Inhalable or Ingestible Lactic Acid Compositions for the Treatment of Chronic Lung Disease - Patent application

Abstract

The technology described herein is directed to pharmaceutical compositions comprising lactate-producing compounds formulated for administration by inhalation and / or oral administration. Also described herein are unit dosage forms of such pharmaceutical compositions, devices comprising such pharmaceutical compositions, methods of making such pharmaceutical compositions, and methods of treating bronchopulmonary diseases using such pharmaceutical compositions.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 290,297, filed December 16, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The technology described herein relates to lactic acid compositions for the treatment of pulmonary diseases. [Background technology]

[0003] Chronic inflammatory lung diseases are associated with dysbiosis of the lung microbiome. As used herein, the term "dysbiosis" is used to refer to an imbalance between commensal and pathogenic bacteria. One way to address dysbiosis is to increase the population of commensal bacteria in the microenvironment. Lactobacillus is a family of lactic acid-producing commensals known for their anti-inflammatory properties. Lactobacillus acidophilus counteracts E. coli-mediated inhibition of butyrate uptake by intestinal epithelial cells. Lacticaseibacillus rhamnosus (formerly Lactobacillus rhamnosus, e.g., strain LGG) reduces the likelihood of hospital-acquired respiratory and gastrointestinal infections in the pediatric population. Lactiplantibacillus plantarum (formerly Lactobacillus plantarum, e.g., strain 299v) protects against antibiotic-mediated short-chain fatty acid (SCFA) depletion. A probiotic blend containing L. acidophilus, rhamnosus, and plantarum showed a decrease in pro-inflammatory factors and an increase in anti-inflammatory factors in healthy samples. See, e.g., Enaud et al. 2020, Front Cell Infect Microbiol 10:9; Saint-Criq et al. 2021, Ageing Res Rev 66:101235; Kumar et al. 2015, Am J Physiol Gastrointest Liver Physiol 309(7):G602-607; Hojsak et al. 2010, Pediatrics 125(5):e1171-1177; Wullt et al. 2007, Digestive Diseases and Sciences 52(9):2082; Moens et al. 2019, International Journal of Pharmaceutics 555:1-10 (the contents of each of which are incorporated by reference in their entirety into this specification).

[0004] The study aims to isolate the active extract or metabolite that confers Lactobacillus with its anti-inflammatory capabilities. Administration of the Lactobacillus blend resulted in a reduction in matrix metalloproteinase-9 (MMP-9), a marker of neutrophilic inflammation, in dysbiosis models of lung injury in vitro and in vivo. Elevated levels of MMP-9 are associated with chronic inflammatory lung disease and non-small cell lung cancer (NSCLC). See, for example, International Patent Application 2018 / 191073; Atkinson and Senior 2003, Am J Respir Cell Mol Biol 28(1):12-24; El-Badrawy et al. 2014, J Bronchology Interv Pulmonol 21(4):327-334, the contents of each of which are incorporated herein by reference in their entirety.

[0005] Therapeutics comprising anti-inflammatory extracts or metabolites from bacteria such as Lactobacillus are needed, particularly as they relate to chronic inflammatory lung diseases. Summary of the Invention

[0006] Lactic acid has been identified herein as an anti-inflammatory compound produced by microbiota.Accordingly, the technology described herein is directed to pharmaceutical compositions comprising lactate-producing compounds formulated for administration by inhalation and / or oral administration.Also described herein are unit dosage forms of such pharmaceutical compositions, devices comprising such pharmaceutical compositions, methods for producing such pharmaceutical compositions, and, inter alia, methods for treating bronchopulmonary diseases using such pharmaceutical compositions.

[0007] Specifically, the present disclosure encompasses embodiments of inhaled or ingested lactic acid products that deliver a matrix of ingredients to the lungs or intestines to reduce the neutrophilic inflammation characteristic of many chronic lung diseases. Administration of lactic acid resulted in a reduction of MMP-9 in E. coli treated human bronchial epithelial cells (HBE) (see, e.g., FIG. 2). Thus, the present disclosure encompasses embodiments of this inhaled or ingested lactic acid-related product, either in a crystalline solid form, an amorphous solid form, or a mixture, that delivers lactic acid or a similar acid.

[0008] In one aspect, described herein is a pharmaceutical composition comprising: (a) a lactate-producing compound selected from (i) a polymeric compound capable of producing lactic acid, (ii) a non-polymeric compound capable of producing lactic acid, or (iii) lactic acid; and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for pulmonary administration.

[0009] In some embodiments of any of the aspects, the composition is formulated for administration by inhalation.

[0010] In some embodiments of any of the aspects, the lactate-generating compound generates lactate upon delivery to the target tissue.

[0011] In some embodiments of any of the aspects, the target tissue is a target bronchopulmonary tissue.

[0012] In some embodiments of any of the aspects, the target bronchiolopulmonary tissue is the lung, trachea, bronchi, bronchioles, and / or alveoli.

[0013] In some embodiments of any of the aspects, the target tissue is a tissue site distal to the lung, delivered via the cardiovascular or lymphatic system.

[0014] In some embodiments of any of the aspects, the lactate-producing compound comprises the D enantiomer of lactic acid, the L enantiomer of lactic acid, or a racemic mixture of the D and L enantiomers of lactic acid.

[0015] In some embodiments of any of the aspects, the non-polymeric lactate-producing compound can be metabolized in the target tissue to produce lactate.

[0016] In some embodiments of any of the aspects, the non-polymeric lactic acid producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide.

[0017] In some embodiments of any of the aspects, the inorganic salt of lactic acid is sodium lactate, potassium lactate, calcium lactate, or magnesium lactate.

[0018] In some embodiments of any of the aspects, the ester of lactic acid is ethyl lactate, propyl lactate, butyl lactate, pentyl lactate, hexyl lactate, heptyl lactate, octyl lactate, nonyl lactate, decyl lactate, undecyl lactate, or dodecyl lactate.

[0019] In some embodiments of any of the aspects, the polymeric lactic acid generating compound can be hydrolyzed in the target tissue to generate lactic acid.

[0020] In some embodiments of any of the aspects, the polymeric lactic acid producing compound is polylactic acid (PLA).

[0021] In some embodiments of any of the aspects, the polylactic acid is poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), or poly(D-lactide) (PDLA).

[0022] In some embodiments of any of the aspects, the polylactic acid is poly(D,L-lactide) (PDLLA).

[0023] In some embodiments of any of the aspects, the polymeric lactic acid producing compound is poly(lactic-co-glycolic acid) (PLGA).

[0024] In some embodiments of any of the aspects, the polymeric lactic acid producing compound is poly(lactic acid-co-caprolactone).

[0025] In some embodiments of any of the aspects, the composition comprises at least 1.0% by weight of a lactate-producing compound.

[0026] In some embodiments of any of the aspects, the composition includes at least one excipient or at least one stabilizer.

[0027] In some embodiments of any of the aspects, the pharmaceutical composition further comprises at least one excipient.

[0028] In some embodiments of any of the aspects, the pharmaceutical composition further comprises at least two excipients.

[0029] In some embodiments of any of the aspects, the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, gluco-oligosaccharides, lacto-oligosaccharides, fructooligosaccharides, inulin, sodium caseinate, goat milk, cow's milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts.

[0030] In some embodiments of any of the aspects, the excipient is leucine and / or trehalose.

[0031] In some embodiments of any of the aspects, the composition comprises at least 5.0% by weight of an excipient.

[0032] In some embodiments of any of the aspects, the composition comprises at least 5.0% by weight of the first excipient and at least 5.0% by weight of the second excipient.

[0033] In some embodiments of any of the aspects, the pharmaceutical composition further comprises at least one stabilizer.

[0034] In some embodiments of any of the aspects, the stabilizer comprises a surfactant.

[0035] In some embodiments of any of the aspects, the stabilizer is selected from the group consisting of mannitol, carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), polysorbate, and poloxamer.

[0036] In some embodiments of any of the aspects, the stabilizer is a polysorbate, a poloxamer, or polyvinyl alcohol.

[0037] In some embodiments of any of the aspects, the stabilizer is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0038] In some embodiments of any of the aspects, the stabilizer is polysorbate 80.

[0039] In some embodiments of any of the aspects, the stabilizer is poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 234, poloxamer 235, poloxamer 238, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 403, or poloxamer 407.

[0040] In some embodiments of any of the aspects, the stabilizer is poloxamer 188.

[0041] In some embodiments of any of the aspects, the composition comprises at least 0.10% by weight of a stabilizer.

[0042] In some embodiments of any of the aspects, the composition comprises at least one excipient and at least one stabilizer.

[0043] In some embodiments of any aspect, the pharmaceutical composition further comprises at least one of the following: (a) a pore-forming agent, (b) an adhesive, (c) a pH adjusting agent, and / or (d) an ester hydrolysis inducer.

[0044] In some embodiments of any of the aspects, the pore-forming agent is selected from the group consisting of: NaCl, sucrose, polyethylene glycol (PEG), and polyvinylpyrrolidone (PVP).

[0045] In some embodiments of any of the aspects, the adhesive is selected from the group consisting of a sugar, an adhesive polymer, and an amine-containing compound.

[0046] In some embodiments of any of the aspects, the pH adjusting agent is a buffer, an acid, or a base.

[0047] In some embodiments of any of the aspects, the ester hydrolysis inducer comprises an amine.

[0048] In some embodiments of any of the aspects, the pharmaceutical composition further comprises at least one acid generating molecule capable of generating acid, wherein the at least one acid generating molecule is not lactic acid or does not comprise lactic acid.

[0049] In some embodiments of any of the aspects, the acid generating molecule is selected from the group consisting of acetic acid, hydroxy acids, polyfunctional acids, and aromatic acids, and esters, salts, and polymers thereof.

[0050] In some embodiments of any of the aspects, the acid generating molecule is selected from the group consisting of acetic acid, glycolic acid, citric acid, and salicylic acid, and esters, salts, and polymers thereof.

[0051] In some embodiments of any of the aspects, the acid generating molecule is acetylsalicylic acid.

[0052] In some embodiments of any of the aspects, the composition comprises at least one additional therapeutic agent for chronic bronchopulmonary disorder.

[0053] In some embodiments of any of the aspects, the at least one additional therapeutic agent is microencapsulated.

[0054] In some embodiments of any of the aspects, the at least one additional therapeutic agent is covalently attached to a degradable linker to the lactate-producing compound.

[0055] In some embodiments of any of the aspects, the pharmaceutical composition is co-administered with at least one additional therapeutic agent for chronic or infectious bronchopulmonary disorders.

[0056] In some embodiments of any of the aspects, the at least one additional therapeutic agent is an anti-inflammatory agent, an antibacterial agent, an antiviral agent, an antifungal agent, a vasodilator, or a bronchodilator.

[0057] In some embodiments of any of the aspects, the anti-inflammatory agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, glucocorticoids, methotrexate, sulfasalazine, leflunomide, anti-tumor necrosis factor (TNF) drugs, cyclophosphamide, inflammation-resolving lipid mediators, mycophenolates, opiates, and barbiturates.

[0058] In some embodiments of any of the aspects, the antibacterial agent is selected from the group consisting of an aminoglycoside, ansamycin, a beta-lactam, a bis-biguanide, a carbacephem, a carbapenem, a cationic polypeptide, a cephalosporin, a fluoroquinolone, a glycopeptide, an iron-sequestering glycoprotein, a linosamide, a lipopeptide, a macrolide, a monobactam, a nitrofuran, an oxazolidinone, a penicillin, a polypeptide, a quaternary ammonium compound, a quinolone, a silver compound, a sulfonamide, and a tetracycline.

[0059] In some embodiments of any of the aspects, the vasodilator is selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and nitric oxide generating compounds.

[0060] In some embodiments of any of the aspects, the bronchodilator is selected from the group consisting of albuterol, levalbuterol, epinephrine, salmeterol, formoterol, ipratropium bromide, tiotropium bromide, theophylline, and aminophylline.

[0061] In some embodiments of any of the aspects, the composition is formulated as a bolus dose.

[0062] In some embodiments of any of the aspects, the pharmaceutical composition comprises (a) a polymeric lactic acid producing compound and / or a non-polymeric lactic acid producing compound, and (b) a bolus dose of lactic acid.

[0063] In some embodiments of any of the aspects, the composition is formulated as microspheres.

[0064] In some embodiments of any of the aspects, the microsphere has a diameter of at least 1 μm up to 1 mm.

[0065] In some embodiments of any of the aspects, the composition comprises a plurality of dry particles.

[0066] In some embodiments of any of the aspects, the dry particles have a Dv50 of at least 0.5 μm.

[0067] In some embodiments of any of the aspects, the dry particles have a median mass aerodynamic diameter (MMAD) of at least 1.5 μm and up to 7.5 μm.

[0068] In some embodiments of any of the aspects, the dry particles have a median mass aerodynamic diameter (MMAD) of up to 5.0 μm.

[0069] In some embodiments of any of the aspects, the dry particles have a dispersibility of less than 2.0.

[0070] In some embodiments of any of the aspects, the dry particles have a dispersibility of at least 0.5 to 1.0.

[0071] In some embodiments of any of the aspects, the dry particles have a dispersibility of at least 0.9.

[0072] In some embodiments of any of the aspects, the dry particles have a delivered dose to the target tissue of at least 25.0% and up to 125% by weight of the composition.

[0073] In some embodiments of any of the aspects, the dry particles have a delivered dose of at least 30% by weight of the lactate-generating compound to the target tissue.

[0074] In some embodiments of any of the aspects, the dry particles have a delivered dose by mass to the target tissue of at least 7.8 mg per unit dose of lactate-producing compound.

[0075] In some embodiments of any of the aspects, the dry particles have a delivered dose of up to 50 mg per unit dose of lactate-producing compound by mass to the target tissue.

[0076] In some embodiments of any of the aspects, the dry particles have a density of at least 0.1 g / cm 3 ~0.8g / cm 3 It has a bulk density of

[0077] In some embodiments of any of the aspects, the dry particles have a density of at least 0.5 g / cm 3 It has a bulk density of

[0078] In some embodiments of any of the aspects, the dry particles have a density of at least 0.2 g / cm 3 ~1.0g / cm 3 The tap density is

[0079] In some embodiments of any of the aspects, the dry particles have a density of at least 0.6 g / cm 3 The tap density is

[0080] In some embodiments of any of the aspects, the dry particles have a moisture content of at least 1.0% to 7.0% % water by weight.

[0081] In some embodiments of any of the aspects, the dry particles have a moisture content of at least 2.3% water by weight.

[0082] In some embodiments of any of the aspects, the composition is formulated for delivery to the trachea, bronchi, bronchioles, and / or alveoli.

[0083] In some embodiments of any of the aspects, the composition is formulated for pulmonary delivery.

[0084] In some embodiments of any of the aspects, the composition is formulated as a tablet or capsule.

[0085] In some embodiments of any of the aspects, the composition comprises at least 7.8 mg of lactate-producing compound per unit dose deliverable to the target tissue.

[0086] In some embodiments of any of the aspects, the composition comprises at least 15 mg of lactate-producing compound per unit dose.

[0087] In some embodiments of any of the aspects, the composition is formulated for delivery by an inhaler.

[0088] In some embodiments of any of the aspects, the composition is formulated for delivery by a dry powder inhaler (DPI).

[0089] In some embodiments of any of the aspects, the composition is formulated for delivery by a metered dose inhaler (MDI).

[0090] In some embodiments of any of the aspects, the composition is formulated for delivery by a soft mist inhaler (SMI).

[0091] In some embodiments of any of the aspects, the pharmaceutical composition is combined with an inhaler.

[0092] In one aspect, described herein is an inhalation device for bronchopulmonary delivery, comprising: (a) an inhaler; and (b) a container containing a pharmaceutical composition described herein.

[0093] In some embodiments of any of the aspects, the inhaler is a dry powder inhaler (DPI).

[0094] In some embodiments of any of the aspects, the inhaler is a metered dose inhaler (MDI).

[0095] In some embodiments of any of the aspects, the inhaler is a soft mist inhaler (SMI).

[0096] In some embodiments of any of the aspects, the inhaler includes (a) a mouthpiece including an opening, and (b) a means for aerosolizing or dispersing the pharmaceutical composition within the container.

[0097] In one aspect, a method of preparing a spray-dried pharmaceutical composition comprising a lactate-generating compound is described herein, the method comprising: (a) preparing a liquid feedstock comprising a lactate-generating compound; (b) introducing droplets of the liquid feedstock into a drying chamber via a spray nozzle; (c) exposing the liquid feedstock droplets to heated and pressurized gas in the drying chamber to produce dry particles; and (d) isolating dry particles of a predetermined range of diameters in a cyclone chamber, wherein the isolated dry particles comprise the lactate-generating compound.

[0098] In one aspect, a method for preparing a spray-dried pharmaceutical composition comprising a lactate-generating compound is described herein, the method comprising: (a) obtaining a liquid feedstock comprising a lactate-generating compound; (b) introducing droplets of the liquid feedstock into a drying chamber via a spray nozzle; (c) exposing the liquid feedstock droplets to heated and pressurized gas in the drying chamber to produce dry particles; and (d) isolating dry particles of a predetermined range of diameters in a cyclone chamber, wherein the isolated dry particles comprise the lactate-generating compound.

[0099] In some embodiments of any of the aspects, the step of preparing the liquid ingredient includes dissolving a solid ingredient in an aqueous solution.

[0100] In some embodiments of any of the aspects, the step of preparing the liquid feedstock includes dissolving a solid feedstock in an organic solution.

[0101] In some embodiments of any of the aspects, preparing the liquid feedstock includes (a) dissolving a lactic acid-producing compound in an organic solution; (b) dissolving a solid feedstock in an aqueous solution; and (c) combining the solutions resulting from (a) and (b) to produce the liquid feedstock.

[0102] In some embodiments of any of the aspects, the solid ingredient comprises (a) at least 50% by weight of a lactic acid-producing compound, (b) at least 10% by weight of an excipient, and / or (c) at least 1% by weight of a stabilizer.

[0103] In some embodiments of any of the aspects, the solid ingredient comprises (a) at least 50% by weight of a lactic acid-producing compound, (b) at least 5% by weight of a first excipient, (c) at least 5% by weight of a second excipient, and / or (d) at least 1% by weight of a stabilizer.

[0104] In some embodiments of any of the aspects, the solid feedstock comprises at least 20% and up to 80% by weight of a lactic acid-producing compound.

[0105] In some embodiments of any of the aspects, the solid ingredient comprises at least 1% and up to 15% by weight of an excipient.

[0106] In some embodiments of any of the aspects, the solid ingredient comprises at least 2.5% to 7.5% by weight of the first excipient and at least 2.5% to 7.5% by weight of the second excipient.

[0107] In some embodiments of any of the aspects, the solid feedstock comprises at least 10% and up to 50% by weight of a stabilizer.

[0108] In some embodiments of any of the aspects, the liquid ingredient comprises at least 0.1 g / L of a solid ingredient dissolved in an aqueous solution.

[0109] In some embodiments of any of the aspects, the liquid ingredient comprises at least 5 g / L of a solid ingredient dissolved in an aqueous solution.

[0110] In some embodiments of any of the aspects, the liquid ingredient comprises at least 0.01% and up to 10% of a solid ingredient dissolved in an aqueous solution.

[0111] In some embodiments of any of the aspects, the liquid ingredient comprises at least 0.5% of a solid ingredient dissolved in an aqueous solution.

[0112] In some embodiments of any of the aspects, 0.5 L of the liquid feedstock comprises (a) at least 2.00 g of a lactic acid-producing compound, (b) at least 0.80 g of an excipient, (c) at least 1.2 g of a stabilizer, (d) at least 31.36 g of an organic solution, and / or (e) at least 464.64 g of an aqueous solution.

[0113] In some embodiments of any of the aspects, 0.5 L of the liquid feedstock comprises (a) at least 2.00 g of a lactic acid-producing compound, (b) at least 0.40 g of a first excipient, (c) at least 0.40 g of a second excipient, (d) at least 1.2 g of a stabilizer, (e) at least 31.36 g of an organic solution, and / or (f) at least 464.64 g of an aqueous solution.

[0114] In some embodiments of any of the aspects, 0.5 L of the liquid feedstock comprises at least 0.1 g and up to 10 g of a lactate-producing compound.

[0115] In some embodiments of any of the aspects, 0.5 L of the liquid ingredient comprises at least 0.1 g and up to 10 g of excipient.

[0116] In some embodiments of any of the aspects, 0.5 L of the liquid ingredient comprises at least 0.05 g and up to 5 g of a first excipient and at least 0.05 g and up to 5 g of a second excipient.

[0117] In some embodiments of any of the aspects, 0.5 L of the liquid ingredient comprises at least 0.1 g and up to 10 g of stabilizer.

[0118] In some embodiments of any of the aspects, 0.5 L of the liquid feedstock comprises at least 10 g and up to 50 g of the organic solution.

[0119] In some embodiments of any of the aspects, 0.5 L of the liquid ingredient comprises at least 420 g and up to 490 g of aqueous solution.

[0120] In some embodiments of any of the aspects, the liquid feedstock comprises (a) at least 0.40% lactic acid-producing compound, (b) at least 0.16% excipient, (c) at least 0.24% stabilizer, (d) at least 6.27% organic solution, and / or (e) at least 92.93% aqueous solution.

[0121] In some embodiments of any of the aspects, the liquid feedstock comprises (a) at least 0.40% by weight of a lactic acid-producing compound, (b) at least 0.08% by weight of a first excipient, (c) at least 0.08% by weight of a second excipient, (d) at least 0.24% by weight of a stabilizer, (e) at least 6.27% by weight of an organic solution, and / or (f) at least 92.93% by weight of an aqueous solution.

[0122] In some embodiments of any of the aspects, the liquid feedstock comprises at least 0.01% and up to 1.0% by weight of a lactic acid-producing compound.

[0123] In some embodiments of any of the aspects, the liquid ingredient comprises at least 0.01% and up to 10% by weight of an excipient.

[0124] In some embodiments of any of the aspects, the liquid ingredient comprises at least 0.005% to at most 5% by weight of a first excipient and at least 0.005% to at most 5% by weight of a second excipient.

[0125] In some embodiments of any of the aspects, the liquid feedstock comprises at least 0.01% and up to 1.0% by weight of a stabilizer.

[0126] In some embodiments of any of the aspects, the liquid feedstock comprises at least 1% and up to 5% by weight of an organic solution.

[0127] In some embodiments of any of the aspects, the liquid feedstock comprises at least 90% and up to 99.9% by weight of an aqueous solution.

[0128] In some embodiments of any of the present aspects, the lactate-producing compound is selected from (a) a polymeric compound capable of producing lactic acid, (b) a non-polymeric compound capable of producing lactic acid, or (c) lactic acid.

[0129] In some embodiments of any of the aspects, the non-polymeric lactic acid producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide.

[0130] In some embodiments of any of the aspects, the polymeric lactic acid producing compound is polylactic acid (PLA).

[0131] In some embodiments of any of the aspects, the polylactic acid is poly(D,L-lactide) (PDLLA).

[0132] In some embodiments of any of the aspects, the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, gluco-oligosaccharides, lacto-oligosaccharides, fructooligosaccharides, inulin, sodium caseinate, goat milk, cow's milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts.

[0133] In some embodiments of any of the aspects, the excipient is leucine and / or trehalose.

[0134] In some embodiments of any of the aspects, the stabilizer is a polysorbate, a poloxamer, or polyvinyl alcohol.

[0135] In some embodiments of any of the aspects, the stabilizer is poloxamer 188.

[0136] In some embodiments of any of the aspects, the organic solution is acetone.

[0137] In some embodiments of any of the aspects, the aqueous solution is water.

[0138] In some embodiments of any of the aspects, the liquid ingredient further comprises at least one additional therapeutic agent.

[0139] In some embodiments of any of the aspects, the at least one additional therapeutic agent is selected from the group consisting of an anti-inflammatory agent, an antibacterial agent, an antiviral agent, an antifungal agent, a vasodilator, and a bronchodilator.

[0140] In some embodiments of any of the aspects, the spray nozzle to the drying chamber has a diameter of at least 1.2 mm.

[0141] In some embodiments of any of the aspects, the droplets of the liquid feedstock produced by the spray nozzle into the drying chamber have a diameter of at least 1.2 um.

[0142] In some embodiments of any of the aspects, the droplets of the liquid feedstock have a flow rate through the drying chamber of at least 5 g / min.

[0143] In some embodiments of any of the aspects, the droplets of the liquid feedstock have a flow rate through the drying chamber of at least 15 g / min.

[0144] In some embodiments of any of the aspects, the droplets of the liquid feedstock have a flow rate through the drying chamber of up to 1000 g / min.

[0145] In some embodiments of any of the aspects, the heated pressurized gas is heated prior to being introduced into the drying chamber.

[0146] In some embodiments of any of the aspects, the heated pressurized gas is introduced into the drying chamber at a temperature of at least 100°C.

[0147] In some embodiments of any of the aspects, the heated pressurized gas is introduced into the drying chamber at a temperature of at least 135°C.

[0148] In some embodiments of any of the aspects, the heated pressurized gas is introduced into the drying chamber at a temperature of up to 195°C.

[0149] In some embodiments of any of the aspects, the heated pressurized gas is exhausted from the drying chamber at a temperature of at least 40°C.

[0150] In some embodiments of any of the aspects, the heated pressurized gas is exhausted from the drying chamber at a temperature of at least 60°C.

[0151] In some embodiments of any of the aspects, the heated pressurized gas is exhausted from the drying chamber at a temperature of up to 85°C.

[0152] In some embodiments of any of the aspects, the heated pressurized gas is pressurized prior to being introduced into the drying chamber.

[0153] In some embodiments of any of the aspects, the heated pressurized gas in the drying chamber has an atomizing gas pressure of at least 10 pounds per square inch gauge (psig).

[0154] In some embodiments of any of the aspects, the heated pressurized gas in the drying chamber has an atomizing gas pressure of at least 20 pounds per square inch gauge (psig).

[0155] In some embodiments of any of the aspects, the heated pressurized gas in the drying chamber has an atomizing gas pressure of up to 150 pounds per square inch gauge (psig).

[0156] In some embodiments of any of the aspects, the heated pressurized gas has a flow rate through the drying chamber of at least 5 kg / hr.

[0157] In some embodiments of any of the aspects, the heated pressurized gas has a flow rate through the drying chamber of at least 18 kg / hr.

[0158] In some embodiments of any of the aspects, the heated pressurized gas has a flow rate through the drying chamber of up to 150 kg / hr.

[0159] In some embodiments of any of the aspects, the heated pressurized gas is discharged through a cyclone chamber.

[0160] In some embodiments of any of the aspects, exposing the liquid feedstock droplets to heated and pressurized gas in the drying chamber takes up to 8 hours.

[0161] In some embodiments of any of the aspects, the dried particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of at least 1.5 μm and up to 7.5 μm.

[0162] In some embodiments of any of the aspects, the dried particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of at least 4.0 μm.

[0163] In some embodiments of any of the aspects, the dried particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of up to 5.0 μm.

[0164] In some embodiments of any of the aspects, the step of isolating the dry particles of the predetermined range of diameters in the cyclone chamber is performed continuously.

[0165] In one aspect, described herein is a method of delivering a spray-dried pharmaceutical composition comprising a lactate-generating compound to a subject, the method comprising: (a) obtaining an inhalation device for bronchopulmonary delivery, the inhalation device comprising: (i) an inhaler; and (ii) a container containing a spray-dried pharmaceutical composition comprising a lactate-generating compound; (b) activating the inhaler to cause aerosolization or dispersion of the spray-dried pharmaceutical composition; and (c) inhaling the aerosolized or dispersed spray-dried pharmaceutical composition.

[0166] In one aspect, described herein is a method of delivering a spray-dried pharmaceutical composition comprising a lactate-producing compound to a subject, the method comprising: (a) obtaining an inhalation device for bronchopulmonary delivery, the inhalation device comprising (i) an inhaler, and (ii) a container containing a pharmaceutical composition described herein, the pharmaceutical composition being spray-dried; (b) activating the inhaler to cause aerosolization or dispersion of the spray-dried pharmaceutical composition; and (c) inhaling the aerosolized or dispersed spray-dried pharmaceutical composition.

[0167] In one aspect, described herein is a method of delivering a spray-dried pharmaceutical composition comprising a lactate-producing compound to a subject, the method comprising: (a) obtaining an inhalation device as described herein; (b) activating the inhaler to cause aerosolization or dispersion of the spray-dried pharmaceutical composition; and (c) inhaling the aerosolized or dispersed spray-dried pharmaceutical composition.

[0168] In some embodiments of any of the aspects, the inhaler is a dry powder inhaler (DPI).

[0169] In some embodiments of any of the aspects, the inhaler is a metered dose inhaler (MDI).

[0170] In some embodiments of any of the aspects, the inhaler is a soft mist inhaler (SMI).

[0171] In some embodiments of any of the aspects, the inhaler includes (a) a mouthpiece including an opening, and (b) a means for aerosolizing or dispersing the spray-dried pharmaceutical composition within the container.

[0172] In some embodiments of any of the aspects, the inhaler has an inhalation flow rate of at least 15 L / min and up to 60 L / min.

[0173] In some embodiments of any of the aspects, at least 25% and up to 125% by weight of the spray-dried pharmaceutical composition is delivered to the target bronchopulmonary tissue.

[0174] In some embodiments of any of the aspects, at least 30% by weight of the spray-dried pharmaceutical composition is delivered to the target bronchopulmonary tissue.

[0175] In some embodiments of any of the aspects, the target bronchiolopulmonary tissue is the lung, trachea, bronchi, bronchioles, and / or alveoli.

[0176] In some embodiments of any of the aspects, the spray dried pharmaceutical composition is delivered to a tissue site distal to the bronchopulmonary tissue via the cardiovascular or lymphatic system.

[0177] In one aspect, described herein is a method of treating a subject in need thereof, the method comprising administering by inhalation an effective dose of a pharmaceutical composition comprising a lactate-producing compound.

[0178] In one aspect, described herein is a method of treating a subject in need of treatment, the method comprising administering by inhalation an effective dose of a pharmaceutical composition described herein.

[0179] In some embodiments of any of the aspects, the lactate-generating compound reduces neutrophilic inflammation in the target tissue.

[0180] In some embodiments of any of the aspects, the target tissue is a target bronchopulmonary tissue.

[0181] In some embodiments of any of the aspects, the target bronchiolopulmonary tissue is the lung, trachea, bronchi, bronchioles, and / or alveoli.

[0182] In some embodiments of any of the aspects, the target tissue is a tissue site distal to the lung, delivered via the cardiovascular or lymphatic system.

[0183] In some embodiments of any of the aspects, the subject has been diagnosed with or is at risk of developing a chronic or infectious bronchopulmonary disease.

[0184] In some embodiments of any aspect, the chronic bronchopulmonary disease is selected from the group consisting of asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), bronchiectasis, non-cystic fibrosis (CF) bronchiectasis, cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), interstitial lung disease (LD), pleural effusion (PE), pulmonary hypertension (PAH), silicosis, and lung cancer.

[0185] In some embodiments of any of the aspects, the lung cancer is non-small cell lung cancer (SCLC) or small cell lung cancer (NSCLC).

[0186] In some embodiments of any of the aspects, the infectious bronchopulmonary disease is caused by or associated with an infectious agent selected from adenovirus, coronavirus, influenza virus, parainfluenza virus, parvovirus, respiratory syncytial virus, rhinovirus, enterovirus, measles virus, rubella virus, varicella virus, Corynebacterium diphtheriae, Haemophilus influenzae, Legionella pneumophila, Bordetella pertussis, Mycobacterium tuberculosis, Streptococcus species, Pseudomonas species, Escherichia coli, Aspergillus species, Cryptococcus species, and Pneumocystis species.

[0187] In some embodiments of any of the aspects, the pharmaceutical composition is a spray dried pharmaceutical composition.

[0188] In some embodiments of any of the aspects, the pharmaceutical composition is for treating chronic or infectious It is administered using standard treatment for bronchopulmonary disease.

[0189] In some embodiments of any of the aspects, the pharmaceutical composition is administered using an inhaler.

