Composition for inhalation

Abstract

The present invention discloses a pharmaceutical composition in the form of a solution comprising a combination of budesonide (or a pharmaceutically acceptable salt thereof) and formoterol (or a pharmaceutically acceptable salt 5 thereof), optionally in further combination with glycopyrronium (or a pharmaceutically acceptable salt thereof), dissolved in a hydrofluoroalkane (HFA) and / or hydrofluoroolefin (HFO) propellant and anhydrous ethanol to provide an extrafine aerosol suitable for administration via a pressurized metered-dose inhaler (pMDI) for the treatment of asthma, chronic obstructive pulmonary disease 10 (COPD), and other respiratory disorders.

Description

COMPOSITION FOR INHALATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Indian Patent Application No.202521077126, filed August 13, 2025, and Indian Patent Application No.202521005306, filed January 22, 2025, the contents of which are incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The present invention relates to pharmaceutical compositions for inhalation administration, particularly pressurized metered-dose inhaler (pMDI) formulations comprising extra-fine particles of budesonide, formoterol, and optionally glycopyrronium, in a hydrofluoroalkane (HFA) and / or hydrofluoroolefin (HFO) propellant system, suitable for the treatment of asthma, chronic obstructive pulmonary disease (COPD), and other respiratory disorders and for providing therapeutically effective treatment at reduced doses of budesonide and formoterol compared to existing commercial products.BACKGROUND OF THE INVENTION

[0003] Asthma, a prevalent respiratory disease, is marked by recurrent wheezing and variable airflow limitation and is now recognized as a chronic inflammatory disorder of the airways, which remains incompletely controlled in a substantial proportion of patients despite advances in therapy. Historically, bronchoconstriction of airway smooth muscle was thought to be the primary mechanism; however, the recognition of asthma as a chronic inflammatory disease has led to a fundamental shift in its management. Inflammation of the airways can cause structural alterations and mucosal damage, leading to airway remodeling and irreversible airway narrowing. Therefore, the goal of therapy should be to manage symptoms to enable a normal life while also treating the underlying inflammation. Chronic obstructive pulmonary disease (COPD) is another respiratory conditionwhose prevalence is rising globally. COPD is characterized by persistent airflow limitation and is commonly caused by emphysema and / or chronic bronchitis and is associated with progressive decline in lung function, frequent exacerbations, and substantial morbidity and mortality.

[0004] In 2001, formoterol, an inhaled beta2-agonist, received approval for use in the United States for the treatment of asthma and COPD. Consequently, treatment guidelines for asthma suggest using formoterol for both maintenance and relief therapy. It can be purchased as a single entity product and in various formulations in combination with long-acting muscarinic antagonists and inhaled corticosteroids. The FDA approved budesonide on February 14, 1999. Budesonide is an antiinflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity, and is used to treat inflammatory conditions of the lungs such as asthma and COPD, typically as part of maintenance inhalation therapy.

[0005] The aerodynamic size distribution of the inhaled particles is a significant factor in determining the location of droplets or particle deposition in the patient's lungs during the development of a therapeutic aerosol. Three physical mechanisms play a major role in lung particle deposition: (i) impaction, which is a function of particle inertia; (ii) sedimentation caused by gravity; and (iii) diffusion, which is the result of fine, submicrometer (< 1 micron) particles moving in a Brownian motion. Which of the three primary mechanisms is dominant depends on the mass of the particles. Administration of “extra-fine” aerosols, i.e., drug delivery particles with a mass median aerodynamic diameter (MMAD) of up to about 0.8 - 3.5 pm (e.g., about 1-2 pm), can enhance deposition in the small peripheral airways and improve treatment of distal lung disease.

[0006] SYMBICORT is available as a metered-dose inhaler containing a combination of budesonide (80 or 160 pg) and formoterol (4.5 pg) as an inhalation aerosol in the following two strengths: 80 / 4.5 and 160 / 4.5. Each dosage strength contains 60 or 120 actuations per canister. However, these conventional products are formulated as suspensions and typically require relatively high nominal dosesof budesonide and formoterol to achieve consistent deep-lung delivery and therapeutic effect.

[0007] FORACORT is available as a pressurized metered-dose inhaler (pMDI) containing a combination of budesonide (400 pg or 200 pg) and formoterol (6 pg) as an inhalation aerosol in the following two strengths: 200 / 6 and 400 / 6. Each dosage strength contains 60 or 120 actuations per canister. Like SYMBICORT, FORACORT is a suspension-based pMDI that relies on relatively high drug loading and is susceptible to sedimentation and potential dose non-uniformity if not adequately shaken before use.

[0008] In the prior art HFA solution formulations of beta-2-agonists for aerosol delivery through pressurized metered-dose inhalers have been disclosed In EP1480615 the applicant disclosed delivery of medication using a pressurized metered-dose inhaler (pMDI) with a suitable shelf-life. It contains formoterol as the active ingredient, an HFA propellant, and an appropriate amount of anhydrous ethanol as a co-solvent. The active ingredient is dissolved in the propellantcosolvent system, and the formulation contains less than 1,500 parts per million (ppm) of residual water based on the total weight. The solution, when actuated, can generate a fraction of particles that are equal to or smaller than 1.1 micron, with a minimum of 30% as determined by the S6-AF content stages of an Andersen Cascade Impactor, relative to the total amount of fine particle dose collected in the S3-AF stages. However, EP1480615 is limited to single-API formoterol solutions and does not disclose or suggest true solution formulations containing both budesonide and formoterol, let alone ternary combinations with glycopyrronium, at therapeutically relevant concentrations.

[0009] The present invention provides highly efficient formoterol formulations further comprising a steroid and / or a long-acting muscarinic antagonist. The high fraction of extrafine particles in these formulations enhances deposition to the small peripheral airways, where the synergistic effects of both drugs can be maximized in distal lung diseases. Moreover, such formulations enable fixed combinations offormoterol and a steroid wherein the formoterol and / or steroid are each present in a lower dose while maintaining therapeutic performance comparable to higher-dose suspension reference products.

[0010] The present invention fills this gap by offering a patient in need a combination composition of budesonide, formoterol and / or glycopyrronium. The combination composition of the present invention also exhibits substantially the same efficacy and reduces the toxicity of high doses of formoterol by lowering the dose.SUMMARY OF THE INVENTION

[0011] The present invention provides a pressurized pharmaceutical composition for inhalation comprising an inhaled corticosteroid, specifically budesonide, a long-acting beta-2 agonist LABA, specifically formoterol or a pharmaceutically acceptable salt or ester thereof, and optionally a long-acting muscarinic antagonist LAMA such as glycopyrronium or a pharmaceutically acceptable salt thereof, formulated as a physically stable, optically clear solution in a propellant-cosolvent system. Notably, the invention encompasses compositions where budesonide the corticosteroid and formoterol the LABA are both substantially dissolved in a selected propellant-cosolvent system, with the optional addition of glycopyrronium the LAMA, thereby providing a single-phase, optically clear true solution suitable for delivery by a pressurized metered dose inhaler pMDI without the need for shaking prior to actuation.

[0012] In certain preferred embodiments, the inhaled corticosteroid is budesonide, the LABA is formoterol or a pharmaceutically acceptable salt or ester thereof (e.g., formoterol fumarate), and the optional LAMA is glycopyrronium or a pharmaceutically acceptable salt thereof (e.g., glycopyrronium bromide), the actives being substantially dissolved in a hydrofluoroalkane (HFA) or hydrofluoroolefin (HFO) propellant with anhydrous ethanol and acid to afford an optically clear, true solution suitable for delivery via a pressurized metered dose inhaler (pMDI). In certain embodiments, budesonide, formoterol e.g., formoterolfumarate, and, where present, glycopyrronium e.g., glycopyrronium bromide, are substantially dissolved in one or more hydrofluoroalkane HFA and / or hydrofluoroolefin HFO propellants, together with anhydrous ethanol and an acid such as hydrochloric acid, thereby providing a single -phase, optically clear solution suitable for delivery by a pressurized metered dose inhaler pMDI without the need for shaking prior to actuation.

[0013] A distinguishing aspect of the invention is the ability to achieve and maintain true solution formulations, even at therapeutically relevant concentrations of budesonide, formoterol, and optionally glycopyrronium, which are conventionally regarded as sparingly soluble in propellant-based vehicles. The compositions employ HFA and / or HFO propellants, anhydrous ethanol as a cosolvent, a mineral acid for pH adjustment, and, in some embodiments, a co-solvent such as glycerol in defined concentration ranges to preserve single -phase solution behavior over the intended shelf life.

[0014] By employing active pharmaceutical ingredients with controlled, reduced particle size in combination with defined ranges of ethanol, acid, and propellant, the compositions can remain as single-phase solutions across the intended shelflife, in contrast to conventional suspension-based inhalation products. By using active pharmaceutical ingredients having controlled, reduced particle size distributions together with specified ranges of ethanol, acid, and propellant, the compositions remain as single -phase solutions with no visible precipitate or suspended particulate over extended storage, in contrast to conventional suspension-based inhalation products that are prone to sedimentation and dose non-uniformity and typically require shaking prior to use.

[0015] Due to the substantial dissolution of actives, the compositions exhibit physical stability and generate aerosols with a high fraction of extra-fine particles (mean diameter approximately 1 micron or less) during actuation. This enables enhanced delivery and deposition of active drug in the peripheral (distal) airways of the lungs, which is relevant for the effective treatment of asthma, COPD, andrelated respiratory diseases. Because the actives are substantially dissolved, the compositions exhibit improved physical stability and, upon actuation, generate aerosols having a desired mass median aerodynamic diameter MMAD with a high fraction of extra-fine particles, thereby enhancing delivery and deposition of drug in the small peripheral airways for the treatment or prevention of asthma, chronic obstructive pulmonary disease COPD, and other obstructive or inflammatory respiratory disorders.

[0016] In particular embodiments, actuation from a pMDI produces aerosols with an MMAD of about 1.0- 1.2 pm and an extra-fine particle fraction greater than 50% by mass, thereby increasing deep-lung deposition relative to reference suspension formulations such as SYMBICORT 160 / 4.5 and FORACORT 200 / 6 or 400 / 6.

[0017] In various embodiments, these solution formulations are configured to provide therapeutic performance that is substantially comparable to that of selected suspension-based inhalation products at one or more lower nominal doses of formoterol and / or budesonide. By reducing the total drug load while maintaining desired pharmacodynamic effects, the inventive compositions can, in certain embodiments, contribute to a reduction in exposure -related adverse effects associated with higher corticosteroid and beta-2 agonist dosing, for example by enabling reduced ex-actuator doses of budesonide and / or formoterol while targeting pharmacodynamic performance comparable to higher-dose suspension reference products. In some embodiments, the solution formulations are designed to provide therapeutic efficacy substantially comparable to that of commercially available budesonide-formoterol suspension products at lower nominal amounts and exactuator doses of budesonide and / or formoterol, which may assist in reducing overall drug load while preserving clinical performance and may reduce the occurrence, frequency, and / or severity of corticosteroid- and beta-2 agonist-associated adverse effects relative to higher-dose suspension-based reference products.

[0018] The invention further embraces fixed-dose combinations of budesonide, formoterol, and glycopyrronium, as well as methods of treating respiratory diseases using such compositions, achieving in certain embodiments improvements in uniformity, stability, delivery efficiency, and safety compared to conventional formulations. The invention further encompasses fixed-dose binary combinations of budesonide and formoterol and ternary combinations of budesonide, formoterol, and glycopyrronium, as well as methods of treating or preventing respiratory diseases by administering such compositions by oral inhalation from a pMDI, thereby providing in some embodiments improved dose uniformity, physical stability, delivery efficiency, and safety relative to conventional suspension formulations.

