Inhalable microparticles comprising a phospholipid and an antibody or antibody fragment

Abstract

Disclosed herein are compositions comprising a plurality of particles, which include dry powder compositions, and unit dose packages, blister packages, and dry powder inhaler devices comprising the dry powder compositions, methods of treating certain disorders, such as respiratory diseases, using the dry powder compositions, and methods of making the dry powder compositions.

Description

INHALABLE MICROPARTICLES COMPRISING A PHOSPHOLIPID ANDAN ANTIBODY OR ANTIBODY FRAGMENTCROSS-REFERENCE WITH RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 612,888, filed on December 20, 2024, which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein.TECHNOLOGICAL FIELD

[0002] Provided herein are compositions comprising a plurality of particles, including dry powder compositions, unit dose packages, blister packages, and dry powder inhaler devices, and methods of using such compositions in treating respiratory disease. Also provided are methods of making such compositions, including spray drying methods incorporating secondary drying.BACKGROUND

[0003] Over the past decade, several monoclonal antibodies have been tested in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Although many antibody-based therapeutics, including antibodies for treating respiratory diseases, are administered systemically via injection, this administration route requires relatively high drug doses and may lead to off-target side effects. Targeted delivery of antibody-based therapeutics via inhalation is an attractive alternative for the treatment of respiratory diseases (Anderson et al., Pharmacol Rev, Vol. 74(1), pp. 50-118 (2022); Parray et al., Appl Microbiol Biotechnol, Vol. 105, pp. 6315-6332 (2021)). Specifically, pulmonary delivery has the potential to improve bioavailability, reduce adverse effects, and increase local drug concentration at the disease site without increasing the cost of goods associated with the therapeutic.

[0004] Nebulizers and dry powder inhalers are commonly used delivery vehicles for inhalable therapeutics. However, nebulization is associated with relatively high costs, poor reproducibility, extended administration time, and low delivery efficiency (Liang et al., Pharmaceutics, Vol. 12(11), Article 1025, pp. 1-30 (2020); Bodier-Montagutelli et al., Expert Opin. Drug Deliv., Vol. 15(8), pp. 729-736 (2018)). Moreover, nebulization of liquid antibody formulations can result in antibody instability (Mayor et al., Drug DelivTransl Res, Vol. 11(4), pp. 1625-1633 (2021)) and aggregation-induced cytotoxicity (Secher et al., Pharmaceutics, Vol. 14(3), Article 671, pp. 1-19 (2022)). While dry powder inhalers may overcome some of the limitations associated with nebulizers for targeted lung delivery of antibody -based therapeutics (Berkenfeld et al., AAPS PharmSciTech Vol. 16(3), pp. 479-490 (2015)), sugar- and sugar alcohol-based excipients, such as sucrose, trehalose, and mannitol, are commonly used in antibody-containing dry powder formulations, where these excipients may serve as cryoprotectants, aid in aerosol performance and dispersion, and improve stability by altering glass transition temperature (Schiile et al., Eur J Pharm Biopharm, Vol. 69(3), pp. 793-807 (2008); Ferrati et al., AAPS PharmSciTech, Vol. 19(7), pp. 2755-2766 (2018); Liao et al., Eur J Pharm Biopharm, Vol. 58(1), pp. 15-24 (2004); Chang & Pikal, J Pharm Sci, Vol. 98(9), pp. 2886-2908 (2009)). Despite these beneficial attributes, sugar- and sugar alcohol-based excipients can be hygroscopic due to their relatively low glass transition temperatures, which may affect the storage stability of the dry powder by rendering it sensitive to the plasticizing effects of residual water and limit its shelf life (Tonnis et al., Mol Pharm, Vol. 12(3), pp. 684-694 (2015); Lechanteur & Evrard, Pharmaceutics, Vol. 12(1), Article 55, pp. 1-21 (2020)).

[0005] Accordingly, there is a need in the art for alternative dry powder formulations for antibody-based therapeutics, including high drug load formulations, that do not contain sugars or sugar alcohols as excipients.SUMMARY

[0006] Provided herein are antibody- or antibody fragment-containing dry powder compositions that can be formulated without using carbohydrate excipients such as sugars and sugar alcohols. These high drug load compositions exhibit aerosolization and stability properties compatible with use in dry powder inhalers and may be useful for pulmonary delivery of biologies. Dry powder compositions, which may alternatively be referred to as powder compositions or compositions, of the present disclosure may contain up to 10% w / w residual solvent (e.g., water or organic solvent used in the preparation of the composition).

[0007] Some embodiments of the present disclosure are directed to a dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises:(a) an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the dry powder composition. For each of components(a), (b), (c), (d), and (e), the % w / w refers to the weight of the component as a percentage of the weight of the entire dry powder composition.

[0008] Some embodiments of the present disclosure are directed to a dry powder composition comprising a plurality of particles, wherein a particle in the plurality of particles, one or more particles in the plurality of particles, a majority of particles in the plurality of particles, substantially all of the particles in the plurality of particles, or all of the particles in the plurality of particles comprises:(a) an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the particle or particles. For each of components (a), (b),(c), (d), and (e), the % w / w refers to the weight of the component as a percentage of the weight of the particle(s).

[0009] In some embodiments, the average concentration of the antibody or antibody fragment is in the range of 50% w / w to 80% w / w of the particles in the plurality of particles. In some embodiments, the average concentration of the phospholipid is in the range of 10% w / w to less than 50% w / w of the particles in the plurality of particles. In some embodiments, the average concentration of the polyvalent cation is in the range of greater than 0% w / w to 10% w / w of the particles in the plurality of particles. In some embodiments, the average concentration of the non-ionic surfactant is in the range of greater than 0% w / w to 10% w / w of the particles in the plurality of particles.

[0010] Some embodiments of the present disclosure are directed to a dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w of the dry powder composition. Some embodiments of the present disclosure are directed to a dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w of the dry powder composition. Some embodiments of the present disclosure are directed to a dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w of the dry powder composition. Some embodiments of the present disclosure are directed to a dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w of the dry powder composition. Some embodiments of the present disclosure are directed to a dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises a buffering agent.

[0011] These dry powder compositions, which may be spray-dried compositions, can be used for targeted lung delivery of a bioactive antibody or antibody fragment. Illustratively, in some embodiments, a dry powder composition disclosed herein is deliverable to a subject at an emitted fraction of at least 60% (such as, e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%) in a dry powder inhaler.

[0012] In some embodiments, none of the plurality of particles comprises a carbohydrate excipient (e.g., a carbohydrate that is not covalently associated with the antibody or antibody fragment) selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.

[0013] In some embodiments, the dry powder composition does not comprise a carbohydrate excipient. In some embodiments, the dry powder composition does not comprise a carbohydrate excipient selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.

[0014] In some embodiments, none of the plurality of particles comprises a carbohydrate excipient (e.g., a carbohydrate that is not covalently associated with the antibody or antibody fragment). Illustratively, in some embodiments, none of the plurality of particles comprises a sugar or sugar alcohol excipient. However, the particles can comprise a glycosylated antibody or antibody fragment.

[0015] In some embodiments, the total concentration of the components of (a), (b), (c), (d), and (e) within the dry powder composition is in the range of 80% w / w to 100% w / w (such as, e.g., in the range of 80% w / w to 95% w / w; in the range of 80% w / w to 90% w / w; in the range of 85% w / w to 100% w / w; in the range of 85% w / w to 95% w / w; in the range of 85% w / w to 90% w / w; 81% w / w, 82% w / w, 83% w / w, 84% w / w, 85% w / w, 86% w / w, 87% w / w, 88% w / w, 89% w / w, 90% w / w, 91% w / w, 92% w / w, 93% w / w, 95% w / w).

[0016] In some embodiments, the dry powder composition comprises an antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgGl, IgG2, or IgG4 antibody. Antibodies included in the dry powder compositions described herein can be glycosylated; such glycosylated antibodies are not considered carbohydrate excipients.

[0017] In some embodiments, the dry powder composition comprises an antibody fragment. In some embodiments, the dry powder composition comprises an antibody fragment of an IgG antibody. In some embodiments, the dry powder composition comprisesan antibody fragment of an IgGl, IgG2, or IgG4 antibody. These antibody fragments can be glycosylated and are not considered carbohydrate excipients.

[0018] In some embodiments, the dry powder composition does not comprise an IgA antibody, or a fragment thereof. In some embodiments, the dry powder composition does not comprise an IgD antibody, or a fragment thereof. In some embodiments, the dry powder composition does not comprise an IgM antibody, or a fragment thereof. In some embodiments, the dry powder composition does not comprise an IgE antibody, or a fragment thereof. In some embodiments, the dry powder composition does not comprise an IgG antibody, or a fragment thereof.

[0019] In some embodiments, the antibody or the antibody fragment is present at a concentration in the range of 70% w / w to 80% w / w of the particle(s) or the dry powder composition (such as, e.g., in the range of 72% w / w to 76% w / w; 70% w / w; 71% w / w; 72% w / w; 73% w / w; 74% w / w; 75% w / w; 76% w / w; 77% w / w; 78% w / w; 79% w / w; 80% w / w).

[0020] In some embodiments, the phospholipid is a saturated phospholipid, such as, e.g., a saturated phosphatidylcholine. In some embodiments, the phospholipid is selected from phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, and combinations of any of the foregoing. In some embodiments, the phospholipid is selected from distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), l,2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), l,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), l-palmitoyl-2-oleoyl-sn-glycero- 3 -phosphoglycerol (POPG), and combinations of any of the foregoing. In some embodiments, the phospholipid is selected from DPPC, DSPC, and combinations thereof. In some embodiments, the phospholipid is DSPC. In some embodiments, the phospholipid is DPPC.

[0021] In some embodiments, the phospholipid is not a phospholipid selected from phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, and combinations of any of the foregoing. In some embodiments, the phospholipid is not a phospholipid selected from distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), l,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), and combinations of any of the foregoing.

[0022] In some embodiments, the phospholipid is present at a concentration in the range of 10% w / w to 20% w / w of the particle(s) or the dry powder composition (such as, e.g., in the range of 14% w / w to 18% w / w; 10% w / w; 11% w / w; 12% w / w; 13% w / w; 14% w / w; 15% w / w; 16% w / w; 17% w / w; 18% w / w; 19% w / w; 20% w / w).

[0023] In some embodiments, the polyvalent cation is a divalent cation. In some embodiments, the polyvalent cation comprises calcium (Ca2+), magnesium (Mg2+), zinc (Zn2+), iron (Fe2+), or combinations of any of the foregoing. In some embodiments, the polyvalent cation is a cation selected from the group consisting of calcium (Ca2+), magnesium (Mg2+), zinc (Zn2+), iron (Fe2+), and combinations of any of the foregoing. In some embodiments, the polyvalent cation comprises calcium. In some embodiments, the polyvalent cation is calcium chloride.

[0024] In some embodiments, the polyvalent cation is not a divalent cation. In some embodiments, the polyvalent cation does not comprise calcium, magnesium, zinc, iron, or combinations of any of the foregoing. In some embodiments, the polyvalent cation does not comprise calcium. In some embodiments, the polyvalent cation is not calcium chloride.

[0025] In some embodiments, the polyvalent cation is present at a concentration in the range of 5% w / w to 10% w / w of the particle(s) or the dry powder composition (such as, e.g., 6% w / w to 9% w / w; 5% w / w; 6% w / w; 7% w / w; 8% w / w; 9% w / w; 10% w / w).

[0026] In some embodiments, the non-ionic surfactant is selected from poloxamers and sorbitan fatty acid esters (such as, e.g., polyoxyethylene sorbitan fatty acid esters). In some embodiments, the non-ionic surfactant is selected from polysorbate 20, polysorbate 80, poloxamer-188, and poloxamer-407. In some embodiments, the non-ionic surfactant is poloxamer-188.

[0027] In some embodiments, the non-ionic surfactant is not a non-ionic surfactant selected from poloxamers and sorbitan fatty acid esters (such as, e.g., polyoxyethylene sorbitan fatty acid esters). In some embodiments, the non-ionic surfactant is not a non-ionic surfactant selected from polysorbate 20, polysorbate 80, poloxamer-188, and poloxamer-407.

[0028] In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 1.5% w / w of the particle(s) or the dry powder composition (such as, e.g., 0.5% w / w; 0.6% w / w; 0.7% w / w; 0.8% w / w; 0.9% w / w; 1% w / w; 1.1% w / w; 1.2% w / w; 1.3% w / w; 1.4% w / w; 1.5% w / w).

[0029] In some embodiments, the buffering agent is selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing. In some embodiments, the buffering agent is selected from phosphoric acid, glutamic acid, acetic acid, citric acid, succinic acid, tartaric acid, histidine, and combinations of any of the foregoing. In some embodiments, the buffering agent is selected from a phosphate salt, a glutamate salt, an acetate salt, a citrate salt, a succinate salt, a tartrate salt, a histidine salt, and combinations of any of the foregoing. In some embodiments, the buffering agent is selected from phosphoric acid and / or a phosphate salt, glutamic acid and / or a glutamate salt, acetic acid and / or a acetate salt, citric acid and / or a citrate salt, succinic acid and / or a succinate salt, tartaric acid and / or a tartrate salt, histidine and / or a histidine salt, and combinations of any of the foregoing. In some embodiments, the buffering agent comprises histidine.

[0030] In some embodiments, the buffering agent is not a buffering agent selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing.

[0031] In some embodiments, the buffering agent is present at a concentration of less than 2% w / w of the particle(s) or the dry powder composition.

[0032] In some embodiments, a dry powder composition comprises:(a) the antibody or the antibody fragment present at a concentration in the range of 70% w / w to 80% w / w;(b) the phospholipid present at a concentration in the range of 10% w / w to 20% w / w;(c) the polyvalent cation present at a concentration in the range of 5% w / w to 10% w / w;(d) the non-ionic surfactant present at a concentration in the range of 0.5% w / w to 1.5% w / w; and(e) the buffering agent present at a concentration of less than 2% w / w.

[0033] In some embodiments, the dry powder composition comprises the antibody or the antibody fragment present at a concentration in the range of 70% w / w to 80% w / w. In some embodiments, the dry powder composition comprises the phospholipid present at a concentration in the range of 10% w / w to 20% w / w. In some embodiments, the dry powder composition comprises the polyvalent cation present at a concentration in the range of 5% w / w to 10% w / w. In some embodiments, the dry powder composition comprises the nonionic surfactant present at a concentration in the range of 0.5% w / w to 1.5% w / w. In some embodiments, the dry powder composition comprises the buffering agent present at a concentration of less than 2% w / w.

[0034] In some embodiments, the dry powder composition comprises:(a) the antibody or the antibody fragment present at a concentration in the range of 72% w / w to 76% w / w;(b) the phospholipid present at a concentration in the range of 14% w / w to 18% w / w;(c) the polyvalent cation present at a concentration in the range of 6% w / w to 9% w / w;(d) the non-ionic surfactant present at a concentration in the range of 0.5% w / w to 1.5% w / w; and(e) the buffering agent present at a concentration of less than 2% w / w.

[0035] In some embodiments, the dry powder composition comprises the antibody or the antibody fragment present at a concentration in the range of 72% w / w to 76% w / w. In some embodiments, the dry powder composition comprises the phospholipid present at a concentration in the range of 14% w / w to 18% w / w. In some embodiments, the dry powder composition comprises the polyvalent cation present at a concentration in the range of 6% w / w to 9% w / w. In some embodiments, the dry powder composition comprises the non- ionic surfactant present at a concentration in the range of 0.5% w / w to 1.5% w / w. In some embodiments, the dry powder composition comprises the buffering agent present at a concentration of less than 2% w / w.

[0036] In some embodiments, the dry powder composition comprises:(a) the antibody or the antibody fragment present at a concentration in the range of 70% w / w to 80% w / w;(b) a saturated phosphatidylcholine (such as, e.g., distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), and combinations of any of the foregoing) present at a concentration in the range of 10% w / w to 20% w / w;(c) calcium chloride present at a concentration in the range of 5% w / w to 10% w / w;(d) a poloxamer (such as, e.g., poloxamer- 188) present at a concentration in the range of 0.5% w / w to 1.5% w / w; and(e) histidine / histidine salt present at a concentration of less than 2% w / w.

[0037] In some embodiments, the dry powder composition comprises the antibody or the antibody fragment present at a concentration in the range of 70% w / w to 80% w / w. In some embodiments, the dry powder composition comprises a saturated phosphatidylcholine (such as, e.g., distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), 1 ,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and combinations of any of the foregoing) present at a concentration in the range of 10% w / w to 20% w / w. In some embodiments, the dry powder composition comprises calcium chloride present at a concentration in the range of 5% w / w to 10% w / w. In some embodiments, the dry powder composition comprises a poloxamer (such as, e.g., poloxamer- 188) present at a concentration in the range of 0.5% w / w to 1.5% w / w. In some embodiments, the dry powder composition comprises histidine / histidine salt present at a concentration of less than 2% w / w.

[0038] In some embodiments, the saturated phosphatidylcholine is DSPC.

[0039] In some embodiments, the dry powder composition comprises:(a) the antibody or the antibody fragment present at a concentration in the range of 72% w / w to 76% w / w;(b) a saturated phosphatidylcholine (such as, e.g., distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and combinations of any of the foregoing) present at a concentration in the range of 14% w / w to 18% w / w;(c) calcium chloride present at a concentration in the range of 6% w / w to 9% w / w;(d) a poloxamer (such as, e.g., poloxamer- 188) present at a concentration in the range of 0.5% w / w to 1.5% w / w; and(e) histidine / histidine salt present at a concentration of less than 2% w / w.

[0040] In some embodiments, the dry powder composition comprises the antibody or the antibody fragment present at a concentration in the range of 72% w / w to 76% w / w. In some embodiments, the dry powder composition comprises a saturated phosphatidylcholine (such as, e.g., distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), 1 ,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and combinations of any of the foregoing) present at a concentration in the range of 14% w / w to 18% w / w. In some embodiments, the dry powder composition comprises calcium chloride present at a concentration in the range of 6% w / w to 9% w / w. In some embodiments, the dry powder composition comprises a poloxamer (such as, e.g., poloxamer- 188) present at a concentration in the range of 0.5% w / w to 1.5% w / w. In some embodiments, the dry powder composition comprises histidine / histidine salt present at a concentration of less than 2% w / w.

[0041] In some embodiments, the saturated phosphatidylcholine is DSPC.

[0042] Dry powder compositions of the present disclosure can include residual solvent (such as, e.g., water or residual blowing agent) from a production process. For example, in some embodiments, a residual solvent content of a dry powder composition disclosed herein can be less than or equal to 5% w / w (e.g., less than or equal to 4.5% w / w; less than or equal to 4% w / w; less than or equal to 3.5% w / w; less than or equal to 3% w / w; less than or equal to 2.5% w / w; less than or equal to 2% w / w; less than or equal to 1.5% w / w; less than or equal to 1% w / w).

[0043] In some embodiments, a water content of a dry powder composition disclosed herein can be less than or equal to 5% w / w (e.g., less than or equal to 4.5% w / w; less than or equal to 4% w / w; less than or equal to 3.5% w / w; less than or equal to 3% w / w; less than or equal to 2.5% w / w; less than or equal to 2% w / w; less than or equal to 1.5% w / w; less than or equal to 1% w / w).

[0044] In some embodiments, a residual blowing agent content of a dry powder composition disclosed herein can be less than or equal to 2% w / w (e.g., less than or equal to 1.75% w / w; less than or equal to 1.5% w / w; less than or equal to 1.25% w / w; less than or equal to 1% w / w). In some embodiments, the residual blowing agent is a fluorinated blowing agent, such as, e.g., perfluorohexane, perfluorooctyl bromide, perfluorodecalin, perfluorotripropylamine, dichlorofluorooctane, or perfluorooctyl ethane.

[0045] In some embodiments, a dry powder composition of the present disclosure further comprises (f) water and (g) a blowing agent (e.g., a fluorinated blowing agent, such as, e.g., perfluorohexane, perfluorooctyl bromide, perfluorodecalin, perfluorotripropylamine, dichlorofluorooctane, or perfluorooctyl ethane). In some embodiments, the total concentration of the components of (a), (b), (c), (d), (e), (f), and (g) is 100% w / w (i.e., the dry powder composition consists of (a) the antibody or antibody fragment, (b) the phospholipid, (c) the polyvalent cation, (d) the non-ionic surfactant, (e) the buffering agent, (f) water, and (g) the blowing agent).

[0046] In some embodiments, a majority of the plurality of particles exhibit a substantially spherical morphology. In some embodiments, a majority of the plurality of particles exhibit a surface rough, porous morphology. In some embodiments, a majority of the plurality of particles exhibit a substantially spherical morphology and a surface rough, porous morphology.

[0047] In some embodiments, the plurality of particles has an X90 in the range of 2.5 pm to 4 pm, such as, e.g., an X90 in the range of 2.5 pm to 3.5 pm or an X90 in the range of 3 pm to 4 pm.

[0048] In some embodiments, the plurality of particles has an X50 of less than 2 pm, such as, e.g., an X50 in the range of 1 pm to 1.5 pm.

[0049] In some embodiments, the plurality of particles has an X10 of less than 1 pm, such as, e.g., an X10 in the range of 0.5 pm to 0.9 pm.

[0050] In some embodiments, the plurality of particles has an X90 in the range of 2.5 pm to 4 pm, an X50 of less than 2 pm, and an X10 of less than 1 pm. In some embodiments, the plurality of particles has an X90 in the range of 2.5 pm to 3.5 pm, an X50 in the range of 1 pm to 1.5 pm, and an X10 in the range of 0.5 pm to 0.9 pm. In some embodiments, the plurality of particles has an X90 in the range of 3 pm to 4 pm, an X50 in the range of 1 pm to 1.5 pm, and an X10 in the range of 0.5 pm to 0.9 pm.

[0051] In some embodiments, the dry powder composition has a fine particle fraction (FPF) of greater than or equal to 40% (such as, e.g., a FPF in the range of 40% to 90% or 60% to 90%).

[0052] In some embodiments, a tapped density of the dry powder composition is in the range of 0.1 g / cm3to 0.2 g / cm3, such as, e.g., in the range of 0.125 g / cm3to 0.175 g / cm3.

[0053] In some embodiments, a bulk density of the dry powder composition is less than or equal to 0.1 g / cm3, such as, e.g., a bulk density of the dry powder composition is in the range of 0.05 g / cm3to 0.1 g / cm3.

