on the composition stearate. The solubility of fatty acid soaps may be increased and intended use of the dry powder formulation. Suitable above the Krafft point. Potassium salts offatty acids generally pharmaceutically acceptable hydrophobic excipients may, in have the lowest Krafft point temperature and greater aqueous general, be selected from the group consisting of long-chain solubility at a given temperature. Calcium salts are expected phospholipids, hydrophobic amino acids and peptides, and to have the lowest solubility. The hydrophobic fatty acid long chain fatty acid soaps. Soaps provide a wax-like coating on the particles. The pro 0085 Phospholipids from both natural and synthetic posed loadings in the spray-dried particles are similar to the Sources may be used in varying amounts. When phospholip phospholipids detailed previously. US 2014/0302147 A1 Oct. 9, 2014

0090 The hydrophobic excipient may also comprise between the micronized drug or drugs and the Small carrier hydrophobic amino acids, peptides, or proteins. Particularly particle results, such that the micronized drug or drugs adhere preferred are the amino acid leucine, and its oligomers dileu to the Small carrier particles forming a stable respirable cine and trileucine. Proteins, such as human serum albumin agglomerate. are also contemplated. Trileucine is particularly preferred, as 0097. It is important that the drug particles be fine enough its solubility profile and other physicochemical properties to adhere to the carrier particles. Accordingly, in some (e.g., Surface activity, log P) facilitate creation of core-shell embodiments the drug particles and the Small porous carrier particles, where trileucine controls the Surface properties and particles are each sized such that adherence is mediated by morphology of the resulting particles. van der Waals forces. In some embodiments the drug particles 0091. In embodiments of the present invention, the carrier particles comprise porous and/or perforated particles which are much smaller than the Small porous carrier particles Such are engineered using the emulsion-based PulmoSphere dry that adherence is mediated by van der Waals forces. powder manufacturing technology, as more fully described in 0098. In embodiments of the invention, the active drug U.S. Pat. No. 6,565,885, U.S. Pat. No. 7,871,598 and U.S. ingredient(s) is/are micronized. An MMD or an x50 (particle Pat. No. 7,442,388. In particular embodiments, a method of size distribution wherein 50% of the particles are sized preparing perforated microstructures for pharmaceutical smaller) of the micronized active ingredients should be less applications comprises spray-drying a feedstock comprising than about 3 micron (Lm), preferably less than about 2 Lum, or an agent (API or drug), a Surfactant (e.g., a phospholipid) and 1 um. In embodiments of the invention, an x50 is about 0.1-3 a blowing agent. The resulting perforated microstructures um. An x90 (particle size distribution wherein 90% of the comprise the agent and the Surfactant and are known as Pul particles are sized smaller) should be less than 7um, prefer moSphere particles. ably less than 5um, or 3 um. As well, the MMAD of the 0092. In embodiments herein, the carrier particles are pre respirable agglomerates will become increasingly influenced pared as spray-dried PulmoSphere particles as described by the size of the drug crystals for particles with an x50 herein and/or in the above-referenced US patents and/or greater than about 2 Lum. applications, but without a drug or API. In some embodiments 0099. If micronized, the drug particles may be prepared by herein, the carrier particles are prepared as spray-dried Pul either top-down or bottom-up manufacturing processes. Top moSphere particles consisting essentially of one or more down manufacturing processes include jet milling, ball mill phospholipids and a multivalent metal cation. In some ing, media milling, and high pressure homogenization. Bot embodiments herein, the carrier particles are prepared as tom-up processes include: spray-drying, spray freeze-drying, spray-dried PulmoSphere particles consisting essentially of Supercritical fluid technologies (rapid expansion and anti DSPC and calcium chloride, or DSPC and magnesium chlo Solvent), templating and microfabrication, lithography, and ride. other particle precipitation techniques (e.g., spinodal decom 0093. In some embodiments the multivalent metal cation position), for example in the presence of ultrasonic energy to comprises a divalent cation, including calcium, magnesium, ensure crystallization of the drug. Note that the term micron and the like. The multivalent cation, in some embodiments, is ized is intended to encompass any and all processes, whether present in an amount effective to increase the T of the phos physical, chemical, mechanical or otherwise, for providing a pholipid such that the particulate composition exhibits a T. Sufficiently sized and/or shaped drug particle. which is greater than its storage temperature T by at least 20° 0100. In embodiments of the invention the drug particles C., preferably at least 40° C. If present, a molar ratio of comprise nano-sized particles with mass median diameters multivalent cation to phospholipid may be at least 0.05, such less than 1000 nm, or less than 200 or less than 100 nm. For as 0.05-2.0, or 0.25-1.0. In some embodiments, there is a embodiments comprising nanoparticles, the x90 may be less molar ratio of multivalent cation:phospholipid of about 0.50. than 1000 nm. Drug particles within these size ranges enable In some embodiments, the polyvalent cation comprises cal their association with the porous particles, to afford the cium, which may be provided as calcium chloride. desired respirability, and drug delivery and drug efficacy of 0094. By control of the formulation and process, it is pos the dry powder comprising respirable agglomerates. sible for the surface of the carrier particles to be comprised 0101 The active agent(s) of the dry powder of the present primarily of the hydrophobic excipient. Surface concentra invention can be any active pharmaceutical ingredient that is tions may be greater than 70%, such as greater than 75% or useful for treating diseases or conditions. Such as lung and/or 80% or 85%. In some embodiments the surface is comprised airway diseases or conditions, for example obstructive or of greater than 90% hydrophobic excipient, or greater than inflammatory airways diseases, particularly asthma and/or 95% or 98% or 99% hydrophobic excipient. COPD, pulmonary arterial hypertension (PAH), idiopathic 0095 Optionally a drug or drugs (one or more APIs) may pulmonary fibrosis (IPF), and cystic fibrosis (CF). The active be incorporated directly with the carrier particles, in addition agent(s) of the dry powder of the present invention can also be to the one or more micronized drugs associated with the any pharmaceutical ingredient that is useful for treating sys carrier particles to form the respirable agglomerates. Such temic diseases or conditions following administration as a dry optional drug-containing carrier particles may be prepared in powder aerosol to the lungs and Subsequent absorption of the accordance with the teachings of U.S. Pat. Nos. 6,565,885, active agent(s) to the systemic circulation. The active ingre 7,871,598 and 7,442,388, for example. dient(s) may be selected, for example, from bronchodilators, anti-inflammatories, and mixtures thereof, especially B-ago Drug Particle nists, muscarinic antagonists, steroids, dual f-agonist-mus 0096 Embodiments of the present invention comprise a carinic antagonists, and nonsteroidal anti-inflammatory dry powder composition comprising Small carrier particles agents (e.g., PDE4 inhibitors, A agonists, cytokine inhibi associated with one, two, three or more drugs (also referred to tors, chemokine antagonists, p38 MAP Kinase inhibitors, herein as API, or active agent) wherein an ordered mixture PI3K inhibitors, PPAR agonists) and mixtures thereof. US 2014/0302147 A1 Oct. 9, 2014