[0019] In some embodiments, the invention provides use of these fixed-dose solution formulations in the treatment or prevention of asthma, COPD, or other obstructive or inflammatory respiratory disorders in a subject in need thereof, by administering one or more actuations of the pMDI to deliver therapeutically effective, extra-fine aerosols of budesonide, formoterol, and optionally glycopyrronium. In some embodiments, one or more actuations of the pMDI deliver a therapeutically effective amount of extra-fine aerosol containing budesonide and formoterol, with or without glycopyrronium, wherein the ex-actuator doses of budesonide and formoterol are selected within defined ranges e.g., about 25-200 pg and about 1.5-5.7 pg, respectively, to achieve a level of efficacy comparable to SYMBICORT 160 / 4.5, FORACORT 200 / 6, or FORACORT 400 / 6 while employing lower nominal drug loading. In further embodiments, the ex-actuator doses of budesonide and formoterol are selected such that the composition provides therapeutic efficacy substantially comparable to a reference suspension product selected from SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6 while employing lower nominal amounts of budesonide and / or formoterol.

[0020] In developing the present invention, it was discovered that, by employing selected excipients within defined concentration ranges, true solution formulations (as opposed to suspensions) of combinations of active pharmaceutical ingredients(APIs) (e.g., budesonide and formoterol) can be obtained, even at therapeutically relevant concentrations. APIs prepared with a small and substantially uniform particle size distribution further facilitate complete dissolution within solvent systems comprising an acid (e.g., IN hydrochloric acid) and a polar solvent such as anhydrous ethanol, in combination with one or more propellants such as HFA152a, HFO-1234ze, or HFA134a.

[0021] This outcome is advantageous. It was found that, by combining budesonide, formoterol, and optionally glycopyrronium with anhydrous ethanol, a mineral acid, and one or more propellants such as HFA152a, HFO-1234ze, or HFA134a, and by controlling API particle size prior to dissolution, true solution formulations can be obtained and maintained at practical, therapeutically relevant concentrations.

[0022] Traditionally, APIs such as budesonide and formoterol are regarded as sparingly soluble in standard HFA propellant / cosolvent systems at therapeutically relevant concentrations when used as bulk drug in conventional formulations, which has necessitated suspension-based inhaler products. Such suspensions are prone to sedimentation, require high drug loading to ensure dose uniformity, and are susceptible to dosing inconsistency due to the risk of incomplete resuspension during patient use. Traditional budesonide-formoterol inhalers are typically formulated as suspensions because of the limited solubility of these APIs in conventional propellant / co-solvent systems, which can lead to sedimentation, the need for relatively high drug loading, and potential dosing inconsistency if the product is not adequately shaken. The inventive solution formulations overcome these limitations by eliminating suspended particulate, thereby improving dose reproducibility and enabling lower total drug content per canister.

[0023] In contrast, the inventive formulations achieve complete dissolution of APIs, leading to optically clear, physically stable solutions. In the disclosed formulations, it was found that APIs such as budesonide and formoterol could be completely dissolved at therapeutically relevant concentrations when combined with selected HFA / HFO propellants, anhydrous ethanol, and acid, and whenintroduced with a controlled reduced particle size, which facilitates dissolution by increasing surface area and enhancing interaction with the solvent system. This represents a marked improvement over traditional suspension-based products, in which these APIs remain sparingly soluble under standard propellant / co-solvent conditions and are typically formulated as suspensions. This configuration expedites dissolution and permits substantial solubilization of the actives at the therapeutically relevant concentrations disclosed herein. In particular, the formulations provide optically clear, physically stable solutions in which the APIs are substantially dissolved within the specified budesonide and formoterol concentration ranges, with the reduced initial particle size contributing to efficient dissolution and sustained solubilization at these target strengths.

[0024] The use of a true solution instead of a suspension offers several benefits. Firstly, dose uniformity is markedly improved, as each actuation consistently delivers the intended therapeutic dose without the risk of inhomogeneity or agglomerate formation. As a result, the required amount of each active ingredient can be significantly reduced while still achieving therapeutic efficacy, minimizing unnecessary exposure. Use of a true solution rather than a suspension affords several advantages, including markedly improved dose uniformity per actuation, reduced risk of inhomogeneity or particle agglomeration, and the ability to lower the amount of each active ingredient while preserving therapeutic efficacy and reducing unnecessary systemic exposure.

[0025] This reduction in total drug load is anticipated to lower the incidence of adverse effects associated with higher systemic or local doses of corticosteroids and beta-agonists Moreover, the full dissolution of APIs and the resulting physical stability permit the generation of aerosol droplets with a consistently small and uniform mass median aerodynamic diameter (MMAD). The reduction in budesonide and / or formoterol dose is expected to decrease the incidence and / or severity of adverse effects associated with higher systemic or local corticosteroid and LABA exposure, while full dissolution of the APIs supports the generation ofaerosol droplets with consistently small and uniform MMAD values in the extrafine range.

[0026] This is supported by preliminary in vitro aerosol characterization, which demonstrates that these extra- fine particles are more likely to reach and be deposited in the small airways and distal regions of the lungs — sites particularly relevant to disease pathology in asthma and COPD. Enhanced peripheral deposition increases local drug concentrations at the site of action and improves clinical efficacy, even at lower nominal doses. In vitro aerosol characterization demonstrates that the resulting extra-fine particles preferentially reach and deposit in the small airways and distal lung regions, which are sites of key pathological involvement in asthma and COPD, thereby increasing local drug concentrations and supporting clinical efficacy at reduced nominal doses.

[0027] In some embodiments, administration of the budesonide-formoterol pressurized inhalation solution one or more times daily in a dosing regimen that delivers ex-actuator doses of budesonide within about 25-200 pg per actuation and formoterol within about 1.5-5.7 pg per actuation provides therapeutic efficacy substantially comparable to that of a reference suspension product selected from SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6, while employing a reduced total nominal drug load of budesonide and / or formoterol in the canister.

[0028] In some embodiments, one or more actuations of the pressurized metered dose inhaler deliver ex-actuator doses of budesonide in the range of about 25-200 pg per actuation and ex-actuator doses of formoterol in the range of about 1.5-5.7 pg per actuation, and the total daily dose is selected so that therapeutic efficacy is substantially comparable to that of a budesonide-formoterol suspension inhaler having the same labeled strengths, such as SYMBICORT 160 / 4.5 or FORACORT 200 / 6 or 400 / 6.

[0029] In such embodiments, systemic exposure to at least one of budesonide or formoterol, as determined by Cmax and / or AUC, is reduced to not more than aboutproduct at its labeled dose, reflecting a reduced systemic exposure at comparable efficacy.

[0030] In further embodiments, such regimens provide systemic exposure to budesonide and / or formoterol, as assessed by Cmax and / or AUC, that is reduced relative to that produced by the reference suspension product at its labeled dose, while maintaining substantially the same efficacy.

[0031] In particular embodiments, systemic exposure to budesonide for the inventive solution formulations, as measured by Cmax and AUC, is not more than about 85% of the budesonide Cmax and AUC values observed with a reference budesonide-formoterol suspension inhaler at its labeled dose, while therapeutic efficacy remains substantially comparable to that of the reference suspension product.

[0032] The achievement of a physically and chemically stable inhalation solution containing substantially dissolved APIs, enabled by both optimized excipient concentrations and the small particle size of the APIs, was neither predicted nor suggested by the prior art in at least certain embodiments. These advances allow for (a) reduced total drug load, (b) improved dose consistency and safety profile, (c) enhanced deep lung delivery and efficacy, and (d) superior formulation stability and ease of use over traditional suspension-based approaches. The combination of optimized excipient concentrations and controlled API particle size yields physically and chemically stable inhalation solutions that were not predicted by prior suspension-based systems, and confers reduced total drug load, improved dose consistency and safety, enhanced deep-lung delivery and efficacy, and superior formulation stability and ease of use compared with traditional products, enabling a potential for reduced occurrence, frequency, and / or severity of a broad range of adverse effects associated with higher-dose budesonide-formoterol therapies.

[0033] These adverse effects include: upper respiratory tract infections (URTIs) such as cough, nasal congestion, sore throat, and sinus infections; headache; throatpain or irritation; stomach discomfort, nausea, or vomiting; back pain; oral thrush (white patches in the mouth or throat); voice changes or loss of voice; cold symptoms (stuffy or runny nose, sneezing, sinus pain); muscle aches; adrenal suppression or insufficiency (characterized by fatigue, low blood pressure, and weakness); increased risk of pneumonia; fast, irregular, or pounding heartbeat; high blood sugar (hyperglycemia); low blood potassium (hypokalemia) with associated muscle cramps and irregular heart rhythm; bone loss (reduced bone mineral density and risk of osteoporosis with long-term use); eye problems including glaucoma, cataracts, and vision changes; slowed growth in children; allergic reactions (rash, itching, swelling, and trouble breathing); paradoxical bronchospasm (sudden worsening of breathing); seizures; and increased risk of infections, when subjects are treated using the inventive compositions instead of the specified reference suspension products such as SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6.

[0034] In additional embodiments, the pressurized pharmaceutical compositions further comprise a long-acting muscarinic antagonist such as glycopyrronium, present for example at a concentration of about 0.01-0.03% w / w, wherein the glycopyrronium is also substantially dissolved in the propellant-co- solvent system. Representative ternary solution formulations containing budesonide, formoterol, and glycopyrronium within the concentration ranges described herein were filled into pMDI canisters and stored under ICH long-term conditions at 25 °C / 60% relative humidity for at least 12 weeks. Throughout this storage period, the ternary formulations remained optically clear, single-phase solutions with no visible precipitate or suspended particulate attributable to any of the active ingredients, including glycopyrronium, when examined under normal laboratory viewing conditions. Assay values for each active, including glycopyrronium, remained within predefined acceptance criteria, related substances / impurities for all actives remained within limits consistent with ICH guidelines, pH remained within the specified range, and dose uniformity and aerodynamic particle size distribution were maintained within target ranges.

[0035] The present invention provides pressurized metered dose inhaler (pMDI) solution formulations that differ fundamentally from conventional suspensionbased products such as SYMBICORT and FORACORT, as well as from the formoterol HFA solution systems described in EP1480615. In particular, the invention discloses “true solution” combinations of budesonide and formoterol, optionally further comprising glycopyrronium, in selected hydrofluoroalkane and hydrofluoroolefin propellants (including HFA134a, HFA152a, HFO-1234ze and HFO-1234yf) and defined co-solvent / acid systems that enable complete dissolution of the active pharmaceutical ingredients at therapeutically relevant concentrations. By employing APIs with controlled, reduced particle size and formulating them as optically clear, physically stable solutions, the disclosed compositions generate aerosols with a desired mass median aerodynamic diameter MMAD (e.g., 0.8-3.5 pm, such as 1.0-1.2 pm) and a high fraction of extra-fine particles (e.g., > 50% by mass), thereby enhancing deposition in the small peripheral airways. As a result, these solution formulations achieve target ex-actuator dose ranges comparable to or lower than those of reference suspension products such as SYMBICORT 160 / 4.5 or FORACORT 200 / 6 and 400 / 6, while allowing for reduced nominal drug loading and an improved safety profile without compromising therapeutic efficacy.