[0054] In some embodiments, the dry powder composition has a tapped density in the range of 0.1 g / cm3to 0.2 g / cm3, such as, e.g., in the range of 0.125 g / cm3to 0.175 g / cm3, and a bulk density of less than or equal to 0.1 g / cm3, such as, e.g., a bulk density in the range of 0.05 g / cm3to 0.1 g / cm3. In some embodiments, the dry powder composition has a tapped density in the range of 0.125 g / cm3to 0.175 g / cm3and a bulk density in the range of 0.05 g / cm3to 0.1 g / cm3.

[0055] In some embodiments, the dry powder composition has a FPF of greater than or equal to 40%, a bulk density of less than or equal to 0.1 g / cm3, and a tapped density in the range of 0.1 g / cm3to 0.2 g / cm3. In some embodiments, the dry powder composition has a FPF in the range of 60% to 90%, a bulk density in the range of 0.05 g / cm3to 0.1 g / cm3, and a tapped density in the range of 0.125 g / cm3to 0.175 g / cm3.

[0056] In some embodiments, the dry powder compositions disclosed herein are stable compositions. A stable composition may be a composition that does not denature or decompose under standard conditions. A stable composition may be a composition where at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%,64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, 100% (or any range derivable therein) of the composition is unchanged after at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (or any range derivable therein), or more days, weeks, months, or years, including when stored under standard conditions. Standard conditions may include ambient temperature, humidity, and pressure. Standard conditions may include a temperature of at least, at most, about, or approximately 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11 °C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C,28°C, 29°C, or 30°C (or any range derivable therein). In some embodiments, a stable composition is a composition that is physically and / or chemically stable at room temperature, which may be approximately 25 °C and / or approximately 60% relative humidity.

[0057] Additionally, some embodiments of the present disclosure are directed to a unit dose package comprising a reservoir containing a unit dose of a dry particle composition disclosed herein. The reservoir can be a receptacle designed to hold fluid. In some embodiments, the reservoir is a capsule (include a size 0, 1, 2, 3, 4, or 5 capsule) or a blister strip. In some embodiments, the unit dose package is insertable into a dry powder inhaler.

[0058] Some embodiments of the present disclosure are directed to a dry powder inhaler device comprising a dry powder composition disclosed herein. The dry powder inhaler devices can further comprise a means for introducing the dry powder composition into a subject via inhalation, such as, e.g., a mechanism that crushes a unit dose package or a portion of a blister package to disperse the dry powder composition into the dosing chamber of the dry powder inhaler.

[0059] Some embodiments of the present disclosure are directed to methods of treating a respiratory disease in a subject in need thereof, comprising administering a dry powder composition disclosed herein to the subject via inhalation, for example, using a dry powder inhaler device disclosed herein. In some embodiments, the respiratory disease is selected from chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, bronchiectasis, pulmonary arterial hypertension, and cystic fibrosis. In some embodiments, the respiratory disease is asthma.

[0060] Some embodiments of the present disclosure are directed to methods of preparing a dry powder composition described herein. For example, in some embodiments, the present disclosure provides preparation methods comprising preparing an emulsion comprising a blowing agent, an antibody or an antibody fragment, a phospholipid, a polyvalent cation, a non-ionic surfactant, and a buffering agent; spray drying the emulsion using a spray dryer to produce a dry powder composition described herein; isolating the dry powder composition; and optionally employing a secondary drying process post-spray drying. The optional secondary drying process can be, for example, a vacuum drying process performed in a lyophilizer, a water-assisted vacuum drying process, or a methanol-assisted vacuum drying process.

[0061] In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 24 hours (e.g., at least 48 hours) at a temperature in the range of 30 °C to 50 °C (e.g., 35 °C to 45 °C) and a pressure in the range of 40 mBar to 60 mBar (e.g., 40 mBar to 50 mBar). In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 6 hours (e.g., at least 12 hours) at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 80 mBar to 120 mBar (e.g., 90 mBar to 110 mBar).

[0062] Additionally, in some embodiments, the secondary drying process can reduce residual solvent (e.g., residual blowing agent and water) levels in the dry powder composition. In some embodiments, a residual solvent content of the dry powder composition following the secondary drying process is less than or equal to 10% w / w (such as, e.g., less than 7% w / w; less than 5% w / w; less than 4% w / w; less than 3% w / w; less than 2% w / w; 7% w / w, 6.5% w / w, 6%, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, 1% w / w). For example, in some embodiments, the residual blowing agent content following the secondary drying process is less than or equal to 5% w / w (such as, e.g., less than 4% w / w; less than 3% w / w; less than 2% w / w; 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, 1% w / w). Additionally, in some embodiments, the water content following the secondary drying process is less than or equal to 2% w / w (such as, e.g., less than 1% w / w; 2% w / w, 1.5% w / w, 1% w / w, 0.5% w / w).

[0063] In some embodiments, the emulsion comprising the blowing agent, the antibody or antibody fragment, the phospholipid, the polyvalent cation, the non-ionic surfactant, and the buffering agent can be prepared by first preparing a lipid emulsion comprising the blowing agent, the phospholipid, and water and preparing a buffered solution comprising the antibody or the antibody fragment, the polyvalent cation, the non-ionic surfactant, and the buffering agent, and then combining the lipid emulsion and the buffered solution to obtain the emulsion to be spray dried. Illustratively, in some embodiments, the lipid emulsion can be prepared by homogenizing the blowing agent, the phospholipid, and water using a homogenizer with a Y-shaped interaction chamber (e.g., a microfluidizer) at a pressure in the range of 15,000 psi to 20,000 psi (e.g., 18,000 psi).

[0064] In some embodiments, the blowing agent, the phospholipid, and water can be homogenized using a mechanical mixer to produce a coarse lipid emulsion and the coarse lipid emulsion can be homogenized using the microfluidizer or homogenizer to produce thelipid emulsion. In some embodiments, the phospholipid can be homogenized in water using a mechanical mixer, and the blowing agent can be added during mechanical mixer operation. In some embodiments, the blowing agent can be added dropwise during mechanical mixer operation.

[0065] The spray drying process can be performed under a variety of conditions so long as the conditions do not lead to denaturation of the antibody or antibody fragment. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 150 °C (e.g., 85 °C to 95 °C). In some embodiments, the outlet temperature of the spray dryer is set at a temperature of less than 80 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 150 °C (e.g., 85 °C to 95 °C), and the outlet temperature of the spray dryer is set at a temperature of less than 80 °C. In some embodiments, a flow rate of the emulsion during spray drying is in the range of 1 mL / min to 10 mL / min (e.g., 4 mL / min to 7 mL / min) and / or a nitrogen flow during spray drying is in the range of 25 mm to 75 mm (e.g., 35 mm to 65 mm).

[0066] In alternative aspects of the present disclosure, a recombinant protein may be used in place of an antibody or an antibody fragment in a composition, unit dose package, blister package, dry powder inhaler device, or method described herein (i.e., references to an antibody or an antibody fragment may be replaced by references to a recombinant protein). Illustratively, in some alternative aspects, the present disclosure provides a dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises:(a) a recombinant protein present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent,wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the dry powder composition. For each of components(a), (b), (c), (d), and (e), the % w / w refers to the weight of the component as a percentage of the weight of the entire dry powder composition.

[0067] Example embodiments of the present disclosure include, but are not limited to, the following:El. A dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises:(a) an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the dry powder composition. For each of components (a), (b), (c), (d), and (e), the % w / w refers to the weight of the component as a percentage of the weight of the entire dry powder composition.E2. A dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises:(a) an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent,wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the dry powder composition; and further wherein none of the plurality of particles comprises a carbohydrate excipient selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol. For each of components (a), (b), (c), (d), and (e), the % w / w refers to the weight of the component as a percentage of the weight of the entire dry powder composition.E3. A dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises:(a) an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the dry powder composition; and further wherein none of the plurality of particles comprises a carbohydrate excipient. For each of components (a), (b), (c), (d), and (e), the % w / w refers to the weight of the component as a percentage of the weight of the entire dry powder composition.E4. The dry powder composition of El, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is in the range of 80% w / w to 100% w / w.E5. The dry powder composition of El, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is in the range of 90% w / w to 100% w / w.E6. The dry powder composition of El, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is in the range of 95% w / w to 100% w / w.E7. The dry powder composition of any one of E1-E6, wherein:(a) the antibody or the antibody fragment is present at a concentration in the range of 70% w / w to 80% w / w;(b) the phospholipid is present at a concentration in the range of 10% w / w to 20% w / w;(c) the polyvalent cation is present at a concentration in the range of 5% w / w to 10% w / w;(d) the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 1.5% w / w; and(e) the buffering agent is present at a concentration of less than 2% w / w.E8. The dry powder composition of any one of E1-E7, wherein:(a) the antibody or the antibody fragment is present at a concentration in the range of 72% w / w to 76% w / w;(b) the phospholipid is present at a concentration in the range of 14% w / w to 18% w / w;(c) the polyvalent cation is present at a concentration in the range of 6% w / w to 9% w / w;(d) the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 1.5% w / w; and(e) the buffering agent is present at a concentration of less than 2% w / w.E9. The dry powder composition of any one of E1-E8, wherein the antibody or the antibody fragment is an antibody.E10. The dry powder composition of E9, wherein the antibody is an IgG antibody.El l. The dry powder composition of E9 or E10, wherein the antibody is an IgGl antibody.E12. The dry powder composition of any one of E9-E11, wherein the antibody is an IgG2 antibody.E13. The dry powder composition of any one of E9-E12, wherein the antibody is an IgG4 antibody.E14. The dry powder composition of any one of E1-E8, wherein the antibody or the antibody fragment is an antibody fragment.E15. The dry powder composition of any one of E1-E14, wherein the phospholipid is a saturated phospholipid.E16. The dry powder composition of any one of E1-E14, wherein the phospholipid is selected from phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, and combinations of any of the foregoing.E17. The dry powder composition of any one of E1-E16, wherein the phospholipid is a saturated phosphatidylcholine.E18. The dry powder composition of any one of E1-E14, wherein the phospholipid is selected from distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero- 3 -phosphoethanolamine (DPPE), l,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), and combinations of any of the foregoing.E19. The dry powder composition of any one of E1-E14, wherein the phospholipid is selected from DPPC, DSPC, and combinations thereof.E20. The dry powder composition of any one of E1-E14, wherein the phospholipid is DPPC.E21. The dry powder composition of any one of E1-E14, wherein the phospholipid is DSPC.E22. The dry powder composition of any one of E1-E21, wherein the polyvalent cation is a divalent cation.E23. The dry powder composition of any one of E1-E22, wherein the polyvalent cation comprises calcium, magnesium, zinc, iron, or combinations of any of the foregoing.E24. The dry powder composition of any one of E1-E23, wherein the polyvalent cation is calcium chloride.E25. The dry powder composition of any one of E1-E24, wherein the non-ionic surfactant is selected from poloxamers and sorbitan fatty acid esters.E26. The dry powder composition of any one of E1-E25, wherein the non-ionic surfactant is selected from polyoxyethylene sorbitan fatty acid esters.E27. The dry powder composition of E26, wherein the non-ionic surfactant is polysorbate 20 or polysorbate 80.E28. The dry powder composition of any one of E1-E24, wherein the non-ionic surfactant is selected from poloxamers.E29. The dry powder composition of E28, wherein the non-ionic surfactant is selected from poloxamer-188, poloxamer-407, and poloxamer-338.E30. The dry powder composition of E28 or E29, wherein the non-ionic surfactant is poloxamer-188.E31. The dry powder composition of any one of E1-E30, wherein the buffering agent is selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing.E32. The dry powder composition of any one of E1-E31, wherein the buffering agent is selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing.E33. The dry powder composition of any one of E1-E32, wherein the buffering agent comprises histidine.E34. The dry powder composition of any one of E1-E33, wherein a water content of the dry powder composition is less than or equal to 5% w / w.E35. The dry powder composition of any one of E1-E34, wherein a water content of the dry powder composition is less than or equal to 2% w / w.E36. The dry powder composition of any one of E1-E35, wherein a blowing agent content of the dry powder composition is less than or equal to 5% w / w.E37. The dry powder composition of any one of E1-E36, wherein a blowing agent content of the dry powder composition is less than or equal to 2% w / w.E38. The dry powder composition of any one of E1-E37, wherein a blowing agent content of the dry powder composition is less than or equal to 1% w / w.E39. The dry powder composition of any one of E36-E38, wherein the blowing agent is a fluorinated blowing agent.E40. The dry powder composition of any one of E36-E39, wherein the blowing agent is selected from perfluorohexane, perfluorooctyl bromide, perfluorodecalin, perfluorotripropylamine, dichlorofluorooctane, and perfluorooctyl ethane.E41. The dry powder composition of any one of E36-E40, wherein the blowing agent is perfluorooctyl bromide.E42. The dry powder composition of any one of E1-E41, wherein a majority of the plurality of particles exhibit a substantially spherical morphology.E43. The dry powder composition of any one of E1-E42, wherein a majority of the plurality of particles exhibit a surface rough, porous morphology.E44. The dry powder composition of any one of E1-E43, wherein the plurality of particles has an X90 in the range of 2.5 pm to 4 pm.E45. The dry powder composition of any one of E1-E44, wherein the plurality of particles has an X90 in the range of 2.5 pm to 3.5 pm.E46. The dry powder composition of any one of E1-E44, wherein the plurality of particles has an X90 in the range of 3 pm to 4 pm.E47. The dry powder composition of any one of E1-E46, wherein the plurality of particles has an X50 of less than 2 pm.E48. The dry powder composition of any one of E1-E47, wherein the plurality of particles has an X50 in the range of 1 pm to less than 2 pm.E49. The dry powder composition of any one of E1-E48, wherein the plurality of particles has an X50 in the range of 1 pm to 1.5 pm.E50. The dry powder composition of any one of E1-E49, wherein the plurality of particles has an X10 of less than 1 pm.E51. The dry powder composition of any one of E1-E50, wherein the plurality of particles has an X10 in the range of 0.5 pm to 0.9 pm.E52. The dry powder composition of any one of E1-E51, wherein the dry powder composition has a fine particle fraction (FPF) of greater than or equal to 40%.E53. The dry powder composition of any one of E1-E52, wherein the dry powder composition has a fine particle fraction (FPF) is in the range of 40% to 90%.E54. The dry powder composition of any one of E1-E53, wherein the dry powder composition has a fine particle fraction (FPF) is in the range of 60% to 90%.E55. The dry powder composition of any one of E1-E54, wherein a tapped density of the dry powder composition is in the range of 0.1 g / cm3to 0.2 g / cm3.E56. The dry powder composition of any one of E1-E55, wherein a tapped density of the dry powder composition is in the range of 0.125 g / cm3to 0.175 g / cm3.E57. The dry powder composition of any one of E1-E56, wherein a bulk density of the dry powder composition is less than or equal to 0.1 g / cm3.E58. The dry powder composition of any one of E1-E57, wherein a bulk density of the dry powder composition is in the range of 0.05 g / cm3to 0.1 g / cm3.E59. The dry powder composition of any one of E1-E58, wherein a glass transition temperature of the dry powder composition is in the range of 40 °C to 80 °C.E60. The dry powder composition of any one of E1-E59, wherein the dry powder composition is suitable for pulmonary delivery.E61. The dry powder composition of any one of E1-E60, wherein the dry powder composition is deliverable at an emitted fraction of at least 60% in a dry powder inhaler.E62. The dry powder composition of any one of E1-E61, wherein the dry powder composition is deliverable at an emitted fraction in the range of 60% to 95% in a dry powder inhaler.E63. A unit dose package comprising a reservoir containing a unit dose of the dry particle composition of any one of E1-E62.E64. The unit dose package of E63, wherein the unit dose package is insertable into a dry powder inhaler.E65. A dry powder inhaler device comprising the dry powder composition of any one of El-E62.E66. A method of treating a respiratory disease in a subject in need thereof, comprising administering the dry powder composition of any one of E1-E62 to the subject via inhalation.E67. The method of E66, wherein the respiratory disease is selected from chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, bronchiectasis, pulmonary arterial hypertension, and cystic fibrosis.E68. A method of delivering an antibody or an antibody fragment to the pulmonary system of a subject, comprising administering the dry powder composition of any one of E1-E62 to the subject via inhalation.E69. A method for preparing a dry powder composition, comprising: preparing an emulsion comprising a blowing agent, an antibody or an antibody fragment, a phospholipid, a polyvalent cation, a non-ionic surfactant, and a buffering agent; spray drying the emulsion using a spray dryer to produce a dry powder composition of any one of E1-E62; and isolating the dry powder composition.E70. A method for preparing a dry powder composition, comprising: preparing an emulsion comprising a blowing agent, an antibody or an antibody fragment, a phospholipid, a polyvalent cation, a non-ionic surfactant, and a buffering agent; spray drying the emulsion using a spray dryer to produce a dry powder composition; and isolating the dry powder composition, wherein the isolated dry powder composition comprises a plurality of particles in which:(a) the antibody or the antibody fragment is present at a concentration in the range of 50% w / w to 80% w / w;(b) the phospholipid is present at a concentration in the range of 10% w / w to less than 50% w / w;(c) the polyvalent cation is present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) the non-ionic surfactant is present at a concentration in the range of greater than 0% w / w to 10% w / w, and(e) the buffering agent is present at a concentration of less than 5% w / w, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the dry powder composition; and further wherein none of the plurality of particles comprises a carbohydrate excipient selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.E71. The method of E69 or E70, wherein preparing an emulsion comprises: preparing a lipid emulsion comprising the blowing agent, the phospholipid, and water; preparing a buffered solution comprising the antibody or the antibody fragment, the polyvalent cation, the non-ionic surfactant, and the buffering agent; and combining the lipid emulsion and the buffered solution to obtain the emulsion.E72. The method of E71, wherein preparing the lipid emulsion comprises homogenizing the blowing agent, the phospholipid, and water using a microfluidizer.E73. The method of E71 or E72, wherein preparing the lipid emulsion comprises homogenizing the blowing agent, the phospholipid, and water using a microfluidizer at a pressure in the range of 15,000 psi to 20,000 psi.E74. The method of E71, wherein preparing the lipid emulsion comprises homogenizing the blowing agent, the phospholipid, and water using a homogenizer with a Y-shaped interaction chamber.E75. The method of E71 or E74, wherein preparing the lipid emulsion comprises homogenizing the blowing agent, the phospholipid, and water using a homogenizer with a Y-shaped interaction chamber at a pressure in the range of 15,000 psi to 20,000 psi.E76. The method of any one of E69-E75, wherein the blowing agent is a fluorinated blowing agent.E77. The method of any one of E69-E76, wherein the blowing agent is selected from perfluorohexane, perfluorooctyl bromide, perfluorodecalin, perfluorotripropylamine, dichlorofluorooctane, and perfluorooctyl ethane.E78. The method of any one of E69-E77, wherein the blowing agent is perfluorooctyl bromide.E79. The method of any one of E69-E78, wherein the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 150 °C.E80. The method of any one of E69-E79, wherein the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 95 °C.E81. The method of any one of E69-E80, wherein the outlet temperature of the spray dryer is set at a temperature of less than 80 °C.E82. The method of any one of E69-E81 , wherein a flow rate of the emulsion during spray drying is in the range of 1 mL / min to 10 mL / min.E83. The method of any one of E69-E82, wherein a flow rate of the emulsion during spray drying is in the range of 4 mL / min to 7 mL / min.E84. The method of any one of E69-E83, wherein a nitrogen flow during spray drying is in the range of 25 mm to 75 mm.E85. The method of any one of E69-E84, wherein a nitrogen flow during spray drying is in the range of 35 mm to 65 mm.E86. The method of any one of E69-E85, wherein a nitrogen flow during spray drying is 65 mm.E87. The method of any one of E69-E86, wherein the spray drying is followed by a secondary drying process.E88. The method of E87, wherein the secondary drying process is vacuum drying.E89. The method of E87 or E88, wherein the secondary drying process is water- assisted vacuum drying.E90. The method of E87 or E88, wherein the secondary drying process is methanol- assisted vacuum drying.E91. The method of E87 or E88, wherein the secondary drying process comprises vacuum drying the dry powder composition for at least 24 hours at a temperature in the range of 30 °C to 50 °C and a pressure in the range of 40 mBar to 60 mBar.E92. The method of E87 or E88, wherein the secondary drying process comprises vacuum drying the dry powder composition for at least 48 hours at a temperature in the range of 35 °C to 45 °C and a pressure in the range of 40 mBar to 50 mBar.E93. The method of E87 or E88, wherein the secondary drying process comprises vacuum drying the dry powder composition for at least 6 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 80 mBar to 120 mBar.E94. The method of E87 or E88, wherein the secondary drying process comprises vacuum drying the dry powder composition for at least 12 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 90 mBar to 110 mBar.E95. The method of any one of E87-E94, wherein a water content of the dry powder composition following the secondary drying process is less than or equal to 2% w / w.E96. The method of any one of E87-E95, wherein a blowing agent content of the dry powder composition following the secondary drying process is less than or equal to 5% w / w.E97. The method of any one of E87-E96, wherein a blowing agent content of the dry powder composition following the secondary drying process is less than or equal to 2% w / w.E98. The method of any one of E87-E97, wherein a blowing agent content of the dry powder composition following the secondary drying process is less than or equal to 1% w / w.E99. A dry powder composition prepared by the method of any one of E69-E98.E100. A dry powder composition comprising:(a) an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w; and further wherein the composition does not comprise a carbohydrate excipient.E101. The dry powder composition of E100, wherein the carbohydrate excipient is selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.E102. A method for preparing a dry powder composition, comprising: preparing an emulsion comprising a blowing agent, an antibody or an antibody fragment, a phospholipid, a polyvalent cation, a non-ionic surfactant, and a buffering agent; spray drying the emulsion using a spray dryer to produce a dry powder composition; and isolating the dry powder composition, wherein the isolated dry powder composition comprises:(a) the antibody or the antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) the phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) the polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) the non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w, and(e) the buffering agent present at a concentration of less than 5% w / w, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w; and further wherein the isolated dry powder composition does not comprise a carbohydrate excipient.El 03. The method of El 02, wherein the carbohydrate excipient is selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol.E104. A dry powder composition prepared by the method of E102 or E103.E105. The dry powder composition, unit dose package, dry powder inhaler device, or method of any one of E1-E101, wherein reference to the antibody or the antibody fragment is replaced by reference to a recombinant protein.BRIEF DESCRIPTION OF THE DRAWINGS

[0068] FIG. 1 provides a schematic representation of the study described in Section 1 of the Examples.

[0069] FIG. 2 shows a schematic representation of certain example steps involved in a preparation method for porous microparticles of the present disclosure.

[0070] FIG. 3 shows the aerosol performance, as assessed by fine particle fraction, for eleven formulations tested in Section 1 of the Examples.