0102 Suitable active agents include B-agonists. Suitable include aclidinium (e.g., bromide), BEA-2 108 (e.g., bro B-agonists include arformoterol (e.g., tartrate), albuterol/ mide), BEA-2180 (e.g., bromide), CHF-5407, darifenacin salbutamol (e.g., racemate or single enantiomer Such as the (e.g., bromide), darotropium (e.g., bromide), glycopyrrolate R-enantiomer, or salt thereof especially sulfate), AZD3199. (e.g., racemate or single enantiomer, or salt thereof especially bambuterol, BI-171800, bitolterol (e.g., mesylate), carmot bromide), dexpirronium (e.g., bromide), iGSK-202405, erol, clenbuterol, etanterol, fenoterol (e.g., racemate or single GSK-203423, GSK-573719, GSK-656398, ipratropium enantiomer Such as the R-enantiomer, or salt thereof espe (e.g., bromide), LAS35201, LAS186368, otilonium (e.g., cially hydrobromide), flerbuterol, formoterol (e.g., racemate bromide), oxitropium (e.g., bromide), oxybutynin, or single diastereomer Such as the R.R-diastereomer, or salt PF-3715455, PF-3635659, pirenzepine, revatropate (e.g., thereof especially fumarate or fumarate dihydrate), GSK hydrobromide), solifenacin (e.g., succinate), SVT-40776, 159802, GSK-597901, GSK-678007, indacaterol (e.g., race TD-4208, terodiline, tiotropium (e.g., bromide), tolterodine mate or single enantiomer Such as the R-enantiomer, or salt (e.g., tartrate), and trospium (e.g., chloride). In some embodi thereof especially maleate, acetate or Xinafoate), ments the muscarinic antagonists is long-acting muscarinic LAS100977, metaproterenol, milveterol (e.g., hydrochlo antagonist Such as darotropium bromide, glycopyrrolate or ride), naminterol, olodaterol (e.g., racemate or single enanti tiotropium bromide. omer Such as the R-enantiomer, or salt thereof especially 0105. In some embodiments one of the active agents is a hydrochloride), PF-610355, pirbuterol (e.g., acetate), pro glycopyrronium salt. Glycopyrronium salts include glycopy caterol, reproterol, salmefamol, salmeterol (e.g., racemate or rronium bromide, also known as glycopyrrolate, which is single enantiomer Such as the R-enantiomer, or salt thereof known to be an effective antimuscarinic agent. More specifi especially Xinafoate), terbutaline (e.g., Sulphate) and cally it inhibits acetyl choline binding to M3 muscarinic vilanterol (or a salt thereof especially trifenatate). In certain receptors thereby inhibiting bronchoconstriction. Glycopyr preferred embodiments the B-agonist is an ultra-long-acting rolate is a quaternary ammonium salt. Suitable counter ions f-agonist such as indacaterol, or potentially carmoterol, are pharmaceutically acceptable counter ions including, for LAS-100977, milveterol, olodaterol, PF-610355 or example, fluoride, chloride, bromide, iodide, nitrate, Sulfate, Vilanterol. phosphate, formate, acetate, trifluoroacetate, propionate, 0103) In some embodiments one of the active agents is butyrate, lactate, citrate, tartrate, malate, maleate. Succinate, indacaterol (i.e., (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1- benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylac hydroxyethyl-8-hydroxy-1H-quinolin-2-one) or a salt etate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydrox thereof. This is a f-adrenoceptor agonist that has an espe ynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-car cially long duration of action (i.e., over 24 hours) and a short boxylate, methanesulfonate and benzenesulfonate. onset of action (i.e., about 10 minutes). This compound is Glycopyrrolate can be prepared using the procedures prepared by the processes described in International Patent described in U.S. Pat. No. 2.956,062. It has two stereogenic Applications WO 2000/75114 and WO 2005/123684. It is centers and hence exists in four isomeric forms, namely (3R, capable of forming acid addition salts, particularly pharma 2R)-, (3S,2R)-, (3R,2S)- and (3S,2S)-3-(cyclopentyl-hy ceutically acceptable acid addition salts. Pharmaceutically droxyphenyl-acetyl)oxy-1,1-dimethylpyrrolidinium bro acceptable acid addition salts of the compound of formula I mide, as described in U.S. Pat. No. 6,307,060 and U.S. Pat. include those of inorganic acids, for example, hydrohalic No. 6,613,795. When the drug substance of the dry powder acids such as hydrofluoric acid, hydrochloric acid, hydrobro formulation is glycopyrrolate, it can be one or more of these mic acid or hydroiodic acid, nitric acid, Sulfuric acid, phos isomeric forms, especially the 3S,2R isomer, the 3R,2R iso phoric acid; and organic acids such as formic acid, acetic acid, mer or the 2S,3R isomer, thus including single enantiomers, propionic acid, butyric acid, benzoic acid, o-hydroxybenzoic mixtures of diastereomers, or racemates, especially (3S,2R/ acid, p-hydroxybenzoic acid, p-chlorobenzoic acid, dipheny 3R,2S)-3-(cyclopentyl-hydroxy-phenylacetyl)oxy-11 lacetic acid, triphenylacetic acid, 1-hydroxynaphthalene-2- dimethylpyrrolidinium bromide. R.R-glycopyrrolate is also carboxylic acid, 3-hydroxynaphthalene-2-carboxylic acid, known as dexpirronium. aliphatic hydroxy acids such as lactic acid, citric acid, tartaric 0106. In some embodiments, suitable active agents acid or malic acid, dicarboxylic acids such as fumaric acid, include bifunctional active agents such as dual 3-agonists maleic acid or Succinic acid, and Sulfonic acids such as meth muscarinicantagonists. Suitable dual B-agonists-muscarinic anesulfonic acid or benzenesulfonic acid. These salts may be antagonists include GSK-961081 (e.g., succinate). prepared from the compound by known salt-forming proce 0107. In some embodiments, suitable active agents dures. A preferred salt of (R)-5-[2-(5,6-diethyl-indan-2- include steroids, for example corticosteroids. Suitable ste ylamino)-1-hydroxyethyl-8-hydroxy-1H-quinolin-2-one is roids include budesonide, beclamethasone (e.g., dipropi the maleate salt. Another preferred salt is (R)-5-[2-(5,6-di onate), butixocort (e.g., propionate), CHF5188, ciclesonide, ethyl-indan-2-ylamino)-1-hydroxyethyl-8-hydroxy-1H dexamethasone, flunisolide, fluticasone (e.g., propionate or quinolin-2-one acetate. Another preferred salt is (R)-5-[2-(5. furoate), GSK-685698, GSK-870086, LAS40369, methyl 6-diethyl-indan-2-ylamino)-1-hydroxyethyl-8-hydroxy prednisolone, mometasone (e.g., furoate), prednisolone, rof 1H-quinolin-2-one Xinafoate. Other useful salts include the leponide, and triamcinolone (e.g., acetonide). In certain pre hydrogen Succinate, fumarate, hippurate, meSylate, hydrogen ferred embodiments the Steroid is long-acting corticosteroids Sulphate, hydrogen tartrate, hydrogen chloride, hydrogen Such as budesonide, ciclesonide, fluticaSone or mometasone. bromide, formate, esylate, tosylate, glycolate and hydrogen 0108. In some embodiments one of the active agents is malonate salts, which, like the acetate and Xinafoate salts, are mometasone (i.e., (11B, 16C.)-9,21-dichloro-17-(2-furanyl disclosed in International Patent Application WO 2008/ carbonyl)oxy-11-hydroxy-16-methylpregna-1,4-diene-3, 000839 together with methods of their respective preparation. 20-dione, alternatively designated 9C,21-dichloro-16C.-me 0104 Suitable active agents comprise muscarinic antago thyl-1,4-pregnadiene-113,17C.-diol-320-dione 17-(2'- nists or antimuscarinics. Suitable muscarinic antagonists furoate)) or a salt thereof, for example mometasone furoate US 2014/0302147 A1 Oct. 9, 2014

and mometaSone furoate monohydrate. Mometasone furoate caterol and darotropium), (indacaterol maleate and glycopy and its preparation are described in U.S. Pat. No. 4,472.393. rrolate); (indacaterol acetate and glycopyrrolate); Its use in the treatment of asthma is described in U.S. Pat. No. (indacaterol Xinafoate and glycopyrrolate); (indacaterol 5,889,015. Its use in the treatment of other respiratory dis maleate and GSK573719), (milveterol hydrochloride and eases is described in U.S. Pat. No. 5,889,015, U.S. Pat. No. glycopyrrolate), (milveterol hydrochloride and tiotropium 6,057,307, U.S. Pat. No. 6,057,581, U.S. Pat. No. 6,677,322, bromide), olodaterol hydrochloride and glycopyrrolate), U.S. Pat. No. 6,677,323 and U.S. Pat. No. 6,365,581. (olodaterol hydrochloride and tiotropium bromide), (salme 0109 Pharmaceutically acceptable esters, acetals, and terol xinafoate and tiotropium bromide), (vilanterol trifena salts of the above therapeutics are contemplated. The deter tate and darotropium), (vilanterol trifenatate and glycopyrro mination of the appropriate esters, acetals, or salt form is late), (vilanterol trifenatate and GSK573719), and (vilanterol driven by the duration of action and tolerability/safety data. trifenatate and tiotropium bromide); and a muscarinicantago As well, API selection may be important from the standpoint nist and a corticosteroid, for example (glycopyrrolate and of selecting therapeutics with the appropriate physical prop mometasone furoate), and (glycopyrrolate and ciclesonide); erties (e.g., solubility) to achieve the embodiments of the or a dual B-agonist-muscarinic antagonist and a corticoster present invention. oid, for example (GSK-961081 succinate and mometasone 0110 Suitable PAH drugs include Notch3 inhibitors, such furoate), (GSK-961081 succinate and mometasone furoate as DAPT, vasodilators, such as serelaxin and sodium nitrite; monohydrate), and (GSK-961081 succinate and ciclesonide). IP receptor agonists, such as selexipag; activators of soluble It should be noted that virtually any combinations are pos guanylate cyclase. Such as cinaciguat and riociguat; prosta sible, including combinations between actives described in cyclin receptor antagonists, such as epoprostenol, iloprost, parentheticals, and with others. treprostinil and beraprost; phosphodiesterase type 5 inhibi 0116. Some embodiments of the present invention com tors, such as Sildenafil and tadalafil; endothelin receptor prise spray-dried particles comprising three active agents antagonists, such as bosentan, ambrisentan and sitaxentan; (triple combinations). platelet derived growth factor receptor