[0036] Accordingly, the invention provides pMDI solution formulations that differ fundamentally from conventional suspension-based budesonide-formoterol products such as SYMBICORT and FORACORT, and from single- API formoterol solution systems such as those described in EP1480615, by offering true solution combinations of budesonide and formoterol, with or without glycopyrronium, in specified HFA / HFO propellant and co-solvent / acid systems that enable complete dissolution at therapeutically relevant strengths and deliver extra-fine aerosols at reduced drug loadings while preserving or improving safety and efficacy profiles.DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention relates to solution formulations for inhalation administration, particularly those comprising a combination of formoterol (a long-acting beta-2 agonist), budesonide (an inhaled corticosteroid), and optionally glycopyrronium (a long-acting muscarinic antagonist) in a propellant-based pressurized metered dose inhaler (pMDI).

[0038] The formulations of the invention are characterized by the substantial dissolution of both formoterol and budesonide in the propellant / co solvent system, resulting in optically clear, physically stable solutions as opposed to conventional suspensions. Through this approach, the formulations exhibit a consistent and reproducible aerodynamic particle size distribution in the aerosolized spray upon actuation.

[0039] In certain embodiments, the formulation contains formoterol at a concentration of 0.002% to 0.0166% w / w, budesonide at a concentration of 0.03% to 0.71% w / w, and, where present, glycopyrronium at a range of 0.01% to 0.03% w / w. Anhydrous ethanol is used as a solvent (co-solvent) at a concentration between 8% and 20% w / w, with a mineral acid, typically hydrochloric acid, added in an amount sufficient to adjust the solution pH to 2-5.

[0040] The propellant may be selected from environmentally friendly options, including HFA134a (1,1,1,2-tetrafluoroethane), HFA152a (1,1-difluoroethane), (trans-l,3,3,3-tetrafluoropropene) HFO1234yf and HFO-1234ze (trans-1, 3,3,3-tetrafluoropropene), wherein the total propellant quantity is sufficient to complete 100% w / w with the other formulation components.

[0041] The innovation herein is grounded in the unexpected ability to produce and maintain true solution formulations, even at practical and therapeutically significant concentrations of budesonide, formoterol, and optionally glycopyrronium, which are poorly soluble in traditional propellant or suspension vehicles. This true solution state eliminates problems associated with sedimentation and the need for resuspension before use, commonly encountered in suspension-based inhalers.

[0042] The reduced initial particle size of the active pharmaceutical ingredients (APIs) facilitates their substantial dissolution, increases the surface area in contact with the solvent, and enhances interaction with the solvent system.

[0043] Upon actuation, the formulation generates aerosol droplets with a desired mass median aerodynamic diameter (MMAD) (e.g., 0.8-3.5 pm, such as 1.0 to 1.2pm), as demonstrated by in vitro cascade impaction analysis. This extra-fine aerosol size results in a higher fraction of particles depositing in the small distal airways, which is associated with improved management of diseases such as asthma and COPD.

[0044] By providing equivalent or greater lung deposition in certain embodiments, the inventive formulations enable the use of reduced nominal doses of formoterol and / or budesonide, while maintaining therapeutic equivalence to, for example, SYMBICORT 160 / 4.5 (budesonide / formoterol) or other marketed suspensionbased PMDI products, thereby diminishing the drug load and minimizing potential side effects.

[0045] In further embodiments, the formulations may contain excipients such as glycerol at 0.3-3.0% w / w to aid in solution stability or aerosol performance.

[0046] In preferred practice, the particle size distribution of both the API drug substance(s) prior to formulation and of the aerosolized product meets stringent limits, such as D10 < 1.2pm, D50 < 3.5pm, D90 < 7.0pm, and D97 < 10.0pm for budesonide and similar for formoterol. The resulting MMAD (in vitro) is typically 0.8-3.5pm.

[0047] As used in the present specification, the following words, phrases, and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0048] All percentages herein are w / w (weight by weight) unless otherwise indicated.

[0049] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. Unless otherwise indicated or apparent from context, the term “about” in reference to a value or parameter is intended to include the value itself as well as values within a range of ±15%, ±10%, ±5%, or ±1% of the indicated value in various embodiments. In some embodiments, “about” encompasses any value or sub-range reasonably understood by a person of ordinary skill in the art to account for experimental, manufacturing, or measurement variability. Reference to “about X” encompasses “X” itself. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0050] The term “active agent” is used herein to include a substance a that may be used on, or administered to, a human or animal for any purpose, including therapeutic, pharmaceutical, pharmacological, diagnostic, cosmetic, and prophylactic agents and immunomodulators. As used herein, “active agent” expressly encompasses therapeutic, pharmaceutical, pharmacological, diagnostic, cosmetic, prophylactic agents, and immunomodulators. Unless expressly specified otherwise, the terms “active agent,” “drug,” “pharmaceutical,” “pharmaceutical active pharmaceutical ingredient (API),” “medicament,” “drug substance,” and “therapeutic agent” are used interchangeably herein.

[0051] The term “inhaled corticosteroid” refers to a synthetic or naturally derived corticosteroid compound that is formulated for administration by inhalation, primarily to treat respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). Inhaled corticosteroids exert potent anti-inflammatory effects within the lungs, reducing airway inflammation, edema, and hyperresponsiveness by modulating glucocorticoid receptors in respiratory tissues. Suitable inhaled corticosteroids for use in such pharmaceutical compositions include, but are not limited to, budesonide, beclomethasone dipropionate, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone,and triamcinolone, as well as their pharmaceutically acceptable salts, esters, or solvates, either alone or in combination. As used herein, the term “inhaled corticosteroid” is not limited to any particular mechanism of action, formulation type (e.g., solution, suspension, or dry powder), particle size, device platform, indication, or dosage, except where expressly specified in a particular embodiment. In inhalation products intended for human administration, inhaled corticosteroids are typically present in dosages selected to provide a therapeutically effective amount of the corticosteroid per delivered dose, including but not limited to dose ranges and strengths known in the art for inhaled corticosteroid products; specific numerical dose ranges and examples may be set forth in particular embodiments without limiting the scope of the term “inhaled corticosteroid” itself.

[0052] The term “long-acting beta-2 agonist” or “LABA” refers to a class of bronchodilator drugs that selectively stimulate beta-2 adrenergic receptors in the airway smooth muscle, resulting in prolonged relaxation of bronchial muscles and sustained airway dilation. LABAs are specifically developed for maintenance treatment of respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD), where their extended duration of action, typically 12 hours or more, provides consistent symptom control and reduction of exacerbations. Suitable long-acting beta-2 agonists for inhalation products include, but are not limited to, formoterol, bambuterol, clenbuterol, arformoterol, salmeterol, carmoterol, milveterol, indacaterol, and vilanterol trifenatate, as well as saligenin-or indole-containing and adamantyl-derived agents and their pharmaceutically acceptable salts, esters, or solvates. As used herein, the term “long-acting beta-2 agonist” or “LABA” is not limited by any particular mechanism of action subclass, molecular scaffold, device platform, formulation type (e.g., solution, suspension, or dry powder), or regulatory status, except where expressly specified in a particular embodiment. The preferred LABA in the provided compositions is formoterol, particularly formoterol fumarate. In inhalation pharmaceutical compositions, LABAs are typically present in dosages selected to provide a therapeutically effective amount of the LABA per delivered dose, including but not limited to doseranges and strengths known in the art for inhaled LABA products; specific numerical dose ranges and examples may be set forth in particular embodiments without limiting the scope of the term “long-acting beta-2 agonist” or “LABA” itself, depending on the specific product formulation, therapeutic indication, and regulatory requirements.

[0053] The term “long-acting muscarinic antagonist” or “LAMA” denotes a class of bronchodilator drugs that block muscarinic acetylcholine receptors, particularly the M3 receptor subtype, in airway smooth muscle. This blockade prevents acetylcholine-induced bronchoconstriction, resulting in prolonged relaxation of airway smooth muscle and sustained dilation of the bronchi. LAMAs are especially valuable in the maintenance treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), providing significant, long-lasting relief from airway obstruction and reducing the frequency of exacerbations. As used herein, the term “long-acting muscarinic antagonist” or “LAMA” is not limited by any particular mechanism-of-action subclass, molecular scaffold, device platform, formulation type (e.g., solution, suspension, or dry powder), or regulatory status, except where expressly specified in a particular embodiment. Suitable long-acting muscarinic antagonists for inhalation therapies include glycopyrronium, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipratropium, atropine, benzatropine, umeclidinium, and oxitropium, as well as their pharmaceutically acceptable salts and esters. Glycopyrronium is a preferred example within the provided compositions. In inhalation pharmaceutical formulations, LAMAs are typically present in ranges selected to provide a therapeutically effective amount of the LAMA per delivered dose, including but not limited to dose ranges and strengths known in the art for inhaled LAMA products; specific numerical dose ranges and examples may be set forth in particular embodiments without limiting the scope of the term “long-acting muscarinic antagonist” or “LAMA” itself, depending on the specific product and indication.

[0054] The terms “solvent” and “co-solvent” refer to pharmaceutically acceptable liquid excipients used in the formulation of inhalation products, particularly for pressurized metered dose inhalers. A “solvent” generally denotes the primary liquid component in which active pharmaceutical ingredients and other excipients are dissolved or dispersed to create a uniform solution or suspension suitable for inhalation delivery. A “co-solvent” is an additional liquid excipient added to enhance the solubility or stability of the active ingredients or to improve formulation characteristics such as preventing drug deposition within the inhaler device. Suitable solvents and co-solvents used in inhalation products include ethanol, glycerol, and polyethylene glycol, either alone or in combination, due to their effectiveness in solubilizing the drugs and their regulatory acceptance for pharmaceutical use. As used herein, the terms “solvent” and “co-solvent” encompass any pharmaceutically acceptable liquid excipient or combination of excipients capable of dissolving, dispersing, or stabilizing one or more formulation components for inhalation delivery, and are not limited to any particular chemical class, volatility, viscosity, or concentration range, except where expressly specified in a particular embodiment. In these formulations, the concentration of ethanol as a co- solvent may be selected within ranges effective to achieve the desired solubility, physical stability, and device compatibility, including but not limited to ranges known in the art for ethanol and other co-solvents in inhalation products; specific numerical ranges and examples may be set forth in particular embodiments without limiting the scope of the terms “solvent” or “co-solvent” themselves, to address specific solubilization or device compatibility needs. These excipients play a significant role in ensuring the stability, delivery efficiency, and reproducibility of the inhalation product dose.

[0055] The term “pharmaceutically acceptable salt” refers to a salt form of a therapeutic compound that is suitable for administration to humans or animals, conferring no undue toxicity or undesirable physiological effect, and maintaining the desired pharmacological activity of the active ingredient. As used herein, a “pharmaceutically acceptable salt” includes any salt form of an active agent thatwould be recognized by a person of ordinary skill in the art as suitable for pharmaceutical use, and is not limited by method of manufacture, polymorphic form, degree of hydration, or counter-ion stoichiometry, except where expressly specified in a particular embodiment. Pharmaceutically acceptable salts can be formed from both acids and bases, depending on whether the active pharmaceutical ingredient is basic or acidic in nature. For active ingredients that are bases, suitable anionic counter-ions may include chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, mesylate, ascorbate, salicylate, acetate, succinate, lactate, glutamate, gluconate, among others. For acidic active ingredients, the salt may be formed with pharmaceutically acceptable cations such as sodium, potassium, magnesium, calcium, or ammonium, as well as organic amines like tromethamine or meglumine. In the formulations referenced here, particularly appropriate salts include formoterol fumarate and glycopyrronium bromide, offering enhanced solubility, stability, and compatibility with the excipients and propellants used in inhalation products. These salts ensure that the active ingredients can be effectively incorporated into the inhaler system and delivered in a reproducible and therapeutically effective dose.