[0071] FIGs. 4A-4F are scanning electron microscopy (SEM) photomicrographs for Formulation 4 (FIG. 4A), Formulation 10 (FIG. 4B), Formulation 12 (FIG. 4C), a spray- dried IgG antibody (FIG. 4D), a spray-dried IgG antibody and poloxamer-188 mixture (FIG. 4E), and a vacuum-dried IgG antibody (FIG. 4F), which are further described in Section 1 of the Examples.

[0072] FIG. 5 shows focus ion beam SEM photomicrographs for Formulation 4 (F4), Formulation 10 (F10), and Formulation 12 (F12) as described in Section 1 of the Examples. The photomicrographs show the internal substructure of the spray-dried formulations.

[0073] FIGs. 6A-6F depict the geometric particle size distributions for six formulations (F4 (FIG. 6A); F10 (FIG. 6B); F12 (FIG. 6C); PP (FIG. 6D); PS (FIG. 6E); and VP (FIG. 6F)) tested in Section 1 of the Examples, where the formulations were dispersed at a pressure of 1 bar or 3 bar.

[0074] FIGs. 7A-7F depict the geometric particle size distributions for six formulations (F4 (FIG. 7A); F10 (FIG. 7B); F12 (FIG. 7C); PP (FIG. 7D); PS (FIG. 7E); and VP (FIG. 7F)) tested in Section 1 of the Examples at baseline, after storage at 4 °C for one month, after storage at 40 °C / 75% RH for one month, and after storage at 25 °C / 60% RH for one month and dispersing at 3 bar.

[0075] FIG. 8 shows x-ray powder diffraction (XRPD) diffractograms for six formulations (F4, F10, F12, PP, PS, and VP) tested in Section 1 of the Examples at baseline, after storage at 4 °C for one month, after storage at 40 °C / 75% RH for one month, and after storage at 25 °C / 60% RH for one month.

[0076] FIG. 9 shows differential scanning calorimetry (DSC) thermograms of six formulations (F4, F10, F12, PP, PS, and VP) tested in Section 1 of the Examples at baseline,after storage at 4 °C for one month, after storage at 40 °C / 75% RH for one month, and after storage at 25 °C / 60% RH for one month.

[0077] FIG. 10 shows the residual water content as measured by Karl Fischer (KF) titration for six formulations (F4, F10, F12, PP, PS, and VP) tested in Section 1 of the Examples at baseline, after storage at 4 °C for one month, after storage at 40 °C / 75% RH for one month, and after storage at 25 °C / 60% RH for one month.

[0078] FIGs. 11A-11F depict dynamic vapor sorption isotherms for six formulations (F4 (FIG. 11A), F10 (FIG. 11B), F12 (FIG. 11C), PP (FIG. 11D), PS (FIG. HE), and VP (FIG. HF)) tested in Section 1 of the Examples at baseline (top left), after storage at 4 °C for one month (top right), after storage at 25 °C / 60% RH for one month (bottom left), and after storage at 40 °C / 75% RH (bottom right) for one month.

[0079] FIG. 12A shows the aerosol performance, as assessed by percentage nominal dose, of six formulations (F4, F10, F12, PP, PS, and VP) tested in Section 1 of the Examples at baseline using a high resistance Plastiape™ device under a 4 kPa pressure drop.

[0080] FIG. 12B shows the aerosol performance, as assessed by percentage nominal dose, of six formulations (F4, F10, F12, PP, PS, and VP) tested in Section 1 of the Examples at baseline using a high resistance Plastiape™ device under a 1 kPa pressure drop.

[0081] FIG. 13A provides a comparison of the aerosol performance, as assessed by emitted fraction, of six formulations (F4, F10, F12, PP, PS, and VP) tested in Section 1 of the Examples at baseline using a high resistance Plastiape™ device under a 1 kPa vs. a 4 kPa pressure drop.

[0082] FIG. 13B provides a comparison of the aerosol performance, as assessed by respirable fraction (less than 5 pm), of six formulations (F4, F10, F12, PP, PS, and VP) tested in Section 1 of the Examples at baseline using a high resistance Plastiape™ device under a 1 kPa vs. a 4 kPa pressure drop.

[0083] FIGs. 14A-14F depict the aerosol performance, as assessed by percentage nominal dose, of six formulations (F4 (FIG. 14A), F10 (FIG. 14B), F12 (FIG. 14C), PP (FIG. 14D), PS (FIG. 14E), and VP (FIG. 14F)) tested in Section 1 of the Examples at baseline and after storage for one month at 4 °C, 25 °C / 60% RH, or 40 °C / 75% RH using a high resistance Plastiape™ device under a 1 kPa pressure drop.

[0084] FIG. 15 depicts the percentage monomer measured by size exclusion chromatography at baseline and after storage for one month at 4 °C, 25 °C / 60% RH, or 40 °C / 75% RH (n = 3 per condition) for six formulations (F4, F10, F12, PP, PS, and VP) tested in Section 1 of the Examples.

[0085] FIG. 16 provides a schematic representation of the design of experiments study described in Section 2 of the Examples.

[0086] FIG. 17 depicts the drying efficiency, as assessed by thermogravimetric analysis (TGA), of various processing conditions tested in Section 2 of the Examples.

[0087] FIGs. 18A-18D show comparisons between changes in percentage monomer (FIG. 18 A), changes in residual water content (FIG. 18B), changes in total residual solvent content (FIG. 18C), and changes in theoretical residual PFOB levels (FIG. 18D) before and after secondary drying for dry powder compositions produced under fifteen different spray drying conditions tested in Section 2 of the Examples.

[0088] FIG. 19 shows SEM photomicrographs of dry powder compositions produced under fifteen different spray drying conditions (Pl -Pl 5) tested in Section 2 of the Examples.

[0089] FIG. 20 depicts XRPD diffractograms of dry powder compositions produced under fifteen different spray drying conditions (Pl -Pl 5) tested in Section 2 of the Examples, as well as their corresponding glass transition temperature (Tg) values as determined by a modulated DSC experiment.

[0090] FIG. 21A depicts the aerosol performance, as assessed by percentage nominal dose, of dry powder compositions produced under fifteen different spray drying conditions (P1-P15) tested in Section 2 of the Examples using a high resistance Plastiape™ RS01 device under a pressure drop of 4 kPa.

[0091] FIG. 21B depicts the aerosol performance, as assessed by emitted fraction as a function of the nominal dose, of dry powder compositions produced under fifteen different spray drying conditions (Pl -Pl 5) tested in Section 2 of the Examples using a high resistance Plastiape™ RS01 device under a pressure drop of 4 kPa.

[0092] FIG. 22 shows circular dichroism (CD) spectra of IgG antibodies in formulations tested in Section 2 of the Examples.

[0093] FIG. 23 provides a SEM photomicrograph of a specific dry powder composition tested in Section 2 of the Examples.

[0094] FIG. 24 depicts a XRPD diffractogram of a specific dry powder composition tested in Section 2 of the Examples.

[0095] FIG. 25 shows a comparison of emitted fractions measured for a specific dry powder composition tested in Section 2 of the Examples when using four different dry powder inhalers.

[0096] FIG. 26 shows a comparison of respirable fraction measured for a specific dry powder composition tested in Section 2 of the Examples when using four different dry powder inhalers.

[0097] FIG. 27 shows a comparison of fine particle fractions (less than 5 pm) measured for a specific dry powder composition tested in Section 2 of the Examples when using four different dry powder inhalers.

[0098] FIG. 28 shows a comparison of device depositions measured for a specific dry powder composition tested in Section 2 of the Examples when using four different dry powder inhalers.

[0099] FIGs. 29A-29D provide a comparison of measured emitted fractions (FIG. 29 A), respirable fractions (FIG. 29B), fine particle fractions (less than 5 pm) (FIG. 29C), and device depositions (FIG. 29D) for a specific dry powder composition tested in Section 2 of the Example using a Plastiape™ RS01 device under a 1 kPa vs. a 4 kPa pressure drop.

[0100] FIG. 30 shows a comparison of emitted fractions, respirable fractions, and device depositions for a specific dry powder composition tested in Section 2 of the Examples using a TwinCaps® inhaler with 15 mg vs. 30 mg powder loading.DETAILED DESCRIPTIONDefinitions:

[0101] Where a range of values is provided herein, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between and including the upper and lower limit of that range and anyother stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0102] Throughout this application, the term “about” or “approximately” is used according to its plain and ordinary meaning in the area of cell and molecular biology to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0103] As used herein, the terms “a” and “an” mean “one or more” unless specifically indicated otherwise. For example, “an antibody” can, in some embodiments, mean one or more antibodies, including at least one antibody capable of binding a first specific protein and at least one antibody capable of binding a second specific protein, where the first specific protein is different from the second specific protein. Additionally, “one or more” and “at least one” are used interchangeably herein. Furthermore, unless otherwise required by context, singular terms include pluralities and plural terms include the singular.

[0104] Throughout this specification and the claims which follow, unless the context requires otherwise, the term “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein, the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”.

[0105] As used herein, “consisting of’ excludes any element, step, or ingredient not specified in the embodiment feature or claim element. As used herein, “consisting essentially of’ does not exclude materials or steps that do not materially affect the basic and novel characteristics of the embodiment feature or claim element.

[0106] In each instance herein, any of the terms “comprising,” “consisting essentially of,” “consisting of,” and their variations may be replaced with any of the other two terms or their variations.

[0107] As used herein, the term “antibody” generally refers to a tetrameric immunoglobulin protein comprising two light chain polypeptides (about 25 kDa each) and two heavy chain polypeptides (about 50-70 kDa each). The term “light chain” or“immunoglobulin light chain” refers to a polypeptide comprising, from amino terminus to carboxyl terminus, a single immunoglobulin light chain variable region (VL) and a single immunoglobulin light chain constant domain (CL). The immunoglobulin light chain constant domain (CL) can be a human kappa (K) or human lambda ( ) constant domain. The term “heavy chain” or “immunoglobulin heavy chain” refers to a polypeptide comprising, from amino terminus to carboxyl terminus, a single immunoglobulin heavy chain variable region (VH), an immunoglobulin heavy chain constant domain 1 (CHI), an immunoglobulin hinge region, an immunoglobulin heavy chain constant domain 2 (CH2), an immunoglobulin heavy chain constant domain 3 (CH3), and optionally an immunoglobulin heavy chain constant domain 4 (CH4). Heavy chains are classified as mu (p), delta (A), gamma (y), alpha (a), and epsilon (a), and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. The IgG-class and IgA-class antibodies are further divided into subclasses, namely, IgGl, IgG2, IgG3, and IgG4, and IgAl and IgA2, respectively. The heavy chains in IgG, IgA, and IgD antibodies have three constant domains (CHI, CH2, and CH3), whereas the heavy chains in IgM and IgE antibodies have four constant domains (CHI, CH2, CH3, and CH4). The immunoglobulin heavy chain constant domains can be from any immunoglobulin isotype, including subtypes. The antibody chains are linked together via inter-polypeptide disulfide bonds between the CL domain and the CHI domain (i.e., between the light and heavy chain) and between the hinge regions of the two antibody heavy chains.

[0108] Variable regions of immunoglobulin chains generally exhibit the same overall structure, comprising relatively conserved framework regions (FR) joined by three hypervariable regions, more often called “complementarity determining regions” or CDRs. The CDRs from the two chains of each heavy chain and light chain pair typically are aligned by the framework regions to form a structure that binds specifically to a specific epitope on the target protein. From N-terminus to C-terminus, naturally-occurring light and heavy chain variable regions both typically conform with the following order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. A numbering system has been devised for assigning numbers to amino acids that occupy positions in each of these domains. This numbering system is defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, MD), or Chothia & Lesk, 1987, J. Mol. Biol. 196:901- 917; Chothia et al., 1989, Nature 342:878-883. The CDRs and FRs of a given antibody may be identified using this system. Other numbering systems for the amino acids inimmunoglobulin chains include IMGT® (the international ImMunoGeneTics information system; Lefranc et al., Dev. Comp. Immunol. 29:185-203; 2005) and AHo (Honegger and Pluckthun, J. Mol. Biol. 309(3):657-670; 2001).

[0109] As used in the context of this disclosure, an “antigen-binding fragment,” used interchangeably herein with “antibody fragment,” is a portion of an antibody that lacks at least some of the amino acids present in a full-length heavy chain and / or light chain, but which is still capable of specifically binding to an antigen. An antigen-binding fragment includes, but is not limited to, a single-chain variable fragment (scFv), a nanobody (e.g., VH domain of heavy chain only antibodies (e.g., camelid heavy chain antibodies); VHH fragment, see Cortez-Retamozo et al., Cancer Research, Vol. 64:2853-57, 2004), a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a Fd fragment, and a CDR fragment, and can be derived from any mammalian source, such as human, mouse, rat, rabbit, or camelid. Antigen-binding fragments may compete for binding of a target antigen with an intact antibody, and the fragments may be produced by the modification of intact antibodies (e.g., enzymatic or chemical cleavage) or synthesized de novo using recombinant DNA technologies or peptide synthesis. In some embodiments, the antigenbinding fragment comprises at least one CDR from an antibody that binds to the antigen, for example, the heavy chain CDR3 from an antibody that binds to the antigen. In other embodiments, the antigen-binding fragment comprises all three CDRs from the heavy chain of an antibody that binds to the antigen or all three CDRs from the light chain of an antibody that binds to the antigen. In still other embodiments, the antigen-binding fragment comprises all six CDRs from an antibody that binds to the antigen (three from the heavy chain and three from the light chain).

[0110] Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment which contains all but the first domain of the immunoglobulin heavy chain constant region. The Fab fragment contains the variable domains from the light and heavy chains, as well as the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Thus, a “Fab fragment” is comprised of one immunoglobulin light chain (light chain variable region (VL) and constant region (CL)) and the CHI domain and variable region (VH) of one immunoglobulin heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule. The “Fdfragment” comprises the VH and CHI domains from an immunoglobulin heavy chain. The Fd fragment represents the heavy chain component of the Fab fragment.

[0111] The “Fc fragment” or “Fc domain” of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain, and optionally comprises a CH4 domain. The Fc domain may be an Fc domain from an IgGl, IgG2, IgG3, or IgG4 immunoglobulin. In some embodiments, the Fc domain comprises CH2 and CH3 domains from a human IgGl or human IgG2 immunoglobulin. The Fc domain may retain effector function, such as Clq binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), and phagocytosis. In other embodiments, the Fc domain may be modified to reduce or eliminate effector function.

[0112] A “Fab' fragment” is a Fab fragment having at the C-terminus of the CHI domain one or more cysteine residues from the antibody hinge region.

[0113] A “F(ab')2 fragment” is a bivalent fragment including two Fab' fragments linked by a disulfide bridge between the heavy chains at the hinge region.

[0114] The “Fv” fragment is the minimum fragment that contains a complete antigen recognition and binding site from an antibody. This fragment consists of a dimer of one immunoglobulin heavy chain variable region (VH) and one immunoglobulin light chain variable region (VL) in tight, non-covalent association. It is in this configuration that the three CDRs of each variable region interact to define an antigen binding site on the surface of the VH-VL dimer. A single light chain or heavy chain variable region (or half of an Fv fragment comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site comprising both VH and VL.

[0115] A “single-chain variable fragment” or “scFv fragment” comprises the VH and VL regions of an antibody, wherein these regions are present in a single polypeptide chain, and optionally comprising a peptide linker between the VH and VL regions that enables the Fv to form the desired structure for antigen binding (see e.g., Bird et al., Science, Vol. 242:423-426, 1988; and Huston et al., Proc. Natl. Acad. Sci. USA, Vol. 85:5879-5883, 1988).

[0116] A “nanobody” is the heavy chain variable region of a heavy-chain antibody. Such variable domains are the smallest fully functional antigen-binding fragment of suchheavy-chain antibodies, with a molecular mass of only 15 kDa. See Cortez-Retamozo et al., Cancer Research 64:2853-57, 2004. Functional heavy-chain antibodies devoid of light chains are naturally occurring in certain species of animals, such as nurse sharks, wobbegong sharks, and Camelidae, such as camels, dromedaries, alpacas and llamas. The antigen-binding site is reduced to a single domain, the VHH domain, in these animals. These antibodies form antigen-binding regions using only heavy chain variable region, i.e., these functional antibodies are homodimers of heavy chains only (referred to as “heavychain antibodies” or “HCAbs”). Camelized VHH reportedly recombines with IgG2 and IgG3 constant regions that contain hinge, CH2, and CH3 domains and lack a CHI domain. Camelized VHH domains have been found to bind to antigen with high affinity (Desmyter et al., J. Biol. Chem., Vol. 276:26285-90, 2001) and possess high stability in solution (Ewert et al., Biochemistry, Vol. 41:3628-36, 2002). Methods for generating antibodies having camelized heavy chains are described in, for example, U.S. Patent Publication Nos. 2005 / 0136049 and 2005 / 0037421. Alternative scaffolds can be made from human variablelike domains that more closely match the shark V-NAR scaffold and may provide a framework for a long penetrating loop structure. Human heavy-chain antibodies can be produced by transgenic animals expressing human immunoglobulin genes, such as UniAb™ antibodies produced by UniRat™ transgenic rats.

[0117] As used herein, the term “blowing agent” refers to a substance capable of generating a cellular structure during a particle production process, such as, for example, spray drying.

[0118] As used herein, the term “emitted dose” is the dose that is emitted from a device.

[0119] As used herein, the term “emitted fraction” or “EF” means the ratio of the dose delivered by a dry powder inhaler to the nominal dose (i.e., the mass of powder per unit dose placed into the dry powder inhaler prior to actuating the device). To determine the EF, a nominal dose of dry powder can be placed into a dry powder inhaler, which is then actuated, dispersing the powder. The resulting aerosol cloud can then be drawn by vacuum from the device, where it is captured on a tared filter attached to the device mouthpiece. EF can be measured in accordance with U.S. Pharmacopeia (USP) 601.

[0120] As used herein, the term “fine particle fraction” or “FPF” means the fraction of an emitted dose having a particle size below 5 pm. FPF can be measured in accordance with USP 601.

[0121] As used herein, the term “respirable fraction” is the fraction of particles, by mass, that are less than 5 pm with respect to a total loaded or nominal dose.

[0122] As used herein, the term “pharmaceutically acceptable” refers to a species or component that is generally safe, non-toxic, and neither biologically nor otherwise undesirable for use in a subject under typical medical treatment conditions.

[0123] As used herein, the term “pharmaceutically acceptable excipient” or “excipient” refers to a broad range of ingredients that may be combined with a compound, solvate, or salt disclosed herein to prepare a pharmaceutically acceptable composition or formulation. Excipients include, for example, vehicles (e.g., solvents, dispersion media), coatings, isotonic and absorption delaying agents, diluents, colorants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, and preservatives (e.g., antibacterial and antifungal agents).

[0124] As used herein, the term “patient” or “subject” refers to humans and other mammals. The term “mammal” as used herein includes, for example, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), and monkeys. Human subjects include neonates, infants, juveniles, adults, and geriatric subjects.

[0125] As used herein, a “stable” composition refers to a composition in which a protein therein essentially retains its physical stability and / or chemical stability and / or biological activity upon storage. In some embodiments, the composition essentially retains its physical and chemical stability, as well as its biological activity upon storage. The storage period is generally selected based on the intended shelf-life of the composition. Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301. Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones. A. Adv. Drug Delivery Rev. 10: 29-90) (1993), for example. Stability can be measured at a selected temperature for a selected time period. Stability can be evaluated qualitatively and / or quantitatively in a variety of different ways, including evaluation of aggregate formation (for example, using size exclusion chromatography, by measuring turbidity, and / or by visual inspection); by assessing charge heterogeneity using cation exchange chromatography, image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis; amino-terminal or carboxy-terminal sequence analysis; mass spectrometric analysis; SDS-PAGE analysis to compare reduced and intactantibody; peptide map (for example tryptic or LYS-C) analysis; evaluating biological activity or antigen binding function of the antibody; etc. Instability may involve any one or more of: aggregation, deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization), clipping / hydrolysis / fragmentation (e.g., hinge region fragmentation), succinimide formation, unpaired cysteine(s), N-terminal extension, C-terminal processing, glycosylation differences, etc.

[0126] As used herein, the terms “X90” and “D90,” in reference to a particle size distribution, refer to a numerical value where 90% of tested particles have a smaller diameter than the numerical value and 10% have a larger diameter than the numerical value. Similarly, the terms “X50” and “D50,” in reference to a particle size distribution, refer to a numerical value where 50% of tested particles have a smaller diameter than the numerical value and 50% have a larger diameter than the numerical value. Additionally, the terms “X10” and “D10,” in reference to a particle size distribution, refer to a numerical value where 10% of tested particles have a smaller diameter than the numerical value and 90% have a larger diameter than the numerical value. X90 / D90, X50 / D50, and X10 / D10, as used herein, are measured by laser diffraction using a HELOS RODOS (Sympatec GmbH, Germany) dry dispersion unit.PHOSPHOLIPIDS

[0127] Phospholipids from natural (e.g., saturated soy phosphatidylcholine) and synthetic (e.g., synthetic distearoylphosphatidylcholine) sources can be used in the dry powder compositions of the present disclosure. Phospholipids are a major component in cell and organelle membranes and can function as lung surfactants. Additionally, phospholipids can be used as hydrophobic shell-forming excipients in spray-dried dry powder formulations, including in the dry powder compositions disclosed herein.

[0128] In some embodiments, a phospholipid used in a dry powder composition of the present disclosure is a saturated phospholipid. In some embodiments, the phospholipid is a saturated phosphatidylcholine.

[0129] In some embodiments, a phospholipid used in a dry powder composition of the present disclosure is selected from phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, and combinations of any of the foregoing. In some embodiments, the phospholipid is a phosphatidylcholine. Insome embodiments, the phospholipid is a phosphatidylethanolamine. In some embodiments, the phospholipid is a phosphatidylglycerol. In some embodiments, the phospholipid is a phosphatidylserine. In some embodiments, the phospholipid is a pho sphatidy lino sitol .

[0130] In some embodiments, the phospholipid is selected from distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3- phosphoethanolamine (DPPE), l,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), and combinations of any of the foregoing. In some embodiments, the phospholipid is DSPC. In some embodiments, the phospholipid is DPPC. In some embodiments, the phospholipid is DOPC. In some embodiments, the phospholipid is DPPE. In some embodiments, the phospholipid is DPPG. In some embodiments, the phospholipid is POPG.

[0131] In some embodiments, the phospholipid is selected from DPPC, DSPC, and combinations of any of the foregoing. In some embodiments, the phospholipid is DPPC or DSPC. In some embodiments, the phospholipid is DSPC. In some embodiments, the phospholipid is DPPC.