[0190] In some embodiments of any of the aspects, the inhaler is a dry powder inhaler (DPI).

[0191] In some embodiments of any of the aspects, the inhaler is a metered dose inhaler (MDI).

[0192] In some embodiments of any of the aspects, the inhaler is a soft mist inhaler (SMI).

[0193] In some embodiments of any of the aspects, the effective dose of the pharmaceutical composition is at least 7.8 mg of lactate-producing compound per unit dose.

[0194] In some embodiments of any of the aspects, the pharmaceutical composition is co-administered with at least one additional therapeutic agent for chronic or infectious bronchopulmonary disorders.

[0195] In some embodiments of any of the aspects, the at least one additional therapeutic agent is an anti-inflammatory agent, an antibacterial agent, an antiviral agent, an antifungal agent, a vasodilator, or a bronchodilator.

[0196] In one aspect, described herein is a unit dosage form comprising at least 1.0 mg and up to 100.0 mg of a pharmaceutical composition comprising a lactate-producing compound.

[0197] In one aspect, described herein is a unit dosage form comprising at least 1.0 mg and up to 100.0 mg of a pharmaceutical composition described herein.

[0198] In one aspect, described herein is a unit dosage form comprising at least 1.0 mg and up to 100.0 mg of a spray dried pharmaceutical composition prepared by the methods described herein.

[0199] In one embodiment, described herein is a unit dosage form comprising at least 15.0 mg and up to 100.0 mg of a pharmaceutical composition comprising at least 15 mg of a lactate-producing compound per unit dose.

[0200] In some embodiments of any of the aspects, the dosage is at least 1.0 mg of the pharmaceutical composition.

[0201] In some embodiments of any of the aspects, the dosage comprises at least 7.8 mg of lactate-generating compound per unit dose deliverable to the target tissue.

[0202] In some embodiments of any of the aspects, the dosage comprises at least 15 mg of lactate-producing compound per unit dose.

[0203] In some embodiments of any of the aspects, the pharmaceutical composition is a spray dried pharmaceutical composition.

[0204] In one aspect, described herein is a pharmaceutical composition comprising (a) a lactate-producing compound and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for oral administration.

[0205] In some embodiments of any of the present aspects, the lactate-producing compound is selected from (a) a polymeric compound capable of producing lactic acid, (b) a non-polymeric compound capable of producing lactic acid, or (c) lactic acid.

[0206] In some embodiments of any of the aspects, the non-polymeric lactic acid producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide.

[0207] In some embodiments of any of the aspects, the polymeric lactic acid producing compound is polylactic acid (PLA).

[0208] In some embodiments of any of the aspects, the polylactic acid is poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), or poly(D-lactide) (PDLA).

[0209] In some embodiments of any of the aspects, the composition includes at least one excipient or at least one stabilizer.

[0210] In some embodiments of any of the aspects, the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, gluco-oligosaccharides, lacto-oligosaccharides, fructooligosaccharides, inulin, sodium caseinate, goat milk, cow's milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts.

[0211] In some embodiments of any of the aspects, the excipient is leucine and / or trehalose.

[0212] In some embodiments of any of the aspects, the stabilizer is a polysorbate, a poloxamer, or polyvinyl alcohol.

[0213] In some embodiments of any of the aspects, the stabilizer is poloxamer 188.

[0214] In some embodiments of any of the aspects, the additive is an adhesive.

[0215] In some embodiments of any of the aspects, the composition comprises a plurality of dry particles.

[0216] In some embodiments of any of the aspects, the composition comprises a plurality of spray-dried particles.

[0217] In some embodiments of any of the aspects, the composition is formulated as a tablet or capsule.

[0218] In one aspect, described herein is a method of treating a subject in need thereof, the method comprising orally administering an effective dose of a pharmaceutical composition comprising a lactate-producing compound.

[0219] In one aspect, described herein is a method of treating a subject in need thereof, the method comprising orally administering an effective dose of a pharmaceutical composition described herein.

[0220] In some embodiments of any of the aspects, the lactate-generating compound reduces neutrophilic inflammation in the target tissue.

[0221] In some embodiments of any of the aspects, the target tissue is a bronchopulmonary target tissue.

[0222] In some embodiments of any of the aspects, the subject has been diagnosed with or is at risk of developing a chronic or infectious bronchopulmonary disorder.

[0223] In some embodiments of any of the aspects, the pharmaceutical composition is a spray dried pharmaceutical composition.

[0224] In some embodiments of any of the aspects, the pharmaceutical composition is co-administered with at least one additional therapeutic agent.

[0225] In some embodiments of any of the aspects, the at least one additional therapeutic agent is an anti-inflammatory agent, an antibacterial agent, a vasodilator, or a bronchodilator. [Brief description of the drawings]

[0226] [Figure 1A] 1 is a series of bar graphs showing lactic acid production for bacterial strains AB101, AB102, and AB103, showing L(+)-lactic acid production in the supernatant of each strain or blends thereof. [Figure 1B] 1 is a series of bar graphs showing lactate production for bacterial strains AB101, AB102, and AB103, showing the production of D(-)-lactate in the supernatant of each strain or blends thereof. [Diagram 2]FIG. 1 is a bar graph showing that increasing concentrations of lactate reduced matrix metalloproteinase-9 (MMP-9) mRNA levels in a dysbiosis model of lung epithelial cells (human primary epithelial (HBE) cells treated with E. coli). [Diagram 3] 1 is a bar graph showing the reduction of MMP-9 mRNA levels in human intestinal epithelial cells (IEC) from the Caco-2 cell line inoculated with E. coli and then treated with various concentrations of L-lactic acid (L-LA). [Figure 4] FIG. 1 is a dot plot showing the reduction of MMP-9 mRNA levels in A549 non-small cell lung cancer (NSCLC) adenocarcinoma cells inoculated with E. coli and then treated with 0.25 μg to 4 μg of L-lactic acid (L-LA). [Diagram 5] FIG. 1 is a dot plot showing MMP-9 mRNA levels in human bronchial epithelial (HBE) cells inoculated with E. coli and then treated with 0.25 μg to 2 μg of D-lactic acid (D-LA). D-LA treatment did not show a statistical difference in MMP9 mRNA levels. [Figure 6] 1 is a bar graph showing L-lactic acid production in vitro for bacterial strains AB101, AB102, or AB103. The left-to-right order of the bars corresponds to the top-to-bottom order in the graph legend. [Figure 7] 1 is a line graph showing the hydrolysis of polylactic acid powder (PLA) to L(+) lactic acid in phosphate buffered saline (PBS) solution. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0227] The technology described herein is directed to pharmaceutical compositions comprising lactate-producing compounds formulated for administration by inhalation and / or oral administration. Also described herein are unit dosage forms of such pharmaceutical compositions, devices comprising such pharmaceutical compositions, methods of making such pharmaceutical compositions, and methods of treating bronchopulmonary diseases using such pharmaceutical compositions, among others.

[0228] Providing doses of lactate-generating compounds to the lungs of chronically ill patients can greatly benefit the patient, especially as it relates to dysbiosis. Dysbiosis occurs when there is an imbalance between commensal (beneficial) and pathogenic (harmful) bacteria. Data shows that active bacterial extracts and metabolites can produce anti-inflammatory effects systemically. See, for example, Jang et al. (2020 Experimental & Molecular Medicine 52(7):1128-1139; Weingarden and Vaughn BP (2017 Gut Microbes 8(3):238-252; Arpaia et al. (2013 Nature 504(7480):451-455; Iraporda et al. (2015) Immunobiology 220(10):1161-1169; Vinolo et al. (2011) Nutrients 3(10):858-876, the contents of each of which are incorporated herein by reference in their entirety. As described herein, it has been found that lactic acid itself is an active element or principle in such bacterial extracts and metabolites, and delivery of lactic acid can provide therapeutic benefits.

[0229] Preparation and delivery format of lactic acid therapeutics Delivery of lactate-generating compounds directly to the lung requires inhalation administration techniques such as nebulized delivery, metered dose inhalers (MDIs), dry powder inhalers (DPIs), or soft mist inhalers (SMIs). In particular, administration of biotherapeutics is challenging due to stability concerns. The presence of moisture makes powdered biotherapeutics difficult to store and use. Stability in this case is a concern for biotherapeutics such as lactate-generating compounds, which may require careful extraction and gentle processing.

[0230] To circumvent these challenges, inhalable dry powders can be used through DPIs. However, the therapeutic agent must be formulated as an inhalable dry powder to be used successfully in a DPI. This powder must have a specific moisture content (usually very low, 1-5%) for stability purposes, as well as specific aerodynamic properties to ensure proper and reliable delivery of the powder. A process known as spray drying can be used to "engineer" this type of dry powder for use in a DPI.

[0231] spray drying Spray drying is a technique in which multiple ingredients are dissolved, sprayed into droplets, and rapidly dried in a drying chamber to produce custom dry, aerosolizable powders with tailored particle characteristics. It can be used to produce inhalable dry powders to treat COPD, cystic fibrosis (CF), asthma, and non-respiratory disorders such as diabetes and migraines.

[0232] Spray drying involves the production of a feedstock containing dissolved solid components intended to be present in the dried particles at some defined concentration (e.g., percent ratio of solvent weight to solvent weight, % w / w). The feedstock is then fed through a nozzle at a specified pressure to produce droplets. The droplets are dried by heated gas flowing through a drying chamber to rapidly produce dry particles. The particles are then collected at the bottom of a cyclone. A cyclone is a device designed to capture a reduced range of particle diameters, with the remaining "waste" particles being collected at the end of the process. The particles captured in these cyclones represent drugs intended or designed to be inhaled for the treatment or prevention of disease.

[0233] The production of an effective spray-dried powder can include more ingredients than just the active pharmaceutical ingredient itself. The powder may include the active ingredient, one or more excipients, residual solvents, and / or emulsion stabilizers. These ingredients are dissolved or suspended in the material to be dried before the start of spray drying. The homogenous solution or suspension is then dried to produce the inhalable dry powder itself.

[0234] The included excipients are used to provide some advantage to the spray-dried powder; that is, they are included to provide certain thermodynamic and physical properties. Excipients are often responsible for the shape of the spray-dried particles themselves, due to their solubility properties. In the source solvent, the solubility of the excipients determines how quickly the sprayed droplets form solid particles and how quickly the solid molecules move toward the center of the droplets during drying. As the particles dry, the chemical and thermodynamic properties of the powders and their stability affect the solubility of the final powder, i.e., over time and beyond temperature and humidity exposure, depending on the polymorphism (or lack thereof) of the final powder. Appropriate selection of excipients results in dried powders that exhibit stable crystallinity, high particle density, consistent shape, and high dispersibility. Often, amino acids such as leucine are combined with salts or sugars to optimize this effect.

[0235] Surfactant stabilizers are often used when spray drying formulations with hydrophobic or insoluble particles. In some embodiments, the formulation includes stabilizers when spray drying the suspension, so that the suspension is uniformly emulsified and dispersed, resulting in a uniform suspension for consistent droplet spraying. These surfactants are often included in low percentages to minimize their impact on the final dry powder. Polysorbates of various purities are frequently used, but other organic acid combinations are possible, along with steric surfactants such as Pluronic F68.

[0236] These spray-dried powders can be encapsulated and used in several forms of dry powder delivery devices that allow the patient to deeply inhale the particles and deposit at a target depth in the airways. These spray-dried powders can be filled into crushable capsules or sachets that can be crushed when used inside the delivery device. Once the enclosure is broken, the patient can inhale deeply through the mouthpiece of the inhaler and the powder can be deposited in the patient's throat, esophagus, and lungs. The goal of dry powders for inhalation is to generate a powder of a specific aerodynamic size and density to deposit a predictable and safe dose of drug in the appropriate portion of the lung airways.

[0237] Described herein is a drug delivery mechanism that allows patients to administer lactate-generating compounds directly to the lungs via inhalation of a spray-dried powder for the treatment of chronic lung diseases characterized by inflammation.

[0238] Pharmaceutical Compositions Described herein are pharmaceutical compositions comprising a lactate-producing compound and a pharma- ceutically acceptable excipient, stabilizer, or additive. In some embodiments, the lactate-producing compound is selected from a polymeric compound capable of producing lactate, a non-polymeric compound capable of producing lactate, or lactic acid. In some embodiments, the lactate-producing compound is a derivative, polymer, or intermediate of lactate. In some embodiments, the pharmaceutical composition is formulated for pulmonary administration (e.g., by inhalation). In some embodiments, the pharmaceutical composition is formulated for administration by inhalation. In some embodiments, the pharmaceutical composition is formulated for oral administration. The spray drying methods further described herein can be used to prepare pharmaceutical compositions formulated for inhalation and / or oral administration.

[0239] In one aspect, described herein is a pharmaceutical composition comprising: (a) a lactic acid-producing compound selected from (i) a polymeric compound capable of producing lactic acid, (ii) a non-polymeric compound capable of producing lactic acid, or (iii) lactic acid; and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for administration by inhalation.

[0240] In one aspect, described herein is a pharmaceutical composition comprising (a) lactic acid and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for administration by inhalation. In one aspect, described herein is a pharmaceutical composition comprising (a) a non-polymeric compound capable of producing lactic acid and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for administration by inhalation. In one aspect, described herein is a pharmaceutical composition comprising (a) a polymeric compound capable of producing lactic acid and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for administration by inhalation. In some embodiments, the composition comprises at least one excipient and at least a stabilizer, as further described herein (see, e.g., Table 1). [Table 1]

[0241] [Table 11]

[0242] In some embodiments, the lactate-producing compound produces lactate upon delivery to the target tissue. In some embodiments, for example, when the pharmaceutical composition is formulated for administration by inhalation and / or administration to the lungs, the target tissue is a target bronchopulmonary tissue. In some embodiments, the target bronchopulmonary tissue is the lung, trachea, bronchi, bronchioles, and / or alveoli. In some embodiments, the target bronchopulmonary tissue is the lung. In some embodiments, the target bronchopulmonary tissue is the trachea. In some embodiments, the target bronchopulmonary tissue is the bronchi. In some embodiments, the target bronchopulmonary tissue is the bronchioles. In some embodiments, the target bronchopulmonary tissue is the alveoli. In some embodiments, the target tissue is a tissue site distal from the lung. In some embodiments, the composition is delivered to the distal target site via the cardiovascular or lymphatic system.

[0243] In one aspect, described herein is a pharmaceutical composition comprising: (a) a lactic acid-producing compound selected from (i) a polymeric compound capable of producing lactic acid, (ii) a non-polymeric compound capable of producing lactic acid, or (iii) lactic acid; and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for oral administration. In some embodiments, the additive is, for example, an adhesive for oral formulations.

[0244] In one aspect, described herein is a pharmaceutical composition comprising (a) lactic acid and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for oral administration. In one aspect, described herein is a pharmaceutical composition comprising (a) a non-polymeric compound capable of producing lactic acid and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for oral administration. In one aspect, described herein is a pharmaceutical composition comprising (a) a polymeric compound capable of producing lactic acid and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for oral administration. In some embodiments, the composition comprises at least one excipient, at least one stabilizer, and at least one additive (e.g., adhesive), as further described herein (see, e.g., Table 2).

[0245] In one aspect, described herein is a pharmaceutical composition comprising: (a) a lactic acid-producing compound selected from (i) a polymeric compound capable of producing lactic acid, (ii) a non-polymeric compound capable of producing lactic acid, or (iii) lactic acid; (b) at least one excipient; (c) at least one stabilizer; and (d) at least one adhesive, wherein the composition is formulated for oral administration. The pharmaceutical compositions formulated for oral administration described herein can be produced by first spray drying a spray-dried matrix and then tableting, which method allows for control of the stability characteristics of the spray-dried matrix as well as the size of the active ingredient (e.g., the lactic acid-producing compound) itself in the tableted matrix. [Table 2]

[0246] Lactic acid producing compounds The pharmaceutical compositions described herein include at least one lactate-producing compound. As used herein, the term "lactate-producing compound" refers to a compound that produces lactate, either because it contains lactate or because lactate is produced when the compound is hydrolyzed, metabolized, or otherwise chemically modified. In some embodiments, the pharmaceutical composition includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more lactate-producing compounds. In some embodiments, the lactate-producing compound is selected from (i) lactate, (ii) a non-polymeric compound capable of producing lactate, or (iii) a polymeric compound capable of producing lactate.

[0247] In some embodiments, the pharmaceutical composition comprises (i) lactic acid. In some embodiments, the pharmaceutical composition comprises (ii) a non-polymeric compound capable of producing lactic acid. In some embodiments, the pharmaceutical composition comprises (iii) a polymeric compound capable of producing lactic acid. In some embodiments, the pharmaceutical composition comprises (i) lactic acid, and (ii) a non-polymeric compound capable of producing lactic acid. In some embodiments, the pharmaceutical composition comprises (i) lactic acid, and (iii) a polymeric compound capable of producing lactic acid. In some embodiments, the pharmaceutical composition comprises (ii) a non-polymeric compound capable of producing lactic acid, and (iii) a polymeric compound capable of producing lactic acid. In some embodiments, the pharmaceutical composition comprises (i) lactic acid, ...

[0248] Lactate is a by-product of metabolism. In animals, L-lactate is produced from pyruvate via the enzyme lactate dehydrogenase (LDH) during normal metabolism and during exercise, during fermentation. The concentration of lactate in human blood is normally 1 mM-2 mM at rest, but may exceed 20 mM during intense exercise and then rise to 25 mM. In addition to other biological roles, L-lactate plays a key role in the regulation of G i / oIt is the major endogenous agonist of hydroxycarboxylic acid receptor 1 (HCA1), a G protein-coupled receptor (GPCR) coupled to Lactic acid fermentation can be carried out by lactic acid bacteria, which convert simple carbohydrates such as glucose, sucrose, or galactose into lactic acid.

[0249] Lactic acid is a chiral compound consisting of two enantiomers. One enantiomer is known as l-lactic acid, (S)-lactic acid, or (+)-lactic acid (see, for example, Formula I below), and its mirror image, the other enantiomer, is d-lactic acid, (R)-lactic acid, or (-)-lactic acid (see, for example, Formula II below). A mixture of the two enantiomers, for example, in equal amounts, is called dl-lactic acid, or racemic lactic acid. When used herein, "racemic mixture" refers to a solution in which both enantiomers of a compound are present in a 50:50 ratio. Aerosol delivery to the lungs of both the D or L form and the DL racemic mixture is contemplated herein. [ka]

[0250] Both the L and D enantiomers of lactic acid have advantages. L-lactic acid is the naturally occurring enantiomer (e.g., in humans). D-lactic acid may be bioavailable for a longer period of time, for example, compared to L-lactic acid. Described herein are methods of inhalation delivery of such lactic acid enantiomers, where it is contemplated that by varying frequency, dose, and / or delivery device (e.g., metered dose inhaler (MDI)), for example, therapeutic effect for a particular indication may be optimized or tailored. D, L, and racemic mixtures may also be used in oral tablet or capsule formulations.

[0251] Thus, in some embodiments, the lactate-producing compound comprises the D enantiomer of lactic acid, the L enantiomer of lactic acid, or a racemic mixture of the D and L enantiomers of lactic acid. In some embodiments, the lactate-producing compound comprises the D enantiomer of lactic acid. In some embodiments, the lactate-producing compound comprises the L enantiomer of lactic acid. In some embodiments, the lactate-producing compound comprises a racemic mixture of the D and L enantiomers of lactic acid.

[0252] In some embodiments, the lactate-producing compound is a non-polymeric compound capable of producing lactate. As used herein, the term "non-polymeric compound" refers to a molecule that does not contain repeating monomers. In some embodiments, the non-polymeric lactate-producing compound can be metabolized in the target tissue to produce lactate. In some embodiments, the non-polymeric lactate-producing compound can be metabolized to produce lactate using hydrolysis in the target tissue. In some embodiments, the non-polymeric lactate-producing compound can be completely metabolized in the target tissue (i.e., all of the compound is broken down into lactate and other by-products) or partially metabolized (i.e., at least a portion of the compound is broken down into lactate and other by-products).

[0253] In some embodiments, the non-polymeric lactic acid producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide. In some embodiments, the pharmaceutical composition comprises an inorganic salt of lactic acid, an ester of lactic acid, or lactide. In some embodiments, the pharmaceutical composition comprises an inorganic salt of lactic acid. In some embodiments, the pharmaceutical composition comprises an ester of lactic acid. In some embodiments, the pharmaceutical composition comprises lactide. In some embodiments, the pharmaceutical composition comprises an inorganic salt of lactic acid and an ester of lactic acid. In some embodiments, the pharmaceutical composition comprises an inorganic salt of lactic acid and lactide. In some embodiments, the pharmaceutical composition comprises an ester of lactic acid and lactide. In some embodiments, the pharmaceutical composition comprises an inorganic salt of lactic acid, an ester of lactic acid, and lactide.

[0254] In some embodiments, the non-polymeric lactate-producing compound is an inorganic salt of lactic acid. In this approach, rather than delivering lactic acid itself, a simple salt such as sodium lactate is delivered. One advantage of such an inorganic salt is that it is slowly converted to lactic acid and therefore does not immediately lower the pH of the microenvironment in the target tissue (i.e., by increasing lactic acid levels). In some embodiments, the inorganic salt of lactic acid is sodium lactate (NaC3H5O3). In some embodiments, the inorganic salt of lactic acid is potassium lactate (KC3H5O3). In some embodiments, the inorganic salt of lactic acid is calcium lactate (Ca(C3H5O3)2). In some embodiments, the inorganic salt of lactic acid is magnesium lactate (Mg(C3H5O3)2).

[0255] In some embodiments, the non-polymeric lactic acid generating compound is an ester of lactic acid. The ester of lactic acid can be hydrolyzed in vivo to produce lactic acid. The series of esters can include water-soluble ethyl lactate to hydrophobic dodecyl lactate. A series of compounds capable of forming hydrolyzable bonds to lactic acid including esters and amines can be used. In some embodiments, the ester of lactic acid is ethyl lactate (CH3CH(OH)CO2CH2CH3). In some embodiments, the ester of lactic acid is dodecyl lactate (CH3CH(OH)CO2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3). In some embodiments, the ester of lactic acid is selected from ethyl lactate, propyl lactate, butyl lactate, pentyl lactate, hexyl lactate, heptyl lactate, octyl lactate, nonyl lactate, decyl lactate, undecyl lactate, or dodecyl lactate.

[0256] In some embodiments, the non-polymeric lactic acid-producing compound is lactide. Lactide is a cyclic dimer formed from lactic acid (see, for example, formula III below). Both the L and D enantiomeric forms of lactide, or their racemic mixtures, can be used. Lactide compounds are stable while dry, but when hydrolyzed in vivo, they produce two lactic acid molecules. [ka]

[0257] In some embodiments, the pharmaceutical composition comprising at least one non-polymeric lactic acid-producing compound further comprises an additive. In some embodiments, the additive is a buffer salt or a surfactant. In some embodiments, the additive allows for encapsulation. For example, lactic acid can be encapsulated in a polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP) capsule that facilitates administration. Such capsules can dissolve upon administration, allowing deeper penetration, longer duration, and slower pH change from the administered lactic acid-producing compound.

[0258] In some embodiments, the lactate-producing compound is a polymeric compound capable of producing lactate. As used herein, the term "polymeric compound" refers to a molecule that includes repeating monomers. In some embodiments, at least one of the monomers in the polymeric compound includes lactate or a derivative thereof. In some embodiments, the polymeric lactate-producing compound can be hydrolyzed in the target tissue to produce lactate. Such hydrolysis occurs wherever there is water, so such a step does not require enzymes. In some embodiments, the polymeric lactate-producing compound can be fully hydrolyzed in the target tissue (i.e., all of the compound is broken down into lactate and other by-products) or partially hydrolyzed (i.e., at least a portion of the compound is broken down into lactate and other by-products).

[0259] The use of biodegradable polymers based on hydroxy acids is known in the art. Uses include a range of medical device applications where the polymer performs mechanical uses, to forms of drug delivery where the polymer is used to maintain delivery over periods of days to months. In such cases, the polymer degrades to the corresponding hydroxy acid during or after its functional use or administration. Examples include both poly(L-lactide), poly(DL-lactide), and their copolymers with glycolic acid (a family commonly abbreviated as PLGA) and caprolactone. Several deliverable forms of the polymeric lactic acid-producing compound are possible. In some embodiments, the polymeric lactic acid-producing compound comprises particulate forms of polylactic acid, prepared, for example, by grinding to a specific particle size. Control variables may include particle size, molecular weight (MW) of the polymer, chirality, and porosity.

[0260] In some embodiments, the polymeric lactic acid-producing compound is polylactic acid (PLA) (see, for example, Formula IV below). Polylactic acid, also known as poly(lactic acid) or polylactide, has the skeletal formula (CHO) n or [-C(CH3)HC(=O)O-] n and is formally obtained by the condensation of lactic acid, C(CH3)(OH)HCOOH, with loss of water. PLA can also be prepared by the ring-opening polymerization of lactide [-C(CH3)HC(=O)O-]2, a cyclic dimer of basic repeating units. In some embodiments, the PLA polymer is composed of at least 2 monomers, at least 3 monomers, at least 4 monomers, at least 5 monomers, at least 10 monomers, at least 50 monomers, at least 100 monomers, at least 10 3 monomers, at least 10 4 monomers, at least 10 5 monomers, at least 10 6 monomers, at least 10 7 monomers, at least 10 8 monomers, at least 10 9monomers, at least 10 10 It contains one or more monomers of lactic acid. [ka]

[0261] In some embodiments, the polylactic acid is poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), or poly(D-lactide) (PDLA). In some embodiments, the pharmaceutical composition comprises PLLA, PDLLA, or PDLA. In some embodiments, the pharmaceutical composition comprises PLLA. In some embodiments, the pharmaceutical composition comprises PDLLA. In some embodiments, the pharmaceutical composition comprises PDLA. In some embodiments, the pharmaceutical composition comprises PLLA and PDLLA. In some embodiments, the pharmaceutical composition comprises PLLA and PDLA. In some embodiments, the pharmaceutical composition comprises PDLLA and PDLA. In some embodiments, the pharmaceutical composition comprises PLLA, PDLLA, and PDLA. In some embodiments, the polylactic acid is poly(L-lactide) (PLLA). In some embodiments, the polylactic acid is poly(D-lactide) (PDLA). In some embodiments, the polylactic acid is poly(D,L-lactide) (PDLLA).

[0262] In some embodiments, the polymeric lactic acid generating compound is poly(lactic-co-glycolic acid) (PLGA) (see, e.g., Formula V below). PLGA, PLG, or poly(lactic-co-glycolic acid) is a highly biodegradable and biocompatible copolymer. In some embodiments, the PLGA polymer is a copolymer of at least 2 monomers, at least 3 monomers, at least 4 monomers, at least 5 monomers, at least 10 monomers, at least 50 monomers, at least 10 ... 3 monomers, at least 10 4 monomers, at least 10 5 monomers, at least 10 6monomers, at least 10 7 monomers, at least 10 8 monomers, at least 10 9 monomers, at least 10 10 It contains one or more monomers of lactic acid. [ka]

[0263] PLGA is synthesized by ring-opening copolymerization of cyclic dimers (e.g., 1,4-dioxane-2,5-dione) of two different monomers, glycolic acid and lactic acid. PLGA polymers can be synthesized as either random or block copolymers, thereby imparting additional polymeric properties. Common catalysts used in the preparation of PLGA polymers include tin(II) 2-ethylhexanoate, tin(II) alkoxides, or aluminum isopropoxide. During polymerization, consecutive monomer units (of glycolic acid or lactic acid) are linked together in PLGA by ester bonds, thus resulting in a linear aliphatic polyester as the product.

[0264] Depending on the ratio of lactide and glycolide used in the polymerization, different forms of PLGA can be obtained, which are usually specified in terms of the molar ratio of the monomers used (e.g., PLGA 75:25 specifies a copolymer whose composition is 75% lactic acid and 25% glycolic acid). In some embodiments, the pharmaceutical composition comprises PLGA 10:90, PLGA 20:80, PLGA 25:75, PLGA 30:70, PLGA 40:60, PLGA 50:50, PLGA 60:40, PLGA 70:30, PLGA 75:25, PLGA 80:20, PLGA 90:10 of lactic acid and glycolic acid. The crystallinity of PLGA varies from completely amorphous to completely crystalline, depending on the block structure and molar ratio. PLGA typically exhibits a glass transition temperature in the range of 40-60°C.

[0265] PLGA undergoes hydrolysis in the body to produce the original monomers, i.e., lactic acid and glycolic acid. PLGA degrades in the presence of water by hydrolysis of its ester bonds. PLGA materials can be tailored to degrade more rapidly than PLA homopolymers. The time required for degradation of PLGA is related to the ratio of monomers used in its production, with a higher content of glycolide units requiring less time to degrade compared to predominantly lactide materials. An exception to this rule is copolymers with a 50:50 monomer ratio, which show more rapid degradation (approximately 2 months). Furthermore, polymers end-capped with esters (as opposed to free carboxylic acids) show longer degradation half-lives. Microspheres can be used for drug delivery with PLGA, e.g., PLGA particles ranging in diameter from a few microns to 100 microns.

[0266] In some embodiments, the polymeric lactic acid generating compound comprises caprolactone (see, for example, Formula VI below). In some embodiments, the polymeric lactic acid generating compound is generated from caprolactone. ε-caprolactone, or simply caprolactone, is a lactone (cyclic ester) with a seven-membered ring. Its name comes from caproic acid. This colorless liquid is miscible with most organic solvents and water. Several other caprolactones are also known. These isomers include α-, β-, γ-, and δ-caprolactone, which are all chiral. Caprolactone is prepared industrially by Baeyer-Villiger oxidation of cyclohexanone with peracetic acid. Ring-opening polymerization of caprolactone produces polycaprolactone. [ka]

[0267] In some embodiments, the polymeric lactic acid producing compound is poly(lactic acid-co-caprolactone) (PLCL, see, e.g., Formula VII below). In some embodiments, the polymeric lactic acid producing compound is poly(D,L-lactide-co-caprolactone). In some embodiments, the poly(lactic acid-co-caprolactone) polymer is a polymer that is composed of at least 2 monomers, at least 3 monomers, at least 4 monomers, at least 5 monomers, at least 10 monomers, at least 50 monomers, at least 100 monomers, at least 10 3 monomers, at least 10 4 monomers, at least 10 5 monomers, at least 10 6 monomers, at least 10 7 monomers, at least 10 8 monomers, at least 10 9 monomers, at least 10 10 It contains one or more monomers of lactic acid. [ka]

[0268] In some embodiments, the polymeric lactic acid generating compound is poly(glycolic acid-epsilon-caprolactone) (PGCL) or poliglecaprone, which is a polymer of e-caprolactone and glycolic acid. In some embodiments, the PGCL polymer is a polymer of at least 2 monomers, at least 3 monomers, at least 4 monomers, at least 5 monomers, at least 10 monomers, at least 50 monomers, at least 100 monomers, at least 10 3 monomers, at least 10 4 monomers, at least 10 5 monomers, at least 10 6 monomers, at least 10 7 monomers, at least 10 8 monomers, at least 10 9 monomers, at least 10 10It contains one or more monomers of lactic acid.

[0269] In some embodiments, the pharmaceutical composition comprises at least 1.0% by weight of a lactate-producing compound, hi some embodiments, the pharmaceutical composition comprises at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0%, at least 10.0% or more by weight of a lactate-producing compound.

[0270] In some embodiments, the pharmaceutical composition comprises at least 1.0 mg of lactate-producing compound per unit dose. In some embodiments, the pharmaceutical composition comprises at least 5.0 mg of lactate-producing compound per unit dose. In some embodiments, the pharmaceutical composition comprises up to 100.0 mg of lactate-producing compound per unit dose. In some embodiments, the pharmaceutical composition comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a lactate-producing compound per unit dose.