[0056] The term “formoterol” refers to a long-acting P2 agonist (LABA) utilized as a bronchodilator in the management of asthma and chronic obstructive pulmonary disease (COPD). The IUPAC name of formoterol is (l?7?,55)-N-[2-hydroxy-5- [ 1 -hydroxy-2- [ 1 -(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide. As used herein, the term “formoterol” is intended to encompass any pharmaceutically acceptable form of formoterol, including free base, salts, solvates (e.g., hydrates), polymorphs, enantiomers, diastereomers, racemates, nanoparticles, microparticles, amorphous forms, crystalline forms, and mixtures thereof, except where a particular form is expressly specified. Formoterol can be formulated into nanoparticles or microparticles, which may include either the crystalline or amorphous form depending on the preparation method. The term “formoterol” encompasses the neutral (uncharged) compound as well as its ionized forms. In combination with an appropriate counterion, formoterolmay exist as a pharmaceutically acceptable salt, such as formoterol fumarate. Furthermore, formoterol may be present in various physical and solvated forms, including amorphous and crystalline forms. When the solvate is water, formoterol may be present as a hydrate, dihydrate, or hemihydrate. Accordingly, references to formoterol as used herein are also intended to specifically encompass, e.g., formoterol fumarate dihydrate.

[0057] The term “budesonide” refers to a steroid used in the long-term management of asthma and chronic obstructive pulmonary disease (COPD). The IUPAC name is 11 P,21 -Dihydroxy- 16a, 17a- [butane- 1 , 1 -diylbis(oxy)]pregna- 1 ,4-diene-3 ,20-dione. As used herein, the term “budesonide” is intended to encompass any pharmaceutically acceptable form of budesonide, including free base or neutral form, salts, solvates (e.g., hydrates), polymorphs, enantiomers, diastereomers, racemates, nanoparticles, microparticles, amorphous forms, crystalline forms, and mixtures thereof, except where a particular form is expressly specified. Budesonide may be present in various physical and solvated forms, including amorphous and crystalline forms. Budesonide is available in both crystalline and amorphous forms and can be incorporated into the solution described herein using these physical states. Budesonide can exist as crystalline powders, which are highly stable. Budesonide can also be converted into an amorphous form through processes such as spray drying or formation of solid dispersions. The amorphous form typically exhibits different solubility and dissolution characteristics compared to the crystalline form. Additionally, budesonide can be formulated into nanoparticles or microparticles, which may include either the crystalline or amorphous form depending on the preparation method.

[0058] The term “glycopyrronium” refers to a muscarinic anticholinergic agent, with the IUPAC name 3-[2-cyclopentyl(hydroxy)phenylacetoxy]-l,l-dimethylpyrrolidinium. As used herein, the term “glycopyrronium” is intended to encompass any pharmaceutically acceptable form of glycopyrronium, including free base or neutral form, salts, solvates (e.g., hydrates), polymorphs, enantiomers, diastereomers, racemates, nanoparticles, microparticles, amorphous forms,crystalline forms, and mixtures thereof, except where a particular form is expressly specified. As used herein, “glycopyrronium” includes both the neutral (uncharged) compound and its ionized forms. In combination with a suitable counterion, glycopyrronium may exist as a pharmaceutically acceptable salt, such as glycopyrronium bromide. Glycopyrronium may be present in a variety of physical and solvated states, including crystalline and amorphous forms, as well as solvates. Glycopyrronium can also be formulated into nanoparticles or microparticles, with either crystalline or amorphous structure depending on the preparation method. Accordingly, references to glycopyrronium as used herein are intended to specifically encompass, e.g., glycopyrronium bromide.

[0059] The term “anhydrous” refers to a substance that contains no water or is free from water. In the context of ethanol, “anhydrous” means that water is not deliberately added to the ethanol, though trace amounts may be present due to impurities or as residual water. Accordingly, “anhydrous” typically specifies a compositional threshold, such as containing less than 5% by weight of water, more often less than 4%, 2%, 1%, or even as low as 0.1% by weight. As used herein, “anhydrous” (including “anhydrous ethanol”) encompasses materials meeting any industry-recognized specification for substantially water-free solvent, and is not limited to a particular analytical method or exact numerical cutoff, except where expressly stated in a specific embodiment.

[0060] The term “anhydrous ethanol” refers to ethanol that contains a minimal amount of water — customarily less than about 1% by weight. It is also described as “absolute ethanol” or “200 proof ethanol.” For industrial purposes, anhydrous ethanol is considered to have a water content sufficiently low (usually at or below levels specified in applicable pharmacopeial or industry standards (for example, often at or below about 1% by weight)) to not affect its use as a solvent. As used herein, “anhydrous ethanol” encompasses ethanol meeting any pharmaceutically or industrially accepted specification for substantially water-free ethanol (e.g., labeled as anhydrous, absolute, or 200 proof), and is not limited to a single numerical purity threshold or testing method, except where a particular specification is expresslyrecited in a given embodiment); numerical purity and water-content examples provided herein are illustrative and non-limiting and are intended to encompass normal manufacturing and analytical variability. For clarity, several sources and industry standards define anhydrous ethanol as having a purity of at least about 95%-99.5% ethanol by weight, with correspondingly low water content, as will be understood by a person of ordinary skill in the art. Numerical purity and water-content examples provided herein are illustrative and non-limiting and are intended to encompass normal manufacturing and analytical variability.

[0061] The term “propellant” refers to a substance, typically a liquefied or gaseous chemical such as a hydrofluoroalkane (HFA) and / or hydrofluoroolefin (HFO), that is stored under pressure with a medicament in a pressurized canister, and, upon actuation, vaporizes to expel and aerosolize the medicament from a pMDI for administration to a subject. As used herein, “propellant” includes any pharmaceutically acceptable liquefied or compressed gas system suitable for generating an inhalable aerosol (for example, HFA, HFO, compressed air, nitrogen, carbon dioxide, or mixtures thereof), and is not limited to a particular chemical class, vapor pressure, or environmental profile except where expressly specified in a particular embodiment. In pMDIs, the propellant both acts as the primary force to expel the medication and forms the aerosol particles that allow the medication to reach the lungs. Unless otherwise indicated, references to a specific propellant (e.g., HFA134a, HFA152a, or HFO-1234ze) are exemplary and do not exclude use of alternative pharmaceutically acceptable propellant systems having comparable functional properties.

[0062] The term “HFA152a” refers to 1,1 -diflu oroethane, a liquefied hydrofluoroalkane propellant (chemical formula CH3CHF2), which is suitable for use in pressurized metered dose inhalers (pMDIs) for the aerosolized delivery of pharmaceutical agents. As used herein, “HFA152a” encompasses any grade or quality of 1, 1 -difluoroethane suitable for pharmaceutical use in inhalation products, including mixtures with other propellants, unless a particular purity, supplier specification, or blend is expressly recited in a given embodiment. References toselection criteria for HFA152a (for example, environmental profile, compatibility, or aerosol performance) are illustrative of desirable attributes and are not intended as admissions that any particular property is required in all embodiments.

[0063] The term “HFO-1234ze” refers to trans-l,3,3,3-tetrafluoropropene, a hydrofluoroolefin propellant (chemical formula C3H2F4, CAS No. 29118-24-9), which is suitable for use in pressurized metered dose inhalers (pMDIs) for the delivery of pharmaceutical aerosols. As used herein, “HFO-1234ze” encompasses any grade or quality of trans-l,3,3,3-tetrafluoropropene suitable for pharmaceutical use in inhalation products, including use alone or in combination with one or more additional propellants, unless a particular purity, supplier specification, or blend ratio is expressly recited in a given embodiment. HFO-1234ze is selected for its near-zero global warming potential, non-ozone depleting properties, physicochemical compatibility with medicaments and formulation excipients, and its ability to provide consistent and effective aerosolization for inhalation therapy.

[0064] The term “HF Al 34a” refers to 1,1,1,2-tetrafluoroethane, a hydrofluoroalkane propellant (chemical formula C2H2F4, CAS No. 811-97-2) suitable for use in pressurized metered dose inhalers (pMDIs). As used herein, “HF Al 34a” encompasses any grade or quality of 1,1,1,2-tetrafluoroethane suitable for pharmaceutical use in inhalation products, whether employed alone or in combination with one or more additional propellants, unless a particular purity, supplier specification, or blend ratio is expressly recited in a given embodiment. HFA134a provides the driving force to aerosolize pharmaceutical compositions for inhalation therapy and is selected for its non-ozone depleting properties, safety, chemical inertness, and compatibility with inhaler formulations.

[0065] The term “solution” refers to a homogeneous mixture in which a solute or solutes are substantially (e.g., completely) dissolved in a solvent to form a singlephase system, optically clear liquid system with no visible particulates, distinct from a “suspension,” which refers to a heterogeneous mixture where undissolved solid particles (e.g., precipitate or suspended particulate) are dispersed within aliquid phase. As used herein, a “solution” (including “true solution”) denotes a single visually uniform liquid phase without significant visible precipitate or suspended particulate under normal inspection conditions, and does not require the absolute absence of all sub-visible or microscopic heterogeneity, unless more stringent criteria are expressly specified in a particular embodiment. Unless otherwise indicated, the term “solution” does not preclude the presence of minor levels of undissolved material that do not materially affect the optical clarity, physical stability, or aerosol performance of the composition.

[0066] As used herein, the phrase “no visible precipitate or suspended particulate” refers to the absence, under normal visual inspection conditions (e.g., unaided eye examination of the canister contents or emitted formulation against light and dark backgrounds), of any macroscopic or readily observable solid phase of active ingredient or excipient that would be recognized by a person of ordinary skill in the art as a precipitate or suspension. This phrase does not require the absolute absence of all subvisible particles, microscopic heterogeneity, and / or trace / transient undissolved material that does not materially affect the optical clarity, physical stability, dose uniformity, or aerosol performance of the composition, except where a more stringent criterion is expressly specified in a particular embodiment. In various embodiments, formulations described as exhibiting “no visible precipitate or suspended particulate” are consistent with the definitions of “solution,” “true solution,” “optically clear,” and “physically stable” set forth herein.

[0067] The term “pressurized inhalation solution” refers to a homogeneous, singlephase liquid formulation in which one or more pharmaceutically active agents are substantially dissolved in a solvent system and propellant under pressure within a canister, such that, upon actuation, the formulation is aerosolized and delivered via inhalation, typically by means of a pressurized metered dose inhaler (pMDI). As used herein, a “pressurized inhalation solution” (including “pMDI solution”) denotes a visually single-phase, optically clear or substantially clear liquid in which the active agents are dissolved in the propellant / solvent system under storage conditions, and does not require the complete absence of all sub-visible particulatesor microscopic heterogeneity, except where expressly specified in a particular embodiment. This is distinct from a suspension, where the active agent is present as undissolved particles dispersed in the propellant.

[0068] The term “dissolve” means to disperse a substance (the solute) at the molecular or ionic level within a solvent, so that the individual molecules or ions of the solute become completely integrated into the solvent to form a single, homogeneous phase (a solution). As used herein, “dissolve” and “dissolved” refer to the formation of a visually homogeneous liquid phase under normal inspection conditions and do not require elimination of all sub-visible particles or analytical evidence of molecular-level uniformity, except where expressly specified in a particular embodiment. Once dissolved, the solute is no longer present as separate particles visible under normal inspection and is not readily separated by ordinary filtration, resulting in a transparent or substantially transparent and uniform mixture.