antagonists, such as 0117 Embodiments of the present invention comprise imatinib (Gleevec); and calcium channel blockers, such as triple combinations such as those that contain a f-agonist, a amlodipine, nifedipine and diltiazem. Suitable drugs to treat muscarinic antagonist and a corticosteroid, for example (sal IPF include TGF-Beta inhibitors, such as pirfenidone and meterol Xinafoate, fluticaSone propionate and tiotropium bro Interferon-gamma, low molecular weight heparin, and Ser mide), (indacaterol maleate, mometasone furoate and glyco elaxin. pyrrolate), (indacaterol acetate, mometasone furoate and 0111 Suitable drugs to treat CF include CFTR modula glycopyrrolate), (indacaterol Xinafoate, mometasone furoate tors, such as ivacaftor (VX-770), PTC-124, N-6022, VX-661 and glycopyrrolate), (vilanterol trifenatate, umeclidinium and VX-809; mucus alteration agents, such as Dornase alfa, bromide, and fluticasone furoate), (olodaterol hydrochloride, Sodium chloride and mannitol; and epthelial sodium channel tiotropium bromide, and mometasone furoate), (olodaterol inhibitors. hydrochloride and tiotropium bromide, and ciclesonide), and 0112 Useful antiinfectives include tobramycin, azithro (indacaterol acetate, tiotropium bromide, and mometaSone mycin, ciprofloxacin, levofloxacin, aztreonam, fosfomycin, furoate). Vancomycin, amikacin, gentamicin and amphotericin B. Respirable Agglomerates Fixed Dose Combinations 0118. In embodiments of the present invention, the bulk 0113. The dry powder composition, comprising respirable dry powder comprising respirable agglomerates is engi aggregates of the present invention can contain one, two, neered to be storage stable for extended periods of time, to three, four or more therapeutically active agents that are use readily and efficiently dispense from both passive and active, ful for treating diseases and/or conditions, such as lung dis single dose or multi-dose, dry powder inhalers, and to provide eases, obstructive or inflammatory airways diseases, particu efficacious delivery to the target region of the lung or pulmo larly asthma and COPD. nary system. 0114. Some embodiments of the present invention com 0119. In embodiments of the present invention, the bulk prise spray-dried particles comprising two active agents dry powder comprising respirable agglomerates is engi (double combinations). neered to reduce interagglomerate forces, such as by the 0115 Embodiments of the present invention comprise inclusion of pores or asperities in the Surface of the carrier combinations such as those that contain a 3-agonist and a particles, and/or by the enrichment of a hydrophobic excipi corticosteroid. Exemplary embodiments of combinations are ent at the surface of the carrier particles. shown by the parentheticals: (carmoterol and budesonide), I0120 In embodiments of the invention, the respirable (formoterol and beclomethasone), (formoterol fumarate and agglomerates of drug and carrier comprises a mass median budesonide), (formoterol fumarate dihydrate and mometa diameter (MMD) less than 10 microns, such as a MMD Sone furoate), (formoterol fumarate and ciclesonide), (inda between about 1 and 5 microns, with an exemplary embodi caterol maleate and mometasone furoate), (indacaterol ment having a MMD of about 2 to 3. In embodiments of the acetate and mometasone furoate), (indacaterol Xinafoate and invention the mass median aerodynamic (MMAD) diameter mometasone furoate), (milveterol hydrochloride and flutica of the powderagglomerate is between about 1 and 5 microns, sone), (olodaterol hydrochloride and fluticasone furoate), with an exemplary embodiment having a MMAD of about 2 (olodaterol hydrochloride and mometaSone furoate), (Salme to 4 microns. In embodiments of the invention, deposition of terol Xinafoate and fluticaSone propionate), (vilanterol trife the respirable agglomerates in the idealized Alberta mouth natate and fluticaSone furoate), and (vilanterol trifenatate and throat is less than 50%, such as less than 35% or deposition mometasone furoate); a B-agonist and a muscarinic antago less than 20%. Hence, embodiments of the invention provide nist, for example (formoterolandaclidinium bromide), (inda delivery of a respirable fraction of drug or drugs to the tar US 2014/0302147 A1 Oct. 9, 2014

geted regions of the lung of greater than about 40%. Such as erably within 15% or 10% for the various mono and combo greater than 50% or 60% or 70% or 80%. products. In some embodiments variation in the fine particle 0121. In embodiments of the present invention, the dry dose (stage 3 to filter) is within 15%, preferably within 10% powder comprising respirable agglomerates has a tapped or 5%. Additionally or alternatively, in some embodiments density of less than about 0.5 g/cm, such as less than 0.3 the variation in the very fine particle fraction (stage 4 to filter) g/cm or less than 0.1 g/cm. is within 15%, preferably within 10% or 5%. 0122 Embodiments of dry powder formulations of the I0133. The engineered powders of the present invention present invention may comprise 0.1% to 30% w/w of active provide excellent uniformity in the emitted dose or emitted ingredient(s), such as about 0.5% to 20% w/w, or 5% to 15% powder mass from measurement to measurement. In some wfw. embodiments, the variability is within the FDA Draft Guid 0123 Embodiments of the present invention are useful for ance which stipulates that 90% of the measurements should engineering particles comprising active ingredients with a be within a 20% deviation from the label claim with none low powder mass per dose, such as less than about 50 milli outside of 25%. In some embodiments 90% of the measure grams, or less than 15 or 5 or 2 or 1 milligrams per dose. ments are within a 15% deviation from the label claim, or 0.124. Embodiments of the present invention are useful for within 10% of the label claim. engineering respirable agglomerate particles comprising I0134. In one or more embodiments of the dry powder highly potent active ingredients with a nominal dose of active formulation comprising respirable agglomerates of the drug of about 100 nanograms (ng) to 5 mg. present invention, the dry powder formulation may addition 0.125 Embodiments of the present invention are useful for ally include additives such as those which may further engineering spray-dried particles comprising respirable enhance the stability, biocompatibility or patient acceptance agglomerates comprising one or more potent active ingredi of the formulation. For example, various salts, buffers, chela ents wherein the one or more active ingredients is character tors, bulking agents, common ions, glass forming excipients, ized by a limited solubility in the feedstock to be spray-dried, and taste masking agents are contemplated. Such optional and wherein the process and formulation maintains crystal agents may be incorporated in the bulk dry powder, or directly linity of the active in the resultant dried drug product. with the carrier particles. 0126. In some embodiments the respirable agglomerates I0135) In some embodiments, the dry powder formulation of the dry powder formulation of the invention suitably have of the present invention contains a pharmaceutically accept a rugosity of greater than 1.5, for example from 1.5 to 20, 3 to able excipient, for example a hydrophobic excipient. 15, or 5 to 10. 0127. In some embodiments the dry powder formulation Process comprising respirable agglomerates of the invention com 0.136. In some embodiments, the carrier particles are prise a fine particle fraction, expressed as a percentage of the formed in a process comprising the step of spray-drying an nominaldose <3.3 Lum (FPF-ss) ofgreater than about 40%, emulsion-based feedstock comprising Submicron droplets of such as greater than about 50%, or greater than about 60%. a perfluorinated liquid, stabilized by a monolayer of a long 0128. In some embodiments of the present invention the chain phospholipid and a multivalent metal ion, such as cal dry powder formulation comprising respirable agglomerates cium chloride. During spray-drying the slow diffusing emul of the invention comprise a fine particle fraction, expressed as sion droplets are concentrated at the receding Surface of the a percentage of the nominal dose less than 4.7 (i.e., FPF, evaporating atomized droplet. As the drying process contin im) of greater than about 50%. Such as greater than about ues and the continuous water phase evaporates, the phospho 60%, or greater than about 70%. lipid forms a skin on the surface of the particle. Eventually the 0129. In some embodiments of the present invention the perfluorinated liquid outgases leaving behind dry powder dry powder formulation comprising respirable agglomerates particles with a sponge-like particle morphology. The carrier of the invention comprise a fine particle fraction, expressed as powderparticles are often porous, and typically have a tapped a percentage of the nominal dose on stage 4 to filter (FPFs) density less than 0.5 g/cm, more often on the order of 0.1 of at least 40% of a nominal dose, such as greater than 50% or g/cm or less. The tapped density can be controlled via control 60% of a nominal dose. of the volume fraction of perfluorinated oil in the emulsion. 