[0271] Pharmaceutically acceptable excipients, stabilizers, and additivesIn some embodiments, the technology described herein relates to a pharmaceutical composition comprising a lactate-generating compound described herein and, optionally, a pharma- ceutically acceptable excipient, stabilizer, and / or additive. In some embodiments, the active ingredient of the pharmaceutical composition comprises a lactate-generating compound described herein. In some embodiments, the active ingredient of the pharmaceutical composition consists essentially of a lactate-generating compound described herein. In some embodiments, the active ingredient of the pharmaceutical composition consists of a lactate-generating compound described herein. In some embodiments, the pharma- ceutically acceptable excipient, stabilizer, and / or additive comprises, for example, saline, aqueous buffer, solvent, and / or dispersion medium. The use of such excipients, stabilizers, and / or additives is well known to those skilled in the art. Some non-limiting examples of materials that can function as pharma- ceutically acceptable excipients, stabilizers, and / or additives include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil; corn oil, and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol (PEG), (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) pH buffer solutions, (21) polyesters, polycarbonates, and / or polyanhydrides, (22) bulking agents, such as polypeptides and amino acids, (23) serum components, such as serum albumin, HDL, and LDL, (24) C2-C12 Alcohols, e.g., ethanol, and (25) other non-toxic, non-toxic compatible substances used in pharmaceutical formulations may be included. Wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the formulation. In some embodiments, the pharma- ceutically acceptable excipients, stabilizers, and / or additives inhibit the decomposition of the active agent (e.g., the lactic acid-producing compounds described herein). In some embodiments, the composition comprises at least one pharma-ceutically acceptable excipient and / or at least one pharma-ceutically acceptable stabilizer.

[0272] Excipients In some embodiments, the pharmaceutical composition comprises at least one excipient. In some embodiments, the pharmaceutical composition comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more excipients. As used herein, the term "excipient" refers to an inert substance that functions as a vehicle, diluent, or medium for an active substance (e.g., a lactate-producing compound described herein). An excipient can facilitate the processability of a pharmaceutical composition (e.g., formulated for respiratory or oral administration) and maintain the physical structure of the pharmaceutical composition to add long-term stability. In some embodiments, the pharmaceutical composition comprises at least two excipients. In some embodiments, the composition comprises two excipients. In some embodiments, the composition comprises three excipients. In some embodiments, the pharmaceutical composition comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more excipients.

[0273] Typically, excipients are used when spray drying pharmaceuticals for two purposes: to add dispersibility to the final powder and to glass-stabilize high viscosity crystalline or amorphous particles. See, for example, Vehring (2008) Pharm Res 25(5):999-1022, the contents of which are incorporated herein by reference in their entirety. Amino acids (e.g., leucine and trileucine) can be used to add dispersibility to the final powder. Dispersible powders tend not to clump easily, are more flowable in bulk, and tend to facilitate encapsulation.

[0274] Because spray drying produces particles in energetically unfavorable conditions, excipients used for glass stabilization help provide long-term stability benefits and reliable solid-state chemical characteristics, such as stable crystallinity or co-crystallinity that results in consistent bioavailability in vivo. The effectiveness of these excipients is typically assessed by measuring the glass transition temperature of the dried particles, which is best maintained well above storage temperatures (e.g., frozen at -18°C, refrigerated at 4°C, or room temperature at 20-22°C) to ensure physical stability. In some embodiments, the minimum Tg is 35°C. In some embodiments, the Tg is at least 30°C, at least 35°C, at least 40°C, at least 45°C, or at least 50°C.

[0275] In some embodiments, the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, gluco-oligosaccharides, lacto-oligosaccharides, fructooligosaccharides, inulin, sodium caseinate, goat milk, cow milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts.

[0276] In some embodiments, the excipient is selected from Table 9. In some embodiments, the excipient is selected from any combination of excipients listed in Table 9, for example, a combination of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, 34, at least 35, at least 36, at least 37, at least 38, or at least 39 excipients from Table 9. [Table 9]

[0277] In some embodiments, the excipient is leucine, trehalose, and / or sodium citrate. In some embodiments, the excipient is leucine and / or trehalose. In some embodiments, the excipient is leucine and / or sodium citrate. In some embodiments, the excipient is trehalose and / or sodium citrate.

[0278] In some embodiments, the excipient is leucine. In some embodiments, the excipient is L-leucine (see, e.g., Formula VIII below). In some embodiments, the excipient is D-leucine. In some embodiments, the excipient is a racemic mixture of L-leucine and D-leucine. Leucine (symbol Leu or L) is an essential amino acid for humans. In some embodiments, the excipient is trileucine (also referred to as Leu-Leu-Leu), a tripeptide composed of three leucine residues (see, e.g., Formula IX below). In some embodiments, trileucine is used instead of leucine as an excipient. In some embodiments, the excipient is trehalose (see, e.g., Formula X below). Trehalose is a sugar composed of two glucose molecules. Trehalose is also known as mycose or tremalose. Trehalose has a high water-holding capacity. Some bacteria, fungi, plants, and invertebrates synthesize trehalose as an energy source and to survive freezing and water shortages. In some embodiments, the excipients are leucine and trehalose. In some embodiments, the first excipient is leucine and the second excipient is trehalose. In some embodiments, the second excipient is leucine and the first excipient is trehalose. In some embodiments, the excipient is sodium citrate (Na3C6H5O7, see e.g., Formula XI below). In some embodiments, the first excipient and the second excipient are leucine and trehalose, and the third excipient is sodium citrate. In some embodiments, the three excipients are leucine, trehalose, and sodium citrate, and the stabilizer is polysorbate 80. [ka]

[0279] In some embodiments, the pharmaceutical composition comprises at least 5.0% by weight of an excipient, hi some embodiments, the pharmaceutical composition comprises at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0%, at least 10.0% or more by weight of an excipient.

[0280] In some embodiments, the pharmaceutical composition comprises at least 5.0% by weight of the first excipient and at least 5.0% by weight of the second excipient, in some embodiments, the pharmaceutical composition comprises at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0%, at least 10.0% or more by weight. and at least 0.1 wt.%, at least 0.2 wt.%, at least 0.3 wt.%, at least 0.4 wt.%, at least 0.5 wt.%, at least 0.6 wt.%, at least 0.7 wt.%, at least 0.8 wt.%, at least 0.9 wt.%, at least 1.0 wt.%, at least 2.0 wt.%, at least 3.0 wt.%, at least 4.0 wt.%, at least 5.0 wt.%, at least 6.0 wt.%, at least 7.0 wt.%, at least 8.0 wt.%, at least 9.0 wt.%, at least 10.0 wt.% or more of a second excipient. In some embodiments, the pharmaceutical composition comprises at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0%, at least 10.0% or more by weight of a first excipient and 5.0% by weight of a second excipient.In some embodiments, the pharmaceutical composition comprises at least 5.0% by weight of a first excipient and at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0%, at least 10.0% or more by weight of a second excipient.

[0281] In some embodiments, the pharmaceutical composition comprises at least 75 mg of excipient per unit dose, in some embodiments, the pharmaceutical composition comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, or more of excipient per unit dose.

[0282] In some embodiments, the pharmaceutical composition comprises at least 75 mg of a first excipient and at least 75 mg of a second excipient per unit dose. In some embodiments, the pharmaceutical composition comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, or more per unit dose. at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, or more of a second excipient.

[0283] In some embodiments, the pharmaceutical composition comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, or more of a first excipient and at least 75 mg of a second excipient per unit dose.

[0284] In some embodiments, the pharmaceutical composition comprises at least 75 mg of a first excipient and at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, or more of a second excipient per unit dose.

[0285] Stabilizer In some embodiments, the pharmaceutical composition comprises at least one stabilizer. In some embodiments, the pharmaceutical composition comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more stabilizers. As used herein, the term "stabilizer" refers to a substance that prevents or reduces degradation of the pharmaceutical composition. The use of stabilizers aids in the process of wetting hydrophobic materials to create a homogenous suspension for spray drying. For example, stabilizers can be included when a wetting agent is needed to bring any poorly soluble compounds into suspension. These stabilizers function as emulsifiers to enhance consistency throughout the bulk spray-dried powder. In addition, some stabilizers (e.g., poloxamers) can also adjust the size of the wet particles down to the nanoscale and can be used to pre-disperse macromolecules in the feedstock solution. See, for example, Da Silva et al. (2019) Front Bioeng Biotechnol 7:137, the contents of which are incorporated herein by reference in their entirety.

[0286] In some embodiments, the stabilizer comprises a surfactant. A surfactant is a substance that tends to reduce the surface tension of the liquid in which it is dissolved. In some embodiments, the stabilizer is selected from the group consisting of mannitol, carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), polysorbate, and poloxamer. In some embodiments, the stabilizer is polysorbate, poloxamer, or polyvinyl alcohol.

[0287] In some embodiments, the stabilizer comprises polysorbate. Polysorbate is a synthetic non-ionic surfactant and emulsifier. Polysorbate is also called MONTANOX, ALKEST TW, TWEEN, or PS. In some embodiments, the stabilizer is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. The number following the "polysorbate" portion relates to the type of fatty acid associated with the polyoxyethylene sorbitan portion of the molecule. Monolaurate is designated by 20 (e.g., polysorbate 20), monopalmitate is designated by 40 (e.g., polysorbate 40), monostearate is designated by 60 (e.g., polysorbate 60), and monooleate is designated by 80 (e.g., polysorbate 80).

[0288] In some embodiments, the stabilizer is polysorbate 80 (see, for example, Formula XII below). Polysorbate 80 is also referred to as polyoxyethylene (20) sorbitan monooleate (the number 20 after the "polyoxyethylene" portion refers to the total number of oxyethylene-(CH2CHO)- groups found in the molecule), (x)-sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl), MONTANOX80, ALKEST TW80, TWEEN80, or PS80. Polysorbate 80 is derived from polyethoxylated sorbitan and oleic acid. The hydrophilic group in this compound is a polyether, also known as a polyoxyethylene group, which is a polymer of ethylene oxide. In the nomenclature of polysorbates, the numerical designation after polysorbate refers to the lipophilic group, in this case oleic acid. The critical micelle concentration of polysorbate 80 in pure water is reported as 0.012 mM. [ka]

[0289] In some embodiments, the stabilizer is a poloxamer. Poloxamers are non-ionic triblock copolymers consisting of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Poloxamers are called PLURONIC, KOLLIPHOR, or SYNPERONIC. Because the length of the polymer block can be customized, there are many different poloxamers with slightly different properties. With respect to the general term poloxamer, these copolymers are generally named with the letter P (for poloxamer) followed by three numbers, the first two numbers are multiplied by 100 to obtain the approximate molecular weight of the polyoxypropylene core, and the last number is multiplied by 10 to obtain the polyoxyethylene content (e.g., P407 = poloxamer with a polyoxypropylene molecular weight of 4000 g / mo and a polyoxyethylene content of 70%). As for the PLURONIC and SYNPERONIC designations, the coding of these copolymers begins with a letter to define its physical form at room temperature (L=liquid, P=paste, F=flake (solid)), followed by two or three numbers. The first number (or two of the three numbers) of the numerical designation multiplied by 300 indicates the approximate molecular weight of the hydrophobe, and the last number multiplied by 10 indicates the polyoxyethylene content (for example, L61 indicates a polyoxypropylene molecular weight of 1800 g / mol and a polyoxyethylene content of 10%). In the given example, Poloxamer 181 (P181) = PLURONIC L61 and SYNPERONIC PE / L61.

[0290] One characteristic of poloxamer solutions is their temperature-dependent self-assembly and thermogelation behavior. Concentrated aqueous solutions of poloxamers are liquid at low temperatures and form gels at higher temperatures in a reversible process. The transitions that occur in these systems depend on the polymer composition. Due to their amphiphilic structure, poloxamers have surfactant properties. Among other things, poloxamers can be used to increase the water solubility of hydrophobic, oily substances, or to otherwise increase the miscibility of two substances with different hydrophobicities. See, for example, Table 10 for the physicochemical properties of exemplary poloxamers.

[0291] Table 10: Physicochemical properties of Pluronic copolymers. MW: molecular weight, PO: propylene oxide, EO: ethylene oxide, cmc: critical micellization concentration, L: liquid, P: paste, F: flake. See, e.g., Bodratti and Alexandridis, J Funct Biomater, 2018, 9(1):11, the contents of which are incorporated by reference in their entirety. [Table 10]

[0292] In some embodiments, the stabilizer is poloxamer 184 (i.e., Pluronic L64), poloxamer 185 (i.e., Pluronic P65), poloxamer 234 (i.e., Pluronic P84), poloxamer 235 (i.e., Pluronic P85), poloxamer 238 (i.e., Pluronic F88), poloxamer 333 (i.e., Pluronic P103), poloxamer 334 (i.e., Pluronic P104), poloxamer 335 (i.e., Pluronic P105), poloxamer 338 (i.e., Pluronic F108), poloxamer 403 (i.e., Pluronic P123), or poloxamer 407 (i.e., Pluronic F127). In some embodiments, the stabilizer is poloxamer 184, poloxamer 185, poloxamer 234, poloxamer 235, poloxamer 238, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 403, or poloxamer 407. In some embodiments, the stabilizer is Pluronic L64, Pluronic P65, Pluronic P84, Pluronic P85, Pluronic F88, Pluronic P103, Pluronic P104, Pluronic P105, Pluronic F108, Pluronic P123, or Pluronic F127.

[0293] In some embodiments, the stabilizer is poloxamer 188, Pluronic F68 or polyoxyethylene-polyoxypropylene block copolymer (linear formula: (CHO.CHO) x (See, for example, Formula XIII below). In some embodiments, the pharmaceutical composition comprises polysorbate 80. In some embodiments, the pharmaceutical composition comprises poloxamer 188 (i.e., Pluronic F68). In some embodiments, the pharmaceutical composition comprises polysorbate 80 and poloxamer 188 (i.e., Pluronic F68). [ka]

[0294] In some embodiments, the stabilizer is polyvinyl alcohol (PVA, see, for example, Formula XIV below). PVA has the idealized formula [CHCH(OH)] n PVA is a water-soluble synthetic polymer with a carboxylate group. It can be used as a thickener and emulsion stabilizer. It exhibits biocompatibility, low tendency for protein adhesion, and low toxicity. PVA is prepared by hydrolysis of polyvinyl acetate or other vinyl ester-derived polymers with formate or chloroacetate groups instead of acetate. Conversion of polyvinyl esters can be carried out by base-catalyzed transesterification with ethanol. [ka]

[0295] In some embodiments, the pharmaceutical composition comprises at least 0.10% by weight of a stabilizer, hi some embodiments, the pharmaceutical composition comprises at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1.0% or more by weight of a stabilizer.

[0296] In some embodiments, the pharmaceutical composition comprises at least 1.5 mg of stabilizer per unit dose, hi some embodiments, the pharmaceutical composition comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, or at least 10 mg of stabilizer per unit dose.

[0297] In some embodiments, the pharmaceutical composition comprises at least one excipient and at least one stabilizer. In some embodiments, the pharmaceutical composition comprises one excipient and one stabilizer. In some embodiments, the pharmaceutical composition comprises at least two excipients and at least one stabilizer. In some embodiments, the pharmaceutical composition comprises two excipients and one stabilizer. In some embodiments, the pharmaceutical composition comprises leucine and trehalose as excipients and poloxamer 188 as stabilizer. In some embodiments, the pharmaceutical composition comprises leucine and trehalose as excipients and polysorbate 80 as stabilizer.

[0298] Additives In some embodiments, the pharmaceutical composition further comprises at least one additive. In some embodiments, the pharmaceutical composition comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more additives. As described herein, some additives can be added to the polymeric particles, and these additives can be incorporated by mixing at the molecular level, dry blending, coating on the particles, or co-administration. In some embodiments, the pharmaceutical composition further comprises at least one of the following: (a) a pore-forming agent, (b) an adhesive, (c) a pH adjusting agent, and / or (d) an ester hydrolysis inducer.

[0299] In some embodiments, the pharmaceutical composition further comprises a pore-forming agent. The pore-forming agent can reduce the density of the particle (i.e., by forming voids or "pores" within the particle), allowing for more rapid water uptake, decomposition, and acid production. In some embodiments, the pore-forming agent is selected from the group consisting of NaCl, sucrose, polyethylene glycol (PEG), and polyvinylpyrrolidone (PVP).

[0300] In some embodiments, the pharmaceutical composition further comprises an adhesive, which may also be referred to herein as an adhesive compound. The adhesive can enhance the bioadhesion of the polymer to biological tissue. In some embodiments, the adhesive is selected from the group consisting of sugars, adhesive polymers, and amine-containing compounds. Non-limiting examples of such adhesive sugars include trehalose, mannitol, lactose, or glucose. In some embodiments, the adhesive is a tablet or tableting adhesive (e.g., hypromellose or mefenamic acid), which can allow for the formation of tablets (e.g., for oral administration).

[0301] In some embodiments, the pharmaceutical composition further comprises a pH adjusting agent. The pH affecting agent can increase or decrease the degradation of the polymer (e.g., the polymeric compound capable of producing lactic acid described herein). In some embodiments, the pH adjusting agent is a buffer such as sodium citrate. In some embodiments, the pH adjusting agent is an acid. In some embodiments, the pH adjusting agent is a base (e.g., NaOH), and such bases can be neutralizing agents when preparing the raw material for spray drying for inhalation powder.

[0302] In some embodiments, the pharmaceutical composition further comprises an ester hydrolysis inducer. In some embodiments, the ester hydrolysis inducer comprises an amine group (e.g., -NH2). In some embodiments, the ester hydrolysis inducer is N-hydroxysuccinimide (see, e.g., Formula XV below). [ka]

[0303] In some embodiments, the pharmaceutical composition further comprises lactic acid. Polymeric compounds (e.g., PLA or PLGA) generate acid upon degradation in target tissues, and the bolus administration of lactic acid may increase this process or serve as a "loading" level of lactic acid. As used herein, the term "bolus" refers to a single dose of a drug or other pharmaceutical formulation administered at one time. In some embodiments, the pharmaceutical composition comprises (a) a lactic acid-producing compound, (b) a pharma-ceutically acceptable excipient, stabilizer, or additive, and (c) a bolus dose of lactic acid. In some embodiments, the pharmaceutical composition comprises (a) a non-polymeric lactic acid-producing compound and / or a polymeric lactic acid-producing compound, (b) a pharma-ceutically acceptable excipient, stabilizer, or additive, and (c) a bolus dose of lactic acid.

[0304] In some embodiments, the pharmaceutical composition includes an acid generating or low pH generating compound in addition to or instead of the lactic acid generating compound. In addition to lactic acid, there are materials that are organic acids or generate organic acids. These include simple acids such as acetic acid, hydroxy acids such as glycolic acid, polyfunctional acids such as citric acid, and aromatic acids such as salicylic acid. Esters, salts, and polymers of these can also be used, including acetylsalicylic acid, which can generate acid upon hydrolysis.

[0305] In some embodiments, the pharmaceutical composition further comprises at least one acid generating molecule capable of generating an acid, wherein the at least one acid generating molecule is not lactic acid or does not comprise lactic acid. In some embodiments, the acid generating molecule is selected from the group consisting of acetic acid, hydroxy acid, polyfunctional acid, and aromatic acid, and esters, salts, and polymers thereof. In some embodiments, the acid generating molecule is selected from the group consisting of acetic acid, glycolic acid, citric acid, and salicylic acid, and esters, salts, and polymers thereof. In some embodiments, the acid generating molecule is acetylsalicylic acid. In one aspect, described herein is a pharmaceutical composition comprising (a) an acid generating compound (e.g., generating acetylsalicylic acid) and (b) a pharma- ceutically acceptable excipient, stabilizer, or additive, wherein the composition is formulated for administration by inhalation or oral administration.

[0306] In addition to focusing on the generation of lactic acid, other acids, or therapies based on lowering pH, the above constructs can also be used to deliver additional therapeutic agents. In some embodiments, the pharmaceutical composition includes at least one additional therapeutic agent, for example, for chronic lung disease. A range of drug classes include anti-inflammatory agents, antibacterial agents, and vasodilators. These drugs can be incorporated using techniques such as microencapsulation, co-formulation, co-administration, or covalent attachment with degradable bonds.

[0307] In some embodiments, the pharmaceutical composition comprises an anti-inflammatory agent, hi some embodiments, the anti-inflammatory agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, glucocorticoids, methotrexate, sulfasalazine, leflunomide, anti-tumor necrosis factor (TNF) drugs, cyclophosphamide, inflammation-resolving lipid mediators, mycophenolates, opiates, and barbiturates.

[0308] In some embodiments, the pharmaceutical composition comprises an antibacterial, antiviral, and / or antifungal agent, hi some embodiments, the antibacterial agent is selected from the group consisting of aminoglycosides, ansamycins, beta-lactams, bis-biguanides, carbacephems, carbapenems, cationic polypeptides, cephalosporins, fluoroquinolones, glycopeptides, iron-sequestering glycoproteins, linosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidinones, penicillins, polypeptides, quaternary ammonium compounds, quinolones, silver compounds, sulfonamides, and tetracyclines.

[0309] Some exemplary specific antibacterial agents include broad spectrum penicillins, amoxicillins (e.g., ampicillin, bacampicillin, carbenicillin indanyl, mezlocillin, piperacillin, ticarcillin), penicillins and beta-lactamase inhibitors (e.g., amoxicillin-clavulanate, ampicillin-sulbactam, benzylpenicillin, cloxacillin, dicloxacillin, methicillin, oxacillin, penicillin G, penicillin V, piperacillin-tazobactam, ticarcillin-clavulanate, nafcillin), cephalosporins (e.g., first generation cephalosporins, cephalosporins (e.g., cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephradine), second-generation cephalosporins (e.g., cefaclor, cefamandole, cefonicid, cefotetan, cefoxitin, cefprozil, cefmetazole, cefuroxime, loracarbef), third-generation cephalosporins (e.g., cefdinir, ceftibuten, cefoperazone, cefixime, cefotaxime, cefpodoxime proxetil, ceftazidime, ceftizoxime, ceftriaxone), fourth-generation cephalosporins (e.g., cefe pim), macrolides and lincosamides (e.g., azithromycin, clarithromycin, clindamycin, dirithromycin, erythromycin, lincomycin, troleandomycin), quinolones and fluoroquinolones (e.g., cinoxacin, ciprofloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, oxolinic acid, gemifloxacin, perfloxacin), Carbapenems (e.g., imipenem-cilastatin, meropenem), monobactams (e.g., aztreonam), aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin), glycopeptides (e.g., teicoplanin, vancomycin), tetracyclines (e.g., demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, tetracycline, chlortetracycline), sulfonamides (e.g.,Mafenide, silver sulfadiazine, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole, sulfamethizole), rifampin (e.g., rifabutin, rifampin, rifapentine), oxazolidinone (e.g., linezolid, streptogramin, quinupristin dalfopristin), bacitracin, chloramphenicol, fosfomycin, isoniazid, methenamine, metronidazole, mupirocin, nitrofurantoin, nitrofurazone, novobiocin, polymyxin, spectinomycin, trimethoprim, colistin, cycloserine, capreomycin, ethionamide, pyrazinamide, para-aminosalicylic acid, erythromycin ethylsuccinate, etc.

[0310] Non-limiting examples of antiviral agents include abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, antiretroviral agents, arbidol, atazanavir, atripla, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, dolutegravir, ecolieber, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, fusion inhibitors, ibacitabine, idoxuridine, imiquimod, immunovir, indinavir, inosine, integrase inhibitors, interferon, interferon type I, interferon type II, interferon type III, lamivudine, lopinavir, loviride, maraviroc, metisazolidine, naphthalene, naphthalene, naphthalene, naphthalene serotonin, moroxydine, nelfinavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogs, oseltamivir (Tamiflu), peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, viral protease inhibitors, pyramidine, raltegravir, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, sovosbuvir, stavudine, synergistic enhancers (antiretroviral agents), telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir (Valtrex), valganciclovir, vicriviroc, vidarabine, pyramidine, zalcitabine, zanamivir (Relenza), or zidovudine.

[0311] Non-limiting examples of antifungal agents (also called antifungal agents) include polyene antifungals, amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, imidazole antifungals, triazole antifungals, thiazole antifungals, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, triazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, Ravuconazole, terconazole, voriconazole, abafungin, allylamine, amorolfine, butenafine, naftifine, terbinafine, echinocandin, anidulafungin, caspofungin, micafungin, aurone, benzoic acid, ciclopirox, flucytosine, 5-fluorocytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, triacetin, crystal violet, castellani paint, orotomide, miltefosine, potassium iodide, coal tar, copper(II) sulfate, selenium disulfide, sodium thiosulfate, piroctone olamine, iodoquinol, clioquinol, acrisorcin, zinc pyrithione, and sulfur.

[0312] In some embodiments, the pharmaceutical composition comprises at least one bacteriophage. Non-limiting examples of bacteriophages include Caudovirales (e.g., Myoviridae, Siphoviridae, and Podiviridae), Ligamenvirales (e.g., Lipothrixviridae, Rudiviridae, Ampullaviridae, Bicaudaviridae, Clavaviridae, Corticoviridae, Cystoviridae, and Fuselloviridae), and other families (e.g., Globuloviridae, Inoviridae, Leviviridae, Microviridae, Plasmaviridae, and Techtiviridae).

[0313] In some embodiments, the pharmaceutical composition comprises a vasodilator, hi some embodiments, the vasodilator is selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and nitric oxide generating compounds.

[0314] In some embodiments, the vasodilator is an ACE inhibitor selected from the group consisting of benazepril (LOTENSIN), captopril (CAPOTEN), enalapril (VASOTEC, EPANED), fosinopril (MONOPRIL), lisinopril (PRINIVIL, ZESTRIL), moexipril (UNIVASC), perindopril (ACEON), quinapril (ACCUPRIL), ramipril (ALTACE), and trandolapril (MAVIK).

[0315] In some embodiments, the vasodilator is an ARB selected from the group consisting of azilsartan (EDARBI), candesartan (ATACAND), eprosartan (TEVETEN), irbesartan (AVAPRO), telmisartan (MICARDIS), valsartan (DIOVAN), losartan (COZAAR), and olmesartan (BENICAR).

[0316] In some embodiments, the vasodilator is a CCB selected from the group consisting of amlodipine (NORVASC), clevidipine (CLEVIPREX), diltiazem (CARDIZEM), felodipine (CARDENE, CARDENE SR), isradipine, nicardipine, nimodipine, nisoldipine (SULAR), and verapamil (CALAN).

[0317] In some embodiments, the vasodilator is a nitric oxide generating compound selected from the group consisting of nitroglycerin (GONITRO, NITROBID, NITROMIST, NITROLINGUAL, NITROSTAT, NITROBID), isosorbide mononitrate (ISMO, MONOKET), isosorbide dinitrate (IMDUR, ISORDIL), hydrazine (APRESOLINE), minoxidil, fenoldopam (CARLOPAM), and nitroprusside (NIPRIDE, NITROPRESS).

[0318] In some embodiments, the pharmaceutical composition further comprises a bronchodilator as an additional therapeutic agent. In some embodiments, the bronchodilator is selected from the group consisting of short-acting beta-adrenergic bronchodilators (e.g., albuterol, levalbuterol, epinephrine), long-acting beta-adrenergic bronchodilators (e.g., salmeterol, formoterol), anticholinergic bronchodilators (e.g., ipratropium bromide, tiotropium bromide), and xanthine derivatives (e.g., theophylline, aminophylline). In some embodiments of any of the aspects, the bronchodilator is albuterol.

[0319] In some embodiments, at least one additional therapeutic agent is microencapsulated. In some embodiments, at least one additional therapeutic agent is microencapsulated within the lactate-generating component (e.g., within the matrix of the lactate-generating component). In some embodiments, at least one additional therapeutic agent is microencapsulated within a PLA matrix or a PLGA matrix. In some embodiments, the pharmaceutical composition includes separate particles or microspheres for the therapeutic agent and lactic acid that are mixed together, e.g., during administration. In some embodiments, the additional therapeutic agent is microencapsulated together with the lactate-generating compound.

[0320] In some embodiments, at least one additional therapeutic agent is covalently attached to the lactate-producing compound using a linker that is biodegradable, degradable, cleavable, or otherwise reversible. A cleavable linker means that the linker can be cleaved to release the two moieties that the linker holds together. In some embodiments, the cleavable linker is polyethylene glycol. The cleavable linker can be sensitive to a cleaving agent, such as, but not limited to, an enzyme, pH, redox potential, or the presence of a degradable molecule. Examples of such cleaving agents include oxidoreductases or reductases that are selective for a particular substrate or have no substrate specificity, such as mercaptans present in cells that can degrade the oxidatively cleavable linking group by reduction, esterases, amidases, endosomes or agents that can create an acidic environment (e.g., those that result in a pH of 5 or less), general acids, peptidases (which can be substrate specific), proteases, and enzymes that can hydrolyze or degrade the acid-cleavable linking group by acting as phosphatases.

[0321] In some embodiments, the pharmaceutical composition is administered simultaneously with at least one additional therapeutic agent for, for example, chronic lung disease. In some embodiments, the pharmaceutical composition is administered simultaneously with at least one additional therapeutic agent for, for example, chronic lung disease. In some embodiments, the pharmaceutical composition is administered before, for example, at least one additional therapeutic agent for, for example, chronic lung disease. In some embodiments, the pharmaceutical composition is administered after, for example, at least one additional therapeutic agent for, for example, chronic lung disease. In some embodiments, the pharmaceutical composition is administered in alternation with, for example, at least one additional therapeutic agent for, for example, chronic lung disease.

[0322] formulation In some embodiments, the pharmaceutical composition is formulated for administration to the lungs. As used herein, the term "formulated for administration to the lungs" means that the composition or formulation is designed or adapted to deliver the active ingredient or agent to the lungs, for example, by inhalation of small particles or droplets containing the active ingredient. In some embodiments, the pharmaceutical composition is formulated for administration by inhalation. As used herein, the term "formulated for administration by inhalation" means that the composition or formulation is designed or adapted to deliver the active ingredient or agent to the bronchiolaryngeal tissues by inhalation of small particles or droplets containing the active ingredient. Thus, a pharmaceutical composition formulated for administration by inhalation generally includes such particles (e.g., as a powder) or can easily generate such droplets (e.g., via a nebulizer). In some embodiments, the pharmaceutical composition is formulated for delivery to the trachea, bronchi, bronchioles, and / or alveoli. In some embodiments, the pharmaceutical composition is formulated for delivery to the trachea. In some embodiments, the pharmaceutical composition is formulated for delivery to the bronchi. In some embodiments, the pharmaceutical composition is formulated for delivery to the bronchioles. In some embodiments, the pharmaceutical composition is formulated for delivery to the alveoli. In some embodiments, the composition is formulated for delivery to the lungs. In some embodiments, the composition is formulated as a capsule or tablet for administration by inhalation (e.g., using an inhaler).

[0323] In some embodiments, the composition is formulated for delivery by an inhaler. In some embodiments, the composition is formulated for delivery by a metered dose inhaler (MDI). A metered dose inhaler (MDI) is a device that delivers a specific amount of drug to the lungs, usually in the form of a short burst of aerosolized drug that is self-administered by the patient via inhalation. In some embodiments, the composition is formulated for delivery by a dry powder inhaler (DPI). A dry powder inhaler (DPI) is a device that delivers drug to the lungs in the form of a dry powder. In some embodiments, the composition is formulated for delivery by a soft mist inhaler (SMI). A soft mist inhaler (SMI) is a device that delivers drug to the lungs in the form of a mist.

[0324] In some embodiments, the pharmaceutical composition is formulated for oral administration. As used herein, the term "formulated for oral administration" means that the composition or formulation is designed or adapted to deliver the active ingredient or agent to gastrointestinal tissues by ingestion of small particles or droplets containing the active ingredient. In some embodiments, the composition formulated for oral administration can include a tablet or tableting adhesive (e.g., hypromellose or mefenamic acid) to allow for tablet formation. Thus, the pharmaceutical composition formulated for oral administration can be chewed or swallowed whole, or otherwise ingestible. In some embodiments, the pharmaceutical composition is formulated for delivery to the colon, mouth, esophagus, stomach, small intestine, duodenum, jejunum, ileum, cecum, ileocecal appendix, ascending colon, transverse colon, descending colon, sigmoid colon, rectum, or anus. In some embodiments, the composition is formulated as a capsule or tablet for oral administration.