[0069] The term “pressurized metered dose inhaler” or “pMDI” refers to a device including a sealed, pressurized canister containing a pharmaceutical formulation — typically a solution or suspension of one or more active ingredients combined with a propellant — which is engineered to deliver a consistent, metered amount of medication as an aerosol when actuated by the patient. As used herein, “pMDI” encompasses any pressurized inhaler device that employs a metering valve to dispense a defined volume of formulation with each actuation, regardless of specific canister geometry, valve design, actuator configuration, or accessory components, except where a particular device design is expressly specified in a given embodiment. The pMDI includes a canister, a metering valve, and an actuator (mouthpiece). Upon activation, the pressurized propellant expels a metered quantity of the formulation through the actuator, producing an inhalable aerosol for delivery to the lungs. Unless otherwise specified, references to a pMDI include devices used alone or in combination with spacers, holding chambers, or breath-actuated mechanisms, provided that a metering valve is employed to define the delivered volume.

[0070] The term “aerosol particles” refers to tiny solid or liquid particles that are suspended in a gas, typically air. For pressurized metered dose inhalers (pMDIs) and related inhalation therapies, aerosol particles refer specifically to the microscopic droplets or particles of medication and excipients that are generated from the device upon actuation. These particles are dispersed into the air by the force of a propellant and are of a size appropriate for inhalation into the respiratory tract, enabling effective delivery of the therapeutic agent to the lungs. As used herein, “aerosol particles” includes any respirable particles or droplets emitted from an inhalation device that are capable of entering the respiratory tract, and is not limited to a particular generation mechanism, morphology, or exact size range, except where expressly specified in a particular embodiment. Aerosol particles produced by pMDIs generally range from sizes effective for pulmonary delivery (for example, often on the order of a few micrometers in aerodynamic diameter, such as about 1 to about 5 micrometers in certain embodiments), which, in various embodiments, are suitable for deposition in central and / or peripheral regions of the lung.

[0071] The term “SYMBICORT” or “SYMBICORT inhalation aerosol” refers to a pharmaceutical product that contains a fixed-dose combination of two active ingredients: budesonide and formoterol. As used herein, “SYMBICORT,” “SYMBICORT inhalation aerosol,” “SYMBICORT 160 / 4.5,” and “SYMBICORT 80 / 4.5” refer to the commercially available budesonide / formoterol pressurized inhalation products (including generic equivalents) having the labeled strengths and indications approved by regulatory authorities, and any reference product used for comparative or bioequivalence assessment, unless otherwise specified. Specifically, “SYMBICORT 160 / 4.5 (budesonide / formoterol)” or “SYMBICORT 160 / 4.5 (budesonide / formoterol) inhalation aerosol” designates a formulation containing 160 micrograms of budesonide and 4.5 micrograms of formoterol (as the fumarate dihydrate) per actuation. Likewise, “SYMBICORT 80 / 4.5 (budesonide / formoterol)” or “SYMBICORT 80 / 4.5 (budesonide / formoterol) inhalation aerosol” designates a formulation containing 80 micrograms ofbudesonide and 4.5 micrograms of formoterol (as the fumarate dihydrate) per actuation. Both are delivered by a pressurized metered dose inhaler (pMDI). Unless otherwise indicated, references to SYMBICORT products herein are made solely to identify representative reference or comparator formulations and are not intended to characterize, admit, or limit any particular clinical use, efficacy, or safety profile.

[0072] The term “FORACORT” or “FORACORT inhalation aerosol” refers to a pharmaceutical product that contains a fixed-dose combination of two active ingredients: budesonide and formoterol. As used herein, “FORACORT,” “FORACORT inhalation aerosol,” “FORACORT 400 / 6,” and “FORACORT 200 / 6” refer to the commercially available budesonide / formoterol pressurized inhalation products (including corresponding generic equivalents) having the labeled strengths and indications approved by applicable regulatory authorities, and any such product used as a reference or comparator in development or testing, unless otherwise specified. Specifically, “FORACORT 400 / 6 (budesonide / formoterol)” or “FORACORT 400 / 6 (budesonide / formoterol) inhalation aerosol” designates a formulation containing 400 micrograms of budesonide and 6 micrograms of formoterol (as the fumarate dihydrate) per actuation. Likewise, “FORACORT 200 / 6 (budesonide / formoterol)” or “FORACORT 200 / 6 (budesonide / formoterol) inhalation aerosol” designates a formulation containing 200 micrograms of budesonide and 6 micrograms of formoterol (as the fumarate dihydrate) per actuation. Both are delivered by a pressurized metered dose inhaler (pMDI). Unless otherwise indicated, references to FORACORT products herein are made solely to identify representative reference or comparator formulations and are not intended to characterize, admit, or limit any particular clinical use, efficacy, or safety profile.

[0073] The term “reference formulation” refers to a specific pharmaceutical formulation that serves as the designated standard for comparison in studies of pharmaceutical equivalence, bioequivalence, or therapeutic equivalence. As used herein, a “reference formulation” may be, for example, a reference listed drug (RLD), a bridge product, a commercially marketed product, a clinicallycharacterized investigational product, or any other formulation prospectively designated as a comparator, and is not limited to any particular regulatory status or jurisdiction unless expressly specified in a given embodiment. In regulatory and generic drug development contexts, the reference formulation is typically the previously approved or commercially marketed product (often called the “reference listed drug” or “RLD”) with which other formulations — such as new or generic products — are compared. The reference formulation is characterized by its established composition, dose, and performance profile, and is used as the benchmark to assess whether a test (e.g., generic or reformulated) product demonstrates equivalent quality, safety, and efficacy attributes.

[0074] The term “side effects” refers to unintended or undesired effects that occur in addition to the intended therapeutic effect of a medication or treatment. As used herein, “side effects” encompasses any adverse or otherwise undesired pharmacological, physiological, or psychological response temporally associated with administration of a drug product, regardless of severity, frequency, dose-dependency, or whether a causal relationship has been formally established, except where a more specific regulatory term (e.g., “adverse event” or “serious adverse event”) is expressly used. Side effects may be common or rare, transient or persistent, expected or unexpected, and are among the factors considered in establishing the safety profile of a medication, without limiting the scope of any efficacy or safety-related claim herein.

[0075] The term “drug substance” refers to the pure active pharmaceutical ingredient(s) (APIs) that provides the intended pharmacological or therapeutic effect in a drug product. As used herein, “drug substance” encompasses any pharmaceutically active material prior to formulation with excipients, including small molecules, biologies, salts, solvates, polymorphs, isomers, prodrugs, complexes, and mixtures thereof, except where a particular form is expressly specified. The drug substance may exist in various forms such as a chemical compound, biologic molecule, or complex mixture, but it does not include any excipients or inactive ingredients. It is the component of the medication responsiblefor the prevention, diagnosis, treatment, or cure of disease, and is subsequently formulated with other substances to create the final drug product administered to patients.

[0076] The term “drug product” refers to the finished dosage form of a medication that is ready for administration to patients. As used herein, “drug product” encompasses any finished pharmaceutical dosage form containing one or more drug substances together with one or more excipients, irrespective of presentation, packaging configuration, or regulatory status, except where a particular presentation is expressly specified. A drug product contains the active pharmaceutical ingredient (also known as the drug substance or API) and generally includes additional components such as excipients, stabilizers, fillers, and other inactive ingredients necessary for formulation, stability, and delivery. Drug products may be presented in a variety of forms, including tablets, capsules, solutions, inhalation aerosols, creams, and injectables. The drug product is the complete, approved and packaged form of the medication distributed for use by patients, as distinguished from the pure drug substance which is only the active ingredient.

[0077] The term “ex-actuator dose” refers to the quantity of drug substance that is emitted through the mouthpiece (actuator) of the inhaler upon actuation, and thus is available for patient inhalation. It represents the actual amount of drug delivered outside the device, after passing through all components including the actuator, as opposed to the amount initially contained or metered within the device. As used herein, “ex-actuator dose” encompasses any experimentally determined emitted dose measured downstream of the actuator (e.g., using in vitro collection or impactor methods) that is representative of the amount of drug available for patient inhalation, and is not limited to any particular test apparatus, flow rate, or regulatory methodology, except where expressly specified in a particular embodiment. The exactuator dose is used as the basis for dosing claims and therapeutic equivalence because it reflects the precise amount available for inhalation by the patient and can be measured directly in product testing and quality control.

[0078] The term “ex-valve dose” refers to the quantity of drug substance that is released from the device’s metering valve during a single actuation. This is sometimes called the “metered dose.” The ex-valve dose represents the amount of drug measured and expelled from the valve, prior to passing through the actuator (mouthpiece), and does not account for any losses that may occur due to deposition inside the device after the valve but before reaching the patient. As used herein, “ex-valve dose” encompasses any experimentally determined metered dose collected or quantified at, or immediately downstream of, the valve prior to the actuator, and is not limited to any particular test apparatus, flow rate, or regulatory methodology, except where expressly specified in a particular embodiment. As such, it typically exceeds the “ex-actuator dose,” which is the amount actually emitted from the mouthpiece and available for patient inhalation. The ex-valve dose is an important parameter for product characterization and regulatory submissions because it reflects the controlled, reproducible dose measured at the valve for each actuation of the pMDI.

[0079] The term “acid” refers to a chemical compound that, when present in a formulation, can donate a proton (hydrogen ion, H+) to the surrounding medium (according to the Brpnsted-Lowry definition) or accept a pair of electrons (according to the Lewis definition). In practical pharmaceutical terms, an acid is often included in inhalation formulations for functions such as pH adjustment, buffering, or stabilization of the active ingredient. Examples of acids commonly used in inhalation products include hydrochloric acid (e.g., IN HC1), sulphuric acid, nitric acid, citric acid, maleic acid, and phosphoric acid. As used herein, the term “acid” encompasses any pharmaceutically acceptable organic or inorganic acid, strong or weak, monobasic or polybasic, capable of providing the desired physicochemical or stability characteristics to the formulation, and is not limited to aqueous systems or to the specific examples listed, except where expressly specified in a particular embodiment. In aqueous solution, acids typically lower the pH and can form salts by reacting with bases.

[0080] The term “co-solvent” refers to a secondary solvent that is added to the primary solvent (often a liquefied propellant) in a formulation to enhance the solubility of one or more active pharmaceutical ingredients or excipients that are poorly soluble or insoluble in the primary solvent alone. Co-solvents are used to create a homogeneous solution, improve drug dissolution, and support stable and effective drug delivery via devices such as pressurized metered dose inhalers (pMDIs). Common co-solvents used in inhalation formulations include glycerol and propylene glycol. As used herein, “co-solvent” encompasses any pharmaceutically acceptable liquid excipient employed in combination with a primary solvent or propellant to aid solubilization, stabilization, and / or aerosol performance of formulation components, and is not limited to particular chemical classes or to the specific examples listed, except where expressly specified in a particular embodiment.

[0081] The term “glycerol” is defined as a simple, colorless, odorless, viscous polyol (trihydric alcohol) with the chemical formula CTFTCh. As a co-solvent, glycerol is added to formulations alongside a primary solvent and / or propellant to enhance the solubility of active pharmaceutical ingredients or excipients that are poorly soluble in the primary solvent alone. Its three hydroxyl groups make it highly miscible with water and compatible with many other solvents, allowing it to support the creation of a homogeneous solution. Glycerol is used to promote drug dissolution, stabilize formulations, and sometimes adjust viscosity or hygroscopicity in inhalation products such as pressurized metered dose inhalers (pMDIs) and nebulizer solutions. As used herein, the term “glycerol” encompasses pharmaceutically acceptable grades of glycerol (including anhydrous and hydrated grades within applicable specifications), whether employed alone or in combination with other solvents or co-solvents, except where a particular grade, purity, or water content is expressly specified in a given embodiment.