0130. In some embodiments of the dry powder formula The complex morphology of interconnected pores provides a tion of the invention comprising respirable agglomerates, unique template for fine micronized or nanonized drug crys lung deposition is at least 40-80% of the nominal dose. In tals to adhere and form an interlocking structure within the Some embodiments, inter-patient variability in lung deposi pores. tion is minimized, such as less than about 20% or 10%. 0.137 In some embodiments, the porous carrier particles 0131 Embodiments of dry powder formulations compris may be formed by a process comprising spray-drying a solu ing respirable agglomerates of the present invention provide tion comprising hydrophobic amino acids or peptides, such as for delivery of the respirable agglomerates from a passive dry leucine, or trileucine or polyols such as mannitol. For leucine powder inhaler in a manner which is substantially indepen and mannitol, the spray-drying process results in primarily dent of the patients peak inspiratory flow rate (PIF). crystalline excipient. Such carrier particles may be spray 0132 Embodiments of the present invention yield respi dried to have a corrugated, or rugous particle morphology. rable agglomerate particles exhibiting a good correlation in Combinations of leucine or trileucine with a carbohydrate the aerodynamic particle size distributions of an active agent (e.g., Sucrose, trehalose, mannitol) is also contemplated. In when it is formulated as a mono product, or in fixed dose this case the surface of the corrugated particles will be combinations with other active agents. The equivalence in the enriched in the hydrophobic amino acid. APSD is assessed by comparison of various stage groupings. 0.138. In some embodiments of the present invention the Embodiments of the present invention yield a variability in dry powder comprising respirable agglomerate particles are the large particle dose (stage 0 to stage 2) within 25%, pref made by a process which has as an initial step dispersing the US 2014/0302147 A1 Oct. 9, 2014

carrier particles in an anti-solvent, and then Subsequently 0144. Moreover, owing to the short timescales of the removing the liquid to create the dry powder agglomerates. spray-drying process (i.e., milliseconds), most drugs which Particularly preferred anti-solvents are perfluorinated liquids are dissolved in an aqueous or non-aqueous feedstock, will be (e.g., perfluorooctyl bromide, perfluorodecalin), or hydrof present as an amorphous Solid in the spray-dried drug prod luoroalkanes (e.g., perfluorooctyl ethane, HFA-134a, HFA uct. For Some drugs formulation as an amorphous Solid may 227ea). Owing to its large body of preclinical and clinical result in increased degradation that may be unacceptable on safety data, perfluorooctyl bromide (PFOB) is preferred. storage. Hence, in Some embodiments, the dry powder com 0.139. The solids loading of drug and carrier particles in prising respirable agglomerates, and process, of the present the anti-solvent is generally greater than about 50 g/L, often invention maintains the crystallinity of the drug Substance greater than 100 g/L or 150 g/L, and may be greater than 200 through the manufacturing process and during storage for an g/L or more. The solids loading will be dictated by the rheo extended period by preventing dissolution of drug(s) in the logical properties and stability of the liquid feedstock and the liquid to be spray-dried. density of carrier particles. The Suspension must be stable 0145 Alternatively, or additionally the respirable agglom enough and Sufficiently flowable in tubing so as to quantita erates may be formed in hydrofluoroalkane propellants under tively feed a uniform composition of material to the spray high pressure. The fluorocarbon may then be removed by drier over time. vaporization at lower pressure without the need for a dedi 0140. The ordered mixture of drug and carrier is formed in cated solvent removal step. the anti-solvent, as a result of the desire of the drug Substance to remove contact with the anti-solvent. This is analogous to Unit Dosage Forms how foods do not stick to the surface of a Teflon(R) frying pan. 0146 Embodiments of the present invention provide a unit 0141. The anti-solvent is then removed via a solvent dosage form, comprising a container containing a dry powder removal or drying process with spray-drying one of the pre formulation comprising the respirable agglomerates of the ferred solvent removal process embodiments. In embodi present invention. ments of the present invention, the liquid dispersion medium 0.147. In one embodiment, the present invention is directed has a vapor pressure/boiling point that enables effective to a unit dosage form, comprising a container containing a dry removal of the liquid during the applicable solvent removal powder formulation comprising respirable agglomerates (e.g., spray-drying) process. It is important that the drug or comprising about 0.5-3% w/windacaterol acetate, about 0.5- drugs have very low solubility in the anti-solvent. This aids in 3% w/w mometasone furoate, about 0.5-3% w/w glycopyr maintaining the crystallinity of the drug substance and pre ronium bromide, and about 91-99% small porous carrier par vention of the formation of amorphous material during spray ticles comprising about a 2:1 molar ratio of DSPC:CaCl. drying. In some embodiments, the drug or drugs comprise a 0.148. In one embodiment, the present invention is directed crystallinity of at least about 95%, such as 99%. In some to a unit dosage form, comprising a container containing a dry embodiments, the initial crystallinity of the drug is main powder formulation comprising respirable agglomerates tained during the manufacture of the respirable agglomerates. comprising about 0.5-3% w/w indacaterol acetate and about 0142. The presence of amorphous drug domains in crys 0.5-3%% w/w mometasone furoate, and about 94-99% small talline micronized drugs for inhalation is generally thought to porous carrier particles comprising a 2:1 molar ratio of be undesirable. Amorphous domains are thermodynamically DSPC:CaC1. unstable, and may convert to a stable crystalline polymorph 0149. In one embodiment, the present invention is directed over time. The recrystallization process often results in coars to a unit dosage form, comprising a container containing a dry ening of the micronized drug particles and decreased aerosol powder formulation comprising respirable agglomerates performance. The higher energy amorphous domains may comprising about 0.5-3% w/w indacaterol acetate and about also exhibit greater Solubility, more rapid dissolution, and 0.5-3% '% w/w glycopyrronium bromide, and about 94-99% decreased chemical stability as compared to the crystalline Small porous carrier particles comprising a 2:1 molar ratio of drug. Embodiments of the present invention minimize the DSPC:CaCl. formation of amorphous domains in the active ingredient 0150. Examples of containers include, but are not limited during spray-drying, by decreasing the percentage dissolved to, capsules, blisters, or container closure systems made of active ingredient in the liquid feedstock to be spray-dried. metal, polymer (e.g., plastic, elastomer), or the like. For cur Embodiments of the present invention minimize exposure of rent marketed asthma/COPD therapeutics, the fill mass in the the micronized drugs to water during the particle formation container may be in the range from about 0.5 mg to 10 mg. process, thus minimizing the possibility of any drug dissolv Such as in the range from 1 mg to 4 mg. In some embodiments, ing in aqueous media and Subsequently being dried in a less the powder comprising the respirable agglomerates is loaded stable amorphous state. into foil blisters. In some embodiments, the powder compris 0143. In some embodiments, the respirable agglomerates ing the respirable agglomerates is loaded into containers with comprise, for example, a carrier particle and indacaterol a fill mass of between about 0.5 and 10 mg, such as 1.0 mg to acetate. Indacaterol acetate exhibits poor physical stability in 4.0 mg. water, rapidly disproportionating to form indacaterol free base and acetic acid. As such, the drug Substance is not suit Delivery System able for spray-drying processes which involve processing the drug in water. Formulation of indacaterol acetate as a suspen 0151. The present invention also provides a delivery sys sion in an oil-in-water emulsion results in rapid dispropor tem, comprising an inhaler and a dry powder formulation of tionation of the drug during the spray-drying process. With the invention. the non-aqueous component of embodiments of the process 0152. In some embodiments, the present invention is of the present invention, the physical stability of the drug directed to a delivery system, comprising a dry powder Substance can be maintained. inhaler and a dry powder formulation comprising the respi US 2014/0302147 A1 Oct. 9, 2014