[0325] In some embodiments, the composition is formulated as a bolus dose. In some embodiments, the pharmaceutical composition comprises a bolus dose of lactic acid. In some embodiments, the pharmaceutical composition comprises (a) a non-polymeric lactic acid-producing compound and / or a polymeric lactic acid-producing compound, and (b) a bolus dose of lactic acid. In some embodiments, the pharmaceutical composition comprises (a) a non-polymeric lactic acid-producing compound and / or a polymeric lactic acid-producing compound, and (b) a bolus dose of a non-polymeric compound capable of producing lactic acid. In some embodiments, the pharmaceutical composition comprises (a) a non-polymeric lactic acid-producing compound and / or a polymeric lactic acid-producing compound, and (b) a bolus dose of a polymeric compound capable of producing lactic acid.

[0326] In some embodiments, the pharmaceutical composition comprises at least 7.8 mg of lactate-producing compound per unit dose deliverable to the target tissue. In some embodiments, the pharmaceutical composition comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of lactate-producing compound per unit dose deliverable to the target tissue.

[0327] In some embodiments, the pharmaceutical composition comprises at least 15 mg of lactate-producing compound per unit dose, hi some embodiments, the pharmaceutical composition comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of lactate-producing compound per unit dose.

[0328] In some embodiments, the pharmaceutical compositions are formulated as microspheres, for example, using methods other than spray drying. Such microspheres can be produced using methods known in the art, including, but not limited to, solvent extraction, solvent evaporation, and complex coacervation. The four main substeps of microsphere preparation by solvent extraction and solvent evaporation include: (i) incorporation of bioactive compounds (e.g., lactate-producing compounds described herein), (ii) formation of microdroplets, (iii) solvent removal, and (iv) particle recovery and drying. Complex coacervation is a microencapsulation technique that involves the interaction of oppositely charged polyelectrolytes in aqueous form. In some embodiments, complex coacervation uses cationic polymers (e.g., gelatin), and various natural and synthetic anionic water-soluble polymers (e.g., gum arabic) interact with gelatin to form complex coacervates. Coacervation is a process in which a homogenous solution of charged macromolecules undergoes liquid-liquid phase separation, resulting in a polymer-rich dense phase at the bottom and a clear solution on top. See, for example, Freitas et al., Journal of Controlled Release 102(2):2 313-332 (2005); Timilsena et al., International Journal of Biological Macromolecules 121:1276-1286 (2019), the contents of each of which are incorporated herein by reference in their entirety.

[0329] In some embodiments, the microspheres have a diameter of at least 1 μm up to 1 mm. In some embodiments, the microspheres have a diameter of at least 1 μm, at least 2 μm, at least 3 μm, at least 4 μm, at least 5 μm, at least 6 μm, at least 7 μm, at least 8 μm, at least 9 μm, at least 10 μm, at least 20 μm, at least 30 μm, at least 40 μm, at least 50 μm, at least 60 μm, at least 70 μm, at least 80 μm, at least 90 μm, at least 100 μm, at least 200 μm, at least 300 μm, at least 400 μm, at least 500 μm, at least 600 μm, at least 700 μm, at least 800 μm, at least 900 μm, or at least 1 mm. In some embodiments, the microspheres have a diameter of up to 1 μm, up to 2 μm, up to 3 μm, up to 4 μm, up to 5 μm, up to 6 μm, up to 7 μm, up to 8 μm, up to 9 μm, up to 10 μm, up to 20 μm, up to 30 μm, up to 40 μm, up to 50 μm, up to 60 μm, up to 70 μm, up to 80 μm, up to 90 μm, up to 100 μm, up to 200 μm, up to 300 μm, up to 400 μm, up to 500 μm, up to 600 μm, up to 700 μm, up to 800 μm, up to 900 μm, or up to 1 mm.

[0330] dry particles In some embodiments, the pharmaceutical composition comprises a plurality of dry particles. In some embodiments, the pharmaceutical composition is a dry powder comprising particles having the physical characteristics set forth in Table 3A, Table 3B, or Table 4. [Table 3A] [Table 3B] [Table 4]

[0331] In some embodiments, the dry particles have a Dv50 of at least 0.5 μm. In some embodiments, the dry particles have a Dv50 of at least 2.0 μm. Dv50 is the size below which 50% of the particles are smaller. Dv50 is substantially the median particle diameter, as measured by the technique used. In some embodiments, Dv50 is measured via laser diffraction techniques. Dv50 can be applied to aerosolized particles or liquid suspended particles. Dv50 is essentially a pure volumetric measurement and does not take into account the aerosol properties of the particles. Dv50 can be a useful measure to estimate the dispersibility of a powder. Dispersibility refers to how easily a powder aerosolizes at different pressures. A fully dispersible powder can be consistently aerosolized regardless of the pressure applied. In some embodiments, the dry particles have a Dv50 of at least 0.5 um, at least 0.6 um, at least 0.7 um, at least 0.8 um, at least 0.9 um, at least 1 μm, at least 1.5 μm, at least 2 μm, at least 2.5 μm, at least 3 μm, at least 3.5 μm, at least 4 μm, at least 4.5 μm, at least 5 μm, at least 5.5 μm, at least 6 μm, at least 6.5 μm, at least 7 μm, at least 7.5 μm, at least 8 μm, at least 8.5 μm, at least 9 μm, at least 9.5 μm, or at least 10 μm.

[0332] In some embodiments, the dry particles have a median mass aerodynamic diameter (MMAD) of at least 1.5 μm to a maximum of 7.5 μm. In some embodiments, the dry particles have a median mass aerodynamic diameter (MMAD) of at least 3.5 μm to a maximum of 7.5 μm. In some embodiments, the dry particles have a median mass aerodynamic diameter (MMAD) of at least 2.5 μm to a maximum of 7.5 μm. In some embodiments, the dry particles have a median mass aerodynamic diameter (MMAD) of at least 2.0 μm to a maximum of 7.5 μm. In some embodiments, the dry particles have a median mass aerodynamic diameter (MMAD) of at least 1.0 μm to a maximum of 10 μm. As used herein, the term "MMAD" refers to the aerodynamic diameter value at which 50% of a given volume in a given aerosol is associated with particles smaller than the MMAD and 50% of the volume is associated with particles larger than the MMAD. In some embodiments, the dry particles have a median mass aerodynamic diameter (MMAD) of at least 4.0 μm. In some embodiments, the dry particles have a mass median aerodynamic diameter (MMAD) of at least 4.8 μm. In some embodiments, the dry particles have a mass median aerodynamic diameter (MMAD) of up to 5.0 μm. In some embodiments, the dry particles have a mass median aerodynamic diameter (MMAD) of at least 1 μm, at least 1.5 μm, at least 2 μm, at least 2.5 μm, at least 3 μm, at least 3.5 μm, at least 4 μm, at least 4.5 μm, at least 5 μm, at least 5.5 μm, at least 6 μm, at least 6.5 μm, at least 7 μm, at least 7.5 μm, at least 8 μm, at least 8.5 μm at least 9 μm, at least 9.5 μm, or at least 10 μm. In some embodiments, the dry particles have a median mass aerodynamic diameter (MMAD) of at most 1 μm, at most 1.5 μm, at most 2 μm, at most 2.5 μm, at most 3 μm, at most 3.5 μm, at most 4.0 μm, at most 4.5 μm, at most 5.0 μm, at most 5.5 μm, at most 6.0 μm, at most 6.5 μm, at most 7.0 μm, at most 7.5 μm, at most 8.5 μm, at most 9 μm, at most 9.5 μm, or at most 10 μm.

[0333] In some embodiments, the dry particles described herein have a fine particle fraction of <5.0 μm of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more. In some embodiments, the dry particles described herein have a fine particle fraction of <3.3 μm of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more.

[0334] Fine particle fraction (FPF) is a value obtained from cascade impaction testing of dry powders. In cascade impaction testing, the powder is run through different stages of gradually decreasing size. The amount of powder deposited at each stage represents a percentage of the size cutoff for the overall powder. Two such methods are Next Generation Impaction (NGI), which flows the powder horizontally across the stages, and Anderson Cascade Impaction (ACI), which flows the powder vertically across the stages. Typically, two values ​​are provided: the percentage of delivered dose smaller than 5.0 μm, and the percentage of delivered dose smaller than 3.3 um. Typically, <5.0 μm is the size cutoff considered for deposition in the central and peripheral airways, and typically <3.3 μm for deposition in the peripheral airways. See, e.g., Bianco et al., Respiratory Research volume 22, Article number: 71 (2021) (see, e.g., Figure 4 in Bianco); Darquenne, J Aerosol Med Pulm Drug Deliv. 2012, 25(3):140-147, Description of the Next Generation Impactor (available worldwide at sanyo-si.com / wp-content / uploads / NGI.pdf), the contents of each of which are incorporated herein by reference in their entirety.

[0335] In some embodiments, the dry particles have a dispersibility of less than 2.0. In some embodiments, the dry particles have a dispersibility of at least 0.5 to 1.0. As used herein, the term "dispersibility" refers to the ability of particles to be spatially well-dispersed in a liquid, in terms of size and concentration, after a controlled dispersion process. Dispersibility is unitless. Dispersibility represents the ratio of particle sizes measured for the same powder at different air pressures used to deliver the particles to the system. Specifically, dispersibility is a measurement of the Dv50 of the powder delivered to the system at "low" pressure divided by the Dv50 of the powder delivered to the system at "high" pressure. In some embodiments, the dispersibility of the dry particles is measured by dividing the Dv50 measured at a pressure of 2 kPa by the Dv50 measured at a pressure of 4 kPa (such a measurement may be referred to herein as "2 / 4KPA"). Dispersibility may be measured for a delivered (e.g., emitted) dose. Dv50 can be measured by impaction, laser diffraction (e.g., RODOS or MASTERSIZER), or both. Low pressure systems may have a higher Dv50 when measured using laser diffraction. Bulk and particle density affect dispersibility, as well as the "stickiness" and shape of the dry particles, and vice versa. Dispersibility is a good dimensionless measure of how "well" a particle will hang in the air, even though the pressure from the air applied to the particle is not constant, since it includes so many other attributes. In some embodiments, an "optimal" powder has a dispersibility of 1 or close to 1, meaning that its Dv50 does not change across air pressures in the aerodynamic system. As a ratio, the minimum value of dispersibility is zero, and dispersibility can be less than 1 or greater than 1.

[0336] In some embodiments, the dry particles have a dispersibility of at least 0.9. In some embodiments, the dry particles have a dispersibility of at least 0.50, at least 0.55, at least 0.60, at least 0.65, at least 0.70, at least 0.75, at least 0.80, at least 0.85, at least 0.90, at least 0.91, at least 0.92, at least 0.93, at least 0.94, at least 0.95, at least 0.96, at least 0.97, at least 0.98, at least 0.99, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, or 2.0. In some embodiments, the dry particles have a viscosity of 0.50-0.55, 0.55-0.60, 0.60-0.65, 0.65-0.70, 0.70-0.75, 0.75-0.80, 0.80-0.85, 0.85-0.90, 0.90-0.91, 0.91-0.92, 0.92-0.93, 0.93-0.94, 0.94-0.95, 0.95-0.96, 0.96-0.97, 0. The dispersibility is 97 to 0.98, 0.98 to 0.99, 0.99 to 1.0, 1.0 to 1.1, 1.1 to 1.2, 1.2 to 1.3, 1.3 to 1.4, 1.4 to 1.5, 1.5 to 1.6, 1.6 to 1.7, 1.7 to 1.8, 1.8 to 1.9, 1.9 to 2.0, 0.5 to 0.75, 0.75 to 1.0, 0.75 to 1.25, 1.0 to 1.25, 1.25 to 1.5, or 0.5 to 1.5.

[0337] In some embodiments, the dry particles have a delivered dose of at least 25.0% to up to 125% by weight of the composition to the target tissue. In some embodiments, the dry particles have a delivered dose of at least 25.0% to up to 80.0% by weight of the composition to the target tissue. As used herein, the term "delivered dose" refers to the percentage of the composition or its active ingredient (e.g., lactate-producing compound) that is expelled from a delivery device (e.g., an inhaler) and / or delivered to a target tissue. In some embodiments, the delivered dose may be greater than 100% when the expected dose (e.g., 1.0 mg) in the delivery device is less than the actual dose (e.g., 1.25 mg, e.g., due to overfilling) in the delivery device, and when the expected dose (e.g., >1.0 mg, e.g., >100%) is greater, but the actual dose (e.g., 1.25 mg, e.g., <125%) is delivered to the target tissue. Factors that influence the delivered dose ultimately relate to dispersibility, powder density, hygroscopicity, and electrostatic charge (e.g., some of these factors affect dispersibility more than others). As a non-limiting example, high density particles may aerosolize and disperse more than low density particles that may disperse unpredictably or be too large. As another non-limiting example, excipients that are too hygroscopic and therefore make the powder less "flowable" or sticky may cause less powder to exit the capsule when the inhaler (e.g., DPI) is actuated. It is expected that not all of the powder from a capsule containing a spray-dried biotherapeutic matrix composition described herein will be able to reach the target tissue (e.g., alveoli). Certain portions of the composition may not be delivered because they remain in the capsule, remain in the device, or hit the tongue or esophagus. In some embodiments, the delivered dose refers to the amount of spray-dried biotherapeutic matrix composition described herein that exits the device and capsule.

[0338] The delivered dose can be measured as the mass % of the powder that escapes the delivery system and reaches the target area(s). The emitted dose is a good measure of what escapes the delivery device in a real system. The uniformity of the emitted dose content can be measured to ensure that what is emitted from the administration device is consistent. In some embodiments, the dry particles have a delivered dose of at least 30% by mass of the lactate-generating compound to the target tissue. In some embodiments, the dry particles have a delivered dose of at least 52% by mass of the lactate-generating compound to the target tissue. In some embodiments, the dry particles have a delivered dose of at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80% by mass of the lactate-generating compound that is expelled from the delivery device (e.g., an inhaler) and / or delivered to the target tissue.

[0339] In some embodiments, the dry particles have a delivered dose of at least 7.8 mg of lactate-generating compound per unit dose to the target tissue. In some embodiments, the dry particles have a delivered dose of up to 50 mg of lactate-generating compound per unit dose to the target tissue. In some embodiments, the dry particles have a delivered dose of at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, or at least 50 mg of lactate-generating compound per unit dose to the target tissue. In humans, lactic acidosis occurs at levels of 4 mmol / L systemically, while the normal range of lactate is 0.5 to 1.5 mmol / L. In some embodiments, administration of the described compositions increases systemic levels of lactate by up to 2.5 mmol / L. Based on the molecular weight of lactate (89 mg / mmol), the delivered dose of lactate is up to 222.5 mg / L of lactate, or up to 1000 mg of lactate overall.

[0340] In some embodiments, the particles have a density of at least 0.1 g / cm3 ~0.8g / cm 3 In some embodiments, the particles have a bulk density of at least 0.2 g / cm 3 ~0.8g / cm 3 As used herein, "bulk density" is defined as the mass of many particles of a material divided by the total volume they occupy, which includes particle volume, interparticle void volume, and internal pore volume. In some embodiments, the particles have a bulk density of at least 0.5 g / cm 3 In some embodiments, the particles have a bulk density of at least 0.1 g / cm 3 , at least 0.2 g / cm 3 , at least 0.3 g / cm 3 , at least 0.4 g / cm 3 , at least 0.5g / cm 3 , at least 0.6g / cm 3 , at least 0.7 g / cm 3 , or at least 0.8 g / cm 3 It has a bulk density of

[0341] In some embodiments, the particles have a density of at least 0.2 g / cm 3 ~1.0g / cm 3 In some embodiments, the particles have a tap density of at least 0.3 g / cm 3 ~1.0g / cm 3 As used herein, "tap density" refers to the bulk density of a powder after a particular compaction process (e.g., involving vibration of a container containing a powder of dry particles). In some embodiments, the particles have a tap density of at least 0.6 g / cm 3 In some embodiments, the particles have a tap density of at least 0.1 g / cm 3 , at least 0.2 g / cm 3 , at least 0.3 g / cm 3 , at least 0.4 g / cm 3 , at least 0.5g / cm 3 , at least 0.6g / cm 3 , at least 0.7 g / cm 3, at least 0.8g / cm 3 , at least 0.9g / cm 3 , or at least 1.0 g / cm 3 The tap density is

[0342] In some embodiments, the particles have a moisture content of at least 1.0% to 7.0% water by weight. As used herein, "moisture content" refers to the amount of water present in a product, measured as a percentage (%). Moisture can affect the physical properties of a substance, including weight, density, viscosity, conductivity, and the like. Moisture content can be determined by weight loss on drying (loss on drying, LOD). In some embodiments, moisture content is measured using Karl Fischer titration. Karl Fischer uses coulometric or volumetric titration to determine trace amounts of water in a sample. The elementary reaction responsible for the quantification of water in Karl Fischer titration is the oxidation of sulfur dioxide by iodine: H2O+SO2+I2→SO3+2HI. This elementary reaction consumes exactly one molar equivalent of water compared to iodine. Iodine is added to the solution until it is present in excess (indicating the endpoint of the titration), which can be detected potentiometrically. The reaction is carried out in an alcoholic solution containing a base which consumes the sulfur trioxide and hydroiodic acid produced. The endpoint is most commonly detected by a two-potentiometric titration method.

[0343] In some embodiments, the particles have a water content of at least 2.3% by weight. In some embodiments, the particles have a water content of up to 2.3% by weight. In some embodiments, the particles have a water content of at least 1%, at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5%, at least 5.5%, at least 6%, at least 6.5%, at least 7% by weight. In some embodiments, the particles have a water content of up to 1%, up to 1.5%, up to 2%, up to 2.5%, up to 3%, up to 3.5%, up to 4%, up to 4.5%, up to 5%, up to 5.5%, up to 6%, up to 6.5%, up to 7% by weight.

[0344] device In one aspect, the pharmaceutical compositions described herein (e.g., lactate-generating pharmaceutical compositions) are combined with a delivery device, such as an inhaler. In one aspect, the device includes (a) an inhaler, and (b) a container containing a pharmaceutical composition described herein (e.g., a lactate-generating pharmaceutical composition). In some embodiments, the inhaler includes (a) a mouthpiece including an opening, and (b) a means for aerosolizing or dispersing the pharmaceutical composition within the container. In some embodiments, the means for aerosolizing or dispersing includes, but is not limited to, a propellant, pressurized air, a spring, or another chemical or mechanical generation of pressure. In some embodiments, the inhaler is a dry powder inhaler (DPI). In some embodiments, the inhaler is a metered dose inhaler (MDI). In some embodiments, the inhaler is a soft mist inhaler (SMI).

[0345] In some embodiments, the pharmaceutical compositions described herein (e.g., lactate-generating pharmaceutical compositions) are administered as aerosolized compositions. Aerosolization is the process or act of converting any physical substance (e.g., a solid) into the form of particles small enough and light enough to be carried in the air. In some embodiments, the pharmaceutical compositions described herein (e.g., lactate-generating pharmaceutical compositions) can also be administered directly to the airways in the form of a dry powder. For use as a dry powder, the pharmaceutical compositions described herein (e.g., lactate-generating pharmaceutical compositions) can be administered by use of an inhaler. The inhaler is a portable handheld device that can be available as a metered dose inhaler (MDI), a dry powder inhaler (DPI), or a soft mist inhaler (SMI).

[0346] A metered dose inhaler or "MDI" is a pressurized canister or container filled with a product such as a pharmaceutical composition dissolved in a liquefied propellant or micronized particles suspended in a liquefied propellant. Propellants that can be used include chlorofluorocarbons, hydrocarbons, or hydrofluoroalkanes. Particularly preferred propellants are P134a (tetrafluoroethane) and P227 (heptafluoropropane), each of which can be used alone or in combination. They are optionally used in combination with one or more other propellants, and / or one or more surfactants, and / or one or more other excipients, such as ethanol, lubricants, antioxidants, and / or stabilizers. Metered dose inhalers allow the correct dosage of the composition to be delivered to the patient.

[0347] Dry powder inhalers (ie, TURBUHALER (ASTRA AB)) are systems operable with a pressurized air source to generate dry powder particles of a pharmaceutical composition compressed into a very small volume.

[0348] Dry powder aerosols for inhalation therapy are generally produced with average diameters mainly in the range of <5 μm. As the particle diameter increases beyond 3 μm, it is less and less phagocytosed by macrophages. However, increasing the particle size has also been found to minimize the probability of particles (with standard mass density) entering the airways and acini due to excessive deposition in the oropharynx or nasal region.

[0349] As an example of a suitable powder composition, a powder preparation of the pharmaceutical composition (e.g., lactate-producing pharmaceutical composition) described herein is thoroughly mixed with lactose or other inert powder acceptable for intrabronchial administration. The powder composition can be administered via an aerosol dispenser or can be enclosed in a frangible capsule that can be punctured by the patient and inserted into a device that expels the powder in a steady stream suitable for inhalation. The composition may include a propellant, surfactant, and cosolvent, and can be filled into a conventional aerosol container that is closed by a suitable metering valve.

[0350] Soft mist inhalers (SMIs, e.g., Respimat® Soft Mist™ inhalers) are multi-dose, propellant-free, handheld liquid inhalers. The aerosol clouds generated by SMIs contain a higher percentage of microspheres than most pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs), and the aerosol spray leaves the inhaler more slowly and for a longer period of time than pMDIs. This leads to higher drug deposition in the lungs and lower deposition in the oropharynx, allowing for a lower nominal dose of drug delivered without reducing efficacy. In some embodiments, the inhaler formulation does not contain a propellant. The drug is stored as a solution in an SMI drug cartridge (e.g., an aluminum cylinder containing a double-walled plastic collapsible bag that shrinks when the solution is used). SMI solutions can be formulated with ethanol or water, and preservatives (e.g., benzalkonium chloride or ethylenediaminetetraacetic acid (EDTA)). The amount of preservative in each dose (eg, puff) can be about 0.44 μg of benzalkonium chloride, or about 2.2 μg of EDTA.

[0351] In some embodiments of any of the aspects, a pharmaceutical composition described herein (e.g., a lactate-generating pharmaceutical composition) is administered using a nasal spray or nebulizer. In some embodiments of any of the aspects, a pharmaceutical composition (e.g., a lactate-generating pharmaceutical composition) is formulated as a nasal spray. In one aspect, a pharmaceutical composition described herein (e.g., a lactate-generating pharmaceutical composition) is combined with a nebulizer. In some embodiments of any of the aspects, a pharmaceutical composition (e.g., a lactate-generating pharmaceutical composition) is formulated for delivery by a nebulizer.

[0352] Nasal sprays typically contain a saline solution containing a pharmaceutical composition (e.g., a lactate-generating pharmaceutical composition) described herein, which is sprayed as a mist into the nasal passages using a mechanical spray nozzle. A nebulizer is an electric or battery-powered machine that converts a liquid pharmaceutical composition (e.g., a lactate-generating pharmaceutical composition) described herein into a fine mist that is inhaled into the lungs. The inhalers or nebulizers described herein may further include a mouthpiece or face mask. Nasal sprays typically administer a pharmaceutical composition (e.g., a lactate-generating pharmaceutical composition) described herein to the upper respiratory tract, while inhalers or nebulizers typically administer a pharmaceutical composition (e.g., a lactate-generating pharmaceutical composition) described herein to the lower respiratory tract.

[0353] The pharmaceutical compositions described herein (e.g., lactate-generating pharmaceutical compositions) can be administered directly to the airways of a subject in the form of an aerosol or by nebulization. For use as an aerosol, the pharmaceutical compositions described herein (e.g., lactate-generating pharmaceutical compositions) in solution or suspension can be packaged in a pressurized aerosol container with a suitable propellant (e.g., a hydrocarbon propellant such as propane, butane, or isobutane) using conventional adjuvants. The pharmaceutical compositions described herein (e.g., lactate-generating pharmaceutical compositions) can also be administered in non-pressurized form, such as with a nebulizer or atomizer.

[0354] The term "nebulization" is well known to include reducing liquid to a fine spray. Preferably, such nebulization produces small droplets of uniform size from larger droplets of liquid in a controlled manner. Thus, nebulization can be achieved by any suitable means, including using many nebulizers known and commercially available today. For example, the AEROMIST pneumatic nebulizer available from Inhalation Plastic, Inc., Niles, Illinois. When active ingredients are adapted to be administered via nebulizer(s), either together or individually, they can be in the form of nebulized aqueous suspension or solution, with or without suitable pH or tonicity adjustment, either as a unit dose or a multi-dose device.

[0355] As is well known, any suitable gas can be used to apply pressure during nebulization.Preferred gases are those that are chemically inert to the pharmaceutical compositions described herein (e.g., lactate-producing pharmaceutical compositions).Exemplary gases, including but not limited to nitrogen, argon, or helium, can be used to great advantage.

[0356] Aerosols for delivery to the respiratory tract are known in the art.See, for example, Adjei, A. and Garren, J. Pharm. Res., 1:565-569(1990); Zanen, P. and Lamm, J.-WJ Int. J. Pharm., 114:111-115(1995); Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract," in Critical Reviews in Therapeutic Drug Carrier Systems, 6:273-313(1990); Anderson et al., Am. Rev. Respir. Dis., 140:1317-1324(1989)).It also has the potential for systemic delivery of peptides and proteins (Patton and Platz, Advanced Drug Delivery Reviews, 8:179-196 (1992)); Timsina et.al., Int. J. Pharm., 101:1-13 (1995); and Tansey, IP, Spray Technol. Market, 4:26-29 (1994); French, DL, Edwards, DA and Niven, RW, Aerosol Sci., 27:769-783 (1996); Visser, J., Powder Technology 58:1-10 (1989)); Rudt, S. and RH Muller, J. Controlled Release, 22:263-272 (1992); Tabata, Y, and Y. Ikada, Biomed. Mater. Res., 22:837-858 (1988), Wall, DA, Drug Delivery, 2:10 1-20 1995), Patton, J. and Platz, R., Adv. Drug Del.Rev.,8:179-196(1992), Bryon,P.,Adv.Drug.Del.Rev.,5:107-132(1990),Patton,JS,et al.,Controlled Release,28:15 79-85(1994),Damms,B.and Bains,W.,Nature Biotechnology (1996), Niven, RW, et al., Pharm.Res., 12(9), 1343-1349 (1995), and Kobayashi, S., et al. al., Pharm. Res., 13(1):80-83 (1996), the contents of each of which are incorporated herein by reference in their entirety.

[0357] Spray drying method Described herein is a method for preparing a spray-dried pharmaceutical composition comprising, for example, a lactate-producing compound as described herein. In one aspect, described herein is a method for preparing a spray-dried pharmaceutical composition comprising a lactate-producing compound, the method comprising: (a) preparing a liquid feedstock comprising a lactate-producing compound; (b) introducing droplets of the liquid feedstock into a drying chamber through a spray nozzle; (c) exposing the liquid feedstock droplets to a heated and pressurized gas in the drying chamber to produce dry particles; and (d) isolating dry particles of a predetermined range of diameters in a cyclone chamber, wherein the isolated dry particles comprise a lactate-producing compound.

[0358] In one aspect, a method for preparing a spray-dried pharmaceutical composition comprising a lactate-generating compound is described herein, the method comprising: (a) obtaining a liquid feedstock comprising a lactate-generating compound; (b) introducing droplets of the liquid feedstock into a drying chamber via a spray nozzle; (c) exposing the liquid feedstock droplets to a heated pressurized gas in the drying chamber to produce dry particles; and (d) isolating dry particles of a predetermined range of diameters in a cyclone chamber, the isolated dry particles comprising the lactate-generating compound. In some embodiments, the method for preparing a spray-dried pharmaceutical composition comprising a lactate-generating compound is performed using at least one of the conditions set forth in Table 5 or Table 6. [Table 5] [Table 6]

[0359] The process conditions shown in Tables 5 and 6 above provide exemplary ranges across the operating sizes of spray units, for example, the higher values ​​of gas pressure and flow rate represent conditions closer to a full-scale production unit, while the lower values ​​represent conditions closer to a bench-top or lab-scale process unit.

[0360] Drying gas flow rates can be expressed in either kg / hr or L / min. The kg / hr value can be calculated from the L / min value using the following formula: Mass (kg / hr) = [[Density of air (g / L) / Volume (L / min)] * (1 kg / 1000 g) * (60 min / 1 hr)], where the density of air is approximately 1.225 g / L (e.g., may vary slightly with temperature, altitude, etc.). For example, 600 L / min corresponds to 44.1 kg / hr. The L / min value can be calculated from the kg / hr value using the following formula: Volume (L / min) = [[Mass (kg / hr) / Density of air (g / L)] * (1000 g / 1 kg) * (1 hr / 60 min)]. For example, 18 kg / hr corresponds to 245 L / min.

[0361] Feed flow rates can be expressed in g / min or mL / min, and such flow rates can be converted depending on the density of the liquid feed (e.g., g / mL). Atomization pressures can be expressed in psig, kPa, or other known units of pressure (1 psig = 6.89475728 kPa, 345 kPa = approximately 50 psig).

[0362] For spray-dried compositions containing the lactic acid-producing compounds described herein, target processing conditions are optimized for three properties: (1) constitutive activity / assay, (2) powder flow and stability, and (3) aerodynamic size and properties (see, e.g., Tables 3A-3B and Table 4 for exemplary properties of spray-dried particles).

[0363] To protect the stability of the ingredients, the powder is spray dried at the lowest possible outlet temperature, which is the effective temperature that the dry powder will experience. During drying, a phenomenon known as evaporative cooling keeps the solid ingredients relatively cool compared to the heated surroundings. Once particle formation is complete, the particles are heated to a temperature between room temperature and the temperature of the inlet drying gas. This temperature (measured at the outlet of the spray drying chamber) needs to be minimized. Working in the opposite direction is the moisture content of the powder, which can also be minimized to improve long-term stability and physical properties. However, higher outlet temperatures of the same formulation are typically attributed to dryer particles. These two process conditions can be optimized to maximize particle stability and minimize moisture content. Furthermore, since reducing the atomization pressure favors ingredient stability, and higher pressures stress living organisms and sensitive therapeutic agents, the atomization pressure used to create the droplets needs to be kept as low as reasonably possible to protect the ingredients.

[0364] Aerodynamic properties are governed by the included excipients, particle density, and particle size. Excipients can be selected to allow dispersibility (e.g., by adding excipients such as amino acids such as leucine) and stability (e.g., by adding high glass transition temperatures, strongly soluble sugars, polyols, or ionic salts, e.g., by adding stabilizers as described herein). Including agents to enhance dispersibility also enhances bulk powder properties such as flowability, making the capsule filling process more efficient.

[0365] During spray drying, particle formation is driven by two factors: (1) the evaporation rate of the solvent, and (2) the solubility of the solute. A dimensionless number called the Peclet number (Pe) provides an indication of which of these two phenomena dominates the droplet drying process in the spray drying chamber. Equation XVI:

number

[0366] At high Peclet numbers, particles tend to be very low density, large, hollow, and brittle. This is because evaporation of the droplets dominates solute transport to the center of the droplet (in most systems), leaving behind a "shell" of solute. Morphology tends to be spherical. At low Peclet numbers, particles are small and dense. Solute mass transfer dominates the system as these solids migrate to the center of the slowly evaporating droplet. Morphology tends to be crumpled.

[0367] In many cases, high process temperatures result in faster evaporation rates, while low process temperatures tend to do the opposite, resulting in dense, crumpled particles, which is the target morphology for our application.

[0368] A lower amount of dissolved solids in the feedstock allows for faster diffusion of solutes, which also contributes to smaller, denser, crumpled particles. A higher amount of solids limits the rate at which solute diffusion can occur, but contributes to higher material yields and improved processing.