[0082] The term “inhalation” refers to the process of breathing in a drug product, typically formulated as an aerosol, vapor, or fine powder, through the mouth or nose for delivery into the respiratory tract — most often targeting the lungs. Inhalation asa route of pharmaceutical administration is used to achieve a local action in the airways (such as bronchodilation or anti-inflammatory effect) or, in some cases, a systemic therapeutic effect when the drug is absorbed through the lung tissue. As used herein, “inhalation” encompasses administration by any pharmaceutically acceptable inhaler or aerosol-generating device (for example, pMDIs, dry powder inhalers, nebulizers, soft-mist inhalers, or other oral or nasal inhalation systems), and is not limited to a particular breathing pattern, inspiratory flow rate, or patient technique, except where expressly specified in a particular embodiment. Inhalation drug products include aerosols delivered by pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), nebulizers, and other specialized inhalation devices.

[0083] The term “inhalation aerosol” refers to a pharmaceutical dosage form consisting of finely divided liquid or solid particles of drug (or a combination of both) that are suspended in a gas, usually with the aid of a propellant, and intended for oral inhalation into the respiratory tract. As used herein, “inhalation aerosol” encompasses any pressurized or non-pressurized aerosol system suitable for pulmonary or airway delivery, including products formulated as suspensions or solutions in propellant and / or solvent, and is not limited to a particular device platform, propellant type, or particle morphology, except where expressly specified in a particular embodiment. Inhalation aerosols are packaged under pressure and, upon actuation, deliver a metered amount of medication as an aerosol spray or mist for direct deposition in the lungs or airways. The formulation typically includes the active pharmaceutical ingredient(s), a propellant, and may also contain co-solvents and excipients to ensure product stability and optimized drug delivery.

[0084] The term “mass median aerodynamic diameter” or “MMAD” as used herein refers to the aerodynamic diameter of an aerosol below which 50% of the mass of the aerosol includes particles having an aerodynamic diameter less than the MMAD. As used herein, unless otherwise indicated, MMAD values may be determined using any pharmaceutically accepted in vitro aerodynamic particle size characterization technique (for example, cascade impactors or time-of-flightmethods), and numerical MMAD ranges are intended to encompass values obtained by such techniques within normal experimental variability. The MMAD is determined / calculated in accordance with monograph 601 of the United States Pharmacopeia (“USP”) , and / or an equivalent standardized cascade impactor method accepted in the relevant jurisdiction.

[0085] “Extra-fine particle” as used herein refers to a particle having a mass median aerodynamic diameter (MMAD) of less than about 3.5 pm, and in certain embodiments less than about 3.25pm, 3.0 pm, 2.75pm, 2.5pm, 2.25pm, 2 pm, 1.8 pm, 1.5 pm, 1.25pm, or about 1 pm, as determined by standardized in vitro aerodynamic particle size distribution methods.

[0086] “Extra-fine aerosol formulation,” “extra-fine composition,” or “extra-fine suspension” as used herein refers to a composition that, upon actuation, produces an aerosol in which a substantial fraction of the emitted particle mass is in the extra-fine range, for example a fine / extra-fine particle fraction (by mass) of at least about 40% of particles having an aerodynamic diameter less than a value effective to promote peripheral airway deposition (for example, in some embodiments less than about 3 pm or less than about 2 pm), in certain embodiments at least about 50%, 60%, or 70%, and in particular embodiments at least about 50% of the emitted dose having an MMAD in the range of about 0.8-3.5 pm (e.g., about 1.0-2.0 pm or about 1.0-1.2 pm). Unless expressly stated otherwise, these numerical values and ranges are intended to be approximate and to accommodate normal experimental variability in aerodynamic particle size measurements. In various embodiments, such extra-fine aerosol formulations are suitable to enhance deposition in small peripheral airways relative to formulations having larger MMAD values or lower extra-fine particle fractions, including but not limited to conventional suspension-based inhalation products.

[0087] A “therapeutically effective amount” is the amount of a compound which achieves a therapeutic effect by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the onset of a disease or disorder,including, in certain embodiments, a respiratory disorder. As used herein, a “therapeutically effective amount” can vary depending on factors such as the specific active agent(s), formulation, route of administration, dosing regimen, patient population, and severity or stage of disease, and expressly encompasses amounts that provide clinically meaningful benefit even if they do not completely eliminate all signs or symptoms of the condition. A therapeutically effective amount may be an amount which relieves to some extent one or more symptoms of a disease or disorder in a patient; partially or completely returns to normal one or more physiological or biochemical parameters associated with or causative of the disease or disorder; and / or reduces the likelihood of the onset of the disease or disorder. Unless otherwise indicated, any specific dose or range disclosed herein is provided as an example of a therapeutically effective amount for particular embodiments and is not intended to limit the broader meaning of the term.

[0088] The term “substantial” refers to an amount, degree, or percentage that is sufficiently high to achieve the desired technical or clinical effect in context and would be understood by a person of ordinary skill in the art as non-trivial or meaningful, for example in some embodiments greater than about 80%, 85%, 90%, 95%, 99%, or 99.99%, as applicable in the context. For example, “substantially the same efficacy” means that the efficacy is within a range that would be recognized by a person of ordinary skill as clinically or technically comparable to that of a marketed product (for example, in certain embodiments within about 80%-125% or within about 90%-110% of the reference value, depending on the metric and regulatory or clinical context). These numerical examples are illustrative and non-limiting and are provided to aid understanding of the term “substantial,” which is intended to be interpreted in view of the specific technical or clinical context in which it is used. Unless expressly stated otherwise, the term “substantial” and its variants (e.g., “substantially”) are intended to accommodate normal experimental, analytical, and inter-subject variability.

[0089] The term “% w / w” or “weight percentage” or “wt.%” refers to the amount by weight of a particular active ingredient or excipient, expressed as a percentageof the total weight of the composition. Unless otherwise indicated, all % w / w values herein are expressed on a formulation basis (i.e., weight of component divided by total weight of the composition, multiplied by 100), and numerical percentages are intended to be approximate and to encompass normal manufacturing and analytical variability.

[0090] The term “environmentally friendly propellant” refers to a liquefied propellant selected to have low or near-zero ozone depletion potential and a reduced global warming potential relative to chlorofluorocarbon (CFC) propellants, while maintaining physicochemical compatibility with the active pharmaceutical ingredients and excipients and providing suitable aerosol characteristics for inhalation therapy, and may include, without limitation, hydrofluoroalkanes (HFAs), hydrofluoroolefins (HFOs), and other pharmaceutically acceptable propellant systems meeting applicable environmental criteria, including, without limitation, HFA152a, HFO-1234ze, and HFO1234yf. For the avoidance of doubt, HF Al 34a is a hydrofluoroalkane propellant with zero ozone-depletion potential but a relatively high global warming potential and is not regarded herein as an environmentally friendly or “green” propellant; however, it may be referenced in certain embodiments or comparative examples as a legacy or transitional propellant. Similarly, while HFA152a has reduced global warming potential relative to HFA134a and HFA227ea, it retains some global warming potential and is classified herein as a “low-GWP HF A” and an “environmentally friendly propellant” when compared to legacy high-GWP alternatives, though HFO1234ze and HFO1234yf remain preferred green alternatives.

[0091] The term “pharmaceutically acceptable propellant system” refers to a liquefied propellant or mixture thereof suitable for use in pressurized metered-dose inhalers, including hydrofluoroalkanes (HFAs) such as HFA134a and HFA227ea, hydrofluoroolefins (HFOs) such as HFO-1234ze and HFO-1234yf, and low-GWP HFAs such as HFA152a. Unless otherwise indicated, references herein to “environmentally friendly” or “green” propellants refer to propellant systems selected from low-GWP inhaler propellants such as HF Al 52a andHFO-1234ze / 1234yf and do not encompass high-GWP HFA propellants such as HFA134a and HFA227ea, which are cited primarily as legacy or comparative propellants.

[0092] The term “green propellant” is used interchangeably with “environmentally friendly propellant” and denotes a propellant having low or near-zero ozone depletion potential and a reduced global warming potential, while maintaining suitability for pharmaceutical inhalation use, such as HFA 152a, HFO-1234ze, or HFO-1234yf. For the avoidance of doubt, high-GWP hydrofluoroalkanes such as HF Al 34a and HFA227ea are not regarded herein as “green” or “environmentally friendly” propellants and are cited primarily as legacy or comparative propellants, as described above.

[0093] The term “true solution” refers to a pharmaceutically acceptable, essentially single-phase liquid in which the active ingredients are substantially dissolved, appearing optically clear or substantially clear to the unaided eye under normal inspection, and distinguished from conventional suspension formulations. As used herein, “true solution” denotes a visually single-phase, solution-type formulation under normal storage and use conditions, and does not require the absolute absence of all sub-visible particulates or microscopic heterogeneity, except where a more stringent criterion is expressly specified in a particular embodiment. In practical manufacturing and commercial use, trace or transient undissolved material or minimal haze that does not materially affect appearance, dose uniformity, stability, or aerosol performance is considered compatible with the solution-type nature of the formulation, unless a particular embodiment specifies otherwise.

[0094] The term “pressurized inhalation solution” refers to a homogeneous, single-phase liquid formulation in which one or more pharmaceutically active agents are substantially dissolved in a solvent system and propellant under pressure within a canister of a pressurized metered dose inhaler (pMDI), such that, upon actuation, the formulation is aerosolized and delivered via inhalation, and exhibits solution-type behavior under normal storage and use conditions. As used herein,“pressurized inhalation solution” does not require the absolute absence of all sub-visible particulates or microscopic heterogeneity, and tolerates trace or transient undissolved material or minimal haze that does not materially affect dose uniformity, stability, or aerosol performance, except where a more stringent criterion is expressly specified in a particular embodiment. Unless otherwise specified, references to a pMDI encompass devices used alone or with accessories such as spacers or holding chambers and include breath-actuated and manually actuated configurations that employ a metering valve.

[0095] The term “physically stable” refers to a formulation that remains a single-phase, optically clear solution without visible precipitation, crystal growth, phase separation, or clinically meaningful changes in aerosol performance (e.g., MMAD and fine / extra-fine particle fraction within pre-specified acceptance criteria) over the intended shelf life when stored under recommended conditions. As used herein, “physically stable” allows for normal manufacturing and analytical variability and encompasses formulations that maintain appearance and performance within acceptable limits established by applicable specifications, regulatory guidance, or study protocols, except where more stringent stability criteria are expressly recited in a particular embodiment. Unless expressly stated otherwise, references to physical stability are intended to describe exemplary performance targets and are not to be construed as limiting admissions regarding the behavior of any particular commercial or comparative product.

[0096] The term “chemically stable” refers to a formulation in which the assay of each active pharmaceutical ingredient remains within pre-specified limits (for example, within an acceptable range around the label claim (for example, in some embodiments about 90-110% of label claim) and all specified related substances and degradation products remain within predefined ICH- and product-specific limits throughout the intended shelf life when stored under recommended conditions. As used herein, “chemically stable” encompasses stability criteria set by applicable regulatory guidance, pharmacopeial standards, or product-specific specifications, and allows for normal analytical variability, except where particularnumerical limits are expressly stated for a given embodiment. Unless otherwise indicated, any numerical assay or impurity ranges recited in connection with chemical stability are provided as illustrative examples of suitable criteria and do not limit the broader concept of chemical stability for purposes of claim construction.

[0097] The term “optically clear” refers to a liquid formulation that appears visually transparent and substantially free of visible particulate matter or pronounced haze when examined by the unaided eye or under standardized visual inspection conditions against both light and dark backgrounds, consistent with an essentially single-phase, solution-type state. As used herein, “optically clear” denotes a visually transparent or substantially transparent appearance under normal inspection and does not require the absolute absence of all sub-visible particles or microscopic heterogeneity, except where a more stringent criterion is expressly specified in a particular embodiment. Minor or transient haze or trace particulates that do not materially impact appearance, dose uniformity, stability, or aerosol performance are regarded as compatible with an ‘optically clear’ formulation, unless a particular embodiment specifies a different acceptance level.