rable agglomerates for inhalation that comprises containing a 0159. In one or more embodiments, a method of treatment dry powder formulation comprising a dry powder formula comprises administering to a subject a dry powder formula tion comprising respirable agglomerates comprising about tion comprising respirable agglomerates comprising about 2.2% w/w indacaterol acetate, about 2.0% w/w mometasone 0.5-3% 96 w/w indacaterol acetate, about 0.5-3% w/w furoate, about 2.4% w/w glycopyrronium bromide, and about mometasone furoate, about 0.5-3% '% w/w glycopyrronium 93.4% Small porous carrier particles comprising a 2:1 molar bromide, and about 93.4% small porous carrierparticles com ratio of DSPC:CaCl. prising a 2:1 molar ratio of DSPC:CaCl. 0153 Suitable inhalers comprise dry powder inhalers (DP (0160. In one or more embodiments, a method of treatment Is). Some such inhalers include unit dose inhalers, where the comprises administering to a subject a dry powder formula dry powder is stored in a capsule or blister, and the patient tion comprising respirable agglomerates comprising about loads one or more of the capsules or blisters into the device 0.5-3% w/w indacaterol acetate and about 0.5-3% w/w prior to use. Other multi-dose dry powder inhalers include mometasone furoate, and about 94-99% small porous carrier those where the dose is pre-packaged in foil-foil blisters, for particles comprising a 2:1 molar ratio of DSPC:CaCl. example in a cartridge, strip or wheel. Other multi-dose dry 0.161. In one or more embodiments, a method of treatment powder inhalers include those where the bulk powder is pack comprises administering to a subject a dry powder formula aged in a reservoir in the device. tion comprising respirable agglomerates comprising about 0154 Embodiments of dry powder inhalers comprise 0.5-3% w/w indacaterol acetate and about 0.5-3% w/w gly multi-dose dry powder inhalers such as the DISKUSTM copyrronium bromide, and about 94-99% small porous car (GSK, described in U.S. Pat. No. 6,536,427), DIS rier particles comprising a 2:1 molar ratio of DSPC:CaCl. KHALERTM (GSK, described in WO 97/25086), GEMINITM 0162 The present invention also relates to the use of any (GSK, described in WO 05/14089), GYROHALERTM (Vec dry powder formulation herein in the manufacture of a medi tura, described in WO 05/37353), PROHALERTM (Valois, cament for the treatment of treating diseases or conditions of described in WO 03/77979) and TWISTHALERTM (Merck, a patientor Subject, Such as diseases or conditions of the lungs described in WO 93/00123, WO 94/14492 and WO and/or airways. 97/30743) inhalers. A reservoir type multi-dose inhaler is the 0163 The present invention also provides any dry powder TURBOHALERTM (AstraZeneca) as described in EP formulation herein comprising respirable agglomerates for 0258238 (Virtanen), CLICKHALER(R), and NOVOLIZER(R) use in the treatment of diseases or conditions of a patient or (Meda). Subject, Such as diseases or conditions of the lungs and/or O155 Embodiments of single dose dry powder inhalers airways. comprise the AEROLIZERTM (Novartis, described in U.S. 0.164 Treatment of a disease in accordance with embodi Pat. No. 3,991.761) and the device referred to sometimes ments of the invention may be symptomatic or prophylactic herein as CONCEPT1 or BREEZHALERTM (Novartis, treatment or both. Obstructive or inflammatory airways dis described in US Patent Application Publication 2007/ eases include asthma of various types or genesis including 0295332 (Ziegler et al.). Other suitable single-dose inhalers both intrinsic (non-allergic) asthma and extrinsic (allergic) include those described in U.S. Pat. Nos. 8,069,851 and asthma. Treatment of asthma is also to be understood as 7.559,325 both to Dunkley et al., and in US Patent Applica embracing treatment of subjects, e.g., of less than 4 or 5 years tion Publication 2010/01 08058 to Glusker et al. of age, exhibiting wheezing symptoms and diagnosed or 0156 Suitable active inhalers comprise pressurizable dry diagnosable as “wheezy infants, an established patient cat powder inhalers, as disclosed, for example in WO 96/09085, egory of major medical concern and now often identified as WO 00/072904, WO 00/021594 and WO 01/043530, and incipient or early-phase asthmatics. (For convenience this ASPIRAIRTM (Vectura) inhalers. Other active devices may particular asthmatic condition is referred to as “wheezy-in include those available from MicroDose Technologies Inc., fant syndrome'.) such as the device described in US Patent Application Publi 0.165 Prophylactic efficacy in the treatment of asthma can cation 2005/0183724, referred to sometimes herein as be evidenced by reduced frequency or severity of symptom “Genie’. atic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways Use in Therapy hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for 0157 Embodiments of the present invention comprise a or intended to restrict or abort symptomatic attack when it dry powder medicament formulation comprising respirable occurs, for example anti-inflammatory (e.g., corticosteroid) agglomerates comprising of two or more active ingredients or bronchodilatory. Prophylactic benefit in asthma may in that are useful for pulmonary administration, such as for particular be apparent in Subjects prone to “morning dip treating diseases of the lungs and/or airways. ping”. “Morning dipping is a recognised asthmatic Syn 0158 Embodiments of the present invention comprise a drome, common to a substantial percentage of asthmatics and method for treating diseases or conditions of a patient or characterised by asthma attack, e.g., between the hours of Subject, Such as diseases or conditions of the lungs and/or about 4 to 6am, i.e., at a time normally substantially different airways, the treatment which comprises administering to a from any previously administered symptomatic asthma patient (or Subject) having a disease or condition an effective therapy. amount of any dry powder formulation herein comprising 0166 Other obstructive or inflammatory airways diseases respirable agglomerates. Exemplary diseases or conditions and conditions include acute/adult respiratory distress Syn include obstructive or inflammatory airways disease, such as drome (ARDS), chronic obstructive pulmonary or airways obstructive pulmonary disease (COPD), asthma, idiopathic disease (COPD or COAD), including chronic bronchitis, or pulmonary fibrosis, bronchiectasis, and cystic fibrosis as well dyspnea associated therewith, emphysema, as well as exac as lung diseases such as pulmonary arterial hypertension. erbation of airways hyperreactivity consequent to other drug US 2014/0302147 A1 Oct. 9, 2014

therapy, in particular other inhaled drug therapy. Embodi with a high shear mixer. The drug crystals associate with the ments of a dry powder formulation comprising respirable Small porous carrier particles in the anti-solvent to form a agglomerates of the invention are also applicable to the treat Suspension comprising an ordered mixture. The resulting Sus ment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid pension is then dried in a second solvent removal step, such as bronchitis. Further obstructive or inflammatory airways dis by spray-drying. eases to which embodiments of the invention are applicable 0177. For some Examples, a laboratory scale process was include pneumoconiosis (an inflammatory, commonly occu pational, disease of the lungs, frequently accompanied by utilized, which made use of Novartis proprietary NSD scale airways obstruction, whether chronic or acute, and occa dryer (Lot #227-74-1 and #227-74-2). Accordingly, a suspen sioned by repeated inhalation of dusts) of whatever type or sion of 5.5% w/v PulmoSphere vehicle particles (comprised genesis, including, for example, aluminosis, anthracosis, of a 2:1 molar ratio of DSPC:CaCl, only) and 0.5% w/v asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis micronized indacaterol maleate were dispersed in PFOB. The and byssinosis. Also contemplated is bronchiectasis associ Suspension was mixed under high shear for 2-3 minutes with ated with cystic fibrosis, and non-CF bronchiectasis, pulmo nary arterial hypertension, and idiopathic pulmonary fibrosis. an IKAT-25 high shear mixer at 4,000 RPM. The resulting 0167 Embodiments of the dry powder formulation of the feedstock was spray dried on the NSD spray dryer at an inlet present invention comprising respirable agglomerates are temperature of 96° C., an outlet temperature of 83° C., an especially useful for treating asthma, COPD or both. atomization gas flow of 19 SLPM, a drying gas flow of 700 0168 Additional embodiments and features are set forth SLPM, and a feed rate of 10 mL/min. in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the 0178 The Niro PSD-1 Scale Process. specification or may be