[0132] In some embodiments, a phospholipid used in a dry powder composition disclosed herein is present at a concentration in the range of 10% w / w to less than 50% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 10% w / w to 45% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 10% w / w to 40% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 10% w / w to 35% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 10% w / w to 30% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 10% w / w to 25% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 10% w / w to 20% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 15% w / w to 40% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 15% w / w to 35% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 15% w / w to 30% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 15% w / w to 25% w / w. In some embodiments, the phospholipid is present at aconcentration in the range of 15% w / w to 20% w / w. In some embodiments, the phospholipid is present at a concentration in the range of 14% w / w to 18% w / w.

[0133] In some embodiments, the dry powder composition comprises 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, 15% w / w, 16% w / w, 17% w / w, 18% w / w, 19% w / w, 20% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 27% w / w, 28% w / w, 29% w / w, 30% w / w, 31% w / w, 32% w / w, 33% w / w, 34% w / w, 35% w / w, 36% w / w, 37% w / w, 38% w / w, 39% w / w, 40% w / w, 41% w / w, 42% w / w, 43% w / w, 44% w / w, 45% w / w, 46% w / w, 47% w / w, 48% w / w, 49% w / w, or 50% w / w phospholipid. In some embodiments, the dry powder composition comprises 14% w / w, 14.25% w / w, 14.5% w / w, 14.75% w / w, 15% w / w, 15.25% w / w, 15.5% w / w, 15.75% w / w, 16% w / w, 16.25% w / w, 16.5% w / w, 16.75% w / w, 17% w / w, 17.25% w / w, 17.5%, 17.75% w / w, or 18% w / w phospholipid.

[0134] In some embodiments, DSPC is present in a dry powder composition disclosed herein at a concentration in the range of 10% w / w to less than 50% w / w. In some embodiments, DSPC is present at a concentration in the range of 10% w / w to 45% w / w. In some embodiments, DSPC is present at a concentration in the range of 10% w / w to 40% w / w. In some embodiments, DSPC is present at a concentration in the range of 10% w / w to 35% w / w. In some embodiments, DSPC is present at a concentration in the range of 10% w / w to 30% w / w. In some embodiments, DSPC is present at a concentration in the range of 10% w / w to 25% w / w. In some embodiments, DSPC is present at a concentration in the range of 10% w / w to 20% w / w. In some embodiments, DSPC is present at a concentration in the range of 15% w / w to 40% w / w. In some embodiments, DSPC is present at a concentration in the range of 15% w / w to 35% w / w. In some embodiments, DSPC is present at a concentration in the range of 15% w / w to 30% w / w. In some embodiments, DSPC is present at a concentration in the range of 15% w / w to 25% w / w. In some embodiments, DSPC is present at a concentration in the range of 15% w / w to 20% w / w. In some embodiments, DSPC is present at a concentration in the range of 14% w / w to 18% w / w.

[0135] In some embodiments, the dry powder composition comprises 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, 15% w / w, 16% w / w, 17% w / w, 18% w / w, 19% w / w, 20% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 27% w / w, 28% w / w, 29% w / w, 30% w / w, 31% w / w, 32% w / w, 33% w / w, 34% w / w, 35% w / w, 36% w / w, 37% w / w, 38% w / w, 39% w / w, 40% w / w, 41% w / w, 42% w / w, 43% w / w, 44% w / w, 45% w / w, 46% w / w, 47% w / w, 48% w / w, 49% w / w, or 50% w / w DSPC. In some embodiments,the dry powder composition comprises 14% w / w, 14.25% w / w, 14.5% w / w, 14.75% w / w, 15% w / w, 15.25% w / w, 15.5% w / w, 15.75% w / w, 16% w / w, 16.25% w / w, 16.5% w / w, 16.75% w / w, 17% w / w, 17.25% w / w, 17.5%, 17.75% w / w, or 18% w / w DSPC.POLYVALENT CATIONS

[0136] Polyvalent cations can be used in a phospholipid-containing dry powder formulation to increase its gel-to-liquid crystal phase transition temperature, improve dispersibility and spreadability, and improve storage stability. Without being bound to any particular theory, polyvalent cations such as calcium ions may intercalate in a phospholipid membrane and interact with the negatively charged portion of a phospholipid’ s zwitterionic headgroup, decreasing hydration of the headgroup and increasing condensation of the acyl- chain packing.

[0137] In some embodiments, a polyvalent cation used in a dry powder composition of the present disclosure is a divalent cation. In some embodiments, the divalent cation comprises calcium, magnesium, zinc, iron, or a combination of any of the foregoing. In some embodiments, the divalent cation comprises calcium, magnesium, zinc, or iron. In some embodiments, the divalent cation comprises calcium. In some embodiments, the divalent cation comprises magnesium. In some embodiments, the divalent cation comprises zinc. In some embodiments, the divalent cation comprises iron.

[0138] In some embodiments, the polyvalent cation is calcium chloride.

[0139] In some embodiments, the polyvalent cation is present in an amount effective to increase the melting temperature (Tm) of the phospholipid such that the dry powder composition exhibits a Tm which is greater than its storage temperature (Ts) by at least 20°C (such as, e.g., at least 25 °C, at least 30 °C, at least 35 °C, at least 40 °C, 20 °C, 21 °C,22 °C, 23 °C, 24 °C, 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, 30 °C, 31 °C, 32 °C, 33 °C, 34 °C,35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C).

[0140] In some embodiments, the polyvalent cation is present at a concentration in the range of greater than 0% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 0.5% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 1% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 1.5% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 2% w / w to 10% w / w. In some embodiments, the polyvalent cation is presentat a concentration in the range of 2.5% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 3% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 3.5% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 4% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 4.5% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 5% w / w to 10% w / w. In some embodiments, the polyvalent cation is present at a concentration in the range of 6% w / w to 9% w / w. In some embodiments, the polyvalent cation comprises calcium. In some embodiments, the polyvalent cation is calcium chloride.

[0141] In some embodiments, the dry powder composition comprises 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 1.25% w / w, 1.5% w / w, 1.75% w / w, 2% w / w, 2.25% w / w, 2.5% w / w, 2.75% w / w, 3% w / w, 3.25% w / w, 3.5% w / w, 3.75% w / w, 4% w / w, 4.25% w / w, 4.5% w / w, 4.75% w / w, 5% w / w, 5.25% w / w, 5.5% w / w, 5.75% w / w, 6% w / w, 6.25% w / w, 6.5% w / w, 6.75% w / w, 7% w / w, 7.25% w / w, 7.5% w / w, 7.75% w / w, 8% w / w, 8.25% w / w, 8.5% w / w, 8.75% w / w, 9% w / w, 9.25% w / w, 9.5% w / w, 9.75% w / w, or 10% w / w polyvalent cation. In some embodiments, the polyvalent cation comprises calcium. In some embodiments, the polyvalent cation is calcium chloride.

[0142] In some embodiments, the dry powder composition comprises 6.0% w / w, 6.1% w / w, 6.2% w / w, 6.3% w / w, 6.4% w / w, 6.5% w / w, 6.6% w / w, 6.7% w / w, 6.8% w / w, 6.9% w / w, 7.0% w / w, 7.1% w / w, 7.2% w / w, 7.3% w / w, 7.4% w / w, 7.5% w / w, 7.6% w / w, 7.7% w / w, 7.8% w / w, 7.9% w / w, 8.0% w / w, 8.1% w / w, 8.2% w / w, 8.3% w / w, 8.4% w / w, 8.5% w / w, 8.6% w / w, 8.7% w / w, 8.8% w / w, 8.9% w / w, or 9.0% w / w polyvalent cation. In some embodiments, the polyvalent cation comprises calcium. In some embodiments, the polyvalent cation is calcium chloride.NON-IONIC SURFACTANTS

[0143] Surfactants are surface-active agents that typically possess a polar head and a hydrophobic tail. Surfactants preferentially accumulate at interfaces and reduce interfacial tension. Surfactants are commonly used in pharmaceutical compositions to reduce surface adsorption, particularly surface adsorption of proteins such as antibodies and antibodyfragments. Additionally, surfactants can mitigate aggregate formation, including agitation-induced aggregation, and control protein conformational stability.

[0144] In some embodiments, a non-ionic surfactant used in a dry powder composition of the present disclosure is selected from cocamides, ethoxylates, and alkoxylates. In some embodiments, the non-ionic surfactant is selected from polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80), poloxamers (e.g., Pluronics®, e.g., Pluronic® F68), and combinations of any of the foregoing, either within a class of surfactants or among classes of surfactants. In some embodiments, the non-ionic surfactant is selected from poloxamers and sorbitan fatty acid esters. In some embodiments, the non-ionic surfactant is selected from poloxamers and polyoxyethylene sorbitan fatty acid esters.

[0145] In some embodiments, the non-ionic surfactant is selected from poloxamers. In some embodiments, the non-ionic surfactant is selected from poloxamer-188 (Pluronic™ F-68), poloxamer-407 (Pluronic™ F-127), poloxamer-338, and combinations of any of the foregoing. In some embodiments, the non-ionic surfactant is poloxamer-188. In some embodiments, the non-ionic surfactant is poloxamer-407. In some embodiments, the non- ionic surfactant is poloxamer-338.

[0146] In some embodiments, the non-ionic surfactant is selected from polyoxyethylene sorbitan fatty acid esters. In some embodiments, the non-ionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and combinations of any of the foregoing. In some embodiments, the non-ionic surfactant is polysorbate 20 or polysorbate 80. In some embodiments, the non-ionic surfactant is polysorbate 20. In some embodiments, the non-ionic surfactant is polysorbate 80.

[0147] In some embodiments, a non-ionic surfactant used in a dry powder composition disclosed herein is present at a concentration in the range of greater than 0% w / w to 10% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.25% w / w to 10% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 10% w / w. In some embodiments, the non- ionic surfactant is present at a concentration in the range of 0.5% w / w to 9.5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 9% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 8.5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 8% w / w. In someembodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 7.5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 7% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 6.5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 6% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 5.5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 4.5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 4% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 3.5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 3% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 2.5% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 2% w / w. In some embodiments, the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 1.5% w / w. In some embodiments, the non-ionic surfactant is polysorbate 20, polysorbate 80, poloxamer-188, or poloxamer-407. In some embodiments, the non-ionic surfactant is poloxamer-188.

[0148] In some embodiments, the dry powder composition comprises 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 1.25% w / w, 1.5% w / w, 1.75% w / w, 2% w / w, 2.25% w / w, 2.5% w / w, 2.75% w / w, 3% w / w, 3.25% w / w, 3.5% w / w, 3.75% w / w, 4% w / w, 4.25% w / w, 4.5% w / w, 4.75% w / w,5% w / w, 5.25% w / w, 5.5% w / w, 5.75% w / w, 6% w / w, 6.25% w / w, 6.5% w / w, 6.75% w / w,7% w / w, 7.25% w / w, 7.5% w / w, 7.75% w / w, 8% w / w, 8.25% w / w, 8.5% w / w, 8.75% w / w,9% w / w, 9.25% w / w, 9.5% w / w, 9.75% w / w, or 10% w / w non-ionic surfactant. In some embodiments, the non-ionic surfactant is polysorbate 20, polysorbate 80, poloxamer-188, or poloxamer-407. In some embodiments, the non-ionic surfactant is poloxamer-188.

[0149] In some embodiments, the dry powder composition comprises 0.5% w / w, 0.55% w / w, 0.6% w / w, 0.65% w / w, 0.7% w / w, 0.75% w / w, 0.8% w / w, 0.85% w / w, 0.9% w / w, 0.95% w / w, 1% w / w, 1.05% w / w, 1.1% w / w, 1.15% w / w, 1.2% w / w, 1.25% w / w, 1.3% w / w, 1.35% w / w, 1.4% w / w, 1.45% w / w, or 1.5% w / w non-ionic surfactant. In someembodiments, the non-ionic surfactant is polysorbate 20, polysorbate 80, poloxamer-188, or poloxamer-407. In some embodiments, the non-ionic surfactant is poloxamer-188.BUFFERING AGENTS

[0150] A buffer is a solution with acid / base conjugate components (i.e., buffering agents) that enable the solution to resist changes in pH. Various buffers are known to persons skilled in the art and include, but are not limited to, organic buffers (such as, e.g., histidine buffers, citrate buffers, gluconate buffers, succinate buffers, acetate buffers, glycylglycine and other organic acid buffers, and phosphate buffers).

[0151] Dry powder compositions of the present disclosure can be produced by spray drying. Specifically, in some embodiments, a dry powder composition may be prepared by preparing an emulsion comprising a blowing agent, an antibody or an antibody fragment, a phospholipid, a polyvalent cation, a non-ionic surfactant, and a buffer (i.e., a solution comprising a buffering agent) and spray drying the emulsion using a spray dryer. During the spray drying process, the aqueous portion of the buffer may be removed, with its associated solute(s) (i.e., the buffering agent) remaining in the spray dried composition.

[0152] Dry powder compositions of the present disclosure comprise one or more pharmaceutically acceptable buffering agents. Non-limiting examples of buffering agents that can be used in dry powder compositions disclosed herein include histidine, sodium phosphate, and sodium succinate.

[0153] In some embodiments, the buffering agent comprises acetic acid / acetate, having a pKa of 4.75 at 25°C. In some embodiments, the buffering agent comprises glutamic acid / glutamate, having a pKa of 4.27 at 25°C. In some embodiments, the buffering agent comprises succinate, having a pKa of 4.21 at 25 °C. In some embodiments, the buffering agent comprises propionate, having a pKa of 4.87 at 25 °C. In some embodiments, the buffering agent comprises malate, having a pKa of 5.13 at 25 °C. In some embodiments, the buffering agent comprises pyridine, having a pKa of 5.23 at 25 °C. In some embodiments, the buffering agent comprises piperazine, having a pKa of 5.33 at 25 °C. In some embodiments, the buffering agent comprises histidine, having a pKa of 6.04 at 25 °C. In some embodiments, the buffering agent can be provided as a sodium salt (or a disodium salt, as appropriate), or in the alternative, as a potassium, magnesium, or ammonium salt.

[0154] In some embodiments, the buffering agent is selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citratesalt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing.

[0155] In some embodiments, the buffering agent is selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing.

[0156] In some embodiments, the buffering agent comprises histidine / histidine salt. In some embodiments, the buffering agent comprises histidine / histidine HC1.

[0157] In some embodiments, a buffering agent used in a dry powder composition of the present disclosure is present at a concentration of less than 2% w / w. In some embodiments, the dry powder composition comprises 1.95% w / w, 1.9% w / w, 1.85% w / w, 1.8% w / w, 1.75% w / w, 1.7% w / w, 1.65% w / w, 1.6% w / w, 1.55% w / w, 1.5% w / w, 1.45% w / w, 1.4% w / w, 1.35% w / w, 1.3% w / w, 1.25% w / w, 1.2% w / w, 1.15% w / w, 1.1% w / w, 1.05% w / w, 1% w / w, 0.95% w / w, 0.9% w / w, 0.85% w / w, 0.8% w / w, 0.75% w / w, 0.7% w / w, 0.65% w / w, 0.6% w / w, 0.55% w / w, or 0.5% w / w buffering agent. In some embodiments, the dry powder composition comprises 1.95% w / w, 1.9% w / w, 1.85% w / w, 1.8% w / w, 1.75% w / w, 1.7% w / w, 1.65% w / w, 1.6% w / w, or 1.55% w / w buffering agent. In some embodiments, the buffering agent comprises histidine / histidine salt. In some embodiments, the buffering agent comprises histidine / histidine HC1.ADDITIONAL EXCIPIENTS

[0158] Additional excipients such as amino acids and salts can help mitigate inter- and intra-molecular interactions between antibodies / antibody fragments and / or excipients and may be formulated in dry powder compositions of the present disclosure. Pharmaceutical excipients that may be formulated in dry powder compositions of the present disclosure include, but are not limited to, proteins, peptides, amino acids, lipids, and polymers. Example protein excipients that can be formulated in dry powder compositions disclosed herein include, but are not limited to, serum albumin (e.g., human serum albumin (HSA)), recombinant human albumin (rHA), gelatin, casein, and the like. In addition, amino acid and polypeptide excipients that can be formulated in dry powder compositions of the present disclosure include, but are not limited to, alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, proline, isoleucine, valine, methionine, phenylalanine, aspartame, di-leucine, and tri-leucine.

[0159] In some embodiments, the additional excipient comprises an amino acid. In some embodiments, the additional excipient comprises an amino acid selected from lysine, proline, serine, and alanine. In some embodiments, the additional excipient comprises lysine. In some embodiments, the additional excipient comprises proline. In some embodiments, the additional excipient comprises serine. In some embodiments, the additional excipient comprises alanine. In some embodiments, the additional excipient comprises two or more amino acids, such as, e.g., two or more of lysine, proline, serine, and alanine.

[0160] Additionally, organic salts (e.g. sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc.) can be formulated in dry powder compositions disclosed herein.

[0161] However, in some embodiments, no carbohydrate excipients are used to formulate a dry powder composition of the present disclosure. For example, in some embodiments, none of the plurality of particles comprises a sugar or sugar alcohol excipient. In some embodiments, none of the plurality of particles comprises a carbohydrate excipient selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.ANTIBODIES AND ANTIBODY FRAGMENTS

[0162] Dry powder compositions of the present disclosure can be used for pulmonary delivery of antibodies or antibody fragments.

[0163] In some embodiments, the antibody or antibody fragment used in the dry powder composition binds to one of more of the following, alone or in any combination: CD proteins including, but not limited to, CD3, CD4, CD5, CD7, CD8, CD19, CD20, CD22, CD25, CD30, CD33, CD34, CD38, CD40, CD70, CD123, CD133, CD138, CD171, and CD 174, HER receptor family proteins, including, for instance, HER2, HER3, HER4, and the EGF receptor, EGFRvIII, cell adhesion molecules, for example, LFA-1, Mol, pl50,95, VLA-4, ICAM-1, VCAM, and alpha v / beta 3 integrin, growth factors, including but not limited to, for example, vascular endothelial growth factor (“VEGF”); VEGFR2, growth hormone, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone, growth hormone releasing factor, parathyroid hormone, mullerian-inhibitingsubstance, human macrophage inflammatory protein (MIP-1 -alpha), erythropoietin (EPO), nerve growth factor, such as, e.g., NGF-beta, platelet-derived growth factor (PDGF), fibroblast growth factors, including, for instance, aFGF and bFGF, epidermal growth factor (EGF), Cripto, transforming growth factors (TGF), including, among others, TGF-a and TGF-P, including TGF-pi, TGF-P2, TGF-P3, TGF-P4, or TGF-P5, insulin-like growth factors-I and -II (IGF-I and IGF-II), des(l-3)-IGF-I (brain IGF-I), and osteoinductive factors, insulins and insulin-related proteins, including, but not limited to, insulin, insulin A chain, insulin B-chain, proinsulin, and insulin-like growth factor binding proteins; coagulation and coagulation-related proteins, such as, among others, factor VIII, tissue factor, von Willebrand factor, protein C, alpha- 1 -antitrypsin, plasminogen activators, such as urokinase and tissue plasminogen activator (“t-PA”), bombazine, thrombin, thrombopoietin, and thrombopoietin receptor, colony stimulating factors (CSFs), including the following, among others, M-CSF, GM-CSF, and G-CSF, other blood and serum proteins, including but not limited to albumin, IgE, and blood group antigens, receptors and receptor-associated proteins, including, for example, flk2 / flt3 receptor, obesity (OB) receptor, growth hormone receptors, and T-cell receptors; neurotrophic factors, including but not limited to, bone-derived neurotrophic factor (BDNF) and neurotrophin-3, -4, -5, or -6 (NT-3, NT-4, NT-5, or NT-6); relaxin A-chain, relaxin B-chain, and prorelaxin, interferons, including for example, interferon- alpha, -beta, and -gamma, interleukins (ILs), e.g., IL-1 to IL-10, IL-12, IL-15, IL-17, IL-23, IL-12 / IL-23, IL-2Ra, IL1-R1, IL-6 receptor, IL-4 receptor and / or IL-13 to the receptor, IL-13RA2, or IL-17 receptor, IL-1RAP; viral antigens, including but not limited to, an AIDS envelope viral antigen, lipoproteins, calcitonin, glucagon, atrial natriuretic factor, lung surfactant, tumor necrosis factor-alpha and -beta, enkephalinase, BCMA, IgKappa, ROR-1, ERBB2, mesothelin, RANTES (regulated on activation normally T-cell expressed and secreted), mouse gonadotropin- associated peptide, DNase, FR-alpha, inhibin, and activin, integrin, protein A or D, rheumatoid factors, immunotoxins, bone morphogenetic protein (BMP), superoxide dismutase, surface membrane proteins, decay accelerating factor (DAF), AIDS envelope, transport proteins, homing receptors, MIC (MIC-a, MIC-B), ULBP 1-6, EPCAM, addressins, regulatory proteins, immunoadhesins, antigen-binding proteins, somatropin, CTGF, CTLA4, eotaxin-1, MUC1, CEA, c-MET, Claudin-18, GPC-3, EPHA2, FPA, LMP1, MG7, NY-ESO-1, PSCA, ganglioside GD2, ganglioside GM2, BAFF, OPGL (RANKL), myostatin, Dickkopf-1 (DKK-1), Ang2, NGF, IGF-1 receptor, hepatocyte growth factor (HGF), TRAIL-R2, c-Kit, B7RP-1, PSMA, NKG2D-1, programmed celldeath protein 1 and ligand, PD1 and PDL1, mannose receptor / hCGp, hepatitis-C virus, mesothelin dsFv[PE38] conjugate, Legionella pneumophila (lly), IFN gamma, interferon gamma induced protein 10 (IP10), IFNAR, TALL-1, thymic stromal lymphopoietin (TSLP), proprotein convertase subtilisin / Kexin Type 9 (PCSK9), stem cell factors, Flt-3, calcitonin gene-related peptide (CGRP), OX40L, a4p7, platelet specific (platelet glycoprotein Ilb / IIIb (PAC-1), transforming growth factor beta (TFGP), Zona pellucida sperm-binding protein 3 (ZP-3), TWEAK, platelet derived growth factor receptor alpha (PDGFRa), sclerostin, and biologically active fragments or variants of any of the foregoing.

[0164] In some embodiments, a dry powder composition of the present disclosure comprises an antibody. In some embodiments, the dry powder composition comprises a human antibody. In some embodiments, the dry powder composition comprises an IgG antibody. In some embodiments, the dry powder composition comprises a human IgG antibody. In some embodiments, the dry powder composition comprises an IgGl, IgG2, or IgG4 antibody. In some embodiments, the dry powder composition comprises a human IgGl, IgG2, or IgG4 antibody. In some embodiments, the dry powder composition comprises an IgGl antibody. In some embodiments, the dry powder composition comprises a human IgGl antibody. In some embodiments, the dry powder composition comprises an IgG4 antibody. In some embodiments, the dry powder composition comprises a human IgG4 antibody. In some embodiments, the dry powder composition comprises an IgG2 antibody. In some embodiments, the dry powder composition comprises a human IgG2 antibody.