[0369] Raw material preparation In some embodiments, the method of preparing a spray-dried pharmaceutical composition includes, for example, preparing a liquid feedstock including a lactate-generating compound. In some embodiments, preparing the liquid feedstock includes dissolving a solid feedstock in a solution. In some embodiments, preparing the liquid feedstock includes dissolving a solid feedstock in an aqueous solution. In some embodiments, preparing the liquid feedstock includes dissolving a solid feedstock in an organic solution, for example, an organic solution of a lactate-generating compound (e.g., PLA) that is not soluble in water or aqueous solutions. In some embodiments, preparing the liquid feedstock includes (a) dissolving a lactate-generating compound in an organic solution; (b) dissolving the solid feedstock in an aqueous solution; and (c) combining the solutions obtained from (a) and (b) to generate a liquid feedstock. An example of a solid feedstock for use in preparing an inhalable lactate-generating formulation at optimal processing conditions on a lab scale can be found in Table 7 below. [Table 7]

[0370] In some embodiments, the solid feed comprises at least 50% by weight of the lactic acid-producing compound, at least 10% by weight of the excipient, and at least 1% by weight of the stabilizer. In some embodiments, the solid feed comprises at least 50% by weight of the lactic acid-producing compound, at least 20% by weight of the excipient, and at least 30% by weight of the stabilizer. In some embodiments, the solid feed comprises at least 50% by weight of the lactic acid-producing compound. In some embodiments, the solid feed comprises at least 20% by weight of the excipient. In some embodiments, the solid feed comprises at least 30% by weight of the stabilizer.

[0371] In some embodiments, the solid ingredient comprises at least 50% by weight of the lactic acid-producing compound, at least 5% by weight of the first excipient, at least 5% by weight of the second excipient, and at least 1% by weight of the stabilizer, hi some embodiments, the solid ingredient comprises at least 5% by weight of the first excipient, and at least 5% by weight of the second excipient.

[0372] In some embodiments, the solid ingredient comprises at least 50% by weight of the lactic acid-producing compound, at least 10% by weight of the first excipient, at least 10% by weight of the second excipient, and at least 30% by weight of the stabilizer, hi some embodiments, the solid ingredient comprises at least 10% by weight of the first excipient, and at least 10% by weight of the second excipient.

[0373] In some embodiments, the solid feedstock comprises at least 20% up to 80% by weight of the lactic acid-producing compound, hi some embodiments, the solid feedstock comprises at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% by weight of the lactic acid-producing compound.

[0374] In some embodiments, the solid ingredient comprises at least 1% and up to 15% by weight of excipients. In some embodiments, the solid ingredient comprises at least 5% and up to 15% by weight of excipients. In some embodiments, the solid ingredient comprises at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% by weight of excipients.

[0375] In some embodiments, the solid ingredient comprises at least 0.5% to 7.5% by weight of a first excipient and at least 0.5% to 7.5% by weight of a second excipient, hi some embodiments, the solid ingredient comprises at least 2.5% to 7.5% by weight of a first excipient and at least 2.5% to 7.5% by weight of a second excipient. In some embodiments, the solid ingredient comprises at least 0.5 wt%, at least 1.0 wt%, at least 1.5 wt%, at least 2.0 wt%, at least 2.5 wt%, at least 3.0 wt%, at least 3.5 wt%, and finally 4.0 wt%, at least 4.5 wt%, at least 5.0 wt%, at least 5.5 wt%, at least 6.0 wt%, at least 6.5 wt%, at least 7.0 wt%, or at least 7.5 wt% of a first excipient and at least 0.5 wt%, at least 1.0 wt%, at least 1.5 wt%, at least 2.0 wt%, at least 2.5 wt%, at least 3.0 wt%, at least 3.5 wt%, and finally 4.0 wt%, at least 4.5 wt%, at least 5.0 wt%, at least 5.5 wt%, at least 6.0 wt%, at least 6.5 wt%, at least 7.0 wt%, or at least 7.5 wt% of a second excipient. In some embodiments, the solid ingredient comprises at least 0.5% by weight, at least 1.0% by weight, at least 1.5% by weight, at least 2.0% by weight, at least 2.5% by weight, at least 3.0% by weight, at least 3.5% by weight, and finally 4.0% by weight, at least 4.5% by weight, at least 5.0% by weight, at least 5.5% by weight, at least 6.0% by weight, at least 6.5% by weight, at least 7.0% by weight, or at least 7.5% by weight of the first excipient and at least 2.5% by weight of the second excipient.In some embodiments, the solid ingredient comprises at least 2.5% by weight of a first excipient and at least at least 0.5% by weight, at least 1.0% by weight, at least 1.5% by weight, at least 2.0% by weight, at least 2.5% by weight, at least 3.0% by weight, at least 3.5% by weight, and finally 4.0% by weight, at least 4.5% by weight, at least 5.0% by weight, at least 5.5% by weight, at least 6.0% by weight, at least 6.5% by weight, at least 7.0% by weight, or at least 7.5% by weight of a second excipient.

[0376] In some embodiments, the solid feedstock comprises at least 10% up to 50% stabilizer by weight, hi some embodiments, the solid feedstock comprises at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% stabilizer by weight.

[0377] As a non-limiting example, preparing the liquid feedstock includes dissolving 50 mg / mL of poly(D,L-lactide) polymer in acetone (e.g., dissolving 2.000 g of PLA in 40 mL of acetone). The PLA and acetone mixture is added to water containing 1% poloxamer 188 (i.e., Pluronic F68) in a ratio of 1:3 parts (e.g., adding 40 mL of PLA and acetone to about 120 mL of water containing 1% poloxamer 188). An exemplary liquid feedstock formulation is provided in Table 8 below. This exemplary liquid feedstock formulation is 0.8% w / w solids, or 500 g of feedstock suspension at 8 g / L (i.e., about 500 mL, assuming about 1 g per mL. Thus, "0.5 L of liquid feedstock" may be used interchangeably with "500 g of liquid feedstock"). Such an exemplary liquid feedstock can be scaled up to a full-scale production unit, for example, using the same or substantially the same ratios of ingredients. [Table 8]

[0378] In some embodiments, the liquid feedstock comprises at least 0.1 g / L of the solid feedstock dissolved in the aqueous solution. In some embodiments, the liquid feedstock comprises at least 0.1 g / L and up to 100 g / L of the solid feedstock dissolved in the aqueous solution. In some embodiments, the liquid feedstock comprises at least 4 g / L of the solid feedstock dissolved in the aqueous solution. In some embodiments, the liquid feedstock comprises at least 5 g / L of the solid feedstock dissolved in the aqueous solution. In some embodiments, the liquid feedstock comprises at least 8 g / L of the solid feedstock dissolved in the aqueous solution. In some embodiments, the liquid feedstock comprises at least 0.1 g / L, at least 0.2 g / L, at least 0.3 g / L, at least 0.4 g / L, at least 0.5 g / L, at least 0.6 g / L, at least 0.7 g / L, at least 0.8 g / L, at least 0.9 g / L, at least 1 g / L, at least 2 g / L, at least 3 g / L, at least 4 g / L, at least 5 g / L, at least 6 g / L, at least 7 g / L, at least 8 g / L, at least 9 g / L, at least 10 g / L, at least 20 g / L, at least 30 g / L, at least 40 g / L, at least 50 g / L, at least 60 g / L, at least 70 g / L, at least 80 g / L, at least 90 g / L, or at least 100 g / L of the solid feedstock dissolved in an aqueous solution.

[0379] In some embodiments, the liquid feedstock comprises at least 0.01% and up to 10% of a solid feedstock dissolved in an aqueous solution. In some embodiments, the liquid feedstock comprises at least 0.4% of a solid feedstock dissolved in an aqueous solution. In some embodiments, the liquid feedstock comprises at least 0.5% of a solid feedstock dissolved in an aqueous solution. In some embodiments, the liquid feedstock comprises at least 0.8% of a solid feedstock dissolved in an aqueous solution. In some embodiments, the liquid ingredient comprises at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% or more of a solid ingredient dissolved in an aqueous solution.

[0380] In some embodiments, the 0.5 L liquid feedstock comprises (a) at least 2.00 g of a lactic acid-producing compound, (b) at least 0.80 g of an excipient, (c) at least 1.2 g of a stabilizer, (d) at least 31.36 g of an organic solution, and (e) at least 464.64 g of an aqueous solution. In some embodiments, the 0.5 L liquid feedstock comprises (a) at least 2.00 g of a lactic acid-producing compound, (b) at least 0.40 g of a first excipient, (c) at least 0.40 g of a second excipient, (d) at least 1.2 g of a stabilizer, (e) at least 31.36 g of an organic solution, and (f) at least 464.64 g of an aqueous solution.

[0381] In some embodiments, 0.5 L of liquid feedstock comprises at least 0.1 g and up to 10 g of lactate-producing compound. In some embodiments, 0.5 L of liquid feedstock comprises at least 2 g of lactate-producing compound. In some embodiments, 0.5 L of liquid feedstock comprises at least 0.1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g, at least 0.5 g, at least 0.6 g, at least 0.7 g, at least 0.8 g, at least 0.9 g, at least 1 g, at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, at least 7 g, at least 8 g, at least 9 g, or at least 10 g of lactate-producing compound.

[0382] In some embodiments, the 0.5 L liquid ingredient comprises at least 0.1 g and up to 10 g of excipient. In some embodiments, the 0.5 L liquid ingredient comprises at least 0.80 g of excipient. In some embodiments, the 0.5 L liquid ingredient comprises at least 0.1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g, at least 0.5 g, at least 0.6 g, at least 0.7 g, at least 0.8 g, at least 0.9 g, at least 1 g, at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, at least 7 g, at least 8 g, at least 9 g, or at least 10 g of excipient.

[0383] In some embodiments, the 0.5 L liquid ingredient comprises at least 0.05 g and up to 5 g of a first excipient and at least 0.05 g and up to 5 g of a second excipient, hi some embodiments, the 0.5 L liquid ingredient comprises at least 0.40 g of a first excipient and at least 0.40 g of a second excipient. In some embodiments, 0.5 L of the liquid ingredient comprises at least 0.05 g, at least 0.06 g, at least 0.07 g, at least 0.08 g, at least 0.09 g, at least 0.1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g, at least 0.5 g, at least 0.6 g, at least 0.7 g, at least 0.8 g, at least 0.9 g, at least 1 g, at least 2 g, at least 3 g, at least 4 g, or at least 5 g of a first excipient and at least 0.05 g, at least 0.06 g, at least 0.07 g, at least 0.08 g, at least 0.09 g, at least 0.1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g, at least 0.5 g, at least 0.6 g, at least 0.7 g, at least 0.8 g, at least 0.9 g, at least 1 g, at least 2 g, at least 3 g, at least 4 g, or at least 5 g of a second excipient.

[0384] In some embodiments, 0.5 L of the liquid ingredient comprises at least 0.05 g, at least 0.06 g, at least 0.07 g, at least 0.08 g, at least 0.09 g, at least 0.1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g, at least 0.5 g, at least 0.6 g, at least 0.7 g, at least 0.8 g, at least 0.9 g, at least 1 g, at least 2 g, at least 3 g, at least 4 g, or at least 5 g of a first excipient and at least 0.4 g of a second excipient. In some embodiments, 0.5 L of the liquid ingredient comprises at least 0.4 g of a first excipient and at least 0.05 g, at least 0.06 g, at least 0.07 g, at least 0.08 g, at least 0.09 g, at least 0.1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g, at least 0.5 g, at least 0.6 g, at least 0.7 g, at least 0.8 g, at least 0.9 g, at least 1 g, at least 2 g, at least 3 g, at least 4 g, or at least 5 g of a second excipient.

[0385] In some embodiments, 0.5 L of the liquid feedstock comprises at least 0.1 g up to 10 g of stabilizer. In some embodiments, 0.5 L of the liquid feedstock comprises at least 1.2 g of stabilizer. In some embodiments, 0.5 L of the liquid feedstock comprises at least 0.1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g, at least 0.5 g, at least 0.6 g, at least 0.7 g, at least 0.8 g, at least 0.9 g, at least 1 g, at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, at least 7 g, at least 8 g, at least 9 g, or at least 10 g of stabilizer.

[0386] In some embodiments, 0.5 L of the liquid feedstock comprises at least 10 g and up to 50 g of organic solution. In some embodiments, 0.5 L of the liquid feedstock comprises at least 31.36 g of organic solution. In some embodiments, 0.5 L of the liquid feedstock comprises at least 10 g, at least 15 g, at least 20 g, at least 25 g, at least 30 g, at least 35 g, at least 40 g, at least 45 g, or at least 50 g of organic solution.

[0387] In some embodiments, 0.5 L of the liquid feedstock comprises at least 420 g up to 490 g of aqueous solution. In some embodiments, 0.5 L of the liquid feedstock comprises at least 464.64 g of aqueous solution. In some embodiments, 0.5 L of the liquid feedstock comprises at least 420 g, at least 425 g, at least 430 g, at least 435 g, at least 440 g, at least 445 g, at least 450 g, at least 455 g, at least 460 g, at least 465 g, at least 470 g, at least 475 g, at least 480 g, at least 485 g, or at least 490 g of aqueous solution.

[0388] In some embodiments, the liquid feedstock comprises (a) at least 0.40% lactic acid-producing compound, (b) at least 0.16% excipient, (c) at least 0.24% stabilizer, (d) at least 6.27% organic solution, and (e) at least 92.93% aqueous solution. In some embodiments, the liquid feedstock comprises (a) at least 0.40% by weight lactic acid-producing compound, (b) at least 0.08% by weight of a first excipient, (c) at least 0.08% by weight of a second excipient, (d) at least 0.24% by weight of a stabilizer, (e) at least 6.27% by weight of an organic solution, and (f) at least 92.93% by weight of an aqueous solution.

[0389] In some embodiments, the liquid feedstock comprises at least 0.01% and up to 1.0% by weight of a lactic acid-producing compound, hi some embodiments, the liquid feedstock comprises at least 0.4% by weight of a lactic acid-producing compound. In some embodiments, the liquid feedstock comprises at least 0.01 wt.%, at least 0.02 wt.%, at least 0.03 wt.%, at least 0.04 wt.%, at least 0.05 wt.%, at least 0.06 wt.%, at least 0.07 wt.%, at least 0.08 wt.%, at least 0.09 wt.%, at least 0.1 wt.%, at least 0.2 wt.%, at least 0.3 wt.%, at least 0.4 wt.%, at least 0.5 wt.%, at least 0.6 wt.%, at least 0.7 wt.%, at least 0.8 wt.%, at least 0.9 wt.%, at least 1 wt.%, at least 2 wt.%, at least 3 wt.%, at least 4 wt.%, at least 5 wt.%, at least 6 wt.%, at least 7 wt.%, at least 8 wt.%, at least 9 wt.%, or at least 10 wt.% or more of a lactic acid producing compound.

[0390] In some embodiments, the liquid ingredient comprises at least 0.01% and up to 10% by weight of an excipient, hi some embodiments, the liquid ingredient comprises at least 0.16% by weight of an excipient. In some embodiments, the liquid ingredient comprises at least 0.01 wt.%, at least 0.02 wt.%, at least 0.03 wt.%, at least 0.04 wt.%, at least 0.05 wt.%, at least 0.06 wt.%, at least 0.07 wt.%, at least 0.08 wt.%, at least 0.09 wt.%, at least 0.1 wt.%, at least 0.2 wt.%, at least 0.3 wt.%, at least 0.4 wt.%, at least 0.5 wt.%, at least 0.6 wt.%, at least 0.7 wt.%, at least 0.8 wt.%, at least 0.9 wt.%, at least 1 wt.%, at least 2 wt.%, at least 3 wt.%, at least 4 wt.%, at least 5 wt.%, at least 6 wt.%, at least 7 wt.%, at least 8 wt.%, at least 9 wt.%, or at least 10 wt.% or more of an excipient.

[0391] In some embodiments, the liquid ingredient comprises at least 0.005% and up to 5% by weight of a first excipient and at least 0.005% and up to 5% by weight of a second excipient, hi some embodiments, the liquid ingredient comprises at least 0.08% by weight of a first excipient and at least 0.08% by weight of a second excipient. In some embodiments, the liquid feedstock comprises at least 0.005%, at least 0.006%, at least 0.007%, at least 0.008%, at least 0.009%, at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% or more by weight. The composition comprises a first excipient and at least 0.005%, at least 0.006%, at least 0.007%, at least 0.008%, at least 0.009%, at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% or more by weight of a second excipient.

[0392] In some embodiments, the liquid ingredient comprises at least 0.005%, at least 0.006%, at least 0.007%, at least 0.008%, at least 0.009%, at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% or more by weight of a first excipient and at least 0.08% by weight of a second excipient. In some embodiments, the liquid ingredient comprises at least 0.08% by weight of a first excipient and at least 0.005%, at least 0.006%, at least 0.007%, at least 0.008%, at least 0.009%, at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% or more by weight of a second excipient.

[0393] In some embodiments, the liquid feedstock comprises at least 0.01% up to 1.0% stabilizer by weight. In some embodiments, the liquid feedstock comprises at least 0.24% stabilizer by weight. In some embodiments, the liquid feedstock comprises at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% or more stabilizer by weight.

[0394] In some embodiments, the liquid feedstock comprises at least 1% and up to 5% by weight of the organic solution. In some embodiments, the liquid feedstock comprises at least 6.27% by weight of the organic solution. In some embodiments, the liquid feedstock comprises at least 1%, at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, or at least 5% by weight of the organic solution.

[0395] In some embodiments, the liquid feedstock comprises at least 90% up to 99.9% by weight of an aqueous solution. In some embodiments, the liquid feedstock comprises at least 92.93% by weight of an aqueous solution. In some embodiments, the liquid feedstock comprises at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, 99.5% or more, 99.9% or more by weight of an aqueous solution.

[0396] In some embodiments, the lactic acid-producing compound is selected from (a) a polymeric compound capable of producing lactic acid, (b) a non-polymeric compound capable of producing lactic acid, or (c) lactic acid. In some embodiments, the non-polymeric lactic acid-producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide. In some embodiments, the polymeric lactic acid-producing compound is polylactic acid (PLA). In some embodiments, the polylactic acid is poly(D,L-lactide) (PDLLA).

[0397] In some embodiments, the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, gluco-oligosaccharides, lacto-oligosaccharides, fructooligosaccharides, inulin, sodium caseinate, goat milk, cow milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts. In some embodiments, the excipient is leucine and / or trehalose.

[0398] In some embodiments, the stabilizer is a polysorbate, a poloxamer, or polyvinyl alcohol. In some embodiments, the stabilizer is poloxamer 188 (i.e., Pluronic F68). In some embodiments, the stabilizer is polysorbate 80.

[0399] In some embodiments, the organic solution is acetone. In some embodiments, the organic solution comprises acetone. In some embodiments, the aqueous solution is water. In some embodiments, the aqueous solution comprises water.

[0400] In some embodiments, the liquid feedstock further comprises at least one additional therapeutic agent. Non-limiting examples of the at least one additional therapeutic agent include an anti-inflammatory agent, an antibacterial agent, an antiviral agent, an antifungal agent, a vasodilator, or a bronchodilator as described herein. In some embodiments, the lactate-producing compound and the at least one additional therapeutic agent are spray dried together. In some embodiments, the lactate-producing compound and the at least one additional therapeutic agent are spray dried separately.

[0401] spray The method of spray drying pharmaceutical compositions is described herein.Such spray drying can be carried out using spray drying equipment or technology known in the art.The method of spray drying is known in the art and is not limited.See, for example, U.S. Patent No. 7258873, U.S. Patent No. 7378110, U.S. Patent No. 8273374, U.S. Patent No. 8293275, U.S. Patent No. 9238005, U.S. Patent No. 9044497, U.S. Patent Publication No. 2013 / 0022728, U.S. Patent No. 2014 / 0086965, U.S. Patent No. 2018 / 0027855 (the contents of each of which are incorporated herein by reference in their entirety).

[0402] In one aspect, a method of preparing a spray-dried pharmaceutical composition includes: (a) introducing droplets of a liquid feedstock described herein into a drying chamber via a spray nozzle; (b) exposing the liquid feedstock droplets to heated and pressurized gas in the drying chamber to produce dry particles; and (c) isolating dry particles of a predetermined range of diameters in a cyclone chamber, wherein the isolated dry particles comprise a lactic acid-producing compound.

[0403] In some embodiments, the method of preparing a spray-dried pharmaceutical composition includes introducing droplets of a liquid ingredient described herein into a drying chamber through a spray nozzle. In some embodiments, the spray nozzle into the drying chamber has a diameter of at least 1.2 mm. Some commercially available full-scale nozzles may have a nozzle diameter much larger than 1.2 mm, but can be sprayed at much higher spray pressures (e.g., greater than 150 psig) to reproduce the ideal droplet size and dry particle characteristics described herein. In some embodiments, the spray nozzle into the drying chamber has a diameter of at least 0.5 mm, at least 1 mm, at least 1.5 mm, at least 2 mm, at least 2.5 mm, at least 3 mm, at least 3.5 mm, at least 4 mm, at least 4.5 mm, or at least 5 mm.

[0404] In some embodiments, the droplets of the liquid feedstock produced by the spray nozzle into the drying chamber have a diameter of at least 1.2 um. In some embodiments, the droplets of the liquid feedstock produced by the spray nozzle into the drying chamber have a diameter of at least 3.5 um. In some embodiments, the droplets of the liquid feedstock produced by the spray nozzle into the drying chamber have a diameter of at least 0.5 um, at least 1 um, at least 1.5 um, at least 2 um, at least 2.5 um, at least 3 um, at least 3.5 um, at least 4 um, at least 4.5 um, or at least 5 um.

[0405] Drying Chamber In some embodiments, a method of preparing a spray-dried pharmaceutical composition comprises exposing liquid feed droplets to heated and pressurized gas in a drying chamber to produce dry particles.

[0406] In some embodiments, the droplets of the liquid feedstock have a flow rate through the drying chamber of at least 5 g / min. In some embodiments, the droplets of the liquid feedstock have a flow rate through the drying chamber of at least 15 g / min. In some embodiments, the droplets of the liquid feedstock have a flow rate through the drying chamber of up to 1000 g / min. In some embodiments, the liquid feed droplets have a flow rate through the drying chamber of at least 5 g / min, at least 10 g / min, at least 15 g / min, at least 20 g / min, at least 25 g / min, at least 30 g / min, at least 35 g / min, at least 40 g / min, at least 45 g / min, at least 50 g / min, at least 60 g / min, at least 70 g / min, at least 80 g / min, at least 90 g / min, at least 100 g / min, at least 200 g / min, at least 300 g / min, at least 400 g / min, at least 500 g / min, at least 600 g / min, at least 700 g / min, at least 800 g / min, at least 900 g / min, or at least 1000 g / min.

[0407] In some embodiments, the heated pressurized gas is filtered before being introduced into the drying chamber. In some embodiments, the filter is a high efficiency particulate air (HEPA) filter. In some embodiments, the filter removes contaminants of at least 0.3 um. In some embodiments, the filter removes contaminants of at least 0.01 um, at least 0.02 um, at least 0.03 um, at least 0.04 um, at least 0.05 um, at least 0.06 um, at least 0.07 um, at least 0.08 um, at least 0.09 um, at least 0.1 um, at least 0.2 um, at least 0.3 um, at least 0.4 um, at least 0.5 um, at least 0.6 um, at least 0.7 um, at least 0.8 um, at least 0.9 um, or at least 1 um.

[0408] In some embodiments, the heated pressurized gas is heated prior to being introduced into the drying chamber. In some embodiments, the heated pressurized gas is introduced into the drying chamber at a temperature of at least 100° C. In some embodiments, the heated pressurized gas is introduced into the drying chamber at a temperature of at least 135° C. In some embodiments, the heated pressurized gas is introduced into the drying chamber at a temperature of up to 195° C. In some embodiments, the heated pressurized gas is introduced into the drying chamber at a temperature of at least 100° C., at least 105° C., at least 110° C., at least 115° C., at least 120° C., at least 125° C., at least 130° C., at least 135° C., at least 140° C., at least 145° C., at least 150° C., at least 155° C., at least 160° C., at least 165° C., at least 170° C., at least 175° C., at least 180° C., at least 185° C., at least 190° C., or at least 195° C.

[0409] In some embodiments, the heated pressurized gas exits the drying chamber at a temperature of at least 40° C. In some embodiments, the heated pressurized gas exits the drying chamber at a temperature of at least 60° C. In some embodiments, the heated pressurized gas exits the drying chamber at a temperature of up to 85° C. In some embodiments, the heated pressurized gas exits the drying chamber at a temperature of at least 40° C., at least 45° C., at least 50° C., at least 55° C., at least 60° C., at least 65° C., at least 70° C., at least 75° C., at least 80° C., or at least 85° C.

[0410] In some embodiments, the heated pressurized gas is pressurized before being introduced into the drying chamber. In some embodiments, the heated pressurized gas in the drying chamber has an atomizing gas pressure of at least 10 pounds per square inch gauge (psig). In some embodiments, the heated pressurized gas in the drying chamber has an atomizing gas pressure of at least 20 pounds per square inch gauge (psig). In some embodiments, the heated pressurized gas in the drying chamber has an atomizing gas pressure of at least 150 pounds per square inch gauge (psig). In some embodiments, the heated pressurized gas in the drying chamber has an atomizing gas pressure of at least 10 psig, at least 20 psig, at least 30 psig, at least 40 psig, at least 50 psig, at least 60 psig, at least 70 psig, at least 80 psig, at least 90 psig, at least 100 psig, at least 110 psig, at least 120 psig, at least 130 psig, at least 140 psig, at least 150 psig.

[0411] In some embodiments, the heated pressurized gas has a flow rate through the drying chamber of at least 5 kg / hr. In some embodiments, the heated pressurized gas has a flow rate through the drying chamber of at least 18 kg / hr. In some embodiments, the heated pressurized gas has a flow rate through the drying chamber of at least 150 kg / hr. In some embodiments, the heated pressurized gas has a flow rate through the drying chamber of at least 5 kg / hr, at least 6 kg / hr, at least 7 kg / hr, at least 8 kg / hr, at least 9 kg / hr, at least 10 kg / hr, at least 11 kg / hr, at least 12 kg / hr, at least 13 kg / hr, at least 14 kg / hr, at least 15 kg / hr, at least 16 kg / hr, at least 17 kg / hr, at least 18 kg / hr, at least 19 kg / hr, at least 20 kg / hr, at least 30 kg / hr, at least 40 kg / hr, at least 50 kg / hr, at least 60 kg / hr, at least 70 kg / hr, at least 80 kg / hr, at least 90 kg / hr, at least 100 kg / hr, at least 110 kg / hr, at least 120 kg / hr, at least 130 kg / hr, at least 140 kg / hr, at least 150 kg / hr.

[0412] Spray drying can be done in batches, depending on the stability of the feedstock and the availability to run the dryer for a certain amount of time. In some embodiments, a spray drying batch lasts for 8 hours a day, but may be longer depending on the manufacturer. After this, the equipment is cleaned and prepared for another run using "new" equipment. This batch time depends on the size of the drying chamber, which determines the scale that can be spray dried (assuming the flow rate and temperature of the drying gas can be lengthened to match). In some embodiments, the step of exposing the liquid feedstock droplets to the heated pressurized gas in the drying chamber takes up to 8 hours, e.g., 8 hours per batch cycle.

[0413] In some embodiments, exposing the liquid feed droplets to the heated pressurized gas in the drying chamber takes at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, or at least 24 hours. In some embodiments, exposing the liquid feed droplets to the heated pressurized gas in the drying chamber takes up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 18 hours, or up to 24 hours.

[0414] To establish the powder production rate in grams / minute, this can be converted from the flow rate of solids into the drying chamber by two values: 1) the mass concentration in the feedstock, and 2) the mass flow rate of the feedstock into the drying chamber.

[0415] Cyclone Chamber In some embodiments, a method of preparing a spray-dried pharmaceutical composition includes isolating dry particles of a predetermined range of diameters in a cyclone chamber, hi some embodiments, heated pressurized gas is discharged through the cyclone chamber.

[0416] In some embodiments, the step of isolating the dry particles of a predetermined range of diameters in the cyclone chamber is performed continuously. The powder that settles into the cyclone chamber and into the collection vessel at the bottom of the cyclone chamber settles continuously. The isolation does not necessarily take a fixed time.

[0417] In some embodiments, the dry particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of at least 1.5 μm to a maximum of 7.5 μm. In some embodiments, the dry particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of at least 3.5 μm to a maximum of 7.5 μm. In some embodiments, the dry particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of at least 4.0 μm. In some embodiments, the dry particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of at least 4.8 μm. In some embodiments, the dry particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of at least 5 μm. In some embodiments, the dried particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of at least 3.5 μm, eventually 4.0 μm, at least 4.5 μm, at least 5.0 μm, at least 5.5 μm, at least 6.0 μm, at least 6.5 μm, at least 7.0 μm, or at least 7.5 μm.

[0418] In embodiments, such as those involving inhalation formulations, particularly for administration using DPIs, the spray-dried particles may be encapsulated (i.e., encapsulated) after they are isolated from the cyclone chamber of the spray dryer. In embodiments, such as those involving oral formulations, the spray-dried particles may be tableted after they are isolated from the cyclone chamber of the spray dryer. Tabletting methods are known in the art and may include the steps of weighing, grinding, mixing, granulating, drying, compressing, coating, and / or packaging.

[0419] Administration In some embodiments, the methods described herein relate to the treatment of subjects with bronchopulmonary disease or subjects diagnosed with bronchopulmonary disease. In some embodiments, the subject has or has been diagnosed with chronic bronchopulmonary disease. In some embodiments, the subject has or has been diagnosed with infectious bronchopulmonary disease. Subjects with chronic bronchopulmonary disease can be identified by physicians using current methods of diagnosing chronic bronchopulmonary disease. Symptoms and / or complications of chronic bronchopulmonary disease that characterize and aid in diagnosis of these conditions are well known in the art and include, but are not limited to, shortness of breath, especially during physical activity, wheezing, chest tightness, chronic coughing that may produce mucus (phlegm), frequent respiratory infections, lack of energy, unintentional weight loss, and / or swelling of the ankles, feet, or legs. For example, tests that may be useful in diagnosing chronic bronchopulmonary disease include, but are not limited to, lung (pulmonary) function tests, chest x-rays, lung CT scans, arterial blood gas analysis, and / or laboratory tests (e.g., genetic testing for gene signatures associated with certain chronic bronchopulmonary diseases). A family history of chronic bronchopulmonary disease or exposure to risk factors for chronic bronchopulmonary disease (e.g., long-term exposure to irritating gases or particulate matter, e.g., exposure to tobacco smoke) may also be useful in determining whether a subject is likely to have chronic bronchopulmonary disease or in making a diagnosis of chronic bronchopulmonary disease.

[0420] Subjects with infectious bronchopulmonary disease can be identified by physicians using current methods for diagnosing infectious bronchopulmonary disease. The symptoms and / or complications of infectious bronchopulmonary disease that characterize these conditions and aid in diagnosis are well known in the art and include, but are not limited to, chest pain when breathing or coughing, confusion or changes in mental awareness (e.g., in adults over 65 years old), cough that may produce phlegm, fatigue, fever, sweating and chills, lower than normal body temperature (e.g., in adults over 65 years old or people with weakened immune systems), nausea, vomiting or diarrhea, and / or shortness of breath. For example, tests that can aid in the diagnosis of infectious bronchopulmonary disease include, but are not limited to, blood tests, blood cultures, oximetry, arterial blood gases, bronchoscopy, transtracheal mucus culture, lung biopsy, thoracentesis, and / or computed tomography (CT) scan. A family history of infectious bronchopulmonary disease, or exposure to risk factors for infectious bronchopulmonary disease (e.g., long-term exposure to irritating gases or particulate matter, exposure to tobacco smoke, autoimmunity, allergy, asthma, pregnancy) may also be helpful in determining whether a subject is likely to have infectious bronchopulmonary disease or in making a diagnosis of infectious bronchopulmonary disease.

[0421] In some embodiments, the subject has been diagnosed with or is at risk of developing a bronchopulmonary disease. In some embodiments, the subject has been diagnosed with or is at risk of developing a chronic or infectious bronchopulmonary disease. In some embodiments, the chronic bronchopulmonary disease is selected from the group consisting of bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), bronchiectasis, non-cystic fibrosis (CF) bronchiectasis, cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), interstitial lung disease (ILD), pleural effusion (PE), pulmonary hypertension (PAH), silicosis, and lung cancer. In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).