learned by the practice of the inven 0179 For some Examples, a suspension comprising Pul tion. moSphere carrier particles, comprised of a 2:1 molar ratio of 0169. This invention is further illustrated by the following DSPC:CaCl, only (10.0% w/v to 16.0% w/v), and one or examples which should not be construed as limiting. more micronized active pharmaceutical ingredients (0.5% KEY TO ABBREVIATIONS USED IN THE w/v to 7.3% w/v) was prepared in PFOB. The suspension was EXAMPLES mixed under high shear for 1-5 minutes with an IKAT-25 0170 The following abbreviations are used in the high shear mixer at 4,000 RPM (in one instance a IKAT-50 Examples: high shear mixer was employed at 3,000 RPM for 3 minutes). (0171 API Active Pharmaceutical Ingredient A second feedstock was prepared comprising a fluorocarbon (0172 DSPC Distearoylphosphatidylcholine in water emulsion. The two feedstocks were spray blended on (0173 PFOB Perfluorooctyl bromide a Niro PSD-1 scale spray dryer with an inlet temperature of 0.174 RSD Relative Standard Deviation 140°C., and outlet temperature of 72-75° C., an atomization (0175 RP-HPLC Reverse phase high performance liquid chromatography gas flow of 70 SLPM, a drying gas flow rate of 180-200 SLPM, a collectorjacket temperature of 70°C., a feed rate for EXAMPLES the PFOB-based feedstock of 14 to 31 g/min, and a feed rate for the emulsion-based feedstock of 47-90 g/min. Example 1 0180 Table 1 provides the compositions for the respirable Manufacture of Ordered Mixes Comprising Small agglomerate lots prepared in the two processes described Porous Particles and Micronized Drug above. In Table 1, the abbreviated description independently 0176 This Example illustrates embodiments for the pro describes the composition of the micronized crystalline drugs duction of respirable agglomerates comprising Small porous in square brackets and the carrier particles (in parentheses) particle carrier particles and one, two and three micronized in the final respirable agglomerate product. Note that empty drug particles wherein the process comprises two discrete parentheses denote a carrier particle as a PulmoSphere par drying steps. In a first step, a plurality of small porous carrier ticle without any active or additional adjuncts. For example, particles are produced by a method comprising spray-drying Lot #227-74-1 contains 7.8% w/w micronized indacaterol an emulsion-based feedstock to produce Small porous par maleate, with the balance being PulmoSphere vehicle par ticles with a foam-like morphology. In this embodiment, the ticles (DSPC/CaCl). Lot #11015A-6-7 contains 2.6% w/w carrier particles comprise a 2:1 molar ratio of distearoylphos micronized indacaterol maleate, 2.0% w/w micronized phatidylcholine to calcium chloride. Such particles are some mometasone furoate, with the Small porous carrier particles times referred to as PulmoSphereTM particles, and are comprising 2.6% w/w amorphous glycopyrronium bromide, described herein. The PulmoSphere particles may optionally 3.6% w/w sodium maleate buffer (pH 3.0), and 91.8% w/w contain buffer and/or active agent. In a second process step in DSPC/CaCl. Lot #11015A-7-6 is comprised of 2.2% w/w this embodiment, a Suspension of the Small porous (Pulmo indacaterol acetate, 2.0% w/w mometasone furoate, 1.5% SphereTM) particles (up to s20% w/v) is prepared in the W/w glycopyrronium bromide, with the Small porous carrier anti-solvent perfluorooctyl bromide (PFOB). Micronized particles comprising 2.3% w/w sodium maleate buffer (pH drug (up to s10% w/v) is then added to this suspension, 3.0) and 92.0% w/w DSPC/CaCl. Drug loadings given are forming a co-suspension. The co-suspension is then mixed for the entire salt. US 2014/0302147 A1 Oct. 9, 2014 14

TABLE 1. Compositions of respirable agglomerate lots Lotti Abbreviated Description Dryer 227-74-1 IQAB-AFA, so () NSD 227-74-2 |QAB-AKA7() NSD 1015A-6-7 IQAB-AFAl26. IMFloo. (NVA26, NaMaleate's go.) PSD-1 1015A-7-1 |MF2, () PSD-1 PSD-1 PSD-1 PSD-1 101SA-7-5 |QAB-AKAI-2, IMFlo (NaMaleates.) PSD-1 1015A-7-6 IQAB-AKA22. IMF.INVAliso (NaMaleate's.) PSD-1 PSD-1 101SA-1O-3 |QAB-AKA220MF2, INVAl2( ) PSD-1 1015A-10-4 IQAB-AKAI-20, IMF2, INVAl2(CaMalate's...) PSD-1 1015A-10-5 IQAB-AFAlso, IMFlo, INVAl2() PSD-1 1015A-10-6 IQAB-AFAlso, IMF2, INVAl2(CaMalate's...) PSD-1 Drug mass percentages are expressed as the whole saltsolvate form, Abbreviations: QAB-AFA (indacaterol maleate); QAB-AKA(indacaterolacetate); MF(mometasome furoate); MF*H2O (mometasome monohydrate); NVA (glycopyrronium bromide); NaMaleate (sodium maleate); Ca malate (calcium malate);

Example 2 TABLE 2 Mean drug contents for indacaterol acetate, mometaSone SEM Photomicrograph of Respirable Agglomerates furoate and glycopyrronium bromide in ordered mixes with Small porous particles 0181 Respirable agglomerates comprising indacaterol Mean Drug and mometaSone drug Substances were manufactured as Drug Content (Ig) RSD (%) described in Example 1 (Loti 11015A-6-7). FIG. 1 is an SEM 2% ww indacaterol 47.2 1.9 photomicrograph of the respirable agglomerates comprising acetate indacaterol and mometasone drug Substances with Small 2% ww mometasone 48.5 2.1 porous carrier particles. The crystals adhering to the porous furoate 1.5% w/w glycopyrronium 30.4 2.9 particles are clearly evident in the photomicrograph. No evi bromide dence of free crystals is observed. Bulk powder fill mass 2SOO 2.4 Example 3 Example 4 Content Uniformity of Respirable Agglomerates 0182 Respirable agglomerates comprising indacaterol Delivered Dose Uniformity of Respirable acetate, mometasone furoate, and glycopyrronium bromide Agglomerates drug Substances were manufactured as described in Example 1 (Loti 11015A-7-6). The bulk powder was filled into size 3 0185. The delivered dose uniformity of respirable hypromellose capsules using a proprietary drum-based filling agglomerates comprising indacaterol acetate, mometaSone furoate, glycopyrronium bromide crystals and Small porous machine. The target fill mass was 2.5 mg. This was achieved carrier particles (Lot 11015A-7-6) is presented in FIG.3. The with high accuracy and precision. The relative standard bulk powder was filled into size 3 hypromellose capsules. The deviation (RSD) for the filling process was 2.4%. capsules were then individually filled into a Concepti dry 0183 The drug content in the respirable agglomerates was powder inhaler (as described herein). The Concepti Inhaler is determined by RP-HPLC. The variability in mean content for a low resistance, capsule-based dry powder inhaler. The each of the three drugs is comparable to the variability in device was emptied at a flow rate of 60 L/min and an inhaled machine filling (Table 2). Moreover, there are no significant volume of 2 L onto a filter. The mass of each individual drug differences in content for capsules filled at the beginning, on the filter was quantitated by RP-HPLC. The total mass of middle, and end of the batch. This indicates that: (a) there was powder on the filter was also determined gravimetrically. a uniform Suspension of drug crystals and porous particles in 0186 The variability in the delivered dose is presented in the anti-solvent; (b) there was no segregation of drug from Table 3. The mean delivered dose and variability in delivered carrier in the powder batch resulting from the filling process, dose is comparable for the three drugs in the respirable as shown also by FIG.2. Drug contents given in Table 2 are for agglomerate. All of the components in the formulation pass the free drug. the FDA Draft Guidance on delivered dose uniformity which 0184 Hence, the suspension of particles in the anti-sol stipulates that 90% of the delivered dose values must be vent provides a novel method to achieve good mixing and within +20% of the nominal dose (or label claim), with none uniformity of micron-sized drug and carrierparticles in a bulk outside of 25%. Hence, excellent delivered dose uniformity is powder. observed for this complex triple combination product. US 2014/0302147 A1 Oct. 9, 2014