[0165] In other embodiments, a dry powder composition of the present disclosure comprises an antibody fragment. In some embodiments, the dry powder composition comprises a fragment of a human antibody. In some embodiments, the dry powder composition comprises a fragment of an IgG antibody. In some embodiments, the dry powder composition comprises a fragment of a human IgG antibody. In some embodiments, the dry powder composition comprises a fragment of an IgGl , IgG2, or IgG4 antibody. In some embodiments, the dry powder composition comprises a fragment of a human IgGl, IgG2, or IgG4 antibody. In some embodiments, the dry powder composition comprises a fragment of an IgGl antibody. In some embodiments, the dry powder composition comprises a fragment of a human IgGl antibody. In some embodiments, the dry powder composition comprises a fragment of an IgG4 antibody. In some embodiments, the dry powder composition comprises a fragment of a human IgG4 antibody. In someembodiments, the dry powder composition comprises a fragment of an IgG2 antibody. In some embodiments, the dry powder composition comprises a fragment of a human IgG2 antibody.

[0166] In some embodiments, an antibody or an antibody fragment is present in a dry powder composition at a concentration in the range of 50% w / w to 80% w / w. In some embodiments, the antibody or antibody fragment is present at a concentration in the range of 55% w / w to 80% w / w. In some embodiments, the antibody or antibody fragment is present at a concentration in the range of 60% w / w to 80% w / w. In some embodiments, the antibody or antibody fragment is present at a concentration in the range of 65% w / w to 80% w / w. In some embodiments, the antibody or antibody fragment is present at a concentration in the range of 70% w / w to 80% w / w. In some embodiments, the antibody or antibody fragment is an IgG antibody. In some embodiments, the antibody or antibody fragment is a human IgG antibody.

[0167] In some embodiments, an antibody or an antibody fragment is present in a dry powder composition at a concentration in the range of 72% w / w to 76% w / w. In some embodiments, the antibody or antibody fragment is an IgG antibody. In some embodiments, the antibody or antibody fragment is a human IgG antibody.

[0168] In some embodiments, the dry powder composition comprises 50% w / w, 51% w / w, 52% w / w, 53% w / w, 54% w / w, 55% w / w, 56% w / w, 57% w / w, 58% w / w, 59% w / w, 60% w / w, 61% w / w, 62% w / w, 63% w / w, 64% w / w, 65% w / w, 66% w / w, 67% w / w, 68% w / w, 69% w / w, 70% w / w, 71% w / w, 72% w / w, 73% w / w, 74% w / w, 75% w / w, 76% w / w, 77% w / w, 78% w / w, 79% w / w, or 80% w / w antibody or antibody fragment. In some embodiments, the dry powder composition comprises 70% w / w, 71% w / w, 72% w / w, 73% w / w, 74% w / w, 75% w / w, 76% w / w, 77% w / w, 78% w / w, 79% w / w, or 80% w / w antibody or antibody fragment. In some embodiments, the dry powder composition comprises 72% w / w, 72.5% w / w, 73% w / w, 73.5% w / w, 74% w / w, 74.5% w / w, 75% w / w, 75.5%, or 76% w / w antibody or antibody fragment. In some embodiments, the antibody or antibody fragment is an IgG antibody. In some embodiments, the antibody or antibody fragment is a human IgG antibody.RESIDUAL SOLVENT

[0169] Dry powder compositions of the present disclosure can include residual solvent (i.e., the compositions may not be entirely dry with no water or residual organic solventpresent in the composition). The residual solvent can be a byproduct of the process by which the dry powder composition was produced (e.g., spray drying).

[0170] In some embodiments, a residual solvent content (e.g., a total residual solvent content) of a dry powder composition disclosed herein is less than or equal to 7% w / w. In some embodiments, the residual solvent content is less than or equal to 6.5% w / w. In some embodiments, the residual solvent content is less than or equal to 6% w / w. In some embodiments, the residual solvent content is less than or equal to 5.5% w / w. In some embodiments, the residual solvent content is less than or equal to 5% w / w. In some embodiments, the residual solvent content is less than or equal to 4.5% w / w. In some embodiments, the residual solvent content is less than or equal to 4% w / w. In some embodiments, the residual solvent content is less than or equal to 3.5% w / w. In some embodiments, the residual solvent content is less than or equal to 3% w / w. In some embodiments, the residual solvent content is less than or equal to 2.5% w / w. In some embodiments, the residual solvent content is less than or equal to 2% w / w. In some embodiments, the residual solvent content is less than or equal to 1.5% w / w. In some embodiments, the residual solvent content is less than or equal to 1% w / w. In some embodiments, the residual solvent content is less than or equal to 0.5% w / w. In some embodiments, the residual solvent content is 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w,0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w,1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2.0% w / w,2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w,2.9% w / w, 3.0% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w,3.7% w / w, 3.8% w / w, 3.9% w / w, 4.0% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w,4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, 5.0% w / w, 5.1% w / w, 5.2% w / w,5.3% w / w, 5.4% w / w, 5.5% w / w, 5.6% w / w, 5.7% w / w, 5.8% w / w, 5.9% w / w, 6.0% w / w,6.1% w / w, 6.2% w / w, 6.3% w / w, 6.4% w / w, 6.5% w / w, 6.6% w / w, 6.7% w / w, 6.8% w / w,6.9% w / w, or 7.0% w / w.

[0171] In some embodiments, a water content of a dry powder composition disclosed herein is less than or equal to 5% w / w. In some embodiments, the water content is less than or equal to 4.5% w / w. In some embodiments, the water content is less than or equal to 4% w / w. In some embodiments, the water content is less than or equal to 3.5% w / w. In some embodiments, the water content is less than or equal to 3% w / w. In some embodiments, the water content is less than or equal to 2.5% w / w. In some embodiments, the water contentis less than or equal to 2% w / w. In some embodiments, the water content is less than or equal to 1.5% w / w. In some embodiments, the water content is less than or equal to 1% w / w. In some embodiments, the water content is less than or equal to 0.5% w / w. In some embodiments, the water content is 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2.0% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 2.9% w / w, 3.0% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.8% w / w, 3.9% w / w, 4.0% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w, 4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, or 5.0% w / w.

[0172] In some embodiments, an organic solvent content of a dry powder composition disclosed herein is less than or equal to 5% w / w. In some embodiments, the organic solvent content is less than or equal to 4.5% w / w. In some embodiments, the organic solvent content is less than or equal to 4% w / w. In some embodiments, the organic solvent content is less than or equal to 3.5% w / w. In some embodiments, the organic solvent content is less than or equal to 3% w / w. In some embodiments, the organic solvent content is less than or equal to 2.5% w / w. In some embodiments, the organic solvent content is less than or equal to 2% w / w. In some embodiments, the organic solvent content is less than or equal to 1.5% w / w. In some embodiments, the organic solvent content is less than or equal to 1% w / w. In some embodiments, the organic solvent content is less than or equal to 0.5% w / w. In some embodiments, the organic solvent content is 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2.0% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 2.9% w / w, 3.0% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.8% w / w, 3.9% w / w, 4.0% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w, 4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, or 5.0% w / w.

[0173] In some embodiments of the present disclosure, a blowing agent can be used to create a cellular structure (e.g., a surface rough, porous morphology) in particles of a dry powder composition during a manufacturing process. In some embodiments, the blowing agent is a pharmaceutically acceptable volatile liquid that is not miscible with water. In some embodiments, a fluorinated blowing agent, such as perfluorohexane, perfluorooctyl bromide, perfluorodecalin, perfluorotripropylamine, dichlorofluorooctane, orperfluorooctyl ethane, can be used during manufacturing. In such cases, the dry powder composition can comprise a residual amount of the blowing agent.

[0174] In some embodiments, a blowing agent content of a dry powder composition disclosed herein is less than or equal to 5% w / w. In some embodiments, the blowing agent content is less than or equal to 4.5% w / w. In some embodiments, the blowing agent content is less than or equal to 4% w / w. In some embodiments, the blowing agent content is less than or equal to 3.5% w / w. In some embodiments, the blowing agent content is less than or equal to 3% w / w. In some embodiments, the blowing agent content is less than or equal to 2.5% w / w. In some embodiments, the blowing agent content is less than or equal to 2% w / w. In some embodiments, the blowing agent content is less than or equal to 1.5% w / w. In some embodiments, the blowing agent content is less than or equal to 1% w / w. In some embodiments, the blowing agent content is less than or equal to 0.5% w / w. In some embodiments, the blowing agent content is 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2.0% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 2.9% w / w, 3.0% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.8% w / w, 3.9% w / w, 4.0% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w, 4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, or 5.0% w / w.PHYSICAL PROPERTIES OF THE PARTICLES

[0175] Dry powder compositions disclosed herein may exhibit certain physical properties such as high porosity and / or low density that facilitate pulmonary delivery.

[0176] In some embodiments, a majority of the plurality of particles in a dry powder composition disclosed herein exhibit a substantially spherical morphology. In some embodiments, a majority of the plurality of particles exhibit a surface rough, porous morphology. In some embodiments, a majority of the plurality of particles exhibit a substantially spherical morphology and a surface rough, porous morphology.

[0177] In some embodiments, the plurality of particles has an X90 in the range of 2.5 pm to 4 pm. In some embodiments, the plurality of particles has an X90 in the range of 2.5 pm to 3.5 pm. In some embodiments, the plurality of particles has an X90 in the range of 3 pm to 4 pm. In some embodiments, the plurality of particles has an X90 of 2.5 pm, 2.55 pm, 2.6 pm, 2.65 pm, 2.7 pm, 2.75 pm, 2.8 pm, 2.85 pm, 2.9 pm, 2.95 pm, 3.0 pm, 3.05pm, 3.1 pm, 3.15 pm, 3.2 pm, 3.25 pm, 3.3 pm, 3.35 pm, 3.4 pm, 3.45 pm, 3.5 pm, 3.55 pm, 3.6 pm, 3.65 pm, 3.7 pm, 3.75 pm, 3.8 pm, 3.85 pm, 3.9 pm, 3.95 pm, or 4.0 pm.

[0178] In some embodiments, the plurality of particles has an X50 of less than 2 pm. In some embodiments, the plurality of particles has an X50 in the range of 1 pm to less than 2 pm. In some embodiments, the plurality of particles has an X50 in the range of 1 pm to 1.5 pm. In some embodiments, the plurality of particles has an X50 of 1 pm, 1.05 pm, 1.1 pm, 1.15 pm, 1.2 pm, 1.25 pm, 1.3 pm, 1.35 pm, 1.4 pm, 1.45 pm, 1.5 pm, 1.55 pm, 1.6 pm, 1.65 pm, 1.7 pm, 1.75 pm, 1.8 pm, 1.85 pm, 1.9 pm, or 1.95 pm.

[0179] In some embodiments, the plurality of particles has an X10 of less than 1 pm. In some embodiments, the plurality of particles has an X10 in the range of 0.5 pm to 0.9 pm. In some embodiments, the plurality of particles has an X10 of 0.5 pm, 0.55 pm, 0.6 pm, 0.65 pm, 0.7 pm, 0.75 pm, 0.8 pm, 0.85 pm, 0.9 pm, or 0.95 pm.

[0180] In some embodiments, the plurality of particles has an X90 in the range of 2.5 pm to 4 pm, an X50 of less than 2 pm, and an X10 of less than 1 pm. In some embodiments, the plurality of particles has an X90 in the range of 2.5 pm to 3.5 pm, an X50 in the range of 1 pm to 1.5 pm, and an X10 in the range of 0.5 pm to 0.9 pm. In some embodiments, the plurality of particles has an X90 in the range of 3 pm to 4 pm, an X50 in the range of 1 pm to 1.5 pm, and an X10 in the range of 0.5 pm to 0.9 pm.

[0181] In some embodiments, the dry powder composition has a fine particle fraction (FPF) of greater than or equal to 40%. In some embodiments, the dry powder composition has a FPF of greater than or equal to 50%. In some embodiments, the dry powder composition has a FPF of greater than or equal to 60%. In some embodiments, the dry powder composition has a FPF of greater than or equal to 70%. In some embodiments, the dry powder composition has a FPF of greater than or equal to 80%. In some embodiments, the dry powder composition has a FPF in the range of 40% to 95%. In some embodiments, the dry powder composition has a FPF in the range of 40% to 90%. In some embodiments, the dry powder composition has a FPF in the range of 45% to 95%. In some embodiments, the dry powder composition has a FPF in the range of 50% to 95%. In some embodiments, the dry powder composition has a FPF in the range of 55% to 95%. In some embodiments, the dry powder composition has a FPF in the range of 60% to 95%. In some embodiments, the dry powder composition has a FPF in the range of 65% to 95%. In some embodiments, the dry powder composition has a FPF in the range of 70% to 95%. In some embodiments,the dry powder composition has a FPF in the range of 75% to 95%. In some embodiments, the dry powder composition has a FPF in the range of 80% to 95%. In some embodiments, the dry powder composition has a FPF in the range of 85% to 95%.

[0182] In some embodiments, the dry powder composition has a FPF of 40%, 41%,42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%.

[0183] In some embodiments, a tapped density of a dry powder composition disclosed herein is in the range of 0.1 g / cm3to 0.2 g / cm3, such as, e.g., a tapped density in the range of 0.125 g / cm3to 0.175 g / cm3. In some embodiments, the tapped density is 0.1 g / cm3, 0.105 g / cm3, 0.11 g / cm3, 0.115 g / cm3, 0.12 g / cm3, 0.125 g / cm3, 0.13 g / cm3, 0.135 g / cm3, 0.14 g / cm3, 0.145 g / cm3, 0.15 g / cm3, 0.155 g / cm3, 0.16 g / cm3, 0.165 g / cm3, 0.17 g / cm3, 0.175 g / cm3, 0.18 g / cm3, 0.185 g / cm3, 0.19 g / cm3, 0.195 g / cm3, or 0.2 g / cm3.

[0184] In some embodiments, a bulk density of a dry powder composition disclosed herein is less than or equal to 0.1 g / cm3, such as, e.g., a bulk density in the range of 0.05 g / cm3to 0.1 g / cm3. In some embodiments, the bulk density is 0.01 g / cm3, 0.015 g / cm3, 0.02 g / cm3, 0.025 g / cm3, 0.03 g / cm3, 0.035 g / cm3, 0.04 g / cm3, 0.045 g / cm3, 0.05 g / cm3, 0.055 g / cm3, 0.06 g / cm3, 0.065 g / cm3, 0.07 g / cm3, 0.075 g / cm3, 0.08 g / cm3, 0.085 g / cm3, 0.09 g / cm3, 0.095 g / cm3, or 0.1 g / cm3.

[0185] In some embodiments, the dry powder composition has a tapped density in the range of 0.1 g / cm3to 0.2 g / cm3, such as, e.g., in the range of 0.125 g / cm3to 0.175 g / cm3, and a bulk density of less than or equal to 0.1 g / cm3, such as, e.g., a bulk density in the range of 0.05 g / cm3to 0.1 g / cm3. In some embodiments, the dry powder composition has a tapped density in the range of 0.125 g / cm3to 0.175 g / cm3and a bulk density in the range of 0.05 g / cm3to 0.1 g / cm3.

[0186] In some embodiments, the dry powder composition has a FPF of greater than or equal to 40%, a bulk density of less than or equal to 0.1 g / cm3, and a tapped density in the range of 0.1 g / cm3to 0.2 g / cm3. In some embodiments, the dry powder composition has a FPF in the range of 60% to 90%, a bulk density in the range of 0.05 g / cm3to 0.1 g / cm3, and a tapped density in the range of 0.125 g / cm3to 0.175 g / cm3.

[0187] In some embodiments, a dry powder composition of the present disclosure has a glass transition temperature in the range of 40 °C to 90 °C. In some embodiments, the glass transition temperature is in the range of 40 °C to 85 °C. In some embodiments, the glass transition temperature is in the range of 40 °C to 80 °C. In some embodiments, the glass transition temperature is in the range of 70 °C to 90 °C. In some embodiments, the glass transition temperature is in the range of 75 °C to 85 °C. In some embodiments, the glass transition temperature is 70 °C, 71 °C, 72 °C, 73 °C, 74 °C, 75 °C, 76 °C, 77 °C, 78 °C, 79 °C, 80 °C, 81 °C, 82 °C, 83 °C, 84 °C, 85 °C, 86 °C, 87 °C, 88 °C, 89 °C, or 90 °C.DRY POWDER INHALER DEVICES, UNIT DOSE PACKAGES, AND BLISTER PACKAGES

[0188] Dry powder inhalers are commonly used to deliver a fine mist or aerosol of dry powder for inhalation by a subject. Dry powder in the device is actuated either by inspiration or by some external delivery force, such as pressurized air, to produce the fine mist or aerosol, which can then be inhaled by the subject for targeted delivery to the lungs. Dry powder inhalers of the present disclosure can be single-dose inhalers or may contain a reservoir capable of metering multiple doses.

[0189] Some embodiments of the present disclosure are directed to dry powder inhalers comprising a dry powder composition disclosed herein. The dry powder inhaler can be a single-use inhaler or a multi-use inhaler. For a single-use inhaler, the dry powder composition can be stored in a unit dose package, such as a unit dose blister package or a capsule, that is inserted into the single-use inhaler prior to use. For a multi-use inhaler, a patient can load a blister package (e.g., a cartridge, strip, or wheel) containing multiple doses into the multi-use inhaler, or the multi-use inhaler may come prepackaged with a reservoir containing multiple doses.

[0190] Single-dose dry powder inhalers that can be used with dry powder compositions disclosed herein include, but are not limited to, those disclosed in U.S. Patent No. 3,991,761, U.S. Patent No. 7,559,325, U.S. Patent No. 8,069,851, U.S. Patent Appln. Pub. No. 2007 / 0295332, and U.S. Patent Appln. Pub. No. 2010 / 0108058. Non-limiting examples of single-dose dry powder inhalers include the AEROLIZER™ and BREEZHALER™ inhalers.

[0191] Multi-dose dry powder inhalers that can be used with dry powder compositions disclosed herein include, but are not limited to, those described in U.S. PatentNo. 6,536,427, EP 0258238, WO 93 / 00123, WO 94 / 14492, WO 97 / 25086, WO 97 / 30743, WO 03 / 77979, WO 05 / 14089, WO 05 / 37353. Non-limiting examples of multi-dose dry powder inhalers include the DISKUS™, DISKHALER™, GEMINI™, GYROHALER™, PROHALER™, TWISTHALER™, TURBOHALER™, CLICKHALER®, and NOVOLIZER® inhalers.

[0192] In some embodiments, the dry powder inhaler further comprises a means for introducing the dry powder composition into a subject via inhalation. In some embodiments, the dry powder inhaler comprises a mechanism that crushes a unit dose package or a portion of a blister package to disperse a unit dose of the dry powder composition into a dosing chamber of the dry powder inhaler.

[0193] In some embodiments, the dry powder composition is deliverable at an emitted fraction of at least 60% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction of at least 65% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction of at least 70% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction of at least 75% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction of at least 80% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction of at least 85% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction in the range of 60% to 95% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction in the range of 65% to 95% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction in the range of 70% to 95% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction in the range of 75% to 95% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction in the range of 80% to 95% in the dry powder inhaler. In some embodiments, the dry powder composition is deliverable at an emitted fraction in the range of 85% to 95% in the dry powder inhaler.

[0194] Some embodiments of the present disclosure relate to a unit dose package comprising a reservoir containing a unit dose of a dry particle composition disclosed herein. In some embodiments, the unit dose package is insertable into a dry powder inhaler (e.g., a single-use inhaler). In some embodiments, the unit dose package is a capsule (e.g., a gelatincapsule) or a foil-foil blister package. In some embodiments, the unit dose package is a capsule. In some embodiments, the unit dose package is a gelatin capsule. In some embodiments, the unit dose package is a foil-foil blister package.

[0195] Additional embodiments of the present disclosure relate to a blister package comprising multiple unit doses of a dry particle composition disclosed herein. In some embodiments, the blister package is insertable into a dry powder inhaler. In some embodiments, the blister package contains two or more reservoirs, wherein each reservoir contains a unit dose of the dry powder composition. When a multi-dose dry powder inhaler comprising the blister package is pierced, its contents are dispersed into the dosing chamber of the multi-dose dry powder inhaler. In some embodiments, the blister package is a foil-foil aluminum strip. In some embodiments, the blister package is a wheel. In some embodiments, the blister package is a cartridge.TREATMENT METHODS

[0196] Dry powder compositions of the present disclosure can be used in the treatment of certain diseases, including respiratory diseases, by enabling pulmonary delivery of an antibody or an antibody fragment. Accordingly, also disclosed are methods of treatment of a disease, including a respiratory disease, comprising administering a dry powder composition, including any dry powder composition disclosed herein, to a patient. In some embodiments, a dry powder composition of the present disclosure can be used to treat an obstructive or inflammatory airways disease, such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, bronchiectasis, or cystic fibrosis, or a lung disease, such as pulmonary arterial hypertension.

[0197] In some embodiments, a dry powder composition of the present disclosure is for use in treating a disease selected from COPD, asthma, idiopathic pulmonary fibrosis, bronchiectasis, cystic fibrosis, and pulmonary arterial hypertension. In some embodiments, the dry powder composition is for use in treating COPD. In some embodiments, the dry powder composition is for use in treating asthma. In some embodiments, the dry powder composition is for use in treating idiopathic pulmonary fibrosis. In some embodiments, the dry powder composition is for use in treating bronchiectasis. In some embodiments, the dry powder composition is for use in treating cystic fibrosis. In some embodiments, the dry powder composition is for use in treating pulmonary arterial hypertension.

[0198] A dry powder composition of the present disclosure can be delivered to a subject in need of such delivery using a dry powder inhaler described herein, or an alternative delivery vehicle (e.g., a metered dose inhaler that utilizes a propellant, e.g., a hydrofluorocarbon) .

[0199] In certain instances, it will be desirable to have multiple administrations of the composition, e.g., 2, 3, 4, 5, 6 or more, or any ranges derivable therein, administrations. The administrations can be at 1, 2, 3, 4, 5, 6, 7, 8, to 5, 6, 7, 8, 9, 10, 11, or 12 day, week, month, or year intervals, including all ranges there between.