[0422] In some embodiments, the infectious bronchopulmonary disease is caused by or associated with an infection selected from the following: adenovirus, coronavirus (e.g., common cold virus, severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), SARS-CoV-2, Middle East Respiratory Syndrome (MERS) CoV), influenza virus (e.g., influenza), parainfluenza virus, parvovirus B19 (e.g., parvovirus B19, fifth disease), respiratory syncytial virus (RSV), rhinovirus (e.g., common cold), enterovirus (e.g., EV-D68), measles virus, rubella virus, varicella virus (e.g., chickenpox), Corynebacterium diphtheriae (e.g., diphtheria), Haemophilus influenzae (e.g., type b), Legionella pneumophila (e.g., Legionnaires' disease), Bordetella pertussis (e.g., whooping cough), Mycobacterium tuberculosis (e.g., tuberculosis), Streptococcus species (e.g., Streptococcus pneumoniae, Streptococcus pyogenes, e.g., pneumonia), Pseudomonas species (e.g., Pseudomonas aeruginosa, pulmonary infections, chronic recurrent respiratory infections), Escherichia coli (e.g., community-acquired pneumonia), Aspergillus species (e.g., Aspergillus fumigatus, Aspergillus flavus, aspergillosis), Cryptococcus species (e.g., Cryptococcus neoformans, Cryptococcus gattii, cryptococcal pneumonia), and Pneumocystis species (e.g., Pneumocystis jirovecii, pneumocystis). See, e.g., Dasaraju and Liu, "Chapter 93: Infections of the Respiratory System," Medical Microbiology. 4th edition (1996), for non-limiting examples of infectious bronchopulmonary diseases.

[0423] In one aspect, described herein is a method of delivering a spray-dried pharmaceutical composition comprising a lactate-generating compound to a subject, the method comprising: (a) obtaining an inhalation device for bronchopulmonary delivery, the inhalation device comprising: (i) an inhaler; and (ii) a container containing a spray-dried pharmaceutical composition comprising a lactate-generating compound; (b) activating the inhaler to cause aerosolization or dispersion of the spray-dried pharmaceutical composition; and (c) inhaling the aerosolized or dispersed spray-dried pharmaceutical composition.

[0424] In one aspect, described herein is a method of delivering a spray-dried pharmaceutical composition (e.g., comprising a lactate-producing compound) to a subject, the method comprising: (a) obtaining an inhalation device for bronchopulmonary delivery, the inhalation device comprising: (i) an inhaler; and (ii) a container containing a spray-dried pharmaceutical composition described herein; (b) activating the inhaler to cause aerosolization or dispersion of the spray-dried pharmaceutical composition; and (c) inhaling the aerosolized or dispersed spray-dried pharmaceutical composition.

[0425] In one aspect, described herein is a method of delivering a spray-dried pharmaceutical composition comprising a lactate-producing compound to a subject, the method comprising: (a) obtaining an inhalation device as described herein; (b) activating the inhaler to cause aerosolization or dispersion of the spray-dried pharmaceutical composition; and (c) inhaling the aerosolized or dispersed spray-dried pharmaceutical composition.

[0426] In some embodiments, the inhaler is a dry powder inhaler (DPI). In some embodiments, the inhaler is a metered dose inhaler (MDI). In some embodiments, the inhaler is a soft mist inhaler (SMI). In some embodiments, the inhaler comprises (a) a mouthpiece comprising an opening, and (b) a means for aerosolizing or dispersing the spray dried pharmaceutical composition in the container. In some embodiments, the inhaler has an inhalation flow rate of at least 15 L / min. In some embodiments, the inhaler has an inhalation flow rate of at least 15 L / min up to 60 L / min. In some embodiments, the inhaler has an inhalation flow rate of at least 15 L / min, at least 20 L / min, at least 25 L / min, at least 30 L / min, at least 35 L / min, at least 40 L / min, at least 45 L / min, at least 50 L / min, at least 55 L / min, or at least 60 L / min.

[0427] In some embodiments, at least 25% to up to 125% by weight of the spray dried pharmaceutical composition is delivered to the target bronchopulmonary tissue. In some embodiments, at least 25% to up to 80% by weight of the spray dried pharmaceutical composition is delivered to the target bronchopulmonary tissue. In some embodiments, at least 30.0% by weight of the spray dried pharmaceutical composition is delivered to the target bronchopulmonary tissue. In some embodiments, at least 52.0% by weight of the spray dried pharmaceutical composition is delivered to the target bronchopulmonary tissue. In some embodiments, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% by weight of the spray dried pharmaceutical composition is delivered to the target bronchopulmonary tissue.

[0428] In some embodiments, at least 25% to up to 125.0% by weight of the spray dried pharmaceutical composition is discharged from the inhalation device (e.g., inhaler). In some embodiments, at least 25% to up to 80.0% by weight of the spray dried pharmaceutical composition is discharged from the inhalation device (e.g., inhaler). In some embodiments, at least 52.0% by weight of the spray dried pharmaceutical composition is discharged from the inhalation device (e.g., inhaler). In some embodiments, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% by weight of the spray dried pharmaceutical composition is discharged from the inhalation device (e.g., inhaler).

[0429] In some embodiments, the target bronchopulmonary tissue is a lung, trachea, bronchi, bronchioles, or alveoli. In some embodiments, the target bronchopulmonary tissue is a lung. In some embodiments, the target bronchopulmonary tissue is a trachea. In some embodiments, the target bronchopulmonary tissue is a bronchi. In some embodiments, the target bronchopulmonary tissue is a bronchioles. In some embodiments, the target bronchopulmonary tissue is an alveolus.

[0430] In some embodiments, the dry particles have a median mass aerodynamic diameter (MMAD) of at least 0.5 μm to a maximum of 10 μm, which may affect the bronchopulmonary regions that the particles can reach. Particles of about 0.5 um to about 2.0 um are deposited in small airways such as alveoli and bronchioles, which are therapeutically useful. Particles of about 2.0 um to about 10.0 um are deposited in the bronchial regions of the airways, which are therapeutically useful. Particles below 0.5 um are essentially exhaled, which are not therapeutically useful. Particles above about 10.0 um are retained in the oropharyngeal region and larynx due to impaction, which are not therapeutically useful. See, for example, Thakur et al., Chapter 22: Mucoadhesive drug delivery systems in respiratory diseases, in Targeting Chronic Inflammatory Lung Diseases Using Advanced Drug Delivery Systems, 2020, pp. 475-491, the contents of which are incorporated by reference in their entirety.

[0431] In some embodiments, the spray dried pharmaceutical composition is delivered from the bronchopulmonary tissue to a distal tissue site (i.e., a non-pulmonary tissue) via the cardiovascular or lymphatic system. In some embodiments, the distal tissue site (i.e., a non-pulmonary tissue) is in the gastrointestinal system, the cardiovascular system, the lymphatic system, the musculoskeletal system, the nervous system, the urinary system, the reproductive system, the endocrine system, or the integumentary system. In some embodiments, the distal tissue site (i.e., a non-pulmonary tissue) is connective tissue, epithelial tissue, muscle tissue, or nervous tissue.

[0432] The compositions and methods described herein may be administered to a subject who has or has been diagnosed with a bronchopulmonary disease (e.g., chronic bronchopulmonary disease). In some embodiments, the methods described herein include administering to a subject an effective amount of a composition described herein, such as a spray-dried pharmaceutical composition described herein (e.g., comprising a lactic acid-generating compound), to alleviate a symptom of a chronic bronchopulmonary disease. As used herein, "alleviating a symptom of a chronic bronchopulmonary disease" refers to improving any condition or symptom associated with a chronic bronchopulmonary disease. Compared to an equivalent untreated control, such reduction is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99%, or more, as measured by any standard technique.

[0433] Oral ingestion and inhalation are two delivery options contemplated herein to modulate the lung microenvironment. The gut-lung axis allows for crosstalk between bacterial metabolic by-products in the gut and the lung microenvironment. Metabolic products degraded by commensal bacteria in the gut translocate across the intestinal barrier into the systemic circulation, thereby influencing lung inflammation and immune responses. There are two main methods of producing orally ingested pharmaceuticals (tabletting and encapsulation). Tabletting requires significant granulation and drying, followed by high pressure tableting and coating. At high pressure, tableting of biotherapeutics becomes difficult due to low stability rates. However, for more robust molecules, tableting can be an effective method to precisely formulate powder blends, which are often themselves spray dried. Encapsulation is an effective method to produce orally ingestible powder blends. Ingredients are blended together with excipients, which allow for flowable powders and well-sealed capsules for storage and consistent ingestion. Both dosage forms can be coated to protect against certain pH levels in the stomach, making absorption more effective and reducing dose loss and potential side effects. See, e.g., Anand and Mande 2018, Front Microbiol 9:2147; Enaud et al. 2020, Front Cell Infect Microbiol 10:9; Encenarro 2018, the contents of each of which are incorporated herein by reference in their entirety.

[0434] Compared to other routes of administration, inhalation offers many unique advantages (see, e.g., Borghardt et al. 2018, the contents of which are incorporated herein by reference in their entirety). Inhalation delivers bacterial by-products or extracts directly to lung tissue, resulting in high pulmonary drug concentrations and low systemic drug concentrations with minimal systemic side effects. Inhalation formulations containing lactic acid can be produced via several processing routes, including spray drying to produce dry powder inhalation formulations, compounding to produce nebulizable formulations, or compounding and pressurization in metered dose inhalers. Each of these routes of administration offers benefits. Dry powder formulations are composed of engineered particles with specific size distributions, allowing for more precisely tailored lung deposition, aerodynamic properties, long-term stability, and relatively easy administration in patients with normal inhalation capabilities. Nebulized solutions containing active pharmaceutical ingredients are well suited to infant or adolescent lungs, as well as patients with weaker lung volumes. These solutions face stability challenges and have size limitations that may prevent aerosolization during administration. Metered dose inhalers are common in the market for bronchodilators and inhaled corticosteroids, but typically require pressurized containers and chemical propellants to function effectively. Some of these propellants have unknown side effects, and the sustained pressure on drug-containing solutions can pose stability challenges, especially when formulated with more sensitive biotherapeutics.

[0435] As used herein, the term "effective amount" refers to the amount of the spray-dried pharmaceutical composition (e.g., including a lactate-generating compound) described herein necessary to alleviate at least one or more symptoms of a disease or disorder, and relates to an amount of the pharmacological composition sufficient to provide the desired effect. Thus, the term "therapeutically effective amount" refers to an amount of the spray-dried pharmaceutical composition (e.g., including a lactate-generating compound) described herein that is sufficient to provide an effect against a particular bronchopulmonary disease when administered to a typical subject. In various contexts, an effective amount as used herein will also include an amount sufficient to delay the onset of a symptom of a disease, alter the disease course of a symptom (e.g., but not limited to, delay the progression of a symptom of a disease), or ameliorate a symptom of a disease. Thus, in general, it is not practical to specify an exact "effective amount". However, in any given case, an appropriate "effective amount" can be determined by one of ordinary skill in the art using only routine experimentation.

[0436] Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, for example, determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).

[0437] Dosages may vary depending on the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compositions and methods that exhibit a high therapeutic index are preferred. Therapeutically effective doses can be estimated initially from cell culture assays. A dose may also be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the lactate-producing compound that achieves half-maximal inhibition of symptoms) as determined in cell culture. Levels in plasma can be measured, for example, by high performance liquid chromatography. The effect of any particular dosage can be monitored by a suitable bioassay, such as pH or apoptosis assays, among others. Dosages are determined by the physician and can be adjusted, if necessary, to the observed effects of the treatment.

[0438] Pharmaceutical compositions containing the lactate-producing compounds described herein can also be formulated to be suitable for oral administration, for example, in separate dosage forms, such as, but not limited to, tablets (including scored or coated tablets), pills, caplets, capsules, chewable tablets, powder packets, cachets, troches, wafers, aerosol sprays, or liquids, such as, but not limited to, syrups, elixirs, solutions or suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. Such compositions contain a predetermined amount of lactate-producing compounds and can be prepared by pharmaceutical methods well known to those skilled in the art. See generally Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005).

[0439] In some embodiments of any of the aspects, a pharmaceutical composition described herein (e.g., comprising a lactate-generating compound) is administered as a monotherapy, e.g., no other treatment for a chronic bronchopulmonary disease is administered to the subject.

[0440] In some embodiments of any of the aspects, the methods described herein can further include administering to the subject a second agent and / or treatment, e.g., as part of a combination therapy. Non-limiting examples of second agents and / or treatments can include cancer therapies selected from the group consisting of radiation therapy, surgery, gemcitabine, cisplatin, paclitaxel, carboplatin, bortezomib, AMG479, vorinostat, rituximab, temozolomide, rapamycin, ABT-737, PI-103, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide, alkylsulfonates such as busulfan, improsulfan, and piposulfan, bevacizumab, cyclophosphamide ... Aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin, kallistatin, CC-1065 (including the synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8), dolastatins, duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1), erytherobin, pancratistatin, sarcodictin, spongiostatin, nitrogen mustards, e.g., chlorambucil, chlornaphazine, clophosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, and u nitrosoureas, such as rasil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., the calicheamicins, particularly calicheamicin gamma 1I and calicheamicin omega 11) (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994)); dynemicins (including dynemicin A); bisphosphonates, such as clodronate; esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin). xorubicin), mitomycins such as epirubicin, esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5-FU), folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate. purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; aceglatone, and aldophosphamide glycosides. , aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, erformitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidynin, maytansinoids such as maytansine and ansamitocin, mitoguazone, mitoxantrone, mopidamol, nitraelin, pentostatin, phenamet, pirarubicin, rosoxantrone, podophyllic acid, 2-ethylhydrazide, procarbazine,PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane, rhizoxin, schizofuran, spirogermanium, tenuazonic acid, triazicon, 2,2',2''-trichlorotriethylamine, trichothecenes (especially T-2 toxin, veracrine A, roridin A, anguidin), urethanes, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, taxoids such as TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® cremophor-free, albumin engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France), chlorambucil, GEMZAR® gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin, oxaliplatin, carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan (camptosar, CPT-11) (5-FU and leucovorin), irinotecan treatment regimens with riboflavin, topoisomerase inhibitor RFS2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, capecitabine, combretastatins, leucovorin (LV), oxaliplatin, including oxaliplatin treatment regimens (FOLFOX), lapatinib (Tykerb®), inhibitors of PKC-alpha, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva®)) and VEGF-A that reduce cell proliferation, and pharmacologic acceptable salts, acids, or derivatives of any of the above.

[0441] Those skilled in the art can easily identify the chemotherapeutic agent to be used (see, for example, Physicians' Cancer Chemotherapy Drug Manual 2014, Edward Chu, Vincent T., DeVita Jr., Jones & Bartlett Learning, Principles of Cancer Therapy, Chapter 85 in Harrison's Principles of Internal Medicine, 18th edition, Therapeutic Targeting of Cancer Cells: Era of Molecularly Targeted Agents and Cancer Pharmacology, Chs. 28-29 in Abeloff's Clinical Oncology, 2013 Elsevier, and Fischer DS (ed): The Cancer Chemotherapy Handbook, 4th ed. St. Louis, Mosby-Year Book, 2003). Furthermore, the treatment method may further include the use of radiation or radiation therapy. Furthermore, the treatment method may further include the use of surgical treatment.

[0442] The methods described herein can further include administering a second agent and / or treatment to the subject, e.g., as part of a combination therapy. As a non-limiting example, when a subject is treated for pain or inflammation according to the methods described herein, the subject can also be administered a second agent and / or treatment known to be beneficial to subjects suffering from pain or inflammation. Examples of such drugs and / or treatments include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs such as aspirin, ibuprofen, or naproxen), corticosteroids including glucocorticoids (e.g., cortisol, prednisolone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclomethasone), methotrexate, sulfasalazine, leflunomide, anti-TNF drugs, cyclophosphamide, inflammation-resolving drugs, mycophenolic acid, or opiates (e.g., enkephalins and dynorphins), steroids, analgesics, barbiturates, oxycodone, morphine, lidocaine, and the like.

[0443] In some embodiments, the spray dried biotherapeutic matrix composition is co-administered with at least one additional therapeutic treatment or intervention for a chronic bronchopulmonary disorder.

[0444] In some embodiments, the chronic bronchopulmonary disorder is chronic obstructive pulmonary disease (COPD) and the at least one additional therapeutic treatment or intervention is smoking cessation, bronchodilators, inhaled steroids, oral steroids, roflumilast (DALIRESP, a phosphodiesterase-4 inhibitor), theophylline (ELIXOPHYLLIN, THEO-24, THEOCHRON), antibiotics, oxygen therapy, pulmonary rehabilitation (e.g., education, breathing exercises, nutritional advice, and / or counseling), home non-invasive ventilation (e.g., bilevel positive airway pressure (BiPAP)), and / or surgery (e.g., lung volume reduction surgery, pulmonary bulla resection, or lung transplant).

[0445] In some embodiments, the chronic bronchopulmonary disorder is lung cancer and the at least one additional therapeutic treatment or intervention is surgery (e.g., wedge resection, segmentectomy, lobectomy, or pneumonectomy), radiation therapy, chemotherapy, stereotactic body radiation therapy, gene-targeted chemotherapy, or immunotherapy.

[0446] In some embodiments, the chronic bronchopulmonary disorder is asthma and the at least one additional therapeutic treatment or intervention is selected from the group consisting of bronchodilators, inhaled corticosteroids (e.g., fluticasone propionate (FLOVENT HFA, FLOVENT DISKUS, XHANCE), budesonide (PULMICORT FLEXHALER, PULMICORT RESPULES, RHINOCORT), ciclesonide (ALVESCO), beclomethasone (QVAR REDIHALER), mometasone (ASMANEX HFA, ASMANEX TWISTHALER), and fluticasone furoate (ARNUITY ELLIPTA), leukotriene modifiers (e.g., montelukast (SINGULAIR), zafirlukast (ACCOLATE), and zileuton (ZYFLO), long-acting beta agonists and corticosteroids (e.g., fluticasone-salmeterol (ADVAIR HFA, AIRDUO DIGIHALER), budesonide-formoterol (SYMBICORT), formoterol-mometasone (DULERA) and fluticasone furoate-vilanterol (BREO ELLIPTA), theophylline (ELIXOPHYLLIN, THEO-24, THEOCHRON), short-acting beta agonists (e.g., albuterol (PROAIR HFA, VENTOLIN HFA) and levalbuterol (XOPENEX, XOPENEX HFA), anticholinergics (e.g., ipratropium (ATROVENT HFA) and tiotropium (SPIRIVA, SPIRIVA RESPIMAT), oral and intravenous corticosteroids (e.g., prednisone (PREDNISONE These include treatments such as INTENSOL, RAYOS) and methylprednisolone (MEDROL, DEPO-MEDROL, SOLU-MEDROL)), allergy injections (e.g., injections of specific allergens to gradually reduce the immune system response), allergy biologics (e.g., omalizumab (XOLAIR), mepolizumab (NUCALA), dupilumab (DUPIXENT), reslizumab (CINQAIR) or benralizumab (FASENRA)), or bronchial thermoplasty.

[0447] In some embodiments, the chronic bronchopulmonary disorder is bronchiectasis and the at least one additional therapeutic treatment or intervention is an antibiotic, a macrolide, a mucus thinning agent (e.g., guaifenesin (MUCINEX)), an airway clearance device (e.g., a positive expiratory pressure (PEP) device, a percussive, wearable device such as a percussive vest), or chest physical therapy (e.g., chest clapping).

[0448] In some embodiments, the chronic bronchopulmonary disorder is emphysema and the at least one additional therapeutic treatment or intervention is a bronchodilator, an inhaled steroid, an antibiotic, pulmonary rehabilitation (e.g., breathing exercises), nutritional therapy, supplemental oxygen, smoking cessation, or surgery (e.g., lung volume reduction surgery, lung transplant).

[0449] In some embodiments, the chronic bronchopulmonary disorder is cystic fibrosis (CF) and the at least one additional therapeutic treatment or intervention is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator (e.g., a combination containing elexacaftor, ivacaftor, and tezacaftor (TRIKAFTA), a combination containing tezacaftor and ivacaftor (SYMDEKO), a combination containing lumacaftor and ivacaftor (ORKAMBI), ivacaftor (KALYDECO), an airway clearance device (e.g., a positive expiratory pressure (PEP) device, a percussive wearable device such as a percussive vest), chest physical therapy (e.g., chest clapping), pulmonary rehabilitation (e.g., breathing exercises), nasal and sinus surgery, oxygen therapy, noninvasive ventilation, a feeding tube, intestinal surgery, a lung transplant, or a liver transplant.

[0450] In some embodiments, the chronic bronchopulmonary disorder is bronchopulmonary dysplasia (BPD) and the at least one additional therapeutic treatment or intervention is a diuretic (e.g., reducing the amount of fluid in and around the alveoli) to prevent or reduce respiratory tract infection, a bronchodilator, a corticosteroid, a cardiac medication, or a respiratory syncytial virus (RSV) immunization.

[0451] In some embodiments, the chronic bronchopulmonary disorder is acute respiratory distress syndrome (ARDS) and the at least one additional therapeutic treatment or intervention is supplemental oxygen, mechanical ventilation, intravenous fluids, smoking cessation, antibiotics, painkillers, anti-inflammatory agents, blood thinners, gastric reflux medications (e.g., esomeprazole (NEXIUM)), or sedatives.

[0452] In some embodiments, the chronic bronchopulmonary disorder is idiopathic pulmonary fibrosis (IPF) and the at least one additional therapeutic treatment or intervention is an antifibrotic agent (e.g., nintedanib (OFEV) or pirfenidone (ESBRIET)), a corticosteroid (e.g., prednisone), an immunosuppressant (e.g., azathioprine (IMURAN), cyclophosphamide (CYTOXAN), or mycophenolate mofetil (CELLCEPT)), an oral or spray antioxidant (e.g., N-acetylcysteine, NAC (MUCOMYST)), oxygen therapy, or pulmonary rehabilitation (e.g., breathing exercises).

[0453] In some embodiments, the chronic bronchopulmonary disorder is an interstitial lung disease (ILD) and the at least one additional therapeutic treatment or intervention is a corticosteroid (e.g., prednisone), an immunosuppressant, a drug to slow the progression of idiopathic pulmonary fibrosis such as pirfenidone (ESBRIET) or nintedanib (OFEV), an H-2 receptor antagonist or a proton pump inhibitor such as lansoprazole (PEVACID 24HR), omeprazole (Prilosec OTC), or pantoprazole (PROTONIX) for symptoms of gastroesophageal reflux disease (GERD) that affects the majority of people with idiopathic pulmonary fibrosis, oxygen therapy, pulmonary rehabilitation, and / or surgery such as a lung transplant.

[0454] In some embodiments, the chronic bronchopulmonary disorder is pleural effusion (PE) and the at least one additional therapeutic treatment or intervention is a diuretic, chemotherapy, radiation therapy, therapeutic thoracentesis, thoracic drainage, sclerosing agents (e.g., talc, doxycycline, and tetracycline), and / or surgery, such as video-assisted thoracoscopic surgery (VATS) or thoracotomy.

[0455] In some embodiments, the chronic bronchopulmonary disorder is pulmonary hypertension (PAH) and the at least one additional therapeutic treatment or intervention is a vasodilator, a guanylate cyclase (GSC) stimulator such as riociguat (ADEMPAS), an endothelin receptor antagonist such as bosentan (TRACLEER), macitentan (OPSUMIT), or ambrisentan (LETAIRIS), a phosphodiesterase 5 (PDE5) inhibitor such as sildenafil (REVATIO, VIAGRA) or tadalafil (ADCIRCA, CIALIS, ALYQ), a calcium channel blocker such as amlodipine (NORVASC), diltiazem (CARDIZEM, TIAZAC), or nifedipine (PROCARDIA), an anticoagulant such as warfarin (JANTOVEN), digoxin (LANOXIN), a diuretic, oxygen therapy, and / or surgery such as atrial septal septum resection, lung transplant, or heart-lung transplant.

[0456] In some embodiments, the chronic bronchopulmonary disorder is silicosis and the at least one additional therapeutic treatment or intervention is a bronchodilator, smoking cessation, supplemental oxygen, pulmonary rehabilitation, and / or surgery such as a lung transplant.

[0457] In some embodiments, the at least one additional therapeutic treatment or intervention for an infectious bronchopulmonary disorder is an antiviral agent, an antibiotic, or an antifungal agent, such as the non-limiting examples listed above.

[0458] In certain embodiments, a composition comprising an effective dose of a lactate-producing compound described herein may be administered once to a patient. In certain embodiments, a composition comprising an effective dose of a lactate-producing compound may be administered repeatedly to a patient. For systemic administration, a subject may be administered a therapeutic amount of a composition comprising a lactate-producing compound, for example, 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, or more.

[0459] In some embodiments, after an initial treatment regimen, treatment may be administered less frequently. For example, after 3 months of biweekly treatment, treatment may be repeated once a month for 6 months or for a year or more. Treatment according to the methods described herein may reduce the level of a marker or symptom of chronic bronchopulmonary disease by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, or more.

[0460] Dosages of the compositions described herein may be determined by a physician and adjusted as necessary to the observed therapeutic effects. With regard to duration and frequency of treatment, a skilled clinician will typically monitor the subject to determine when the treatment is providing therapeutic benefit and to determine whether to increase or decrease the dosage, increase or decrease the frequency of administration, discontinue treatment, resume treatment, or make other changes to the treatment regimen. Dosing schedules may vary from once a week to once a day, depending on several clinical factors, such as the subject's sensitivity to the lactate-producing compound. The desired dose or amount may be administered once or divided into subdoses (e.g., 2-4 subdoses) and administered over a period of time, e.g., at appropriate intervals throughout the day or on other suitable schedules. In some embodiments, administration may be chronic, e.g., one or more doses and / or treatments daily for a period of weeks or months. Examples of dosing and / or treatment schedules are administration once a day, twice a day, three times a day, or four times a day or more for a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more. The composition comprising the lactate-producing compound may be administered over a period of time (e.g., 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes).

[0461] The dosage range for administration of pharmaceutical compositions (e.g., including lactate-producing compounds) according to the methods described herein will depend, for example, on the form of the lactate-producing compound, its potency, and the degree to which it is desired to reduce the symptoms, markers, or indicators of the conditions described herein. The dosage should not be so large as to cause adverse side effects, such as acidosis or tissue damage. In general, dosages will vary with the age, condition, and sex of the patient, and can be determined by one of skill in the art. Dosages can also be adjusted by the individual physician in the event of any complications.

[0462] The efficacy of a pharmaceutical composition (e.g., comprising a lactate-producing compound) in treating a condition described herein can be determined by a skilled clinician. However, if one or more of the signs or symptoms of a condition described herein are altered in a beneficial manner and other clinically recognized symptoms are improved or even ameliorated, or if, for example, a desired response is induced by at least 10% following treatment with the methods described herein, the treatment is considered to be an "effective treatment" as that term is used herein. Efficacy can be assessed, for example, by measuring the occurrence of markers, indicators, symptoms, and / or conditions being treated according to the methods described herein or any other measurable parameters as appropriate. Efficacy can also be measured by failure of an individual to deteriorate as assessed by hospitalization or need for medical intervention (i.e., progression of the disease is halted). Methods for measuring these indicators are known to those of skill in the art and / or described herein. Treatment includes any treatment of a disease in an individual or animal (some non-limiting examples include humans or animals), including (1) inhibiting the disease, e.g., preventing the worsening of symptoms, or (2) reducing the severity of the disease, e.g., causing regression of symptoms. An effective amount for the treatment of a disease means an amount that, when administered to a subject in need thereof, is sufficient to provide effective treatment for that disease, as that term is defined herein. The efficacy of an agent can be determined by assessing physical indicators of the condition or desired response. It is within the ability of one of ordinary skill in the art to monitor the efficacy of administration and / or treatment by measuring any one of such parameters, or any combination of parameters. Efficacy can be evaluated in animal models of treatment of conditions described herein, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), bronchiectasis, non-cystic fibrosis (CF) bronchiectasis, cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), or lung cancer. When using experimental animal models, the efficacy of treatment is demonstrated when a statistically significant change in the marker is observed.

[0463] In vitro and animal model assays that allow for the evaluation of a given dose of a pharmaceutical composition (e.g., including a lactate-generating compound) are provided herein (see, e.g., Figures 1-7, Example 1). As non-limiting examples, the effect of a dose of a pharmaceutical composition (e.g., including a lactate-generating compound) can be evaluated using a dysbiosis model of lung epithelial cells using human primary epithelial (HBE) cells (see, e.g., Figure 2, Figure 5), human intestinal epithelial cells (IEC) derived from the Caco-2 cell line (see, e.g., Figure 3), A549 non-small cell lung cancer (NSCLC) adenocarcinoma cells (see, e.g., Figure 4), or a mouse model of dysbiosis. Non-limiting examples of protocols for such assays are provided in Example 1.

[0464] Treatment method The compositions described herein can be administered to a subject in need thereof, for example, for the treatment of bronchopulmonary disease, including, but not limited to, chronic bronchopulmonary disease. In some embodiments, the treatment method can include first diagnosing a subject or patient that can benefit from treatment with a composition described herein. In some embodiments, the method further includes administering a composition described herein to the patient.

[0465] In one aspect, a method of treating a subject in need of treatment is described herein, the method comprising administering by inhalation an effective dose of a pharmaceutical composition comprising a lactate-producing compound.In one aspect, a method of treating a subject in need of treatment is described herein, the method comprises administering by inhalation an effective dose of a pharmaceutical composition described herein.

[0466] In some embodiments, the lactate-generating compound reduces neutrophilic inflammation in the target tissue, hi some embodiments, the lactate-generating compound reduces neutrophilic inflammation in the target tissue by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more.

[0467] In some embodiments, the target tissue is a target bronchopulmonary tissue. In some embodiments, the target bronchopulmonary tissue is a lung, trachea, bronchi, bronchioles, and / or alveoli. In some embodiments, the target tissue is a tissue site distal to the lung that is delivered via the cardiovascular or lymphatic system.

[0468] In some embodiments, the subject is diagnosed with or at risk of developing a chronic bronchopulmonary disease. In some embodiments, the chronic bronchopulmonary disease is selected from the group consisting of asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), bronchiectasis, non-cystic fibrosis (CF) bronchiectasis, cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), interstitial lung disease (ILD), pleural effusion (PE), pulmonary hypertension (PAH), silicosis, and lung cancer. In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).

[0469] In some embodiments, the chronic bronchopulmonary disease is bronchopulmonary dysplasia (BPD). In some embodiments, the chronic bronchopulmonary disease is chronic obstructive pulmonary disease (COPD). In some embodiments, the chronic bronchopulmonary disease is bronchiectasis. In some embodiments, the chronic bronchopulmonary disease is non-cystic fibrosis (CF) bronchiectasis. In some embodiments, the chronic bronchopulmonary disease is cystic fibrosis (CF). In some embodiments, the chronic bronchopulmonary disease is acute respiratory distress syndrome (ARDS). In some embodiments, the chronic bronchopulmonary disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the chronic bronchopulmonary disease is interstitial lung disease (ILD). In some embodiments, the chronic bronchopulmonary disease is pleural effusion (PE). In some embodiments, the chronic bronchopulmonary disease is pulmonary hypertension (PAH). In some embodiments, the chronic bronchopulmonary disease is silicosis. In some embodiments, the chronic bronchopulmonary disease is lung cancer. In some embodiments, the chronic bronchopulmonary disease is small cell lung cancer (SCLC). In some embodiments, the chronic bronchopulmonary disease is non-small cell lung cancer (NSCLC). In some embodiments, the chronic bronchopulmonary disease is asthma. In some embodiments, the chronic bronchopulmonary disease is emphysema.