TABLE 3 TABLE 4 Delivered dose uniformity for respirable agglomerates Comparison of the aerodynamic particle size distributions for indacaterol comprising indacaterol acetate, mometaSone furoate, maleate formulations manufactured by three discrete processes glycopyrronium bromide and Small porous carrier particles delivered from the Concept1 dry powder inhaler Difference from MMAD FPFs, standard Indacaterol Mometasone Glycopyrronium Bulk Formulation (Lm) (% nominal) PulmoSphere acetate furoate bromide powder Lactose blend 2.8 26.2 -62.0% Mean delivered 83.5 84.8 82.1 91.0 (On Brez) dose Standard 2.8 68.9 (% nominal) PulmoSphere RSD 4.8 4.9 4.3 4.4 Respirable 3.3 60.6 -12.0% Agglomerate Lothi - 11015A-6-7 0187. The pattern in the variability for different capsules tested at the beginning, middle, and end of the filled batch (illustrated also in FIG.3), are consistent for each of the drugs and consistent with the gravimetric emitted powder mass Example 6 results across the batch. This provides additional strong evi dence that the drugs are strongly associated with the Small Comparison of the Aerodynamic Particle Size porous particle carrier, and remain so throughout the aero Distributions of Mometasone in Mono, Combo Solization process. (Double), and Triple (“Trombo') Formulations Example 5 (0190 FIG. 5 and Table 5 provide a comparison of the aerodynamic particle size distributions of respirable agglom Comparison of Aerodynamic Particle Size erate formulations comprising mometasone furoate as Distributions of Respirable Agglomerates with described in Example 1 delivered with the Conceptidry pow PulmoSpheres Particles and with Traditional Lactose der inhaler at a flow rate of 60 L/min. The three respirable Blend agglomerate formulations comprise the mono mometaSone 0188 A comparison of the aerodynamic particle size dis formulation (Lot #11015-7-1), its combination with inda tributions (APSD) of three formulations comprising inda caterol acetate (Lot #11015-7-4), and its triple combination caterol delivered with the Concepti single dose dry powder with indacaterol acetate and glycopyrronium bromide (Lot inhaler is presented in Table 4 and FIG. 4. The APSD were #11015-7-6). These three formulations have comparable determined on a Next Generation Impactorata flow rate of 60 aerosol performance, as indicated by the close agreement in L/min. The first formulation tested was the currently mar MMAD and FPF. The variation in FPF for the com keted lactose blend comprising indacaterol maleate (On bination products was within 5% of the value observed for the brezR), Novartis). The second formulation is a standard small mono formulation. Thus, the in-vitro performance is within porous particle formulation where the crystalline drug Sub the +15% required for equivalence between the three formu stance is coated with a porous matrix of phospholipid via lations, indicating that they pass the in vitro combination rule. spray drying an emulsion-based feedstock (PulmoSphereTM A comparison is also made with the marketed ASmaneXOR) technology). Finally, the third formulation comprised respi formulation (Merck) delivered with the Twisthaler R, at a flow rable agglomerates in accordance with embodiments of the rate of 60 L/min. The FPF for the respirable agglomerate present invention, the respirable agglomerates comprising formulations was more than 4-fold higher than that observed Small porous carrier particles and micronized indacaterol for Asmanex, despite the fact that the MMAD of Asmanex is acetate. The overall mass balance of the composition of the lower. This is a consequence of the bimodal versus unimodal spray-dried formulations is similar, comprising the inda particle size distribution for the lactose blend relative to the caterol drug substance and a 2:1 molar ratio of DSPC to respirable agglomerates of the present invention. calcium chloride. The MMAD of the respirable agglomerates is slightly larger than the standard porous particle formula TABLE 5 tion, yet the overall fine particle fraction, expressed as the Aerosol performance of respirable agglomerates comprising percentage of the nominal dose on stage 3 to filter in the NGI mometaSone furoate in comparison with the marketed remains very high, validating the usefulness of the formula ASmanex B drug product tion and process in being capable of efficaciously delivering multiple drug actives in fixed dose combinations. Difference (0189 These properties are further illustrated in FIG. 4 MMAD FPFs, from which is a comparison of the aerodynamic particle size dis Formulation (Lm) (% nominal) OO tributions for indacaterol maleate formulations manufactured Mono (Lot # - 11015A-7-1) 3.1 63.8 Combo (with indacaterol 3.0 62.5 -2.0% by the two prior art process and by an embodiment of the acetate) method and formulation of the present invention. Thus, com (Lot # - 11015A-7-5) position and process embodiments of the present invention Trombo (with indacaterol 2.9 66.9 +4.8% provide a respirable agglomerate fixed dose combination par acetate and glycopyrronium bromide ticle, wherein the respirable agglomerates comprise three (Lot # - 11015A-7-6) different actives (with varying aqueous solubilities) and the ASmanex (R) (Merck) 2.6 15.2 -76.2% respirable fraction (FPFs) remains high-comparable to that of a PulmoSphere particle. US 2014/0302147 A1 Oct. 9, 2014

Example 7 at a flow rate of 60 L/min, while the Genie device was oper ated at a flow rate of 36 L/min (4 kPa pressure drop). Preservation of the Physical Form of Indacaterol Acetate in Respirable Agglomerates TABLE 6 0191) When indacaterol acetate is suspended in an aque Aerosol performance of respirable agglomerates comprising ous feedstock to be spray-dried, the drug Substance rapidly a triple combination of indacaterol, glycopyrrolate, and disproportionates to form indacaterol free base and acetic nonetaSone in two inhaler devices: Concept1 and Genie acid. In the process of the present invention, an ordered mix FPF % (SD ture of micronized indacaterol acetate crystals and Small porous particles are created by Suspending the particles in a Lotti Device Indacaterol Glycopyrrolate Mometasone liquid perfluorocarbon, and then removing the liquid in a 11015A-10-4 Genie 91.5 (3) 62.0 (2) 90.9 (3) drying process. The physical form of the indacaterol acetate Concept1 76.7 (1) 48.4 (1) 74.3 (1) 11015a-10-5 Genie 66.3 (5) 53.6 (6) 69.9 (5) drug substance can be determined by X-ray powder diffrac Concept1 70.9 (4) 39.7 (3) 69.5 (3) tion (XRPD). FIG. 6 shows XRPD patterns for a series of SCOOO3 Genie 60.1 powders. FIG. 6 (top) shows the characteristic XRPD pattern (Indacaterol obtained for indacaterol free base, following disproportion PSph) ation of suspended indacaterol acetate in water. FIG. 6 SCOOO2 Genie 30.8 (middle) shows the XRPD pattern for indacaterol acetate (Indacaterol suspended in perfluorooctyl bromide (PFOB). This is identi LB) cal to the XRPD pattern found for indacaterol acetate drug substance (FIG. 6, bottom) showing that the salt form of the (0195. The differences in FPF sa, between indacaterol drug is maintained following dispersion in PFOB. and mometaSone relative to glycopyrrolate is reflective of the (0192 FIG. 7 shows XRPD patterns. The top curve shows differences in the size of the micronized drug crystals present the pattern for the indacaterol acetate drug Substance, while in the respirable agglomerates. For indacaterol and mometa the middle curve presents the XRPD pattern for respirable Sone the drug crystals are Small enough so that the aerody agglomerates of the present invention made according to namic properties of the respirable agglomerate are substan Example 1 —lot 227-74-2 of 7% w/windacaterolacetate with tially controlled by properties of the small porous carrier Small porous particles. The pattern is dominated by the char particles. The x50 and x90 for micronized indacaterolacetate acteristic phospholipid peak at 20–21. The bottom curve of crystals were 1.63 um and 3.08 um, respectively. The x50 and FIG. 7 represents the PulmoSphere (placebo) particles, and x90 for micronized mometasone furoate crystals were 1.22 also shows the characteristic phospholipid peak. In the um and 2.45 um, respectively. In contrast, the larger sized middle curve, the characteristic peaks associated with the salt crystals of glycopyrrolate utilized (x50=2.96 um, x90=6.52 form of indacaterol acetate are clearly evident, suggesting um) has an impact on the size of the respirable agglomerates that the physical form of the indacaterol acetate drug Sub comprising the glycopyrrolate crystals, and the correspond stance is preserved through the nonaqueous manufacturing ing FPF-su. It is worth noting that the FPF-s, is signifi process. Peaks characteristic of indacaterol free base are not cantly larger for the respirable agglomerates than is observed present. Similar results demonstrating the maintenance of the for traditional lactose blends, by a factor of 2-fold to 3-fold. physical form of the indacaterol acetate drug Substance were obtained with near infrared diffuse reflectance spectroscopy. Example 9 Hence, the formation of respirable agglomerates via the non aqueous manufacturing process presented herein provides a means to protect drugs that may be physically or chemically Comparative Example of Dry Blending of unstable in aqueous media from degradation. Micronized Drugs and Small Porous Particles 0196. As noted herein the strong cohesion between fine Example 8 drug particles results in difficulties with dry blending fine particles in the respirable size range. To further contrast the Aerosol Performance of Respirable Agglomerates in features, advantages and aspects of embodiments of the Concept1 and Genie Dry Powder Inhalers manufacturing process of the present invention (compared, for example, with Example 3), simple blends of micronized 0193 In this Example, the performance of a dry powder mometasone furoate crystals with Small porous carrier par comprising a triple-combination of respirable agglomerates