[0200] The quantity to be administered, both according to number of treatments and unit dose, depends on the treatment effect desired. An effective dose is understood to refer to an amount necessary to achieve a particular effect. In some embodiments, the effective dose is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, or 100 mg of the dry powder composition, including all ranges there between. In some embodiments, the effective dose is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg of the antibody, including all ranges there between. Precise amounts of the therapeutic composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the patient, the route of administration, the intended goal of treatment (e.g., alleviation of symptoms versus cure) and the potency, stability, and toxicity of the particular therapeutic substance or other therapies a subject may be undergoing.METHODS OF PREPARING DRY POWDER COMPOSITIONS

[0201] Dry powder compositions of the present disclosure can be prepared by spray drying. For example, in some embodiments, a dry powder composition of the present disclosure can be manufactured by preparing an emulsion comprising a blowing agent, an antibody or an antibody fragment, a phospholipid, a polyvalent cation, a non-ionicsurfactant, and a buffering agent; spray drying the emulsion using a spray dryer to produce a dry powder composition described herein; isolating the dry powder composition; and optionally employing a secondary drying process post-spray drying.

[0202] In some embodiments, the blowing agent is a pharmaceutically acceptable volatile liquid that is not miscible with water.

[0203] In some embodiments, the blowing agent is a fluorinated blowing agent. Fluorinated blowing agents (which may be retained to some extent in spray-dried powders) can provide resistance to particle charging and promote a surface rough, porous particle morphology. In some embodiments, the fluorinated blowing agent comprises from 1 to 16 carbon atoms and includes, but is not limited to, linear, cyclic, or polycyclic perfluoroalkanes, bis(perfluoroalkyl)alkenes, perfluoroethers, perfluoroamines, perfluoroalkyl bromides, and perfluoroalkyl chlorides, such as dichlorooctane. In some embodiments, the blowing agent is selected from perfluorohexane, perfluorooctyl bromide, perfluorodecalin, perfluorotripropylamine, dichlorofluorooctane, perfluorooctyl ethane, and combinations of any of the foregoing. In some embodiments, the blowing agent is perfluorooctyl bromide. In some embodiments, the blowing agent is perfluorodecalin. In some embodiments, the blowing agent is perfluorotripropylamine. In some embodiments, the blowing agent is perfluorooctyl ethane.EMULSION PREPARATION

[0204] In some embodiments, preparing an emulsion comprising the blowing agent, the antibody or the antibody fragment, the phospholipid, the polyvalent cation, the nonionic surfactant, and the buffering agent comprises preparing a lipid emulsion comprising the blowing agent, the phospholipid, and water; preparing a buffered solution comprising the antibody or the antibody fragment, the polyvalent cation, the non-ionic surfactant, and the buffering agent; and combining the lipid emulsion and the buffered solution to obtain the emulsion to be spray dried. In some embodiments, the buffered solution can be filtered (e.g., through a sterile filter) prior to the combining.

[0205] In some embodiments, preparing the lipid emulsion comprises homogenizing the blowing agent, the phospholipid, and water using a microfluidizer or a homogenizer with a Y-shaped interaction chamber. In some embodiments, the blowing agent, the phospholipid, and water can be homogenized using a mechanical mixer to produce a coarselipid emulsion and the coarse lipid emulsion can then be homogenized using the microfluidizer or homogenizer to produce the lipid emulsion.

[0206] In some embodiments, the phospholipid can be initially homogenized in water using a mechanical mixer. In some embodiments, the temperature of the water when homogenizing with the phospholipid can greater than or equal to 60 °C (e.g., greater than or equal to 65 °C, greater than or equal to 70 °C, greater than or equal to 75 °C, greater than or equal to 80 °C, greater than or equal to 85 °C, greater than or equal to 90 °C, 61 °C, 62 °C, 63 °C, 64 °C, 65 °C, 66 °C, 67 °C, 68 °C, 69 °C, 70 °C, 71 °C, 72 °C, 73 °C, 74 °C, 75 °C, 76 °C, 77 °C, 78 °C, 79 °C, 80 °C, 81 °C, 82 °C, 83 °C, 84 °C, 85 °C, 86 °C, 87 °C, 88 °C, 89 °C, 90 °C, 91 °C, 92 °C, 93 °C, 94 °C, 95 °C, 96 °C, 97 °C, 98 °C, 99 °C, 100 °C). In some embodiments, the mechanical mixer can be operated at 5000 rpm to 10,000 rpm (e.g., 5000 rpm, 5500 rpm, 6000 rpm, 6500 rpm, 7000 rpm, 7500 rpm, 8000 rpm, 8500 rpm, 9000 rpm, 9500 rpm, 10000 rpm) for a time in the range of 2 minutes to 10 minutes (e.g., 2 minutes to 5 minutes, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes). In some embodiments, the blowing agent can be added during mechanical mixer operation. In some embodiments, the blowing agent can be added dropwise during mechanical mixer operation.

[0207] In some embodiments, preparing the lipid emulsion comprises homogenizing using a microfluidizer or a homogenizer with a Y-shaped interaction chamber at a pressure in the range of 10,000 psi to 25,000 psi. In some embodiments, the pressure is in the range of 15,000 psi to 20,000 psi. In some embodiments, the pressure is in the range of 12,000 psi to 18,000 psi. In some embodiments, the pressure is 10,000 psi, 10,500 psi, 11,000 psi, 11,500 psi, 12,000 psi, 12,500 psi, 13,000 psi, 13,500 psi, 14,000 psi, 14,500 psi, 15,000 psi, 15,500 psi, 16,000 psi, 16,500 psi, 17,000 psi, 17,500 psi, 18,000 psi, 18,500 psi, 19,000 psi, 19,500 psi, 20,000 psi, 20,500 psi, 21,000 psi, 21,500 psi, 22,000 psi, 22,500 psi, 23,000 psi, 23,500 psi, 24,000 psi, 24,500 psi, or 25,000 psi.

[0208] In some embodiments, the microfluidizer or the homogenizer is operated for 3, 4, 5, or 6 discrete passes. In some embodiments, the microfluidizer or the homogenizer is operated for 3 discrete passes. In some embodiments, the microfluidizer or the homogenizer is operated for 4 discrete passes. In some embodiments, the microfluidizer or the homogenizer is operated for 5 discrete passes. In some embodiments, the microfluidizer or the homogenizer is operated for 6 discrete passes.

[0209] Microfluidizers and homogenizers that can be used in these methods are commercially available, for example, from Microfluidics International Corporation. Mechanical mixers that can be used in these methods are also commercially available, for example, from IKA-Werke GmbH & Co. (such as, e.g., Ultra-Turrax™ mixers).

[0210] In alternative embodiments, the antibody or the antibody fragment, the polyvalent cation, the non-ionic surfactant, and the buffering agent can be solubilized or dispersed directly in the lipid emulsion without preparing a separate buffered solution.SPRAY DRYING

[0211] Spray drying is a process in which a solution or emulsion is atomized into droplets, which can be dried in a gas stream (e.g., a stream of air, nitrogen, argon, carbon dioxide, helium, or combinations of any of the foregoing) to form particles. Commercially available spray dryers (e.g., spray dryers manufactured by Biichi Ltd. and Niro, Inc.) suitable for use in producing dry powder compositions of the present disclosure are known to those in the art.

[0212] Operating conditions for spray drying, such as inlet and outlet temperature, feed rate, atomization pressure, flow rate of the drying air, and nozzle configuration can be adjusted to produce particles with specific physical properties while maintaining the bioactivity of an antibody or antibody fragment.

[0213] In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 150 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 140 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 130 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 120 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 110 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 100 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 95 °C. In some embodiments, the inlet temperature of the spray dryer is set at 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C, 140 °C, 145 °C, or 150 °C. In some embodiments, the inlet temperature of the spray dryer is set at 90 °C.

[0214] In some embodiments, the outlet temperature of the spray dryer is set at a temperature of less than 80 °C. In some embodiments, the outlet temperature of the spray dryer is set at a temperature of less than 60 °C.

[0215] In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 150 °C, and the outlet temperature of the spray dryer is set at a temperature of less than 80 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 150 °C, and the outlet temperature of the spray dryer is set at a temperature of less than 60 °C.

[0216] In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 95 °C, and the outlet temperature of the spray dryer is set at a temperature of less than 80 °C. In some embodiments, the inlet temperature of the spray dryer is set at a temperature in the range of 85 °C to 95 °C, and the outlet temperature of the spray dryer is set at a temperature of less than 60 °C.

[0217] In some embodiments, a flow rate of the emulsion during spray drying is in the range of 1 mL / min to 10 mL / min. In some embodiments, the flow rate of the emulsion is in the range of 2 mL / min to 9 mL / min. In some embodiments, the flow rate of the emulsion is in the range of 3 mL / min to 8 mL / min. In some embodiments, the flow rate of the emulsion is in the range of 4 mL / min to 7 mL / min. In some embodiments, the flow rate of the emulsion is in the range of 4.5 mL / min to 6.5 mL / min. In some embodiments, the flow rate of the emulsion is 1 mL / min, 1.25 mL / min, 1.5 mL / min, 1.75 mL / min, 2 mL / min, 2.25 mL / min, 2.5 mL / min, 2.75 mL / min, 3 mL / min, 3.25 mL / min, 3.5 mL / min, 3.75 mL / min, 4 mL / min, 4.25 mL / min, 4.5 mL / min, 4.75 mL / min, 5 mL / min, 5.25 mL / min, 5.5 mL / min, 5.75 mL / min, 6 mL / min, 6.25 mL / min, 6.5 mL / min, 6.75 mL / min, 7 mL / min, 7.25 mL / min, 7.5 mL / min, 7.75 mL / min, 8 mL / min, 8.25 mL / min, 8.5 mL / min, 8.75 mL / min, 9 mL / min, 9.25 mL / min, 9.5 mL / min, 9.75 mL / min, or 10 mL / min. In some embodiments, the flow rate of the emulsion is 5.5 mL / min.

[0218] In some embodiments, a nitrogen flow during spray drying is in the range of 25 mm to 75 mm. In some embodiments, the nitrogen flow is in the range of 35 mm to 65 mm. In some embodiments, the nitrogen flow is in the range of 60 mm to 75 mm. In some embodiments, the nitrogen flow is 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70 mm, or 75 mm. In some embodiments, the nitrogen flow is 65 mm.SECONDARY DRYING

[0219] In some embodiments, the spray drying process can followed by a secondary drying process to reduce residual solvent levels (e.g., residual water and / or blowing agent levels).

[0220] In some embodiments, the secondary drying process is vacuum drying.

[0221] In some embodiments, the secondary drying process is vacuum drying using a lyophilizer. In some embodiments, the secondary drying process is water-assisted vacuum drying. In some embodiments, the secondary drying is methanol-assisted vacuum drying.

[0222] In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 24 hours at a temperature in the range of 30 °C to 50 °C and a pressure in the range of 40 mBar to 60 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 48 hours at a temperature in the range of 30 °C to 50 °C and a pressure in the range of 40 mBar to 60 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for 48 hours at a temperature in the range of 30 °C to 50 °C and a pressure in the range of 40 mBar to 60 mBar.

[0223] In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 24 hours at a temperature in the range of 35 °C to 45 °C and a pressure in the range of 40 mBar to 60 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 48 hours at a temperature in the range of 35 °C to 45 °C and a pressure in the range of 40 mBar to 60 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for 48 hours at a temperature in the range of 35 °C to 45 °C and a pressure in the range of 40 mBar to 60 mBar. In some embodiments, the pressure is in the range of 40 mBar to 50 mBar.

[0224] In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 24 hours at a temperature in the range of 30 °C to 50 °C and a pressure in the range of 40 mBar to 50 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 48 hours at a temperature in the range of 30 °C to 50 °C and a pressure in the range of 40 mBar to 50 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for 48 hours at a temperature in the range of 30 °C to50 °C and a pressure in the range of 40 mBar to 50 mBar. In some embodiments, the temperature is in the range of 35 °C to 45 °C.

[0225] In some embodiments, the temperature is 35 °C, 35.5 °C, 36 °C, 36.5 °C, 37 °C, 37.5 °C, 38 °C, 38.5 °C, 39 °C, 39.5 °C, 40 °C, 40.5 °C, 41 °C, 41.5 °C, 42 °C, 42.5 °C,43 °C, 43.5 °C, 44 °C, 44.5 °C, or 45 °C.

[0226] In some embodiments, the pressure is 40 mBar, 41 mBar, 42 mBar, 43 mBar,44 mBar, 45 mBar, 46 mBar, 47 mBar, 48 mBar, 49 mBar, or 50 mBar.

[0227] In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 6 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 80 mBar to 120 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 12 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 80 mBar to 120 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for 12 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 80 mBar to 120 mBar.

[0228] In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 6 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 90 mBar to 110 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for at least 12 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 90 mBar to 110 mBar. In some embodiments, the secondary drying process comprises vacuum drying the dry powder composition for 12 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 90 mBar to 110 mBar. In some embodiments, the temperature is in the range of -45 °C to -35 °C. In some embodiments, the pressure is in the range of 95 mBar to 105 mBar.

[0229] In some embodiments, the temperature is -50 °C, -49.5 °C, -49 °C, -48.5 °C, - 48 °C,-47.5 °C, -47 °C, -46.5 °C, -46 °C, -45.5 °C, -45 °C, -44.5 °C, -44 °C, -43.5 °C, - 43 °C, -42.5 °C,-42 °C, -41.5 °C, -41 °C, -40.5 °C, -40 °C, -39.5 °C, -39 °C, -38.5 °C, -38 °C, -37.5 °C, - 37 °C,-36.5 °C, -36 °C, -35.5 °C, -35 °C, -34.5 °C, -34 °C, -33.5 °C, -33 °C, -32.5 °C, -32 °C, -31.5 °C,-31 °C, -30.5 °C, or -30 °C. In some embodiments, the temperature is -40 °C.

[0230] In some embodiments, the pressure is 95 mBar, 96 mBar, 97 mBar, 98 mBar, 99 mBar, 100 mBar, 101 mBar, 102 mBar, 103 mBar, 104 mBar, 105 mBar, 106 mBar, 107 mBar, 108 mBar, 109 mBar, or 110 mBar. In some embodiments, the pressure is 100 mBar.

[0231] In some embodiments, a residual solvent content (e.g., a total residual solvent content) of the dry powder composition following the secondary drying process is less than or equal to 7% w / w. In some embodiments, the residual solvent content is less than or equal to 6.5% w / w. In some embodiments, the residual solvent content is less than or equal to 6% w / w. In some embodiments, the residual solvent content is less than or equal to 5.5% w / w.In some embodiments, the residual solvent content is less than or equal to 5% w / w. In some embodiments, the residual solvent content is less than or equal to 4.5% w / w. In some embodiments, the residual solvent content is less than or equal to 4% w / w. In some embodiments, the residual solvent content is less than or equal to 3.5% w / w. In some embodiments, the residual solvent content is less than or equal to 3% w / w. In some embodiments, the residual solvent content is less than or equal to 2.5% w / w. In some embodiments, the residual solvent content is less than or equal to 2% w / w. In some embodiments, the residual solvent content is less than or equal to 1.5% w / w. In some embodiments, the residual solvent content is less than or equal to 1% w / w. In some embodiments, the residual solvent content is less than or equal to 0.5% w / w. In some embodiments, the residual solvent content is 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w,0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2.0% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 2.9% w / w, 3.0% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.8% w / w, 3.9% w / w, 4.0% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w, 4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, 5.0% w / w, 5.1% w / w, 5.2% w / w, 5.3% w / w, 5.4% w / w, 5.5% w / w, 5.6% w / w, 5.7% w / w, 5.8% w / w, 5.9% w / w, 6.0% w / w, 6.1% w / w, 6.2% w / w, 6.3% w / w, 6.4% w / w, 6.5% w / w, 6.6% w / w, 6.7% w / w, 6.8% w / w, 6.9% w / w, or 7.0% w / w.

[0232] In some embodiments, a water content of the dry powder composition following the secondary drying process is less than or equal to 5% w / w. In some embodiments, thewater content is less than or equal to 4.5% w / w. In some embodiments, the water content is less than or equal to 4% w / w. In some embodiments, the water content is less than or equal to 3.5% w / w. In some embodiments, the water content is less than or equal to 3% w / w. In some embodiments, the water content is less than or equal to 2.5% w / w. In some embodiments, the water content is less than or equal to 2% w / w. In some embodiments, the water content is less than or equal to 1.5% w / w. In some embodiments, the water content is less than or equal to 1% w / w. In some embodiments, the water content is less than or equal to 0.5% w / w. In some embodiments, the water content is 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2.0% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 2.9% w / w, 3.0% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.8% w / w, 3.9% w / w, 4.0% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w, 4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, or 5.0% w / w.

[0233] In some embodiments, an organic solvent content of the dry powder composition following the secondary drying process is less than or equal to 5% w / w. In some embodiments, the organic solvent content is less than or equal to 4.5% w / w. In some embodiments, the organic solvent content is less than or equal to 4% w / w. In some embodiments, the organic solvent content is less than or equal to 3.5% w / w. In some embodiments, the organic solvent content is less than or equal to 3% w / w. In some embodiments, the organic solvent content is less than or equal to 2.5% w / w. In some embodiments, the organic solvent content is less than or equal to 2% w / w. In some embodiments, the organic solvent content is less than or equal to 1.5% w / w. In some embodiments, the organic solvent content is less than or equal to 1% w / w. In some embodiments, the organic solvent content is less than or equal to 0.5% w / w. In some embodiments, the organic solvent content is 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w,0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w,1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2.0% w / w,2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w,2.9% w / w, 3.0% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w,3.7% w / w, 3.8% w / w, 3.9% w / w, 4.0% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w, 4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, or 5.0% w / w.

[0234] In some embodiments, a blowing agent content of the dry powder composition following the secondary drying process is less than or equal to 5% w / w. In some embodiments, the blowing agent content is less than or equal to 4.5% w / w. In some embodiments, the blowing agent content is less than or equal to 4% w / w. In some embodiments, the blowing agent content is less than or equal to 3.5% w / w. In some embodiments, the blowing agent content is less than or equal to 3% w / w. In some embodiments, the blowing agent content is less than or equal to 2.5% w / w. In some embodiments, the blowing agent content is less than or equal to 2% w / w. In some embodiments, the blowing agent content is less than or equal to 1.5% w / w. In some embodiments, the blowing agent content is less than or equal to 1% w / w. In some embodiments, the blowing agent content is less than or equal to 0.5% w / w. In some embodiments, the blowing agent content is 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.1% w / w, 1.2% w / w,1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2.0% w / w,2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w,2.9% w / w, 3.0% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w,3.7% w / w, 3.8% w / w, 3.9% w / w, 4.0% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w,4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, or 5.0% w / w.

[0235] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art will appreciate readily that the present disclosure is well- adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends, and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.EXAMPLES

[0236] This section provides specific examples of dry powder compositions of the present disclosure and methods of making the same.List of AbbreviationsSECTION 1 : Formulation Design Space

[0237] Provided in this section is a description of a design of experiments study evaluating the formulation design space for phospholipid-based dry powder compositions comprising an IgGl antibody, as well as a follow-up study assessing the physicochemical and stability properties of certain dry powder compositions (FIG. 1).

[0238] Materials: l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) was purchased from Avanti Polar Eipids (Birmingham, Alabama). Poloxamer-188 was purchased fromCroda (Snaith, United Kingdom). Calcium chloride was purchased from Spectrum Chemicals (New Brunswick, New Jersey). L-histidine was purchased from Sigma Aldrich (Saint Louis, Missouri). Perfluorooctyl bromide (PFOB) was purchased from TCI Chemicals (Tokyo, Japan). The model Immunoglobulin G1 (IgGl) antibody was provided by Amgen Inc. (Thousand Oaks, California). Prior to spray drying, the IgGl antibody was stored in 1 mM L-histidine buffer.

[0239] Formulation Processing: The formulations were processed by high-pressure homogenization using the Microfluidizer® (Idex Material Processing Technologies, Ontario, Canada), and the final dry powders were prepared using spray drying (BUCHI Corporation, Delaware, United States) (FIG. 2). Briefly, DSPC was homogenized with water and PFOB using the Ultra-Turrax™ (Ika-Werke, Staufen, Germany) at 8,000 rpm for 5 minutes at 80 °C. This coarse emulsion was then homogenized using the Microfluidizer® at 18,000 psi for 4 discrete passes. In a separate vial, the IgG antibody was mixed with poloxamer-188 and calcium chloride in histidine buffer. A portion of the emulsion was added to the IgG solution to form the final feedstock. The spray drying conditions for all the formulations in this study were kept constant. Briefly, the inlet temperature was maintained at 85 °C, the feed flow rate was set to 1.5 mL / min, and the nitrogen flow rate was kept constant at 740 L / hr. Preliminary experiments were conducted to define constraints for each of the components. Following preliminary studies, the constraints for each component of the formulation were established as: DSPC 10-60% w / w; IgG 30-90% w / w; poloxamer-188 0-1% w / w; and calcium chloride 0-7.5% w / w. The histidine concentration was held constant at 1.74% w / w. These mass (w / w) percentages are calculated based on the theoretical weight of only the dry formulation components. Mass (w / w) percentages used in these examples to describe formulation composition are also calculated based on the theoretical weight of only the dry formulation components.

[0240] Design of Experiments (DoE): A design of experiments approach, specifically a mixture design approach, was utilized to assess the constraints on the solid components. Design Expert® (Stat-Ease, Minneapolis, United States) software was used to obtain the matrix of different formulation compositions. The formulation compositions tested are provided in Table 1.Table 1. Formulation Compositions Using a Mixture DoE Approach

[0241] Size Exclusion Chromatography (SEC): The prepared powders were reconstituted in sodium phosphate buffer (pH 6.7) at a concentration of 0.3 mg / mL. The level of high molecular weight (HMW) aggregates and low molecular weight (LMW) fragments were detected using high-performance liquid chromatography (HPLC; Thermo Scientific™ Dionex™) at a wavelength of 280 nm, using a 75 pL injection volume for a run time of 40 minutes.

[0242] Aerosol Performance via Fast Screening Impactor: The aerosol performance of the powders was screened using a Fast Screening Impactor (FSI) (Copley Scientific, Nottingham, United Kingdom). In brief, the Plastiape® RS01 high resistance device (RS01 DPI; Plastiape, Osnago LC, Italy) was run at 60 L / min using a pre-seperator insert corresponding to the flow rate for a period of time equivalent to pass 4 L of air across the device. The pressure drop across the device was approximately 4 kPa. The amount of IgG deposited in each stage was quantified using an ultraviolet-visible spectrophotometer (Tecan) at a wavelength of 280 nm.

[0243] Selection and Measurement of Dose: The amount of powder and thus IgG capable of being loaded on to a size 3 capsule was measured. Powders from each formulation were added to a size 3 HPMC capsule until three-quarters of the capsule was filled. For accuracy, a marking was made in the capsule shell and was used for allformulations. The amount of IgG delivered per dose for each formulation was then calculated based on the IgG loading.