[0098] The term “single-phase” refers to a macroscopically uniform liquid state comprising one continuous phase in which the active ingredients and excipients are substantially dissolved or uniformly dispersed, without any separate, macroscopically distinct solid, liquid, or gas phase of active ingredient or excipient under normal storage and use conditions. As used herein, “single-phase” denotes a visually uniform, continuous phase under normal inspection and storage / use conditions and does not require complete absence of all sub-visible or microscopic heterogeneity, except where a more stringent criterion is expressly specified in a particular embodiment. Minor or transient amounts of undissolved material or haze that do not materially affect appearance, dose uniformity, stability, or aerosol performance are considered compatible with a ‘single-phase’ state, unless expressly excluded in a particular embodiment.

[0099] The terms “reference suspension product” and “reference formulation” refer to an approved, commercially marketed inhalation product comprising budesonide and formoterol formulated as a suspension in a pMDI, such as SYMBICORT 160 / 4.5 or FORACORT 200 / 6 or 400 / 6 budesonide-formoterol inhalation aerosols, which serve as benchmarks for pharmaceutical, pharmacokinetic, or therapeutic comparison. As used herein, these terms also encompass corresponding generic or follow-on suspension pMDI products and any such budesonide-formoterol suspension inhalation product prospectively designated as a comparator in a given study or embodiment, unless a particular branded product is expressly specified. Unless otherwise indicated, identification of a reference suspension product is for comparative or benchmarking purposes only and is not intended to admit or limit any particular performance, safety, or regulatory characteristic of that product or of the inventive formulations.

[0100] The term “binary system” refers to a fixed-dose combination comprising an inhaled corticosteroid and a long-acting beta-2 agonist (LABA), and the term “ternary system” refers to a fixed-dose combination comprising an inhaled corticosteroid, a LABA, and a long-acting muscarinic antagonist (LAMA), in each case formulated together in a single pressurized inhalation solution. As used herein, “binary system” and “ternary system” are not limited to any particular actives, strengths, device design, or dosing regimen, except where expressly specified in a particular embodiment. Unless expressly stated otherwise, such systems may encompass any pharmaceutically acceptable corticosteroid, LABA, and, where applicable, LAMA suitable for formulation in a pressurized inhalation solution.

[0101] The terms “corticosteroid:LABA ratio” and “corticosteroid:LABA:LAMA ratio” refer to the ratio of the nominal or ex-actuator masses of the respective active ingredients delivered per actuation (for example, micrograms of budesonide : micrograms of formoterol : micrograms of glycopyrronium per actuation), unless otherwise explicitly specified. As used herein, these ratios may be expressed using any consistent basis (e.g., nominal canister content, ex -valve dose, or ex-actuator dose), and, unless expressly stated otherwise in a given context, reference to such aratio is intended to encompass corresponding ratios across these related dosing measures within normal manufacturing and analytical variability.

[0102] The terms “drug load,” “nominal drug loading,” and “total drug load” refer to the total quantity of active pharmaceutical ingredient(s) contained in the filled canister of a pMDI, expressed as micrograms or milligrams of each active per canister, independent of the fraction ultimately emitted per actuation. Unless otherwise indicated, these terms encompass both label-claim amounts and actual filled amounts within normal manufacturing tolerances, and may be used on a per-active or combined-actives basis, as will be understood by a person of ordinary skill in the art.

[0103] The term “shelflife” refers to the labeled storage period over which the drug product is demonstrated to remain within approved specifications for appearance, assay, degradation products, pH, water content (where applicable), and aerosol performance (including MMAD and fine / extra-fine particle fraction), when stored under the recommended conditions. As used herein, “shelf life” encompasses any regulatory-accepted or scientifically justified expiry period established on the basis of stability data (e.g., real-time and / or accelerated studies) and allows for normal analytical and manufacturing variability, except where a particular duration or set of criteria is expressly specified in a given embodiment.

[0104] The term “actuation” refers to a single operation of the pMDI that results in discharge of a metered quantity of formulation from an inhalation device, typically involving depression and release of a valve or activation of an equivalent triggering mechanism, and generation of an inhalable aerosol or spray (for example, via an actuator, mouthpiece, or spacer). As used herein, “actuation” (or “puff’) denotes one complete dosing event of the inhaler mechanism, regardless of the specific force, speed, or technique employed by the user, the particular device geometry or actuation mechanism, the use or non-use of spacers or holding chambers, or whether the device is manually triggered or breath-actuated, except where aparticular actuation profile or test condition is expressly specified in a given embodiment.Budesonide-Formoterol Compositions for Inhalation

[0105] The invention provides pressurized pharmaceutical compositions for inhalation that deliver budesonide and formoterol, with or without glycopyrronium, as true solution formulations in pressurized metered dose inhalers rather than as suspensions. These compositions are designed to generate extra-fine aerosol particles that preferentially reach the small, peripheral airways of the lungs, enabling effective treatment of asthma, chronic obstructive pulmonary disease, and related respiratory disorders at therapeutically effective doses while employing lower nominal amounts of budesonide and formoterol than many existing budesonide-formoterol inhalation products. By formulating these active ingredients in a pharmaceutically acceptable propellant system, together with anhydrous ethanol, acid, and, in some embodiments, glycerol, the invention achieves optically clear, physically and chemically stable pressurized inhalation solutions that support improved dose uniformity, deep-lung deposition, and safety, and that can be implemented across a range of commercially relevant strengths, devices, and treatment regimens.Pressurized Pharmaceutical Composition

[0106] In general, the pressurized pharmaceutical composition is a single-phase, optically clear pressurized inhalation solution suitable for administration from a pressurized metered dose inhaler and comprises budesonide, formoterol, anhydrous ethanol, hydrochloric acid, and a pharmaceutically acceptable propellant system (e.g., HFA134a, HFA152a, HFO-1234ze, and / or HFO-1234yf). In certain embodiments the composition optionally further comprises glycopyrronium and / or glycerol, and is formulated so that budesonide and formoterol, and where present glycopyrronium, are substantially dissolved in the solvent-propellant system, such that no visible precipitate or suspended particulate is detectable after extended storage under typical pharmaceutical conditions. The composition is configured tobe contained within a canister of a pressurized metered dose inhaler together with a metering valve and actuator, so that upon actuation it produces an aerosol having a defined mass median aerodynamic diameter (MM AD) and extra-fine particle fraction that support efficient peripheral airway deposition and consistent delivery of therapeutically effective doses of the active ingredients.

[0107] In specific embodiments, the composition is described as a true solution pressurized inhalation solution, indicating that, under normal inspection, it appears optically clear and single-phase, with the active components substantially dissolved and distributed throughout the formulation rather than existing as discrete suspended particles. The terms true solution, optically clear, single-phase, pressurized inhalation solution, and physically and chemically stable are used herein in a manner that accommodates normal manufacturing and analytical variability while preserving the essential technical feature that the formulation behaves as a solution-type system under storage and use conditions, thereby supporting dose reproducibility and robust aerosol performance.Components of the Composition

[0108] The active component budesonide is an inhaled corticosteroid present in the composition at concentrations less than 0.71 percent weight by weight, with specific embodiments describing budesonide concentration ranges of about 0.03 to about 0.71 percent and narrower subranges such as 0.17, 0.22, 0.28, 0.36, 0.56, and 0.71 percent weight by weight for different product strengths. Formoterol, typically present as formoterol fumarate, is a long-acting beta-2 agonist included at concentrations less than 0.0166 percent weight by weight, with specific embodiments describing ranges such as about 0.002 to about 0.0166 percent and particular values such as 0.0042, 0.0052, 0.0054, 0.0067, 0.0083, 0.0086, 0.0103, 0.0107, and 0.0133 percent weight by weight. In certain ternary embodiments, glycopyrronium, usually present as glycopyrronium bromide, is also included as a long-acting muscarinic antagonist, typically at concentrations of about 0.01 to about 0.03 percent weight by weight, with example formulas using values such as 0.017 and 0.021 percent weight by weight.

[0109] Anhydrous ethanol functions as a primary cosolvent and is present in the compositions in amounts of about 8 to about 20 percent weight by weight, with specific ranges such as, e.g., 8-18, 8-15, 12.5-20, and 12.5-15 percent weight by weight disclosed to accommodate different actives, strengths, and propellant combinations. Hydrochloric acid, often provided as a IN aqueous solution, is added in an amount sufficient to adjust the pH of the pressurized pharmaceutical composition to, e.g., between about 2 and about 5, with further embodiments describing narrower pH ranges and target values within this interval to balance solubility, stability, and device compatibility. The remainder of the formulation is made up by a pharmaceutically acceptable propellant system (e.g., at least one of HFA134a, HFA152a, and HFO-1234ze), and in some embodiments the composition additionally contains glycerol at concentrations of, e.g., about 0.3 to about 3.0 percent weight by weight to further support solution stability and aerosol performance.Concentrations, Amounts, and Ranges

[0110] The invention provides a wide range of specific values and ranges for each component, and supports commercially relevant strengths and configurations. For budesonide, example formulations include concentrations of 0.17, 0.22, 0.28, 0.36, 0.56, and 0.71 percent weight by weight, with these concentrations used in combination with various formoterol levels to create products that deliver different ex-valve and ex-actuator doses spanning clinical dose ranges of interest, such as products intended to deliver nominal ex-actuator budesonide doses from about 25 micrograms up to about 200 micrograms per actuation. For formoterol fumarate, example formulations include concentrations such as 0.0020, 0.0030, 0.0042, 0.0052, 0.0054, 0.0067, 0.0083, 0.0086, 0.0103, 0.0107, and 0.0133 percent weight by weight, again in combinations that yield ex-actuator dose ranges of about 1.5 to about 5.7 micrograms per actuation, depending on the particular strength and propellant system.

[0111] The invention likewise sets out ranges for ethanol, pH, glycerol, total canister fill mass, and delivered mass per actuation, including, for example,propellant-cosolvent formulations where the pMDI contains 7 to 12 grams of drug product per canister and delivers about 45 to about 75 milligrams of liquid formulation per actuation. The pH of the compositions is specified in broad terms as between 2 and 5, with specific embodiments highlighting narrower ranges or target points such as 2.25 ± 0.25, 2.5 ± 0.25, 2.75 ± 0.25, 2.9 ± 0.1, 3.0 ± 0.25, 3.25 ± 0.25, 3.5 ± 0.25, 3.5 ± 0.1, 3.6 ± 0.1, 3.75 ± 0.25, 4.0 ± 0.25, 4.25 ± 0.25, 4.5 ± 0.25, and 4.75 ± 0.25, thereby defining a rich set of combinations to select and optimize within the scope of the invention. The presence or absence of glycerol, and the choice among HFA134a, HFA152a, and / or HFO-1234ze as propellants, allow tailoring to specific device designs, regulatory environments, and commercial strategies.Aerosol Properties and Extra-Fine Particle Size

[0112] A central property of the invention is that, upon actuation of the pressurized metered dose inhaler, the pressurized pharmaceutical composition produces aerosol particles having a mass median aerodynamic diameter (MMAD) between, e.g., about 0.8 and about 3.5 micrometers, and in particular embodiments about 1.0 to about 2.0 micrometers. The aerosol emitted from the device also exhibits an extrafine particle fraction greater than, e.g., 50 percent by mass, meaning that a substantial proportion of the emitted drug mass is contained in particles small enough to reach the small peripheral airways and distal regions of the lungs. These particle size characteristics can be measured according to standard in vitro aerodynamic particle size distribution methods, such as pharmacopeial cascade impaction techniques, and the specification defines terms such as mass median aerodynamic diameter, extra-fine particle, and extra-fine aerosol formulation in a manner that encompasses normal experimental variability while capturing the intended performance profile of the compositions.