ticles were made on a Turbula R mixer. A Turbula mixer is a made in accordance with Example 1 (Lot is 11015A-10-3, standard mixer utilized to make blends of coarse lactose with 11015A-10-4 and 11015A-10-5) were tested in a two differ micronized drug particles. Following mixing on the Turbula, ent dry powder inhaler devices: Genie, an active, multi-dose, the bulk powder was sampled and the variability in content blister-based device, and Concept 1, a passive, unit dose, was assessed via RP-HPLC (Table 7). Poor accuracy and capsule-based device. The Genie device utilizes a piezoelec precision were observed for mometaSone contents of less tric element to actively fluidize and disperse the dry powder. than 10% w/w, with measured RSD values between 21% and The results are shown in Table 6. Also shown for comparative 38%. This example illustrates the difficulty encountered in purposes are the results for a conventional PulmoSphere for forming stable, respirable blends of dry powders in the (size mulation of indacaterol maleate, and a lactose blend formu range from 1-5 microns) using standard powder mixing meth lation of indacaterol maleate. ods, and points to the utility of the anti-solvent evaporation 0194 The fine particle dose less than 5um was determined method for forming the ordered mixture respirable agglom by a drug specific HPLC method. The Concepti was operated erates of embodiments of the present invention. US 2014/0302147 A1 Oct. 9, 2014

TABLE 7 0.03 to 0.5 g/cm, a MMAD of about 1 to 5 microns, and a FPF, Lin of at least 50%. Variability in content observed for micronized 14. The dry powderpharmaceutical composition of claim 1 mometaSone furoate blended with Small porous carrier particles in a Turbula & mixer characterized by particles comprising: a porous carrier particle comprising a MMD of 1 to 5 Content % (w.fw) microns; MF Detected by HPLC a first species of active agent particles comprising glyco MF Ave (% w/w) Stdew % RSD pyrrolate, including any pharmaceutically acceptable 2 2.67 O.64 24.0 salts, esters, isomers or Solvates thereof, wherein at least 3.4 3.70 0.79 21.2 50% of the first active agent particles have a geometric 5.2 5.32 1.91 35.8 diameter of 0.01-3 microns; 7.4 7.24 2.74 37.9 a second species of active agent particles comprising inda 11.5 11.86 1.55 13.1 16.7 1842 1.90 10.3 caterol, including any pharmaceutically acceptable salts, esters, isomers or Solvates thereof, wherein at least 50% of the first active agent particles have a geometric 1. A pharmaceutical composition for pulmonary delivery, diameter of 0.01-3 microns; the composition comprising a dry powder comprising a plu a third species of active agent particles comprising rality of small porous carrier particles and a plurality of active mometasone including any pharmaceutically acceptable agent particles and wherein the Small porous carrier particles salts, esters, isomers or Solvates thereof, wherein at least and the active agent particles form an ordered mixture of 50% of the first active agent particles have a geometric respirable agglomerates. diameter of 0.01-3 microns; 2. (canceled) wherein each of the first, second and third active agent 3. The pharmaceutical composition of claim 1 wherein the particles adhere to the carrier particle to forman ordered plurality of active agent particles comprise two different mixture of respirable agglomerate particles, and actives. wherein the composition is characterized by a tapped 4. The pharmaceutical composition of claim 1 wherein the density of 0.03 to 0.5 g/cm, and a FPF <4.7 un of at least plurality of active agent particles comprise three different about 50%. actives. 15. The dry powder formulation of claim 14 wherein the 5. The pharmaceutical composition of claim 4 wherein the respirable agglomerates comprise three different actives comprise beta-adrenoceptor agonist, (i) about 91-99% small porous carrier particles comprising anticholinergic, and corticosteroid. a 2:1 molar ratio of DSPC:CaCl; and 6. (canceled) 7. The pharmaceutical composition of claim 1 wherein the (ii) the active species comprise about 0.5-3% w/w inda dry powder is characterized by a tap density of 0.03 to 0.5 caterol acetate, about 0.5-3% w/w mometasone furoate, g/cm, the small porous carrier particles comprise an MMD and about 0.5-3% w/w glycopyrronium bromide. of about 1-5 microns, and the active agent particles comprise 16. (canceled) an MMD of less than about 3 microns. 17. An inhalation unit dosage form comprising 8. The pharmaceutical composition of claim 1 wherein the a receptacle; and dry powder is characterized by a fine particle fraction, a dry powder composition contained within the receptacle, expressed as a percentage of the nominal dose <3.3 um the dry powder composition deliverable from a passive (FPF-ss) of greater than about 40%. dry powder inhaler, the dry powder composition com 9. The pharmaceutical composition of claim 1 wherein the prising particles comprising: dry powder is characterized by a fine particle fraction, a small porous carrier particle comprising a MMD of about expressed as a percentage of the nominal dose less than 4.7 1 to 5 microns and a tapped density of less than about 0.5 um (i.e. FPF-47) of greater than about 50%. g/cm; 10. The pharmaceutical composition of claim 1 wherein a first species of active agent particles comprising glyco the dry powder is characterized by a fine particle fraction, pyrrolate, including any pharmaceutically acceptable expressed as a percentage of the nominal dose on stage 4 to salts, esters, isomers or Solvates thereof, wherein at least filter (FPF) of at least 40% of a nominal dose. 50% of the first active agent particles have a geometric 11. The pharmaceutical composition of claim 1 wherein diameter of less than 3 microns; the dry powder is characterized by a lung deposition of at least a second species of active agent particles comprising inda 40% of a nominal dose. caterol, including any pharmaceutically acceptable 12. The pharmaceutical composition of claim 1 wherein salts, esters, isomers or Solvates thereof, wherein at least the dry powder is characterized by delivery from a passive dry 50% of the first active agent particles have a geometric powder inhaler Substantially independently of a peak inspira diameter of less than 3 microns; tory flow rate. a third species of active agent particles comprising 13. The pharmaceutical composition of claim 1 wherein: mometasone including any pharmaceutically acceptable the plurality of Small porous carrier particles have a geo salts, esters, isomers or Solvates thereof, wherein at least metric diameter of 2-3 microns, and consist essentially 50% of the first active agent particles have a geometric of distearoylphosphatidylcholine and calcium chloride: diameter of less than 3 microns; at least 50% of the active agent particles have a geomet wherein each of the first, second and third active agent ric diameter of less than 3 microns; and the dry powder particles and the Small porous carrier particles form an is characterized by one or more of a tapped density of ordered mixture of respirable agglomerates, and US 2014/0302147 A1 Oct. 9, 2014

wherein the composition is characterized by a tapped ized drug particles, wherein the respirable agglomerate density of 0.03 to 0.5 g/cm and an FPF, of at least particles are characterized by a tapped density of 0.03 to about 50%. 0.5 g/cm, and a FPF, of at least about 50%. 18. A process for making a dry powder formulation of 19. The process of claim 18 wherein the hydrophobic respirable agglomerate particles, the process comprising the excipient comprises DSPC and calcium chloride. steps of: 20. The process of claim 19 wherein the first active com (a) preparing a first feedstock comprising a hydrophobic prises a beta adrenoreceptor agonist, and the second active excipient dispersed in an aqueous liquid phase and comprises an anti-inflammatory. spray-drying said first feedstock to provide a bulk pow 21. The process of claim 20 wherein the beta adrenorecep der composition comprising a plurality of Small porous toragonist comprises indacaterol, and the anti-inflammatory powder carrier particles; comprises mometasone. (b) providing at least a first active drug ingredient to having 22. The process of claim 21 and further including a third a size of at least 50% having a geometric diameterofless active. than 3 microns; 23. The process of claim 22 wherein the third active com (c) preparing a second feedstock comprising a suspension prises a glycopyrrolate. of the carrier particles of step (a) and the drug particles of step (b) in a non-aqueous anti-solvent; and 24. A method of treating a patient comprising administer (d) Subjecting the second feedstock to a solvent removal ing, via an inhaler, to a patient in need of treatment a dry process to yield a bulk powder formulation comprising powder formulation according to claim 1. an ordered mixture of respirable aggregate particles 25. (canceled) comprising Small porous carrier particles and micron