[0244] Selection of Formulations for Further Study: The primary response variables for the screening study were the stability and aerosol performance of IgG, as well as the amount of powder and thus the IgG dose capable of being filled into a size 3 HPMC capsule. Based on the model chosen and the dosing requirements for an inhaled monoclonal antibody product, three formulations were chosen for further analysis and stability studies. The criteria for selection of these formulations were having a fine particle dose (FPD) of about 10 mg of IgG while considering both the IgG loading and amount capable of being loaded in the capsule and maintaining a less than 2% decline in stability after processing. Batches of IgG alone and in combination with poloxamer-188 were spray dried as control formulation. A separate control of vacuum-dried protein was also included in the study.

[0245] Measurement of Primary Particle Size: The primary geometric particle size was measured by laser diffraction using a HELOS RODOS (Sympatec GmbH, Germany) dry dispersion unit. The powders were dispersed at 3 bar and 1 bar, where the optical concentration is between 5 and 25%

[0246] Powder Flow: Powder flow properties such as bulk and tapped density were measured using a 2 mL flat bottomed tube that was calibrated to 0.25 mL. Due to the limited amount of powder available, a 1 mL volume was used for the bulk and tapped density measurements. Briefly, powder was added to the tube until the 1 mL mark was reached and then the tube was weighed. Tapped density was determined by tapping 50 times and then recording the volume. Bulk and tapped density were measured in triplicate, and the compressibility index (CI) was calculated from it as per equation (1).Compressibility Index (Cl) =

[0247] Specific Surface Area (SSA): A single point dynamic flow method was used to evaluate the surface area of the prepared formulations. Briefly, samples were initially degassed using a Thermoflow™ degasser (Qunatachrome Instruments, USA) at 35 °C for 72 hours. After degassing, the surface area of the prepared powders was analyzed based on the physical adsorption of nitrogen gas on the surface of the powders while submerged in liquid nitrogen using the Braummer-Emmett-Teller method (Monosorb, Quantachrome Instruments, USA). Measurements were made until consecutive measurements differed byless than 5%. The resultant surface area was normalized to the sample weight to obtain the specific surface area.

[0248] X-Ray Powder Diffraction (XRPD): Powder x-ray diffraction was conducted on about 10 mg of powder using a Rigaku MiniFlex II (Rigaku, The Woodlands, TX, USA) at 40 kV and 15 mA. The samples were scanned from 5-45° at a rate of 27min using a step size of 0.025°.

[0249] Modulated Differential Scanning Calorimetry (mDSC): The thermal behavior of the prepared powders was assessed using a Q20 DSC (TA Instruments, New Castle, DE, USA). 5-10 mg of powder was placed in a hermetically sealed Tzero pan (DSC Consumables Incorporated, Austin, MN, USA). In a modulated DSC setup, the sample was cooled to -30°C and held isothermally for 5 min, and then heated to 200°C at a ramp rate of 2°C / min while being modulated by about 0.3 °C every 60 s, under a nitrogen flow of 50 mL / min. The thermal behavior of individual components was also assessed to identify each component in the formulation.

[0250] Scanning Electron Microscopy (SEM): Photomicrographs of the powders were taken using a FEI Quanta™ 650 FEG SEM located in Portland, Oregon, USA to observe the morphology. The powder samples were added onto a conductive carbon tape and sputter coated with gold for 1 minute. Images of the powders were taken under high vacuum conditions.

[0251] Dynamic Vapor Sorption (DVS): The moisture sorption and desorption properties of the samples were evaluated using a DVS Adventure instrument (Surface Measurement Systems, UK). A known mass of each sample was mounted on a microbalance in a chamber with controlled temperature and humidity. Samples were evaluated through a desorption phase from 40% to 0% RH, followed by a sorption phase from 0% to 75% RH, followed by desorption from 75% to 40% RH. Humidity was changed in 10% steps with an equilibrium condition set to less than 0.002% total mass change.

[0252] Water Content (Karl Fischer (KF)): Residual water content in the prepared formulations was evaluated using coulometric Karl Fischer titration using a C20 titrator (Mettler Toledo, OH, USA). About 15 mg of each sample was dispersed in 2 mL methanol and agitated for 30 min at 75 rpm using an orbital shaker to extract residual water. Afterward, samples were filtered using 0.45 pm syringe filters. Analysis was done byinjecting 0.5 mL of the filtered solution. All samples were measured in triplicate and measurements reported as mean ± standard deviation.

[0253] Aerosol Performance Testing: The complete aerodynamic particle size distribution (APSD) of each IgG powder and control was measured using a Next Generation Impactor (NGI) (Copley Scientific, Nottingham, United Kingdom). Prior to the start of experiments, all stages were coated with 1% v / v glycerin in ethanol and allowed to dry. A USP throat was used in the setup without a pre-separator for all experiments. Processed powders were dispersed using the Plastiape™ RS01 high resistance device (RS01 DPI; Plastiape, Osnago LC, Italy) at 55.5 L / min for a duration equivalent to 4L of air (corresponding to a 4 kPa pressure drop). The aerosol performance was also measured at a lower pressure drop of 1 kPa (flow rate -27.7 L / min) using the Plastiape™ high resistance device. All parts of the setup were washed with 100 mM sodium phosphate and 250 mM sodium chloride buffer (pH 6.8), and the absorbance was measured at 280 nm using a UV- Visible spectrophotometer Tecan Infinite 200 PRO multimode microplate reader (Tecan Systems, Inc., San Jose, CA, USA). As per USP 601, APSD metrics were calculated, including the fine particle dose (FPD), fine particle fraction (FPF), respirable fraction (RF), emitted dose (ED), emitted fraction (EF), mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD).

[0254] Storage Stability and Performance: To assess the storage stability of the formulations, the powders were stored in stability chambers at 25 °C / 60% RH and 40 °C / 5% RH for 1 month. The powders were packed in scintillation vials that were kept in an aluminum zip-lock bag. At the 1-month time point, the formulations were assessed for protein stability using SEC, solid state stability using DSC, XPRD, DVS, water content testing, and performance using the NGI as per the methods described above.

[0255] Focus Ion Beam SEM: A Thermo Scientific Scios 2HiVac DualBeam Focus Ion Beam (Thermo Fisher Scientific, Waltham, MA) was used to slice samples and obtain photomicrographs. Each sample was mounted on an aluminum stub with carbon tape. A few selected particles were milled with the focused ion beam at 0.1 nA and imaged using a Everhart-Thornley secondary electron detector at a working distance of 7 mm.

[0256] Statistical Analysis: Analysis of variance (ANOVA) with post-hoc Tukey HSD test was utilized to assess the statistical significance of the experimental result using GraphPad Prism®. Additionally, a correlation matrix in the form of a heat map usingcomputed Pearson's coefficients was used to evaluate the association between the formulation components and their properties. This matrix was computed using SAS® Version 9.4. Positive coefficients indicate a positive association whereas negative coefficients indicate an inverse relationship. The significance level was set to p<0.05.INITIAL FORMULATION SCREENING AND STATISTICAL ANALYSIS

[0257] Stability of the IgG-Lipid Microparticles Upon Processing: SEC analysis was used to study the influence of formulations components on the stability of IgG when processed as described herein. The stability of IgG was expressed as a percentage of monomer peak after integrating all HMW and LMW peaks. The results revealed induced aggregation of generally less than 3% in several formulations, while other formulations retained their monomer content completely as determined by SEC analysis. This contrasted with the IgG-only powder that had an approximately 5% reduction in the monomer content. Use of poloxamer-188 alone with IgG resulted in less than a 2% reduction in monomer content.

[0258] Aerosol Performance of the IgG-Lipid Microparticles Upon Processing: Aerosol performance results from the FSI revealed differences between the fine particle fraction, that is the fraction of the powder that has an aerodynamic size lower than 5 pm, for the matrix of different formulations. The FPF of the eleven formulations was spread over a range from 36% to 86% (Table 2).Table 2. Fine Particle Dose and IgG Stability

[0259] Total Powder and IgG Loading of IgG-Lipid Microparticles: Based on the amount of powder that could be filled into the size 3 HMPC capsule and the fine particle fraction, the respirable IgG dose (fine particle dose) was also determined. The fine particle dose for the eleven formulations ranged from as low as 1 mg for powders that had lower IgG fraction combined with poor aerosol performance up to 13 mg FPD for powders with higher IgG loading fraction and moderate to superior aerosol performance. The dosing considerations and IgG stability data are outlined in Table 2, while the aerosol performance is depicted in FIG. 3.PHYSICOCHEMICAL AND STABILITY STUDIES OF CERTAIN FORMULATIONS

[0260] Statistical Analysis of the Design of Experiments: The DoE analysis of the mixture design led to a statistically significant model for both FPD and % monomer responses. The fit summary of the model is outlined in Table 3. Upon optimizing the two models simultaneously in order to maximize protein stability and FPD using the desirability function, the statistically optimized formulation was indicated to have the following composition: 15.86% DSPC, 73.9 % IgG, 1% poloxamer-188, and 7.5% calcium chloride. Two formulations (Formulations 4 and 10) were also manually chosen (i.e., outside the statistical software predictions) based on their observed performance and stability. The formulations chosen based on these criteria for further analysis are outlined in Table 4.Table 3. Model Fit SummaryTable 4. Formulations and Controls for Physicochemical and Stability Tests

[0261] SEM: All tested spray-dried formulations and controls were spherical. The surface structure of PP was smooth and did not contain any pores (FIG. 4D). In the case of PS, the particles were spherical but were characterized by surface dimples (FIG. 4E). Powders from all 3 DSPC-containing formulations were observed to have surface pores and / or surface roughness (FIGs. 4A-4C). VP had irregularly sized particles with no surface roughness (FIG. 4F).

[0262] Focus Ion Beam SEM: Focus Ion Beam SEM was utilized to visualize the internal substructure of the protein powders. Milling of individual spray-dried formulation particles revealed the porous core of the formulations (FIG. 5). Formulation 4 (F4) contained 10% w / w DSPC and 79% w / w IgG and was characterized by a small porous core. On the other hand, Formulation 10 (F10) had the lowest concentration of IgG at 52% w / w and 40% w / w DSPC; F10 was characterized by the largest internal pore size. Finally, Formulation 12 (Fl 2) containing 73% w / w IgG and 15% w / w DSPC had an internal pore structure that was smaller than F10 but larger than F4.

[0263] Powder Flow Properties: Bulk density, tapped density, CI, and specific surface area properties for the tested formulations are summarized in Table 5. Formulation 4 (41% CI) and Formulation 12 (44%) CI had comparable flow properties, while Formulation 10 (30% CI) demonstrated lower compressibility. Based on compressibility index, VPexhibited poor flow properties, while PS and PP were significantly denser than F4, F10, and F12.Table 5. Powder Flow Properties

[0264] The primary particle size distributions of the powders at t=0 are plotted in FIGs. 6A-6F. At a dispersing pressure of 3 bar, the X90 for each of the spray-dried formulations (F4, F10, F12) and controls (PS, PP) was between 3 pm and 4 pm, while the X90 for VP was found to be 34.79 ± 8.9 pm. At 1 bar, the X90 of each spray-dried formulation and control (PS, PP) was found to be in the range of 3 pm to 6 pm, while VP had an X90 of 98.73 ± 0.43 pm. The X50 for all spray-dried formulations was below 3 pm at both pressures; however, the X50 for VP was substantially larger at 15 pm (3 bar) and 48 pm (1 bar). The spray-dried formulations and controls did not show a strong dispersing pressure-dependent disaggregation, as indicated by the similar particle sizes at both pressures. By contrast, pressure dependence was noticeable in the VP control, where the particle size was 2.8 times lower at higher pressures (3 bar) than at lower pressures (1 bar).

[0265] Upon storage, Formulation 4 and Formulation 10 did not show an increase in the particle size distribution at 4 °C or at 25 °C / 60% RH (FIGs. 7A, 7B). However, at 40 °C / 75% RH, an increase in the particle size distribution was observed. Formulation 12, on the other hand, maintained its particle size distribution, irrespective of the tested storage conditions (FIG. 7C). The controls PP, PS, and VP showed changes from baseline in the tested storage conditions (FIGs. 7D-7F).

[0266] Powder Crystallinity: XRPD analysis indicated that spray drying produced amorphous product in each spray-dried formulation (FIG. 8). All of the spray-dried formulations lacked crystalline peaks and were characterized by the formation of a halo, which is typical to amorphous substances. This was also the case for the VP, PS, and PP controls. Upon storage, all formulations retained their amorphous nature. The higher intensity of Formulation 10 around 15-25° 29 is likely due to its DSPC content. XRPD analysis of spray-dried DSPC showed a similar peak (data not shown). In contrast, the control formulations exhibited evidence of crystallinity upon storage at 4 °C, 25 °C / 60% RH and 40 °C / 75% RH.

[0267] Thermal Stability: DSC thermograms of F4, F10, and F12 at baseline and on storage indicated two peaks around 80 °C and 90 °C, corresponding to the gel phase of processed DSPC. No changes were observed upon storage at any of the tested conditions for all formulations and controls. The differences in intensities of the DSPC peaks corresponded to the concentration of DSPC in the formulation. VP indicated signs of degradation at 110 °C upon storage at 40 °C / 75% RH (FIG. 9).

[0268] Water Content: KF titration results showed that F4 had a water content compared to F10 and F12. The controls PP, PS, and VP had substantially higher water content at baseline compared to the lipid microparticle formulations. Upon storage, F4 exhibited a statistically significant increase in water content under intermediate (25 °C / 60% RH) and accelerated (40 °C / 75% RH) stability conditions, but at 4°C the change was not statistically significant. For F12, a change in water content was only observed when stored at 40 °C / 75% RH. F10, on the other hand, did not show a substantial change in the water content, irrespective of tested storage condition. PS, PP, and VP all showed a substantial increase in water content upon storage at all of the conditions. PP and VP had the highest water content at all conditions across all groups (FIG. 10).

[0269] FIGs. 11A-11F show the moisture sorption-desorption isotherms for the formulations and controls. F4 (FIG. 11A) and F10 (FIG. 11B) had 10% moisture sorption at 75% RH at baseline, while F12 (FIG. 11C) had 13% moisture sorption at baseline. However, upon storage, F4 showed a 12% increase in the moisture sorption at 75% RH, while F10 did not show any change. F12, on the other hand, had only a 5% change in moisture sorption upon storage. The spray-dried controls PP (FIG. 1 ID) and PS (FIG. 1 IE) had 20% change in mass at 75% RH at baseline, which doubled upon storage for PP toabout 40% and was between 30-40% for PS. VP (FIG. 11F) had low change in mass at baseline but was prone to significant change in mass, up to 25%, upon storage.

[0270] Aerosol Performance: At a 4 kPa pressure drop, F4, F10, and F12 exhibited high deposition in the stages with a cut-off below 5 pm (stages 2-7) (FIG. 12A). The controls PS, PP, and VP had higher deposition in the earlier stages as well as the USP induction port, device, and capsule. VP had the lowest EF, followed by PP and PS; these EF were significantly lower than those measured for F4, F10, and F12. RF (< 5pm) was low for both VP (19%) and PP (24%), while PS (60%) showed a higher RF than the other two controls. However, the RF (< 5pm) for F4, F10, and F12 were significantly higher (between 80-90% nominal dose) than those measured for the controls. Among the tested lipid microparticle formulations, F10 had the highest RF (< 5pm), followed by F4 and F12. Similar trends were seen at a 1 kPa pressure drop across all three formulations, although slight differences were noted in the EF and RF at 4 kPa and 1 kPa (FIGs. 12B, 13A, 13B). On the other hand, the controls (PP, PS, and VP) were characterized by a decline in the EF and the RF at the lower pressure drop (FIG. 13A). Upon storage, F4 maintained a high EF and RF at 4 °C, 25 °C / 60% RH, but exhibited a slight decline at 40 °C / 75% RH (FIG. 14A). F10 (FIG. 14B) and F12 (FIG. 14C) demonstrated a similar trend with the exception of a reduction in RF (< 3pm) for F10 and a reduction in RF (< 5 pm) for F12 at 25 °C / 60% RH. All reductions seen in EF or RF were below 15% of the baseline (FIGs. 14A-14F).

[0271] IgG Stability: The propensity for the IgG antibody to aggregate or fragment upon processing and storage was measured using size exclusion chromatography. The monomer is generally the main peak responsible for therapeutic efficacy. As indicated in FIG. 15, PP lost 5% of monomer to degradation by aggregation upon spray drying. PS and VP, on the other hand, maintained stability upon processing by spray drying and vacuum drying respectively. F4, F10, and F12 also maintained 100% stability after spray drying. Upon storage at 4 °C for 1 month, all formulations and controls maintained their stability with the exception of PP and VP. At 25 °C / 60% RH, a similar trend was observed. At 40 °C / 75% RH, PP showed a sharp decline in % monomer to 79%; VP and PS were also characterized by 7% and 3% declines, respectively. F4 and F10 were also characterized by a slight decline in % monomer at 40 °C / 75% RH (<5 %), while F12 maintained stability with no change in monomer content under the tested conditions.

[0272] Correlation Co-Efficient Heat Map: Tables 6-9 indicate the correlation between the tested formulation components and formulation properties at different conditions. A in the Table * indicates a significant correlation (p< 0.05)Table 6. Correlation Coefficients at Baseline (t = 0)

[0273] At baseline (Table 6), both bulk and tapped density are negatively correlated with the concentration of DSPC in the formulation and were positively correlated with the concentration of IgG. However, this relationship was only significant for tapped density (p < 0.05). The bulk and tapped densities also positively correlated with the MMAD but were negatively correlated with EF. The EF was negatively correlated with the concentration of IgG in the formulation (p< 0.05). Although not significant, water content, Dv50, FPF, and SSA also indicated strong correlations with the concentration of IgG and DSPC in the formulation.Table 7. Correlation Coefficients at 40 °C / 75% RH

[0274] Upon storage at 40 °C / 75% RH for 1 month (Table 7), the FPF had a significant negative correlation with the moisture sorption at 75% RH. Water content, water sorption, FPF, and MMAD exhibited a strong correlation with the formulation composition (% IgG, % DSPC). However, the correlation of Dv50, and EF was weaker than at baseline. Upon storage at 40 °C / 75% RH, the monomer content indicated a strong negative correlation with the water content.Table 8. Correlation Coefficients at 25 °C / 60% RH

[0275] The sorption at 75% RH exhibited a significant negative correlation with the DSPC content and a positive correlation with the IgG content in formulations stored at 25 °C / 60% RH for 1 month (Table 8). The aerosol performance metrics (FPF, MMAD, and EF) also indicated correlations with the formulation composition, although these correlations were not significant.

[0276] Finally, at 4°C (Table 9), FPF showed a significant positive correlation against the concentration of DSPC in the formulation. At 4°C, the sorption at 75% RH also exhibited strong negative correlation with the EF. Similar to the other conditions, the aerosol performance metrics (FPF, EF, and MMAD) correlated with formulation composition, water content, and sorption.Table 9. Correlation Coefficients at 4 °CSECTION 2: Formulation Processing

[0277] Provided in this section is a description of a study evaluating the processing design space for spray-dried phospholipid-based dry powder compositions comprising an IgG antibody (FIG. 16). A three-factor response surface design of experiment's approach was employed to systematically vary the following spray drying parameters: feed flow, inlet temperature, and nitrogen flow. In addition, secondary drying following spray drying was studied. The device suitability of certain formulations was assessed using five different inhalers with varying dispersion mechanisms to investigate their robustness of aerosolization.

[0278] Materials: l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) was purchased from Avanti Polar Eipids (Birmingham, Alabama). Poloxamer-188 was purchased from Croda (Snaith, United Kingdom). Calcium chloride was purchased from Spectrum Chemicals (New Brunswick, New Jersey). E-histidine was purchased from Sigma Aldrich (Saint Eouis, Missouri). Perfluorooctyl bromide (PFOB) was purchased from TCI Chemicals (Tokyo, Japan). The model Immunoglobulin G1 (IgGl) antibody was provided by Amgen Inc. (Thousand Oaks, California). Prior to spray drying, the IgGl antibody was stored in 1 mM E-histidine buffer.

[0279] Formulation Processing: A 15.86% w / w DSPC, 73.90% w / w IgG, 1% w / w poloxamer-188, 7.5% w / w calcium chloride, and 1.74% w / w histidine formulation was used for this study. As in the prior Section, these mass (w / w) percentages are calculated based on the theoretical weight of only the dry formulation components. Each composition was processed by high-pressure homogenization using the Microfluidizer® (Idex Material Processing Technologies, Ontario, Canada), and a dry powder was prepared by spray drying (BUCHI Corporation, Delaware, United States). Briefly, DSPC was homogenized with water and PFOB using the Ultra-Turrax™ (Ika-Werke, Staufen, Germany) at 8,000 rpm for 5 minutes at 80 °C. This coarse emulsion was then homogenized using the Microfluidizer® at 18,000 psi for 4 discrete passes. In a separate vial, the IgG antibody was mixed with poloxamer-188 and calcium chloride in histidine buffer. A portion of the emulsion was added to the IgG solution to form the final feedstock. The spray drying conditions for the formulations of this study were determined using a Box-Behnken DoE approach and are summarized below.

[0280] Statistical Design of Experiments (DoE): A Box-Behnken DoE approach with three factors at three levels was utilized to explore the spray drying design window for preparing IgG-phospholipid microparticles. The three variables tested in this study were feed flow rate (1 to 10 mL / min), inlet temperature (85-150 °C), and nitrogen flow rate (35- 65 mm). The chosen design space was intended to simulate spray drying conditions that may be encountered during the particle engineering process for inhalable biopharmaceutical powders. Design Expert® (Stat-Ease, Minneapolis, United States) software was used to obtain the Box-Behnken matrix of spray drying parameters (Table 10). The responses assessed using this design were the percent change in the monomer content, residual water content, residual PFOB, and total residual solvent, along with aerosol performance, primary particle size, chemical and physical stability of IgG, and powder flow. The assessment of the responses was done as described below.Table 10. Three Factor Box Behnken Design

[0281] Secondary Drying: The effects of secondary drying were evaluated usingPowder 13 (P13). P13 powders were further dried at either -40 °C / 100 mBar or 40 °C / 46.7 mBar for 12-48 hours.

[0282] SEC, KF, Particle Size, Powder Flow, SEM, mDSC: The SEC, KF, particle size, powder flow, SEM, and mDSC methods described in Section 1 were also used in this study. For particle size distribution measurements, the dispersion was performed at a pressure of 1 bar.