[0470] In some embodiments, the subject has been diagnosed with or is at risk for developing infectious bronchopulmonary disease. In some embodiments, the infectious bronchopulmonary disease is caused by or associated with an infection selected from the following: adenovirus, coronavirus (e.g., common cold virus, severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), SARS-CoV-2, Middle East Respiratory Syndrome (MERS) CoV), influenza virus (e.g., influenza), parainfluenza virus, parvovirus B19 (e.g., parvovirus B19, fifth disease), respiratory syncytial virus (RSV), rhinovirus (e.g., common cold), enterovirus (e.g., EV-D68), measles virus, rubella virus, varicella virus (e.g., chickenpox), Corynebacterium diphtheriae (e.g., diphtheria), Haemophilus influenzae (e.g., type b), Legionella pneumophila (e.g., Legionnaires' disease), Bordetella pertussis (e.g., whooping cough), Mycobacterium tuberculosis (e.g., tuberculosis), Streptococcus species (e.g., Streptococcus pneumoniae, Streptococcus pyogenes, e.g., pneumonia), Pseudomonas species (e.g., Pseudomonas aeruginosa, pulmonary infections, chronic recurrent respiratory infections), Escherichia coli (e.g., community-acquired pneumonia), Aspergillus species (e.g., Aspergillus fumigatus, Aspergillus flavus, aspergillosis), Cryptococcus species (e.g., Cryptococcus neoformans, Cryptococcus gattii, cryptococcal pneumonia), and Pneumocystis species (e.g., Pneumocystis jirovecii, pneumocystis).

[0471] In some embodiments, the effective dose of the pharmaceutical composition is at least 1 mg of lactate-producing compound per unit dose. In some embodiments, the effective dose of the pharmaceutical composition is at least 5 mg of lactate-producing compound per unit dose. In some embodiments, the effective dose of the pharmaceutical composition is at least 7.8 mg of lactate-producing compound per unit dose. In some embodiments, the effective dose of the pharmaceutical composition is up to 50 mg of lactate-producing compound per unit dose. In some embodiments, the effective dose of the pharmaceutical composition is at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, or at least 50 mg of lactate-producing compound per unit dose.

[0472] In some embodiments, the pharmaceutical composition formulated for oral administration is co-administered with at least one additional therapeutic agent for chronic or infectious bronchopulmonary disorders. In some embodiments, the at least one additional therapeutic agent is an anti-inflammatory agent, an antibacterial agent, an antiviral agent, an antifungal agent, a vasodilator, or a bronchodilator as further described herein. In some embodiments, the pharmaceutical composition comprises a lactate-generating compound and at least one additional therapeutic agent in the same composition or unit dosage. As a non-limiting example, the lactate-generating compound and at least one additional therapeutic agent can be spray-dried together and formulated, for example, in a single capsule, for administration together. In some embodiments, the lactate-generating compound and at least one additional therapeutic agent are each spray-dried separately and formulated, for example, in the same or different capsules. In some embodiments, the lactate-generating compound and at least one additional therapeutic agent are co-administered using a combination delivery device, such as an inhalation device, that administers multiple different formulations at once.

[0473] In one aspect, a method of treating a subject in need of treatment is described herein, the method comprising orally administering an effective dose of a pharmaceutical composition comprising a lactate-producing compound. In one aspect, a method of treating a subject in need of treatment is described herein, the method comprising orally administering an effective dose of a pharmaceutical composition described herein. In some embodiments, the target tissue (e.g., a target tissue of an orally formulated pharmaceutical composition described herein) is a bronchopulmonary target tissue. In some embodiments, the subject (e.g., a subject being treated with an orally formulated pharmaceutical composition described herein) has been diagnosed with or is at risk of developing a bronchopulmonary disorder, including, but not limited to, a chronic or infectious bronchopulmonary disorder.

[0474] In some embodiments, pharmaceutical compositions comprising lactate-generating compounds are administered in conjunction with standard of care treatments for chronic or infectious bronchopulmonary diseases, as known to those of skill in the art. As used herein, the term "standard of care" refers to the level at which an average, conscientious provider in a given community would, for example, practice in treating a given indication.

[0475] As a non-limiting example, COPD standard of care varies based on the GOLD staging of severity, but may include a variety of therapies combining anti-inflammatory effects (e.g., inhaled steroids) with symptomatic relief (e.g., long-acting beta agonists (LABAs), long-acting muscarinic antagonists (LAMAs)). Standard of care for pulmonary fibrosis is typically at least one of two anti-fibrotic agents: nintedanib and pirfenidone. Standard of care for bronchopulmonary dysplasia includes a variety of treatments based on the patient's risk profile, including supplemental oxygen, surfactants, and bronchodilators. See, e.g., Safka et al., Chronic Obstr Pulm Dis. 2017;4(1):45-55 (see, e.g., Table 1 in Safka), the 2022 Gold Reports available on the World Wide Web at goldcopd.org / 2022-gold-reports (see, e.g., pages 49-57, Table 3.3 on page 49, Table 3.4 on page 51, and Table 3.5 on page 53 of the Gold Reports), and Maher et al. “Respiratory Research volume 20, Article number:205 (2019). Non-limiting examples of additional therapeutic treatments or interventions for certain chronic or infectious bronchopulmonary diseases are further described herein.

[0476] Unit dosage form In one aspect, a unit dosage form comprising the pharmaceutical composition described herein is described herein. In some embodiments, the single unit dosage is one capsule comprising the pharmaceutical composition described herein. In some embodiments, the single unit dosage is a plurality (e.g., 1, 2, 3, 4, 5, or more) capsules, each comprising the pharmaceutical composition described herein. In some embodiments, the unit dosage is administered (e.g., inhaled) during one inhalation (e.g., less than 10, 20, or 30 seconds). In some embodiments, the unit dosage is administered (e.g., inhaled) over a period of time (e.g., more than 30, 60, or 120 seconds) and / or administered (e.g., inhaled) using multiple dose inhalers.

[0477] In some embodiments, unit dosages comprising the pharmaceutical compositions described herein result in approximately 7.8 mg of PLA per dose administered directly to the lungs via inhalation. Intravenous doses of PLA previously used for encapsulation of active drugs have been safely used in the range of 40-165 mg per dose. See, e.g., Jain et al. (2016) Adv Drug Deliv Rev 107:213-227, the contents of which are incorporated herein by reference in their entirety. Once the final dry powder is produced, it can be filled into capsules or tablets for ingestion. The dry powder blend itself can undergo several process steps that will result in a uniform blend and a robust solid dosage form. Such unit dosages can be formulated for administration via inhalation or oral administration (see, e.g., Tables 1, 2, 11).

[0478] In one aspect, described herein is a unit dosage form comprising at least 1.0 mg and up to 100 mg of a pharmaceutical composition comprising a lactate-producing compound. In one aspect, described herein is a unit dosage form comprising at least 5.0 mg and up to 100 mg of a pharmaceutical composition comprising a lactate-producing compound. In some embodiments, the unit dosage form comprises at least 15.0 mg of lactate-producing compound per unit dose. In some embodiments, the unit dosage form comprises at least 50.0 mg of lactate-producing compound per unit dose. In some embodiments, the unit dosage form contains at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of lactate-producing compound per unit dose.

[0479] In one embodiment, described herein is a unit dosage form comprising at least 1.0 mg to up to 100 mg of a pharmaceutical composition described herein. In one embodiment, described herein is a unit dosage form comprising at least 5.0 mg to up to 100 mg of a pharmaceutical composition described herein. In one embodiment, described herein is a unit dosage form comprising at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a pharmaceutical composition described herein.

[0480] In one embodiment, described herein is a unit dosage form comprising at least 1.0 mg to up to 100 mg of a spray dried pharmaceutical composition prepared by the methods described herein. In one embodiment, described herein is a unit dosage form comprising at least 5.0 mg to up to 100 mg of a spray dried pharmaceutical composition prepared by the methods described herein. In one embodiment, described herein is a unit dosage form comprising at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a spray dried pharmaceutical composition prepared by the methods described herein.

[0481] In one embodiment, described herein is a unit dosage form comprising at least 15.0 mg to up to 100 mg of a pharmaceutical composition comprising at least 15 mg of a lactate-producing compound per unit dose. In one embodiment, described herein is a unit dosage form comprising at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a pharmaceutical composition comprising at least 15 mg of a lactate-producing compound per unit dose.

[0482] In some embodiments, the dosage is at least 1.0 mg of the pharmaceutical composition. In some embodiments, the dosage is at least 5.0 mg of the pharmaceutical composition. In some embodiments, the dosage is at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of the pharmaceutical composition.

[0483] In some embodiments, the dosage comprises at least 1.0 mg of lactate-generating compound per unit dose deliverable to the target tissue. In some embodiments, the dosage comprises at least 5.0 mg of lactate-generating compound per unit dose deliverable to the target tissue. In some embodiments, the dosage comprises at least 7.8 mg of lactate-generating compound per unit dose deliverable to the target tissue. In some embodiments, the dosage comprises at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of lactate-generating compound per unit dose deliverable to the target tissue.

[0484] In some embodiments, the dosage comprises at least 1.0 mg of lactate-generating compound per unit dose discharged from the delivery device (e.g., an inhaler). In some embodiments, the dosage comprises at least 5.0 mg of lactate-generating compound per unit dose discharged from the delivery device (e.g., an inhaler). In some embodiments, the dosage comprises at least 7.8 mg of lactate-generating compound per unit dose discharged from the delivery device (e.g., an inhaler). In some embodiments, the dosage comprises at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of lactate-producing compound per unit dose emitted from the delivery device (e.g., an inhaler).

[0485] In some embodiments, the dosage comprises at least 1 mg of lactate-producing compound per unit dose. In some embodiments, the dosage comprises at least 5 mg of lactate-producing compound per unit dose. In some embodiments, the dosage comprises at least 15 mg of lactate-producing compound per unit dose. In some embodiments, the dosage comprises at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of lactate-producing compound per unit dose. In some embodiments, the dosage comprises up to 1.0 mg, up to 2.0 mg, up to 3.0 mg, up to 4.0 mg, up to 5.0 mg, up to 10 mg, up to 15 mg, up to 20 mg, up to 25 mg, up to 30 mg, up to 35 mg, up to 40 mg, up to 45 mg, up to 50 mg, up to 55 mg, up to 60 mg, up to 65 mg, up to 70 mg, up to 75 mg, up to 80 mg, up to 85 mg, up to 90 mg, up to 95 mg, or up to 100 mg of lactate-producing compound per unit dose.

[0486] In some embodiments, the dosage comprises at least 14.25 mg of excipient(s) per unit dose. In some embodiments, the dosage comprises at least 144 mg of excipient(s) per unit dose. In some embodiments, the dosage comprises at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 110 mg, at least 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, at least 180 mg, at least 190 mg, at least 200 mg, or more of excipient(s) per unit dose. In some embodiments, the dosage comprises up to 1.0 mg, up to 2.0 mg, up to 3.0 mg, up to 4.0 mg, up to 5.0 mg, up to 10 mg, up to 15 mg, up to 20 mg, up to 25 mg, up to 30 mg, up to 35 mg, up to 40 mg, up to 45 mg, up to 50 mg, up to 55 mg, up to 60 mg, up to 65 mg, up to 70 mg, up to 75 mg, up to 80 mg, up to 85 mg, up to 90 mg, up to 95 mg, up to 100 mg, up to 110 mg, up to 120 mg, up to 130 mg, up to 140 mg, up to 150 mg, up to 160 mg, up to 170 mg, up to 180 mg, up to 190 mg, or up to 200 mg of excipient(s) per unit dose.

[0487] In some embodiments, the dosage comprises at least 7.125 mg of the first excipient and at least 7.125 mg of the second excipient per unit dose. In some embodiments, the dosage comprises at least 72 mg of the first excipient and at least 72 mg of the second excipient per unit dose. In some embodiments, the dosage comprises at least 0.5 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 9 ...10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 9 mg, at least 10 mg, at least 10 mg, 0 mg, at least 95 mg, or at least 100 mg of a first excipient and at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a second excipient per unit dose.

[0488] In some embodiments, the dosage comprises at least 7.125 mg of a first excipient per unit dose and at least 0.5 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a second excipient per unit dose. In some embodiments, the dosage comprises at least 0.5 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of the first excipient per unit dose and at least 7.125 mg of the second excipient per unit dose.

[0489] In some embodiments, the dosage comprises at least 0.45 mg of stabilizer per unit dose. In some embodiments, the dosage comprises at least 3.0 mg of stabilizer per unit dose. In some embodiments, the dosage comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, or at least 20 mg of stabilizer(s) per unit dose. In some embodiments, the dosage comprises up to 0.45 mg of stabilizer per unit dose. In some embodiments, the dosage comprises up to 0.1 mg, up to 0.2 mg, up to 0.3 mg, up to 0.4 mg, up to 0.5 mg, up to 0.6 mg, up to 0.7 mg, up to 0.8 mg, up to 0.9, up to 1.0 mg, up to 2.0 mg, up to 3.0 mg, up to 4.0 mg, up to 5.0 mg, up to 10 mg, up to 15 mg, or up to 20 mg of stabilizer(s) per unit dose.

[0490] In some embodiments, the dosage, such as an orally formulated dosage, comprises at least 3.0 mg of adhesive per unit dose. In some embodiments, the dosage comprises at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 2.0 mg, at least 3.0 mg, at least 4.0 mg, at least 5.0 mg, at least 10 mg, at least 15 mg, or at least 20 mg of stabilizer(s) per unit dose. In some embodiments, the dosage comprises up to 0.45 mg of adhesive per unit dose. In some embodiments, the dosage comprises up to 0.1 mg, up to 0.2 mg, up to 0.3 mg, up to 0.4 mg, up to 0.5 mg, up to 0.6 mg, up to 0.7 mg, up to 0.8 mg, up to 0.9, up to 1.0 mg, up to 2.0 mg, up to 3.0 mg, up to 4.0 mg, up to 5.0 mg, up to 10 mg, up to 15 mg, or up to 20 mg of adhesive per unit dose.

[0491] In some embodiments, the pharmaceutical composition comprises at least 1.0% lactate-producing compound by dry weight. In some embodiments, the unit dosage comprises at least 25.0% lactate-producing compound by dry weight. In some embodiments, the unit dosage comprises at least 50% lactate-producing compound by dry weight. In some embodiments, the unit dosage comprises at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more lactate-producing compound by dry weight. In some embodiments, the unit dosage comprises up to 0.5%, up to 1%, up to 2%, up to 3%, up to 4%, up to 5%, up to 6%, up to 7%, up to 8%, up to 9%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, or up to 95% lactic acid producing compound by dry weight.

[0492] In some embodiments, the unit dosage comprises at least 10.0% excipient(s) by dry weight. In some embodiments, the unit dosage comprises at least 47.2% excipient(s) by dry weight. In some embodiments, the unit dosage comprises at least 70% excipient(s) by dry weight. In some embodiments, the unit dosage comprises at least 72% excipient(s) by dry weight. In some embodiments, the unit dosage comprises at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more excipient(s) by dry weight. In some embodiments, the unit dosage comprises up to 0.5%, up to 1%, up to 2%, up to 3%, up to 4%, up to 5%, up to 6%, up to 7%, up to 8%, up to 9%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, or up to 95% excipient(s) by dry weight.

[0493] In some embodiments, the unit dosage comprises at least 5.0% of the first excipient and at least 5.0% of the second excipient. In some embodiments, the unit dosage comprises at least 23.75% of the first excipient and at least 23.75% of the second excipient. In some embodiments, the unit dosage comprises at least 36% of the first excipient and at least 36% of the second excipient. In some embodiments, the unit dosage comprises at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more by dry weight. The composition comprises a first excipient and at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more by dry weight of a second excipient.

[0494] In some embodiments, the unit dosage comprises at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more by dry weight of the first excipient and at least 5.0% by dry weight of the second excipient. In some embodiments, the unit dosage comprises at least 5.0% by dry weight of a first excipient and at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more by dry weight of a second excipient.

[0495] In some embodiments, the unit dosage comprises at least 0.1% stabilizer(s) by dry weight. In some embodiments, the unit dosage comprises at least 1.5% stabilizer(s) by dry weight. In some embodiments, the unit dosage comprises at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more stabilizer(s) by dry weight. In some embodiments, the unit dosage comprises up to 0.5%, up to 1%, up to 2%, up to 3%, up to 4%, up to 5%, up to 6%, up to 7%, up to 8%, up to 9%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, or up to 95% stabilizer(s) by dry weight.

[0496] In some embodiments, the unit dosage comprises at least 1.5% adhesive by dry weight, hi some embodiments, the unit dosage comprises at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more adhesive by dry weight. In some embodiments, the unit dosage comprises up to 0.5%, up to 1%, up to 2%, up to 3%, up to 4%, up to 5%, up to 6%, up to 7%, up to 8%, up to 9%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, or up to 95% adhesive by dry weight.

[0497] In some embodiments, the pharmaceutical composition is a spray-dried pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a spray-dried pharmaceutical composition. In some embodiments, the pharmaceutical composition essentially comprises a spray-dried composition.

[0498] definition For convenience, the meanings of some terms and phrases used in the specification, examples, and appended claims are provided below. Unless otherwise stated or implied from the context, the following terms and phrases include the meanings provided below. The definitions are provided to help explain certain embodiments and are not intended to limit the claimed invention, as the scope of the invention is limited only by the claims. Unless otherwise expressly stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of an apparent discrepancy between the use of a term in the art and its definition provided herein, the definition provided in the specification shall prevail.

[0499] For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

[0500] The terms "reduce", "reduced", "reduction", or "inhibit" are all used herein to mean a statistically significant amount of reduction. In some embodiments, "reduce", "reduce", or "reduce" or "inhibit" typically means a reduction of at least 10% compared to a reference level (e.g., the absence of a given treatment or agent), and can include, for example, a reduction of at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reduce" or "inhibit" does not encompass complete inhibition or reduction compared to a reference level. "Complete inhibition" is 100% inhibition compared to a reference level. The decrease is preferably to a level that is accepted as being within the normal range, for example, for individuals without a given disorder.

[0501] The terms "increased," "increase," "enhance," or "activate" are all used herein to mean a statically significant amount of increase. In some embodiments, the terms "increased," "increase," "enhance," or "activate" can mean an increase of at least 10% compared to a reference level, e.g., at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to 100% (including 100%) compared to a reference level, or any increase between 10-100%, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold and 10-fold, or more, compared to a reference level. In the context of a marker or condition, an "increase" is a statistically significant increase in such level.

[0502] As used herein, "subject" means a human or an animal. Typically, an animal is a vertebrate, such as a primate, a rodent, a livestock animal, or a game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys. Rodents include mice, rats, marmots, ferrets, rabbits, and hamsters. Livestock and game animals include cattle, horses, pigs, deer, bison, buffalo, feline species, such as house cats, canine species, such as dogs, foxes, wolves, avian species, such as chickens, emus, ostriches, and fish, such as trout, catfish, and salmon. In some embodiments, the subject is a mammal, such as a primate, such as a human. "Individual," "patient," and "subject" are used interchangeably herein.

[0503] Preferably, the subject is a mammal. The mammal may be, but is not limited to, a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse, or a cow. Mammals other than humans can be advantageously used as subjects representing animal models of chronic bronchopulmonary disease. The subject may be male or female.

[0504] The subject may be a subject who has been previously diagnosed with or identified as suffering from a condition requiring treatment (e.g., chronic bronchopulmonary disease) or one or more complications associated with such a condition, optionally a subject who has already been treated for chronic bronchopulmonary disease or one or more complications associated with chronic bronchopulmonary disease. Alternatively, the subject may be a subject who has not previously been diagnosed with chronic bronchopulmonary disease or one or more complications associated with chronic bronchopulmonary disease. For example, the subject may be a subject who exhibits one or more risk factors for chronic bronchopulmonary disease or one or more complications associated with chronic bronchopulmonary disease, or a subject who does not exhibit risk factors.

[0505] A "subject" in need of treatment for a particular condition can be a subject who has the condition, a subject who has been diagnosed with the condition, or a subject who is at risk for developing the condition.

[0506] As used herein, the terms "treat", "treatment", "treating" or "ameliorating" refer to therapeutic treatment, the purpose of which is to reverse, alleviate, improve, inhibit, slow or stop the progression or severity of a condition associated with a disease or disorder (e.g., chronic bronchopulmonary disease). The term "treat" includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder associated with chronic bronchopulmonary disease. A treatment is generally "effective" if one or more symptoms or clinical markers are alleviated. Alternatively, a treatment is "effective" if the progression of the disease is reduced or stopped. That is, "treatment" includes not only the improvement of symptoms or markers, but also the halting or at least slowing of the progression or worsening of symptoms compared to that expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms, whether detectable or undetectable, reduction in the extent of the disease, a stable (i.e., non-worsening) state of the disease, a delay or slowing of disease progression, improvement or alleviation of the condition, remission (partial or complete), and / or reduced mortality. The term "treatment" of a disease also includes providing relief from the symptoms or side effects of the disease (including palliative treatment).

[0507] The term "pharmaceutical composition" as used herein refers to an active agent in combination with pharma- ceutically acceptable excipients, stabilizers, and / or additives, e.g., excipients, stabilizers, and / or additives commonly used in the pharmaceutical industry. The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problems or complications, within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. In some embodiments of any of the aspects, the pharma-ceutically acceptable excipients, stabilizers, and / or additives may be excipients, stabilizers, and / or additives other than water. In some embodiments of any of the aspects, the pharma-ceutically acceptable excipients, stabilizers, and / or additives may be artificial or engineered excipients, stabilizers, and / or additives (e.g., excipients, stabilizers, and / or additives with which the active ingredient is not found to occur in nature or in nature).

[0508] "Pharmaceutically acceptable" excipients, stabilizers, and / or additives are those that may be reasonably administered to a subject to provide an effective dose of the active ingredient (e.g., a lactic acid-generating compound) being used. In some embodiments, these are excipients that the Federal Drug Administration (FDA) has designated as "Generally Regarded as Safe" (GRAS).

[0509] By "powder" is meant a composition consisting of finely divided solid particles which are relatively free flowing and can be readily dispersed in an inhalation device and then inhaled by a patient, such that the particles are suitable for intranasal or pulmonary administration via the upper respiratory tract.

[0510] "Glass transition temperature" is represented by the symbol T g and is the temperature at which the composition changes from a glassy or vitreous state to a syrupy or rubbery state. g is determined using differential scanning calorimetry (DSC) and is typically taken as the temperature at which the heat capacity (Cp) of a composition begins to change when scanned through a transition. T gThe definition of T has always been arbitrary, and currently there is no international agreement. g can be defined as the beginning, middle, or end of the transition. See CA Angell, "Formation of Glasses from Liquids and Biopolymers," Science, 267, 1924-1935 (Mar. 31, 1995) and Jan P. Wolanczyk, "Differential Scanning Calorimetry Analysis of Glass Transitions," Cryo-Letters, 10, 73-76 (1989). For a detailed mathematical treatment, see Gibbs and DiMarzio, "Nature of the Glass Transition and the Glassy State," Journal of Chemical Physics, 28, No. 3, 373-383 (March, 1958). These articles are incorporated herein by reference.

[0511] A "stable" formulation or composition is one in which the active agent therein (e.g., lactic acid-producing compound) essentially retains its physical stability and / or chemical stability and / or biological activity upon storage. Various analytical techniques for measuring stability are available in the art and are reviewed, for example, in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature and over a selected period of time. Trend analysis can be used to estimate the expected shelf life before the material is actually stored for that period. In some embodiments, the composition is stable at room temperature (~25°C) for at least 3 months, or at least 1 year at about 2-8°C. In some embodiments, the composition is stable after freezing (e.g., at -70°C) and thawing the composition.

[0512] "Unit dosage" or "unit dose" refers to a receptacle containing a therapeutically effective amount of a pharmaceutical composition described herein designed or formulated for administration in a single dose.

[0513] As used herein, the term "administering" refers to the placement of a compound disclosed herein into a subject by a method or route that results in at least partial delivery of the agent at a desired site. A pharmaceutical composition comprising a compound disclosed herein may be administered by any suitable route that results in an effective treatment in the subject. In some embodiments, administration includes physical human activity, such as the act of inhaling, ingesting, and / or operating a delivery device or machine. Such activities may be performed, for example, by a medical professional and / or the subject being treated.

[0514] The terms "statistically significant" or "significantly" refer to statistical significance, generally meaning a difference of 2 standard deviations (2 SD) or greater.

[0515] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as being modified in all instances by the term "about." When used in connection with percentages, the term "about" can mean ±1%.

[0516] As used herein, the term "comprising" means that other elements may be present in addition to the defined elements presented. The use of "comprising" indicates inclusion rather than limitation.

[0517] The term "consisting of" refers to compositions, methods, and their respective components described herein, excluding any element not recited in the description of the embodiment.

[0518] As used herein, the term "consisting essentially of" refers to elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention.

[0519] The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The abbreviation "eg" is derived from the Latin exempli gratia and is used herein to denote a non-limiting example. Thus, the abbreviation "eg" is synonymous with the term "for example."

[0520] Groupings of alternative elements or embodiments of the invention disclosed herein should not be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to include the groups as modified herein to satisfy the written description of all Markush groups used in the appended claims.

[0521] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meaning commonly understood by those skilled in the art to which this disclosure belongs. It is to be understood that the present invention is not limited to the specific methodology, protocols, and reagents, etc. described herein, as such may vary. The terms used herein are for the purpose of describing particular embodiments only, and are not intended to limit the scope of the present invention, which is defined solely by the claims. Definitions of common terms in cell biology, immunology, and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 20th Edition, published by Merck Sharp&Dohme Corp., 2018 (ISBN 0911910190, 978-0911910421), Robert S.Porter et al.(eds.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908), and Robert A.Meyers(ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers,Inc., 1995 (ISBN 1-56081-569-8), Immunology by Werner Luttmann, published by Elsevier, 2006, Janeway's Immunobiology, Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), WWNorton & Company, 2016 (ISBN 0815345054,978-0815345053), Lewin's Genes XI, published by Jones & Bartlett Publishers, 2014 (ISBN-1449659055), Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor,NY,USA(2012)(ISBN 1936113414), Davis et al.,Basic Methods in Molecular Biology,Elsevier Science Publishing,Inc.,New York,USA(2012)(ISBN 044460149X),Laboratory Methods in Enzymology:DNA,Jon Lorsch(ed.)Elsevier,2013(ISBN 0124199542), Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, 2014 (ISBN 047150338X, 9780471503385), Current Protocols in Protein Science (CPPS), John E. Coligan (ed.), John Wiley and Sons, Inc., 2005, and Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), the contents of all of which are incorporated herein by reference in their entireties.

[0522] Other terms are defined herein in the context of the description of various aspects of the invention.

[0523] All patents and other publications, including references, issued patents, published patent applications, and co-pending patent applications, cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that may be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to dates or representations regarding the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the accuracy of the dates or contents of these documents.

[0524] The description of the embodiments of the present disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. Although specific embodiments and examples of the present disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the present disclosure, as will be recognized by those skilled in the relevant art. For example, while method steps or functions are presented in a given order, alternative embodiments may perform the functions in a different order, or the functions may be performed substantially simultaneously. The teachings of the present disclosure provided herein may be applied to other procedures or methods as appropriate. The various embodiments described herein may be combined to provide further embodiments. Aspects of the present disclosure may be modified as appropriate to provide still further embodiments of the present disclosure using the compositions, functions, and concepts of the above references and applications. These and other changes may be made to the present disclosure in light of the detailed description. All such modifications are intended to be within the scope of the appended claims.

[0525] Specific elements of any of the foregoing embodiments may be combined with or substituted for elements of other embodiments. Additionally, although advantages associated with certain embodiments of the present disclosure have been described in connection with those embodiments, other embodiments may also exhibit such advantages, and not all embodiments necessarily must exhibit such advantages, to fall within the scope of the present disclosure.