[0283] Thermogravimetric Analysis (TGA): TGA was conducted to analyze residual solvent content in the spray-dried formulations. TGA was conducted using a Mettler Thermogravimetric Analyzer, Model TGA / DSC. During the analysis, approximately 5-6 mg of spray-dried powder was loaded into a 70 pL alumina crucible covered with a pierced lid. The samples were heated from 35 °C to 300 °C at a rate of 10 °C / min.

[0284] Theoretical Residual PFOB Content: The theoretical amount of residual PFOB in the samples was calculated as the difference between the weight loss measured by TGA and the residual water content measured by KF analysis.

[0285] Nuclear Magnetic Resonance (NMR): The presence of PFOB was assessed through the use of NMR spectroscopy. Between 10-20 mg of each sample was dissolved in 1 mF of 10 mM K2HPO4 (5% H2O and 95% D2O). Each solution was then filtered using a 0.45 pm nylon syringe filter before being added to a 5 mm NMR tube. A19F NMR spectra was acquired at 376.4 MHz on a Varian M400 spectrometer (Palo Alto, CA) and analyzed using Mnova® software from Mestrelab Research (Escondido, CA). The presence of PFOB was determined by comparing the sample spectra to a control containing PFOB only.

[0286] Fast Screening Impactor (FSI): The aerodynamic particle size distribution (APSD) of the IgG-phospholipid powders was measured using a Fast Screening Impactor (Copley Scientific, Nottingham, United Kingdom). A USP throat was used in the setup with the pre-separator for all experiments. Processed powders were dispersed using the Plastiape™ RS01 high resistance device (RS01 DPI; Plastiape, Osnago EC, Italy) at about 60 E / min for a duration equivalent to 4 E of air (corresponding to 4 kPa pressure drop). All parts of the setup were washed with 100 mM sodium phosphate and 250 mM sodium chloride buffer (pH 6.8), and the absorbance was measured at 280 nm using a UV-Visible spectrophotometer Tecan Infinite 200 PRO multimode microplate reader (Tecan Systems, Inc., San Jose, CA, USA).

[0287] Next Generation Impactor (NGI): The complete aerodynamic particle size distribution of IgG-phospholipid microparticles was assessed using a Next Generation Impactor (NGI) with a USP throat. The aerodynamic performance of the powder wasassessed using 5 different dry powder inhalers at different flow rates, as summarized in Table 11. The amount of powder in each stage was measured by FSI.Table 11. Dry Powder Inhalers and Associated Pressure Drops and Flow Rates

[0288] Cation Exchange Chromatography (CEX): CEX was conducted in an HPLC system (Thermo Scientific™ Dionex™) using a cation exchange column (YMC BioPro SP-F, 4.6 x 100 mm, 5 pm). Approximately 70 pg of IgG-containing formulation was dissolved in a sodium phosphate buffer (pH 6.8). Mobile Phases A and B consisted of pH gradient buffers obtained from Thermo Fisher (Waltham, MA). A gradient method was used with a flow rate of 1 mL / min and a run time of 45 minutes. Each peak on the chromatogram was integrated. Typically, CEX chromatograms consist of an acidic peak, a basic peak, and the main peak. IgG standard (not spray-dried or vacuum dried) was also tested. Results are expressed as % main peak in relation to the % main peak for IgG standard.

[0289] Circular Dichroism (CD): CD spectroscopy was employed to examine changes in the secondary structure of the protein in its liquid state using a method previously described in Brunaugh et al., J Pharm Sci, 111(2), pp. 403-416 (2022). Briefly, investigations were carried out using a Jasco J-815 CD Spectrometer (Jasco, Inc., Tokyo, JP). The protein samples were diluted with phosphate-buffered saline to achieve a protein concentration of approximately 0.1 mg / mL and were analyzed in a 1 mm quartz cuvette. The scan range was 185 nm to 260 nm, with a step size of 0.5 nm and 3 accumulations. To eliminate the contribution from the formulation matrix, the CD spectrum of the matrixwithout IgG was subtracted from the CD spectrum of the matrix without IgG. CD spectra were then converted to molar ellipticity (u) units based on the antibody's assumed average residue molecular weight of 113 g / mol. The secondary structure analysis was performed using the CDPro33 software (Colorado State University, Ft. Collins, US), employing the CONTINLL algorithm and the reference protein data set SP37.

[0290] Statistical Analysis: Analysis of variance (ANOVA) with post hoc Tukey HSD test was used to assess the differences between multiple groups. Student's t-test was utilized when only two groups were compared for the statistical difference using GraphPad Prism. The significance level was set to p < 0.05. STABILITY AND DRYING EFFICIENCY WITHOUT SECONDARY DRYING

[0291] Spray drying at different feed flow, inlet temperatures, and nitrogen flow conditions gave rise to powders that maintained their monomer stability with a loss of less than 2% across all runs. Pl, P3, P5, P10, and P12 also maintained their stability, with a 100% retention of the monomer content. The results from the SEC-HPLC study for all spray-drying runs performed as part of the DoE analysis of the processing design space are outlined in Table 12.Table 12. Stability and Residual Solvent Levels in Spray-Dried Powders

[0292] While all of the formulations remained stable upon spray drying, the removal of solvents from the powders (i.e., the drying efficiency) was suboptimal. All runs, irrespective of the spray drying conditions used, led to powders with high levels of residual water and PFOB. TGA results revealed a weight loss of 20-40% prior to degradation. Further, KF analysis of water content revealed that spray-dried powders contained 2.7% w / w to 8.1% w / w of residual water. The samples contained residual PFOB in the range of 7% w / w to 30%w / w. The presence of PFOB was also qualitatively confirmed using solution- state NMR. Data from NMR studies showed that all of the formulations contained some residual PFOB (data not shown). Furthermore, correlation analysis indicated a strong negative correlation (-0.799) between water content and monomer retention. At higher water content, the loss in monomer content was also higher. For example, the maximum loss in monomer content was observed at a relatively high water content level of 8.1% w / w and 5.8% w / w.STABILITY AND DRYING EFFICIENCY WITH SECONDARY DRYING

[0293] P13 was used to evaluate the impact of secondary drying on stability and drying efficiency. P13 had one of the highest recorded weight losses by TGA and the highest water content among powders tested. Upon secondary drying at -40 °C / 100 mBar for 12 hours, no change in residual solvent level was observed by TGA. However, following secondary drying at 40 °C / 46.7 mBar for 12 hours, a 20% decline in residual solvent level to 10% w / w was observed. Upon drying the powders at 40 °C / 46.7 mBar for 24 hours, the residual solvent was still 10% w / w. However, upon drying at this condition for 48 hours, only about 5% w / w of residual solvent was observed in the powder (FIG. 17). Based on these results, all 15 formulations were subjected to secondary drying at 40 °C / 46.7 mBar for 48 hours to ensure efficient removal of residual solvent.

[0294] Upon secondary drying, most formulations exhibited a consistent decline in monomer content, while a few retained their stability (P4, P8, and P15). FIG. 18A indicatesthe stability of the spray-dried powders before and after secondary drying. The water content of the formulations post- secondary drying, as measured by KF, was limited to less than 2% w / w (FIG. 18B). The total residual solvent in all formulations was below about 5% w / w upon secondary drying, when compared to high residual solvent levels before secondary drying (FIG. 18C). NMR analysis of the secondary dried samples also indicated an absence of PFOB in all the formulations (data not shown). The difference in the calculated PFOB content before and after secondary drying is shown in FIG. 18D, which indicates a significant decline in the possible PFOB content in the IgG-lipid microparticles to less than 5% w / w.POWDER PROPERTIES

[0295] SEM photomicrographs (FIG. 19) were utilized to examine the morphological characteristics of the powders created using different processing conditions. All formulations, except for P7, exhibited a spherical morphology by SEM. Additionally, the majority of the formulations displayed surface roughness accompanied by the presence of pores. Specifically, P2 demonstrated particles with a relatively smooth surface, while P4 displayed a combination of both surface rough and smooth particles. Conversely, P13 exhibited particles that were entirely smooth without any surface pores. In contrast, P7 resulted in the fusion of particles, thereby failing to generate spherical particles.

[0296] Table 13 summarizes the geometric particle size and flow properties of the IgG- lipid microparticles prepared using spray drying followed by secondary drying. P2 and P4 led to the formation of larger- sized particles as compared to the rest of the runs in this DoE study, which yielded an average D90 of about 3pm. P2, P4, P7, P9, and P14 were also characterized by relatively higher densities than the other DoE runs. P7 had the highest tapped density (0.26 g / cm3), which correlates with the fused morphology of the powders obtained using these conditions. Pl l was characterized by the lowest tapped density of 0.102 g / cm3and corresponded to a surface rough, porous particle morphology, as shown in FIG. 19.Table 13. Powder Particle Size and Flow Properties

[0297] FIG. 20 presents powder X-ray diffractograms of the powders obtained using spray drying and secondary drying conditions described herein. The diffractograms of all formulations exhibited a halo pattern, indicative of their amorphous nature. Notably, P4, P9, and P12 showed an additional minor peak at approximately 22° 29, which can be attributed to the presence of DSPC.

[0298] The glass transition temperature (Tg) of the powders generated powders is shown in FIG. 20 with their corresponding diffractograms. A lowering of Tg to about 40- 55 °C was observed when the powders were spray dried at a higher inlet temperature, such as for P2, P4, P7, and P9, which were spray dried at 150 °C, as well as powders from runs dried at a slower rate, such as P8 and Pl l, which were spray dried at 118 °C, 1 mL / min, and 35 or 65 mm nitrogen flow.AERODYNAMIC PERFORMANCE

[0299] FIGs. 21 A and 2 IB summarize the aerodynamic performance of the fifteen spray-dried and secondary dried IgG-lipid microparticles as measured by the fast screening impactor using the high resistance Plastiape™ RS01 inhaler. Drying at different conditions led to the formation of microparticles with fine particle fractions (FPF) between 40% and 92% (FIG. 21A). P6, Pl l, and P12 were characterized by the highest FPF (about 90%), while P4, P7, and P9 demonstrated the lowest fine particle fractions (about 40%). The resultant fine particle doses (FPD) of the IgG-lipid microparticles ranged from 5 mg to 13 mg. P5 and P7 had the highest retention in the capsule. P4 had the highest device retention. P9 and P10 had relatively higher deposition in the USP throat. The emitted fraction (EF) of the powders ranged from 60% to 93% depending upon the conditions at which they were spray dried (FIG. 2 IB).CHEMICAE AND SECONDARY STRUCTURE STABILITY

[0300] The CD spectra of the IgG antibody in the IgG-lipid microparticles are depicted in FIG. 22. Peaks were observed at about 196, 209, and 223 nm, which are characteristic of the a-helix structure of a protein. Secondary structure analysis of the CD spectra using CDPro and K2D3 revealed no significant changes across the different spray drying runs for helix, unordered, and turns. Slight changes in % strand were observed across the runs depending on the spray drying conditions employed (Table 14). CEX analysis of IgG formulations allows the assessment of covalent modifications that may result in structural and functional changes. CEX analysis of the IgG-lipid microparticles revealed no significant differences in % main peak, % acidic peak, and % basic peak across all of the tested runs. The lack of difference in these peaks is indicative of the chemical stability of the IgG antibody in the IgG-lipid microparticles, irrespective of the processing conditions.Table 14. Secondary Structure Components and Chemical StabilitySTATISTICAL MODELING

[0301] The responses summarized above were used as numerical responses for the analysis of the Box-Behnken response surface design analysis. The tested spray drying and secondary drying process conditions induced changes in powder properties and aerosol performance while maintaining IgG stability. Each of the responses was assessed for model significance, with individual variables iteratively added or removed using a stepwise regression method. The model with the lowest p-value (<0.05) was chosen, and the lack of fit of the model was ensured to be non-significant. Table 15 reports the predictive equations for the significant responses, including water content before and after secondary drying, monomer content before and after secondary drying, FPF, percent change in the strand, and the calculated span from the geometric particle size distribution analysis. The feed flow rate appeared to be an influential variable as all generated significant models included this variable.Table 15. Statistical Model Equations and Fit Summary for Significant Responses

[0302] In order to validate the predictive capability and accuracy of the generated models, the models were further tested. Using the desirability function, the models for each response were simultaneously optimized to achieve high aerosolization efficiency, superior powder properties, and IgG stability. The desirability predicted processing conditions included a feed flow rate of 5.5 mL / min, an inlet temperature of 90 °C, and a nitrogen flow rate of 65 mm. The observed and predicted values of each of the responses for the desirability function suggested processing conditions as outlined in Table 16. Statistical t- test comparisons of the predicted and experimentally determined values indicated no significant differences. The lack of a significant difference between the predicted and experimental values validated the model and suggests future usability.Table 16. Predicted and Experimentally Determined Values

[0303] The solid-state characteristics of powders produced using the desirability predicted processing conditions are shown in FIG. 23 (SEM photomicrograph) and FIG. 24 (XRPD) diffractogram. The Tg of this powder was found to be 78.68 °C, and the amorphous state was maintained. SEM photomicrographs revealed that the powders had a surface rough morphology, and the particles were within the respirable size range. The properties of the desirability predicted processing conditions powder are summarized in Table 17. Table 17. Powder Properties and Stability CharacteristicsDEVICE SUITABILITY

[0304] Five dry powder inhaler (DPI) devices were tested at a pressure drop of 4 kPa to assess the robustness of the aerosol performance of the formulated powders (FIGs. 25-29). The EF was the lowest from the Rotahaler® (69%), while the TwinCaps®, Plastiape™ LR, Plastiape™ HR, and Handihaler® devices had higher EF (> 80%). Significant differences were observed in the RF and EF across all groups, except for TwinCaps® vs Plastiape™ LR. Despite the statistical differences, the FPF from all devices was >80%, while the RF was 54% for Rotahaler® and > 70% for all other devices. The percentage of powder deposited in the device was also compared to study the direct impact of the different inhalers. Rotahaler® was characterized by the highest device deposition, followed by TwinCaps® and Handihaler®, while the Plastiape™ HR and Plastiape™ LR devices had the least amount of powder deposited in the device.

[0305] The impact of pressure drop was evaluated using the Plastiape™ LR device at 4 kPa and 1 kPa. While significant differences were observed in each aerosol performance metric using a student t-test, the numerical declines in EF, RF, FPF, and device deposition were only 4%, 7%, 6%, and 4.5%, respectively.

[0306] FIG. 30 summarizes differences in performance observed for the TwinCaps® inhaler based upon powder loading. Upon loading 30 mg of powder in a single chamber, the EF and RF were significantly lower than when 30 mg was equally distributed between the two sample chambers. The device deposition on the other hand, increased significantly when the powder load was increased.

Claims

CLAIMS1. A dry powder composition comprising:(a) an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w; and further wherein the dry powder composition does not comprise a carbohydrate excipient.

2. The dry powder composition of claim 1, wherein the carbohydrate excipient is selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.

3. A dry powder composition comprising a plurality of particles, wherein the plurality of particles comprises:(a) an antibody or an antibody fragment present at a concentration in the range of 50% w / w to 80% w / w;(b) a phospholipid present at a concentration in the range of 10% w / w to less than 50% w / w;(c) a polyvalent cation present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) a non-ionic surfactant present at a concentration in the range of greater than 0% w / w to 10% w / w; and(e) a buffering agent, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the dry powder composition; and further wherein none of the plurality of particles comprises a carbohydrate excipient selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.

4. The dry powder composition of any one of claims 1 to 3, wherein:(a) the antibody or the antibody fragment is present at a concentration in the range of 70% w / w to 80% w / w;(b) the phospholipid is present at a concentration in the range of 10% w / w to 20% w / w;(c) the polyvalent cation is present at a concentration in the range of 5% w / w to 10% w / w;(d) the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 1.5% w / w; and(e) the buffering agent is present at a concentration of less than 2% w / w.

5. The dry powder composition of any one of claims 1 to 4, wherein:(a) the antibody or the antibody fragment is present at a concentration in the range of 72% w / w to 76% w / w;(b) the phospholipid is present at a concentration in the range of 14% w / w to 18% w / w;(c) the polyvalent cation is present at a concentration in the range of 6% w / w to 9% w / w;(d) the non-ionic surfactant is present at a concentration in the range of 0.5% w / w to 1.5% w / w; and(e) the buffering agent is present at a concentration of less than 2% w / w.

6. The dry powder composition of any one of claims 1 to 5, wherein the antibody is an IgG antibody.

7. The dry powder composition of any one of claims 1 to 6, wherein the phospholipid is selected from phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, and combinations of any of the foregoing.

8. The dry powder composition of any one of claims 1 to 7, wherein the phospholipid is selected from distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3- phosphoethanolamine (DPPE), l,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), and combinations of any of the foregoing.

9. The dry powder composition of any one of claims 1 to 8 wherein the phospholipid is DPPC or DSPC.

10. The dry powder composition of any one of claims 1 to 9, wherein the polyvalent cation is calcium chloride.

11. The dry powder composition of any one of claims 1 to 10, wherein the non-ionic surfactant is selected from poloxamers and sorbitan fatty acid esters.

12. The dry powder composition of any one of claims 1 to 11, wherein the non-ionic surfactant is poloxamer-188.

13. The dry powder composition of any one of claims 1 to 12, wherein the buffering agent comprises histidine.

14. The dry powder composition of any one of claims 1 to 13, wherein the plurality of particles has an X90 in the range of 3 pm to 4 pm.

15. The dry powder composition of any one of claims 1 to 14, wherein the plurality of particles has an X50 of less than 2 pm.

16. The dry powder composition of any one of claims 1 to 15, wherein the dry powder composition has a fine particle fraction (FPF) of greater than or equal to 40%.

17. The dry powder composition of any one of claims 1 to 16, wherein a tapped density of the dry powder composition is in the range of 0.1 g / cm3 to 0.2 g / cm3.

18. The dry powder composition of any one of claims 1 to 17, wherein a bulk density of the dry powder composition is less than or equal to 0.1 g / cm3.

19. The dry powder composition of any one of claims 1 to 18, wherein the dry powder composition is suitable for pulmonary delivery.

20. The dry powder composition of any one of claims 1 to 19, wherein the dry powder composition is deliverable at an emitted fraction of at least 60% in a dry powder inhaler.

21. A unit dose package comprising a reservoir containing a unit dose of the dry particle composition of any one of claims 1 to 20.

22. The unit dose package of claim 21, wherein the unit dose package is insertable into a dry powder inhaler.

23. A dry powder inhaler device comprising the dry powder composition of any one of claims 1 to 20.

24. A method of treating a respiratory disease in a subject in need thereof, comprising administering the dry powder composition of any one of claims 1 to 20 to the subject via inhalation.

25. A method of delivering an antibody or an antibody fragment to the pulmonary system of a subject, comprising administering the dry powder composition of any one of claims 1 to 20 to the subject via inhalation.

26. A method for preparing a dry powder composition, comprising: preparing an emulsion comprising a blowing agent, an antibody or an antibody fragment, a phospholipid, a polyvalent cation, a non-ionic surfactant, and a buffering agent; spray drying the emulsion using a spray dryer to produce a dry powder composition; and isolating the dry powder composition, wherein the isolated dry powder composition comprises a plurality of particles in which:(a) the antibody or the antibody fragment is present at a concentration in the range of 50% w / w to 80% w / w;(b) the phospholipid is present at a concentration in the range of 10% w / w to less than 50% w / w;(c) the polyvalent cation is present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) the non-ionic surfactant is present at a concentration in the range of greater than 0% w / w to 10% w / w, and(e) the buffering agent is present at a concentration of less than 5% w / w, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w of the dry powder composition; and further wherein none of the plurality of particles comprises a carbohydrate excipient selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.

27. A method for preparing a dry powder composition, comprising: preparing an emulsion comprising a blowing agent, an antibody or an antibody fragment, a phospholipid, a polyvalent cation, a non-ionic surfactant, and a buffering agent; spray drying the emulsion using a spray drier to produce a dry powder composition; andisolating the dry powder composition, wherein the isolated dry powder composition comprises:(a) the antibody or the antibody fragment is present at a concentration in the range of 50% w / w to 80% w / w;(b) the phospholipid is present at a concentration in the range of 10% w / w to less than 50% w / w;(c) the polyvalent cation is present at a concentration in the range of greater than 0% w / w to 10% w / w;(d) the non-ionic surfactant is present at a concentration in the range of greater than 0% w / w to 10% w / w, and(e) the buffering agent is present at a concentration of less than 5% w / w, wherein the total concentration of the components of (a), (b), (c), (d), and (e) is less than or equal to 100% w / w; and further wherein the isolated dry powder composition does not comprise a carbohydrate excipient.

28. The method of claim 27, wherein the carbohydrate excipient is selected from the group consisting of cyclodextrins, dextrans, dextrose, D-mannose, fructose, galactose, glucose, lactitol, lactose, maltitol, maltodextrins, maltose, mannitol, melezitose, myoinositol, raffinose, sorbitol, sorbose, sucrose, trehalose, and xylitol.

29. The method of any one of claims 26 to 28, wherein preparing an emulsion comprises: preparing a lipid emulsion comprising the blowing agent, the phospholipid, and water; preparing a buffered solution comprising the antibody or the antibody fragment, the polyvalent cation, the non-ionic surfactant, and the buffering agent; and combining the lipid emulsion and the buffered solution to obtain the emulsion.

30. The method of claim 29, wherein preparing the lipid emulsion comprises homogenizing the blowing agent, the phospholipid, and water using a homogenizer with a Y-shaped interaction chamber.

31. The method of any one of claims 26 to 30, wherein the blowing agent is perfluorooctyl bromide.

32. The method of any one of claims 26 to 31, wherein the inlet temperature of the spray drier is set at a temperature in the range of 85 °C to 150 °C.

33. The method of any one of claims 26 to 32, wherein the outlet temperature of the spray drier is set at a temperature of less than 80 °C.

34. The method of any one of claims 26 to 33, wherein a flow rate of the emulsion during spray drying is in the range of 1 mL / min to 10 mL / min.

35. The method of any one of claims 26 to 34, wherein the spray drying is followed by a secondary drying process.

36. The method of any one of claims 26 to 35, wherein the secondary drying process is vacuum drying.

37. The method of any one of claims 26 to 36, wherein the secondary drying process comprises: vacuum drying the dry powder composition for at least 24 hours at a temperature in the range of 30 °C to 50 °C and a pressure in the range of 40 mBar to 60 mBar; or vacuum drying the dry powder composition for at least 6 hours at a temperature in the range of -50 °C to -30 °C and a pressure in the range of 80 mBar to 120 mBar.

38. The method of any one of claims 29 to 35, wherein a water content of the dry powder composition following the secondary drying process is less than or equal to 2% w / w.

39. A dry powder composition prepared by the method of any one of claims 26 to 38.

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