[0526] Some embodiments of the technology described herein may be defined according to any of the following numbered paragraphs. 1. A pharmaceutical composition comprising: a) i) a polymeric compound capable of producing lactic acid; ii) a non-polymeric compound capable of producing lactic acid, or iii) a lactate-producing compound selected from lactic acid; b) a pharma- ceutically acceptable excipient, stabilizer, or additive; A composition, wherein the composition is formulated for pulmonary administration. 2. The pharmaceutical composition of paragraph 1, wherein the composition is formulated for administration by inhalation. 3. The pharmaceutical composition of paragraph 1 or 2, wherein the lactate-generating compound generates lactate upon delivery to a target tissue. 4. The pharmaceutical composition described in paragraph 3, wherein the target tissue is a target bronchopulmonary tissue. 5. The pharmaceutical composition of paragraph 4, wherein the target bronchiolopulmonary tissue is the lung, trachea, bronchi, bronchioles, and / or alveoli. 6. The pharmaceutical composition described in paragraph 4, wherein the target tissue is a tissue site distal to the lung delivered via the cardiovascular or lymphatic system. 7. The pharmaceutical composition of any one of paragraphs 1-6, wherein the lactic acid-producing compound comprises the D enantiomer of lactic acid, the L enantiomer of lactic acid, or a racemic mixture of the D and L enantiomers of lactic acid. 8. The pharmaceutical composition of any one of paragraphs 1 to 7, wherein the non-polymeric lactic acid producing compound can be metabolized in the target tissue to produce lactic acid. 9. The pharmaceutical composition of any one of paragraphs 1-8, wherein the non-polymeric lactic acid producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide. 10. The pharmaceutical composition of paragraph 9, wherein the inorganic salt of lactic acid is sodium lactate, potassium lactate, calcium lactate, or magnesium lactate. 11. The pharmaceutical composition of paragraph 9, wherein the ester of lactic acid is ethyl lactate, propyl lactate, butyl lactate, pentyl lactate, hexyl lactate, heptyl lactate, octyl lactate, nonyl lactate, decyl lactate, undecyl lactate, or dodecyl lactate. 12. The pharmaceutical composition according to any one of paragraphs 1 to 11, wherein the polymeric lactic acid-producing compound can be hydrolyzed in the target tissue to produce lactic acid. 13. The pharmaceutical composition according to any one of paragraphs 1 to 12, wherein the polymeric lactic acid producing compound is polylactic acid (PLA). 14. The pharmaceutical composition of any one of paragraphs 1 to 13, wherein the polylactic acid is poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), or poly(D-lactide) (PDLA). 15. The pharmaceutical composition of any one of paragraphs 1 to 14, wherein the polylactic acid is poly(D,L-lactide) (PDLLA). 16. The pharmaceutical composition according to any one of paragraphs 1 to 15, wherein the polymeric lactic acid producing compound is poly(lactic-co-glycolic acid) (PLGA). 17. The pharmaceutical composition according to any one of paragraphs 1 to 16, wherein the polymeric lactic acid producing compound is poly(lactic acid-co-caprolactone). 18. The pharmaceutical composition of any one of paragraphs 1 to 17, wherein the composition comprises at least 1.0% by weight of a lactic acid-producing compound. 19. The pharmaceutical composition according to any one of paragraphs 1 to 18, wherein the composition comprises at least one excipient or at least one stabilizer. 20. The pharmaceutical composition according to any one of paragraphs 1 to 19, further comprising at least one excipient. 21. The pharmaceutical composition of any one of paragraphs 1 to 20, further comprising at least two excipients. 22. The pharmaceutical composition according to paragraph 20 or 21, wherein the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, gluco-oligosaccharides, lacto-oligosaccharides, fructo-oligosaccharides, inulin, sodium caseinate, goat milk, cow milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts. 23. The pharmaceutical composition according to any one of paragraphs 20 to 22, wherein the excipient is leucine and / or trehalose. 24. A pharmaceutical composition according to any one of paragraphs 1 to 23, wherein the composition comprises at least 5.0% by weight of an excipient. 25. The pharmaceutical composition of any one of paragraphs 1 to 24, wherein the composition comprises at least 5.0% by weight of the first excipient and at least 5.0% by weight of the second excipient. 26. The pharmaceutical composition of any one of paragraphs 1 to 25, further comprising at least one stabilizer. 27. The pharmaceutical composition according to paragraph 26, wherein the stabilizer comprises a surfactant. 28. The pharmaceutical composition according to paragraph 26 or 27, wherein the stabilizer is selected from the group consisting of mannitol, carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), polysorbate, and poloxamer. 29. The pharmaceutical composition according to paragraph 26 or 27, wherein the stabilizer is a polysorbate, a poloxamer, or a polyvinyl alcohol. 30. The pharmaceutical composition according to any one of paragraphs 26 to 29, wherein the stabilizer is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. 31. The pharmaceutical composition according to any one of paragraphs 26 to 30, wherein the stabilizer is polysorbate 80. 32. The pharmaceutical composition according to any one of paragraphs 26 to 31, wherein the stabilizer is poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 234, poloxamer 235, poloxamer 238, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 403, or poloxamer 407. 33. The pharmaceutical composition according to any one of paragraphs 26 to 32, wherein the stabilizer is poloxamer 188. 34. The pharmaceutical composition of any one of paragraphs 1 to 33, wherein the composition comprises at least 0.10% by weight of a stabilizer. 35. The pharmaceutical composition according to any one of paragraphs 1 to 34, wherein the composition comprises at least one excipient and at least one stabilizer. 36. The pharmaceutical composition according to any one of paragraphs 1 to 35, further comprising at least one of the following: a) a pore former; b) adhesive, c) pH adjusters, and / or d) Ester hydrolysis inducers. 37. The pharmaceutical composition according to paragraph 36, wherein the pore-forming agent is selected from the group consisting of NaCl, sucrose, polyethylene glycol (PEG), and polyvinylpyrrolidone (PVP). 38. The pharmaceutical composition according to paragraph 36, wherein the adhesive is selected from the group consisting of sugars, adhesive polymers, and amine-containing compounds. 39. The pharmaceutical composition according to paragraph 36, wherein the pH adjusting agent is a buffer, an acid, or a base. 40. The pharmaceutical composition of paragraph 36, wherein the ester hydrolysis inducer comprises an amine. 41. The pharmaceutical composition according to any one of paragraphs 1 to 40, further comprising at least one acid generating molecule capable of generating acid, wherein the at least one acid generating molecule is not lactic acid or does not comprise lactic acid. 42. The pharmaceutical composition according to paragraph 41, wherein the acid generating molecule is selected from the group consisting of acetic acid, hydroxy acids, polyfunctional acids, and aromatic acids, and esters, salts, and polymers thereof. 43. The pharmaceutical composition according to paragraph 41, wherein the acid generating molecule is selected from the group consisting of acetic acid, glycolic acid, citric acid, and salicylic acid, and esters, salts, and polymers thereof. 44. The pharmaceutical composition according to any one of paragraphs 41 to 43, wherein the acid generating molecule is acetylsalicylic acid. 45. A pharmaceutical composition according to any one of paragraphs 1 to 45, wherein the composition comprises at least one additional therapeutic agent for chronic bronchopulmonary disorder. 46. ​​The pharmaceutical composition of paragraph 45, wherein the at least one additional therapeutic agent is microencapsulated. 47. The pharmaceutical composition of paragraph 45, wherein the at least one additional therapeutic agent is covalently attached to the lactate-producing compound with a degradable linker. 48. A pharmaceutical composition according to any one of paragraphs 1 to 47, co-administered with at least one additional therapeutic agent for chronic or infectious bronchopulmonary disorders. 49. The pharmaceutical composition of paragraph 48, wherein the at least one additional therapeutic agent is an anti-inflammatory agent, an antibacterial agent, an antiviral agent, an antifungal agent, a vasodilator, or a bronchodilator. 50. The pharmaceutical composition of paragraph 49, wherein the anti-inflammatory agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, glucocorticoids, methotrexate, sulfasalazine, leflunomide, anti-tumor necrosis factor (TNF) agents, cyclophosphamide, inflammation-resolving lipid mediators, mycophenolates, opiates, and barbiturates. 51. The pharmaceutical composition of paragraph 49, wherein the antibacterial agent is selected from the group consisting of aminoglycosides, ansamycins, beta-lactams, bis-biguanides, carbacephems, carbapenems, cationic polypeptides, cephalosporins, fluoroquinolones, glycopeptides, iron-sequestering glycoproteins, linosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidinones, penicillins, polypeptides, quaternary ammonium compounds, quinolones, silver compounds, sulfonamides, and tetracyclines. 52. The pharmaceutical composition according to paragraph 49, wherein the vasodilator is selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and nitric oxide generating compounds. 53. The pharmaceutical composition according to paragraph 49, wherein the bronchodilator is selected from the group consisting of albuterol, levalbuterol, epinephrine, salmeterol, formoterol, ipratropium bromide, tiotropium bromide, theophylline, and aminophylline. 54. The pharmaceutical composition of any one of paragraphs 1 to 53, wherein the composition is formulated as a bolus dose. 55. a) the polymeric lactic acid producing compound and / or the non-polymeric lactic acid producing compound, b) a bolus dose of lactic acid. 56. The pharmaceutical composition of any one of paragraphs 1 to 55, wherein the composition is formulated as a microsphere. 57. The pharmaceutical composition according to paragraph 56, wherein the microspheres have a diameter of at least 1 μm and up to 1 mm. 58. The pharmaceutical composition of any one of paragraphs 1 to 57, wherein the composition comprises a plurality of dry particles. 59. The pharmaceutical composition according to paragraph 58, wherein the dry particles have a Dv50 of at least 0.5 μm. 60. The pharmaceutical composition of paragraph 58 or 59, wherein the dry particles have a median mass aerodynamic diameter (MMAD) of at least 1.5 μm and up to 7.5 μm. 61. The pharmaceutical composition of any one of paragraphs 58 to 60, wherein the dry particles have a median mass aerodynamic diameter (MMAD) of up to 5.0 μm. 62. The pharmaceutical composition of any one of paragraphs 58 to 61, wherein the dry particles have a dispersibility of less than 2.0. 63. The pharmaceutical composition of any one of paragraphs 58 to 62, wherein the dry particles have a dispersibility of at least 0.5 to 1.0. 64. The pharmaceutical composition of any one of paragraphs 58 to 63, wherein the dry particles have a dispersibility of at least 0.9. 65. The pharmaceutical composition of any one of paragraphs 58 to 64, wherein the dry particles have a delivered dose to the target tissue of at least 25.0% by weight and up to 125% by weight of the composition. 66. The pharmaceutical composition of any one of paragraphs 58 to 65, wherein the dry particles have a delivered dose of the lactate-producing compound to a target tissue of at least 30% by weight. 67. The pharmaceutical composition of any one of paragraphs 58 to 66, wherein the dry particles have a delivered dose by mass to a target tissue of at least 7.8 mg per unit dose of the lactate-producing compound. 68. The pharmaceutical composition of any one of paragraphs 58 to 67, wherein the dry particles have a delivered dose by mass to a target tissue of up to 50 mg per unit dose of the lactate-producing compound. 69. The dry particles have a density of at least 0.1 g / cm 3 ~0.8g / cm 3 69. The pharmaceutical composition according to any one of paragraphs 58 to 68, having a bulk density of 70. The dry particles have a density of at least 0.5 g / cm 3 70. The pharma...

Claims

1. 1. A pharmaceutical composition comprising: a) i) a polymeric compound capable of producing lactic acid; ii) a non-polymeric compound capable of producing lactic acid, or iii) a lactate-producing compound selected from lactic acid; b) a pharmaceutically acceptable excipient, stabilizer, or additive; The composition, wherein the composition is formulated for pulmonary administration.

2. 10. The pharmaceutical composition of claim 1, wherein the composition is formulated for administration by inhalation.

3. 10. The pharmaceutical composition of claim 1, wherein the lactate-producing compound produces lactic acid upon delivery to a target tissue.

4. 4. The pharmaceutical composition of claim 3, wherein the target tissue is a target bronchopulmonary tissue.

5. 5. The pharmaceutical composition of claim 4, wherein the target bronchopulmonary tissue is the lung, trachea, bronchi, bronchioles, and / or alveoli.

6. 5. The pharmaceutical composition of claim 4, wherein the target tissue is a tissue site distal to the lung delivered via the cardiovascular or lymphatic system.

7. 10. The pharmaceutical composition of claim 1, wherein the lactate-producing compound comprises the D enantiomer of lactic acid, the L enantiomer of lactic acid, or a racemic mixture of the D and L enantiomers of lactic acid.

8. The pharmaceutical composition of claim 1 , wherein the non-polymeric lactic acid-producing compound can be metabolized in the target tissue to produce lactic acid.

9. 10. The pharmaceutical composition of claim 1, wherein the non-polymeric lactic acid-producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide.

10. 10. The pharmaceutical composition of claim 9, wherein the inorganic salt of lactic acid is sodium lactate, potassium lactate, calcium lactate, or magnesium lactate.

11. 10. The pharmaceutical composition of claim 9, wherein the ester of lactic acid is ethyl lactate, propyl lactate, butyl lactate, pentyl lactate, hexyl lactate, heptyl lactate, octyl lactate, nonyl lactate, decyl lactate, undecyl lactate, or dodecyl lactate.

12. The pharmaceutical composition of claim 1 , wherein the high molecular weight lactic acid-producing compound can be hydrolyzed in the target tissue to produce lactic acid.

13. 2. The pharmaceutical composition of claim 1, wherein the polymeric lactic acid-producing compound is polylactic acid (PLA).

14. 2. The pharmaceutical composition of claim 1, wherein the polylactic acid is poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), or poly(D-lactide) (PDLA).

15. 2. The pharmaceutical composition of claim 1, wherein the polylactic acid is poly(D,L-lactide) (PDLLA).

16. 2. The pharmaceutical composition of claim 1, wherein the polymeric lactic acid-producing compound is poly(lactic-co-glycolic acid) (PLGA).

17. 2. The pharmaceutical composition of claim 1, wherein the polymeric lactic acid-producing compound is poly(lactic acid-co-caprolactone).

18. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least 1.0% by weight of a lactate-producing compound.

19. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least one excipient or at least one stabilizer.

20. 10. The pharmaceutical composition of claim 1, further comprising at least one excipient.

21. 10. The pharmaceutical composition of claim 1, further comprising at least two excipients.

22. 21. The pharmaceutical composition of claim 20, wherein the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, glucooligosaccharides, lacto-oligosaccharides, fructooligosaccharides, inulin, sodium caseinate, goat milk, cow milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts.

23. 21. The pharmaceutical composition of claim 20, wherein the excipient is leucine and / or trehalose.

24. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least 5.0% by weight of an excipient.

25. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least 5.0% by weight of a first excipient and at least 5.0% by weight of a second excipient.

26. 10. The pharmaceutical composition of claim 1, further comprising at least one stabilizer.

27. 27. The pharmaceutical composition of claim 26, wherein the stabilizer comprises a surfactant.

28. 27. The pharmaceutical composition of claim 26, wherein the stabilizer is selected from the group consisting of mannitol, carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), polysorbate, and poloxamer.

29. 27. The pharmaceutical composition of claim 26, wherein the stabilizer is a polysorbate, a poloxamer, or a polyvinyl alcohol.

30. 27. The pharmaceutical composition of claim 26, wherein the stabilizer is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

31. 27. The pharmaceutical composition of claim 26, wherein the stabilizer is polysorbate 80.

32. 27. The pharmaceutical composition of claim 26, wherein the stabilizer is poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 234, poloxamer 235, poloxamer 238, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 403, or poloxamer 407.

33. 27. The pharmaceutical composition of claim 26, wherein the stabilizer is poloxamer 188.

34. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least 0.10% by weight of a stabilizer.

35. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least one excipient and at least one stabilizer.

36. a) a pore-forming agent; b) adhesive; c) a pH adjuster, and / or d) an ester hydrolysis inducer;

37. 37. The pharmaceutical composition of claim 36, wherein the pore-forming agent is selected from the group consisting of NaCl, sucrose, polyethylene glycol (PEG), and polyvinylpyrrolidone (PVP).

38. 37. The pharmaceutical composition of claim 36, wherein the adhesive is selected from the group consisting of a sugar, an adhesive polymer, and an amine-containing compound.

39. 37. The pharmaceutical composition of claim 36, wherein the pH adjusting agent is a buffer, an acid, or a base.

40. 37. The pharmaceutical composition of claim 36, wherein the ester hydrolysis inducer comprises an amine.

41. 10. The pharmaceutical composition of claim 1, further comprising at least one acid-generating molecule capable of generating acid, wherein the at least one acid-generating molecule is not or does not contain lactic acid.

42. 42. The pharmaceutical composition of claim 41, wherein the acid-generating molecule is selected from the group consisting of acetic acid, hydroxy acids, polyfunctional acids, and aromatic acids, and esters, salts, and polymers thereof.

43. 42. The pharmaceutical composition of claim 41, wherein the acid-generating molecule is selected from the group consisting of acetic acid, glycolic acid, citric acid, and salicylic acid, and esters, salts, and polymers thereof.

44. 42. The pharmaceutical composition of claim 41, wherein the acid-generating molecule is acetylsalicylic acid.

45. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least one additional therapeutic agent for chronic bronchopulmonary disorders.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the at least one additional therapeutic agent is microencapsulated.

47. 46. ​​The pharmaceutical composition of claim 45, wherein the at least one additional therapeutic agent is covalently attached to the lactate-producing compound with a degradable linker.

48. 10. The pharmaceutical composition of claim 1, wherein the composition is co-administered with at least one additional therapeutic agent for chronic or infectious bronchopulmonary disorders.

49. 49. The pharmaceutical composition of claim 48, wherein the at least one additional therapeutic agent is an anti-inflammatory agent, an antibacterial agent, an antiviral agent, an antifungal agent, a vasodilator, or a bronchodilator.

50. 50. The pharmaceutical composition of claim 49, wherein the anti-inflammatory agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, glucocorticoids, methotrexate, sulfasalazine, leflunomide, anti-tumor necrosis factor (TNF) drugs, cyclophosphamide, inflammation-resolving lipid mediators, mycophenolate, opiates, and barbiturates.

51. 50. The pharmaceutical composition of claim 49, wherein the antibacterial agent is selected from the group consisting of aminoglycosides, ansamycins, beta-lactams, bis-biguanides, carbacephems, carbapenems, cationic polypeptides, cephalosporins, fluoroquinolones, glycopeptides, iron-sequestering glycoproteins, linosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidinones, penicillins, polypeptides, quaternary ammonium compounds, quinolones, silver compounds, sulfonamides, and tetracyclines.

52. 50. The pharmaceutical composition of claim 49, wherein the vasodilator is selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and nitric oxide-generating compounds.

53. 50. The pharmaceutical composition of claim 49, wherein the bronchodilator is selected from the group consisting of albuterol, levalbuterol, epinephrine, salmeterol, formoterol, ipratropium bromide, tiotropium bromide, theophylline, and aminophylline.

54. 10. The pharmaceutical composition of claim 1, wherein the composition is formulated as a bolus dose.

55. a) a polymeric lactic acid-producing compound and / or a non-polymeric lactic acid-producing compound; b) a bolus dose of lactic acid.

56. 10. The pharmaceutical composition of claim 1, wherein the composition is formulated as a microsphere.

57. 57. The pharmaceutical composition of claim 56, wherein the microspheres have a diameter of at least 1 μm and up to 1 mm.

58. 10. The pharmaceutical composition of claim 1, wherein the composition comprises a plurality of dry particles.

59. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a Dv50 of at least 0.5 μm.

60. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a median mass aerodynamic diameter (MMAD) of at least 1.5 μm and at most 7.5 μm.

61. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a median mass aerodynamic diameter (MMAD) of up to 5.0 μm.

62. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a dispersibility of less than 2.

0.

63. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a dispersibility of at least 0.5 to 1.

0.

64. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a dispersibility of at least 0.

9.

65. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a delivered dose to a target tissue of at least 25.0% and up to 125% by weight of the composition.

66. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a delivered dose of the lactate-producing compound to the target tissue of at least 30% by weight.

67. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a delivered dose of at least 7.8 mg by mass per unit dose of the lactate-producing compound to a target tissue.

68. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a delivery dose of up to 50 mg by mass per unit dose of the lactate-producing compound to the target tissue.

69. The dry particles have a density of at least 0.1 g / cm ３ ~0.8g / cm ３ 59. The pharmaceutical composition of claim 58, having a bulk density of

70. The dry particles have a density of at least 0.5 g / cm ３ 59. The pharmaceutical composition of claim 58, having a bulk density of

71. The dry particles have a density of at least 0.2 g / cm ３ ~1.0 g / cm ３ 59. The pharmaceutical composition of claim 58, having a tap density of

72. The dry particles have a density of at least 0.6 g / cm ３ 59. The pharmaceutical composition of claim 58, having a tap density of

73. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a moisture content of at least 1.0% to 7.0% water by weight.

74. 59. The pharmaceutical composition of claim 58, wherein the dry particles have a moisture content of at least 2.3% water by weight.

75. 10. The pharmaceutical composition of claim 1, wherein the composition is formulated for delivery to the trachea, bronchi, bronchioles, and / or alveoli.

76. 10. The pharmaceutical composition of claim 1, wherein the composition is formulated for pulmonary delivery.

77. 10. The pharmaceutical composition of claim 1, wherein the composition is formulated as a capsule or tablet.

78. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least 7.8 mg of the lactate-producing compound per unit dose deliverable to a target tissue.

79. 10. The pharmaceutical composition of claim 1, wherein the composition comprises at least 15 mg of the lactate-producing compound per unit dose.

80. 80. The pharmaceutical composition of claim 79, wherein the composition is formulated for delivery by an inhaler.

81. 81. The pharmaceutical composition of claim 80, wherein the composition is formulated for delivery by a dry powder inhaler (DPI).

82. 81. The pharmaceutical composition of claim 80, wherein the composition is formulated for delivery by a metered dose inhaler (MDI).

83. 81. The pharmaceutical composition of claim 80, wherein the composition is formulated for delivery by a soft mist inhaler (SMI).

84. The pharmaceutical composition of claim 1 in combination with an inhaler.

85. 1. An inhalation device for bronchopulmonary delivery, comprising: a) an inhaler, and and b) a container containing the pharmaceutical composition of claim 1.

86. 86. The device of claim 85, wherein the inhaler is a dry powder inhaler (DPI).

87. 86. The device of claim 85, wherein the inhaler is a metered dose inhaler (MDI).

88. 86. The device of claim 85, wherein the inhaler is a soft mist inhaler (SMI).

89. The inhaler comprises: a) a mouthpiece including an opening; and b) means for aerosolizing or dispersing the pharmaceutical composition in the container.

90. 1. A method for preparing a spray-dried pharmaceutical composition comprising a lactic acid-producing compound, comprising: a) preparing a liquid raw material containing the lactic acid-producing compound; b) introducing droplets of said liquid feedstock into a drying chamber through a spray nozzle; c) exposing the liquid feedstock droplets to heated and pressurized gas in the drying chamber to produce dried particles; d) isolating dry particles of a predetermined range of diameters in a cyclone chamber, wherein the isolated dry particles comprise the lactic acid-producing compound.

91. 1. A method for preparing a spray-dried pharmaceutical composition comprising a lactic acid-producing compound, comprising: a) obtaining a liquid feedstock containing the lactic acid-producing compound; b) introducing droplets of said liquid feedstock into a drying chamber through a spray nozzle; c) exposing the liquid feedstock droplets to heated and pressurized gas in the drying chamber to produce dried particles; d) isolating dry particles of a predetermined range of diameters in a cyclone chamber, wherein the isolated dry particles comprise the lactic acid-producing compound.

92. 91. The method of claim 90, wherein the step of preparing the liquid ingredient comprises dissolving a solid ingredient in an aqueous solution.

93. 91. The method of claim 90, wherein the step of preparing the liquid feedstock comprises dissolving a solid feedstock in an organic solution.

94. The step of preparing the liquid raw material includes: a) dissolving a lactic acid-producing compound in an organic solution; b) dissolving a solid raw material in an aqueous solution; c) combining the solutions resulting from (a) and (b) to produce a liquid feedstock.

95. The solid raw material is a) at least 50% by weight of a lactic acid-producing compound; b) at least 10% by weight of an excipient, and / or 91. The method of claim 90, comprising: c) at least 1 wt. % of a stabilizer.

96. The solid raw material is a) at least 50% by weight of a lactic acid-producing compound; b) at least 5% by weight of a first excipient; c) at least 5% by weight of a second excipient, and / or d) at least 1 wt. % of a stabilizer.

97. 91. The method of claim 90, wherein the solid feedstock comprises at least 20% and up to 80% by weight of the lactic acid-producing compound.

98. 91. The method of claim 90, wherein the solid ingredient comprises at least 1% and up to 15% by weight of an excipient.

99. 91. The method of claim 90, wherein the solid ingredient comprises at least 2.5% to 7.5% by weight of the first excipient and at least 2.5% to 7.5% by weight of the second excipient.

100. 91. The method of claim 90, wherein the solid feedstock comprises at least 10% and up to 50% by weight of the stabilizer.

101. 91. The method of claim 90, wherein the liquid feedstock comprises at least 0.1 g / L of a solid feedstock dissolved in an aqueous solution.

102. 91. The method of claim 90, wherein the liquid feedstock comprises at least 5 g / L of a solid feedstock dissolved in an aqueous solution.

103. 91. The method of claim 90, wherein the liquid ingredient comprises at least 0.01% and up to 10% of a solid ingredient dissolved in an aqueous solution.

104. 91. The method of claim 90, wherein the liquid ingredient comprises at least 0.5% solid ingredients dissolved in an aqueous solution.

105. 0.5 L of the liquid raw material, a) at least 2.00 g of a lactic acid-producing compound; b) at least 0.80 g of an excipient; c) at least 1.2 g of a stabilizer; d) at least 31.36 g of an organic solution, and / or e) at least 464.64 g of an aqueous solution.

106. 0.5 L of the liquid raw material, a) at least 2.00 g of a lactic acid-producing compound; b) at least 0.40 g of a first excipient; c) at least 0.40 g of a second excipient; d) at least 1.2 g of a stabilizer; e) at least 31.36 g of an organic solution, and / or 91. The method of claim 90, comprising: f) at least 464.64 g of an aqueous solution.

107. 91. The method of claim 90, wherein 0.5 L of the liquid feedstock comprises at least 0.1 g and up to 10 g of a lactic acid-producing compound.

108. 91. The method of claim 90, wherein 0.5 L of the liquid ingredient comprises at least 0.1 g and up to 10 g of excipient.

109. 91. The method of any one of claims 90, wherein 0.5 L of the liquid ingredient comprises at least 0.05 g and up to 5 g of a first excipient and at least 0.05 g and up to 5 g of a second excipient.

110. 91. The method of claim 90, wherein 0.5 L of the liquid feedstock comprises at least 0.1 g and up to 10 g of stabilizer.

111. 91. The method of claim 90, wherein 0.5 L of the liquid feedstock comprises at least 10 g and up to 50 g of organic solution.

112. 91. The method of claim 90, wherein 0.5 L of the liquid feedstock comprises at least 420 g and up to 490 g of aqueous solution.

113. The liquid raw material is a) at least 0.40% of a lactic acid-producing compound; b) at least 0.16% excipients; c) at least 0.24% of a stabilizer; d) at least 6.27% organic solution, and / or e) at least 92.93% aqueous solution.

114. The liquid raw material is a) at least 0.40% by weight of a lactic acid-producing compound; b) at least 0.08% by weight of a first excipient; c) at least 0.08% by weight of a second excipient; d) at least 0.24% of a stabilizer; e) at least 6.27% organic solution, and / or 91. The method of claim 90, comprising: f) at least 92.93% by weight of an aqueous solution.

115. 91. The method of claim 90, wherein the liquid feedstock comprises at least 0.01% and up to 1.0% by weight of a lactic acid-producing compound.

116. 91. The method of claim 90, wherein the liquid ingredient comprises at least 0.01% and up to 10% by weight of an excipient.

117. 91. The method of claim 90, wherein the liquid ingredient comprises at least 0.005% to a maximum of 5% by weight of a first excipient and at least 0.005% to a maximum of 5% by weight of a second excipient.

118. 91. The method of claim 90, wherein the liquid feedstock comprises at least 0.01% and up to 1.0% by weight of a stabilizer.

119. 91. The method of claim 90, wherein the liquid feedstock comprises at least 1% and up to 5% by weight of an organic solution.

120. 91. The method of claim 90, wherein the liquid feedstock comprises at least 90% and up to 99.9% by weight of an aqueous solution.

121. The lactic acid-producing compound a) a polymeric compound capable of producing lactic acid; b) a non-polymeric compound capable of producing lactic acid, or c) lactic acid.

122. 91. The method of claim 90, wherein the non-polymeric lactic acid-producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide.

123. 91. The method of claim 90, wherein the polymeric lactic acid-producing compound is polylactic acid (PLA).

124. 91. The method of claim 90, wherein the polylactic acid is poly(D,L-lactide) (PDLLA).

125. 91. The method of claim 90, wherein the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, glucooligosaccharides, lacto-oligosaccharides, fructooligosaccharides, inulin, sodium caseinate, goat milk, cow milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts.

126. 91. The method of claim 90, wherein the excipient is leucine and / or trehalose.

127. 91. The method of claim 90, wherein the stabilizer is a polysorbate, a poloxamer, or a polyvinyl alcohol.

128. 91. The method of claim 90, wherein the stabilizer is poloxamer 188.

129. 91. The method of claim 90, wherein the organic solution is acetone.

130. 91. The method of claim 90, wherein the aqueous solution is water.

131. 91. The method of claim 90, wherein the liquid feedstock further comprises at least one additional therapeutic agent.

132. 132. The method of claim 131, wherein the at least one additional therapeutic agent is selected from the group consisting of anti-inflammatory agents, antibacterial agents, antiviral agents, antifungal agents, vasodilators, and bronchodilators.

133. 91. The method of claim 90, wherein the spray nozzle into the drying chamber has a diameter of at least 1.2 mm.

134. 91. The method of claim 90, wherein the droplets of liquid feedstock produced by the spray nozzle into the drying chamber have a diameter of at least 1.2 um.

135. 91. The method of claim 90, wherein the droplets of liquid feedstock have a flow rate through the drying chamber of at least 5 g / min.

136. 91. The method of claim 90, wherein the droplets of liquid feedstock have a flow rate through the drying chamber of at least 15 g / min.

137. 91. The method of claim 90, wherein the droplets of liquid feedstock have a flow rate through the drying chamber of up to 1000 g / min.

138. 91. The method of claim 90, wherein the heated pressurized gas is heated before being introduced into the drying chamber.

139. 91. The method of claim 90, wherein the heated pressurized gas is introduced into the drying chamber at a temperature of at least 100°C.

140. 91. The method of claim 90, wherein the heated pressurized gas is introduced into the drying chamber at a temperature of at least 135°C.

141. 91. The method of claim 90, wherein the heated pressurized gas is introduced into the drying chamber at a temperature of up to 195°C.

142. 91. The method of claim 90, wherein the heated pressurized gas is discharged from the drying chamber at a temperature of at least 40°C.

143. 91. The method of claim 90, wherein the heated pressurized gas is discharged from the drying chamber at a temperature of at least 60°C.

144. 91. The method of claim 90, wherein the heated pressurized gas is discharged from the drying chamber at a temperature of up to 85°C.

145. 91. The method of claim 90, wherein the heated pressurized gas is pressurized before being introduced into the drying chamber.

146. 91. The method of claim 90, wherein the heated pressurized gas in the drying chamber has an atomizing gas pressure of at least 10 pounds per square inch gauge (psig).

147. 91. The method of claim 90, wherein the heated pressurized gas in the drying chamber has an atomizing gas pressure of at least 20 pounds per square inch gauge (psig).

148. 91. The method of claim 90, wherein the heated pressurized gas in the drying chamber has an atomizing gas pressure of up to 150 pounds per square inch gauge (psig).

149. 91. The method of claim 90, wherein the heated pressurized gas has a flow rate through the drying chamber of at least 5 kg / hr.

150. 91. The method of claim 90, wherein the heated pressurized gas has a flow rate through the drying chamber of at least 18 kg / hr.

151. 91. The method of claim 90, wherein the heated pressurized gas has a flow rate through the drying chamber of up to 150 kg / hr.

152. 91. The method of claim 90, wherein the heated pressurized gas is discharged through the cyclone chamber.

153. 91. The method of claim 90, wherein exposing the liquid feedstock droplets to heated and pressurized gas in the drying chamber takes up to 8 hours.

154. 91. The method of claim 90, wherein the dried particles isolated in the cyclone chamber have a mass median aerodynamic diameter (MMAD) of at least 1.5 μm and up to 7.5 μm.

155. 91. The method of claim 90, wherein the dry particles isolated in the cyclone chamber have a mass median aerodynamic diameter (MMAD) of at least 4.0 μm.

156. 91. The method of claim 90, wherein the dried particles isolated in the cyclone chamber have a median mass aerodynamic diameter (MMAD) of up to 5.0 μm.

157. 91. The method of claim 90, wherein the step of isolating dry particles of a predetermined range of diameters in the cyclone chamber is performed continuously.

158. A unit dosage form comprising at least 1.0 mg and up to 100.0 mg of a pharmaceutical composition comprising a lactic acid-producing compound.

159. 10. A unit dosage form comprising at least 1.0 mg and up to 100.0 mg of the pharmaceutical composition of claim 1.

160. 91. A unit dosage form comprising at least 1.0 mg and up to 100.0 mg of the spray-dried pharmaceutical composition prepared by the method of claim 90.

161. A unit dosage form comprising a pharmaceutical composition comprising at least 15 mg of a lactate-producing compound per unit dose of at least 15.0 mg up to 100.0 mg.

162. 159. The unit dosage form of claim 158, wherein the dosage is at least 1.0 mg of the pharmaceutical composition.

163. 159. The unit dosage form of claim 158, wherein the dosage comprises at least 7.8 mg of lactic acid-producing compound per unit dose deliverable to a target tissue.

164. 159. The unit dosage form of claim 158, wherein the dosage comprises at least 15 mg of lactic acid-producing compound per unit dose.

165. 159. The unit dosage form of claim 158, wherein the pharmaceutical composition is a spray-dried pharmaceutical composition.

166. 1. A pharmaceutical composition comprising: a) a lactic acid-producing compound; b) a pharmaceutically acceptable excipient, stabilizer, or additive; A pharmaceutical composition, wherein the composition is formulated for oral administration.

167. The lactic acid-producing compound a) a polymeric compound capable of producing lactic acid; b) a non-polymeric compound capable of producing lactic acid, or c) lactic acid.

168. The pharmaceutical composition of claim 166, wherein the non-polymeric lactic acid-producing compound is an inorganic salt of lactic acid, an ester of lactic acid, or lactide.

169. The pharmaceutical composition of claim 166, wherein the polymeric lactic acid-producing compound is polylactic acid (PLA).

170. 170. The pharmaceutical composition of claim 169, wherein the polylactic acid is poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), or poly(D-lactide) (PDLA).

171. 167. The pharmaceutical composition of claim 166, wherein the composition comprises at least one excipient or at least one stabilizer.

172. 172. The pharmaceutical composition of claim 171, wherein the excipient is selected from the group consisting of De Man, Rogosa and Sharpe (MRS) growth medium, gelatin, whey isolate, sweet whey, reconstituted skim milk powder, maltodextrin, glucooligosaccharides, lacto-oligosaccharides, fructooligosaccharides, inulin, sodium caseinate, goat milk, cow milk, proline, carnitine, acetylcarnitine, propionylcarnitine, glutamate, glycine betaine, glycogen, trehalose, mannose, xylose, mannitol, sorbitol, maltose, dextrose, starch, lactose, sucrose, glucose, leucine, trileucine, sodium salts, potassium salts, lithium salts, and calcium salts.

173. 172. The pharmaceutical composition of claim 171, wherein the excipient is leucine and / or trehalose.

174. 172. The pharmaceutical composition of claim 171, wherein the stabilizer is a polysorbate, a poloxamer, or a polyvinyl alcohol.

175. 172. The pharmaceutical composition of claim 171, wherein the stabilizer is poloxamer 188.

176. 172. The pharmaceutical composition of claim 171, wherein the additive is an adhesive.

177. 167. The pharmaceutical composition of claim 166, wherein the composition comprises a plurality of dry particles.

178. 167. The pharmaceutical composition of claim 166, wherein the composition comprises a plurality of spray-dried particles.

179. 167. The pharmaceutical composition of claim 166, wherein the composition is formulated as a capsule or tablet.

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