[0113] The pressurized pharmaceutical composition is further characterized by the particle size distribution of the budesonide and formoterol drug substances prior to formulation and by the aerodynamic size distribution of the aerosolized product. Example data describe drug substance particle size distributions meeting criteriasuch as, e.g., DIO not more than 1.0 or 1.2 micrometers, D50 not more than 3.0 or 3.5 micrometers, D90 not more than 5.0 or 7.0 micrometers, and D97 not more than 10.0 micrometers, for both budesonide and formoterol, which facilitate rapid and substantial dissolution in the ethanol-acid mixture and contribute to the consistent generation of extra-fine droplets upon actuation. In vitro aerodynamic performance data show that example inhalation solutions exhibit mass median aerodynamic diameters of, e.g., about 0.8 to 3.5 micrometers, e.g., about 1.0 to 1.2 micrometers, and fine or extra-fine particle fractions that are consistent with efficient deposition in the small airways, supporting the claimed technical and clinical benefits across multiple formulations and strengths.Budesonide-Formoterol Dose Levels and Performance

[0114] The pressurized pharmaceutical composition encompasses multiple strengths and dose configurations of budesonide and formoterol suitable for maintenance and symptomatic treatment of asthma and chronic obstructive pulmonary disease. In various embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler delivers exactuator doses of budesonide within, e.g., about 25 to about 200 micrograms per actuation, and ex-actuator doses of formoterol within, e.g., about 1.5 to about 5.7 micrograms per actuation, with example strengths aligned with values such as 40, 80, 100, 160, 200, and 400 micrograms of budesonide and 2.3, 3.0, 4.5, 4.8, and 6 micrograms of formoterol per actuation. Tables and examples herein provide exvalve and ex-actuator dose data corresponding to the disclosed compositions, including, for instance, inhalation solutions where 9.86 grams of solution per canister delivers about 58 milligrams per actuation and yields ex-actuator doses near 80 to 90 micrograms of budesonide and 5.0 to 5.5 micrograms of formoterol, or near 80 to 90 micrograms of budesonide and 2.2 to 2.7 micrograms of formoterol.

[0115] Described herein are compositions in which the ex-actuator doses of budesonide and formoterol are selected so that the pressurized pharmaceutical composition provides therapeutic efficacy substantially comparable to reference budesonide-formoterol suspension inhalers, while employing lower nominalamounts of budesonide and or formoterol, thereby supporting reduced total drug load while maintaining clinical performance. For example, in certain embodiments, the solution formulations are configured to target therapeutic efficacy comparable to products delivering (i) 160 micrograms of budesonide and 4.5 micrograms of formoterol, or (ii) 400 micrograms of budesonide and 6 micrograms of formoterol, per actuation, even though the compositions contain lower nominal amounts of one or both active ingredients, which can be attributed, at least in part to the enhanced deep-lung deposition and dose uniformity associated with the extra-fine, true solution aerosols.Ternary Compositions with Glycopyrronium

[0116] The invention also encompasses ternary pressurized pharmaceutical compositions in which budesonide and formoterol are combined with glycopyrronium in the same pressurized inhalation solution, forming fixed-dose triple-therapy products in a single pressurized metered dose inhaler. In specific embodiments, these ternary compositions can include budesonide at concentrations such as, e.g., 0.17, 0.28, or 0.56 percent weight by weight, formoterol fumarate at concentrations such as, e.g., 0.0020, 0.0030, 0.0042, 0.0052, 0.0067, 0.0083, 0.0103, or 0.0107 percent weight by weight, and glycopyrronium at concentrations such as, e.g., 0.017 or 0.021 percent weight by weight, together with anhydrous ethanol at, e.g., about 8 to about 20 percent weight by weight, hydrochloric acid sufficient to adjust pH to e.g., between about 2 and about 5, and propellants such as, e.g., HFA134a, HFA152a, and HFO-1234ze. Example formula tables demonstrate combinations corresponding to strengths such as, e.g., 100 / 12.5 / 3, 100 / 12.5 / 4.8, 100 / 12.5 / 6, 200 / 12.5 / 3, 200 / 12.5 / 4.8, 200 / 12.5 / 6, 400 / 12.5 / 3, 400 / 12.5 / 4.8, and 400 / 12.5 / 6 micrograms of budesonide / glycopyrronium / formoterol fumarate per actuation.

[0117] As with the binary budesonide-formoterol compositions, the ternary solutions are configured so that all three active ingredients are substantially dissolved and that, upon actuation, the inhaler produces aerosols with mass median aerodynamic diameters of, e.g., about 0.8 to about 3.5, e.g., about 1.0 to about 1.2micrometers, and extra-fine particle fractions, e.g., greater than 50 percent by mass, thereby supporting deep-lung deposition of budesonide, formoterol, and glycopyrronium. These ternary compositions are therefore suitable for methods of treating or preventing asthma and chronic obstructive pulmonary disease in subjects who may benefit from combined inhaled corticosteroid, long-acting beta-2 agonist, and long-acting muscarinic antagonist therapy in a single inhaler platform that offers extra-fine aerosol delivery and reduced drug load.Pressurized Metered Dose Inhaler and Kits

[0118] The invention includes a pressurized metered dose inhaler comprising a canister charged with any of the disclosed pressurized pharmaceutical compositions and an actuator configured to deliver the composition as an inhalation aerosol for use in the treatment of asthma or chronic obstructive pulmonary disease. In specific embodiments, the pMDI is configured to contain, e.g., about 7 to about 12 grams of drug product, with illustrative examples including canister fill masses such as 7.4 grams, 9.28 grams, 9.6 grams, 9.86 grams, 10 grams, 11 grams, 11.68 grams, and 12 grams, and to deliver about 45 to about 75 milligrams of solution per actuation. The metering valve and actuator geometry are selected so that the emitted aerosol exhibits the desired extra-fine particle size distribution and ex-actuator doses described for budesonide, formoterol, and, where present, glycopyrronium, and the device can be used alone or in combination with accessories such as spacers or holding chambers.

[0119] Kits and packaged articles can include the pressurized metered dose inhaler together with labeling, instructions for use, and, optionally, spacers or other accessories, for administration of the compositions to subjects in need of treatment or prevention of asthma, chronic obstructive pulmonary disease, or other obstructive or inflammatory respiratory disorders. These kits can be configured for different strengths and dosing regimens, including once- or twice-daily maintenance use, with or without additional as-needed dosing, and can support transition from existing budesonide-formoterol suspension inhalers to the inventive solution formulations while maintaining or improving clinical control.Cans

[0120] The pressurized pharmaceutical composition can be contained within a canister selected from plain metal cans and plasma-coated metal cans, each configured for use in a pressurized metered dose inhaler (pMDI). The canister can be formed of aluminum or stainless steel and can be employed as a plain (unlined) can, alternatively the canister can include an internal plasma-deposited coating, such as an inorganic or organosilicon-based plasma polymer layer, applied to at least a portion of the interior surface of the can.

[0121] The use of a plain metal can provides a robust and cost-effective container suitable for maintaining the physical and chemical stability of the optically clear, single-phase budesonide-formoterol solution, optionally further comprising glycopyrronium, over the intended shelf life. The use of a plasma-coated can may reduce or prevent interaction between the pressurized inhalation solution and the metal substrate of the canister (for example, adsorption, catalysis, or corrosion), thereby further enhancing long-term stability, minimizing leachables and extractables, and helping to preserve dose uniformity and aerosol performance parameters such as mass median aerodynamic diameter (MMAD) and extra-fine particle fraction.

[0122] The plasma coating may be selected and applied such that the composition remains an optically clear, single-phase solution with no visible precipitate or suspended particulate after storage under long-term and accelerated conditions, for example at 25 °C / 60% relative humidity or 40 °C / 75% relative humidity, for at least 12 weeks, 6 months, 12 months, or longer. Use of a plasma-coated can in combination with the disclosed HFA and / or HFO propellant system, anhydrous ethanol, and acid can maintain the desired ex-actuator dose ranges of budesonide and formoterol (and, where present, glycopyrronium) and the targeted extra-fine MMAD (e.g., about 0.8-3.5 pm), thereby supporting deep-lung deposition and enabling, in certain embodiments, clinical performance that is comparable to or improved relative to reference suspension products while employing reduced nominal drug load.Gasket

[0123] The metering valve of the pMDI comprises a gasket, seal, or diaphragm formed of a material comprising cycloolefin copolymer (COC), ethylene propylene diene monomer (EPDM), or a combination thereof. The gasket may include a blend of COC and EPDM, or may comprise a multilayer structure in which at least one layer comprises COC and at least one layer comprises EPDM, the gasket being configured to provide a fluid-tight seal between the valve and the canister while being compatible with the pressurized pharmaceutical composition.

[0124] Use of a COC- and / or EPDM-based gasket reduces sorption, swelling, or degradation in the presence of the HFA and / or HFO propellants, anhydrous ethanol, acid, and the dissolved active pharmaceutical ingredients, thereby improving valve performance and dose reproducibility over the life of the inhaler. The COC / EPDM gasket may limit the formation or release of leachables into the solution formulation and can help maintain the ex-valve and ex-actuator doses of budesonide, formoterol, and optionally glycopyrronium within specified limits throughout the labeled number of actuations, while preserving the targeted MMAD and extra-fine particle fraction of the emitted aerosol.

[0125] The COC / EPDM gasket, optionally in combination with the plain or plasma-coated can, may be selected such that the device meets predefined stability, valve sealing, and actuation force specifications under long-term storage and in-use conditions, including repeated actuation at room temperature and under typical patient handling and environmental conditions.Methods of Use

[0126] The present invention includes methods of treating asthma or chronic obstructive pulmonary disease in a subject by administering to the subject, by oral inhalation from a pressurized metered dose inhaler, a pressurized pharmaceutical composition described herein, thereby delivering budesonide and formoterol as an extra-fine aerosol having a mass median aerodynamic diameter, e.g., of about 0.8 to about 3.5, (e.g., of about 1.0 to about 1.2 micrometers), and an extra-fine particlefraction, e.g., greater than 50 percent by mass. In these methods, the doses of budesonide and formoterol delivered per actuation are selected within the ranges described for the compositions so that therapeutic efficacy is substantially comparable to reference budesonide-formoterol inhalation aerosols, while employing lower nominal amounts of budesonide and or formoterol and reducing total drug load. Additional methods relate to reducing systemic exposure to corticosteroid and or beta-2 agonist by replacing a suspension-based budesonide-formoterol therapy with twice-daily administration of the inventive pressurized pharmaceutical compositions, in each case delivering extra-fine aerosols with deeplung deposition and configured to maintain clinical control at reduced active ingredient dosages.

[0127] In some embodiments, the reduced total drug load and / or reduced systemic exposure to budesonide and / or formoterol achievable with the inventive pressurized inhalation solutions is associated with a reduced occurrence, frequency, and / or severity of adverse effects relative to higher-dose budesonide-formoterol suspension inhalers such as SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6. In some embodiments, the reduced total drug load and / or reduced systemic exposure to budesonide and / or formoterol achievable with the inventive pressurized inhalation solutions is associated with a reduced occurrence, frequency, and / or severity of adverse effects relative to higher-dose budesonide-formoterol suspension inhalers such as SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6. Representative adverse effects that may be reduced include: upper respiratory tract infections (URTIs) such as cough, nasal congestion, sore throat, and sinus infections; headache; throat pain or irritation; stomach discomfort, nausea, or vomiting; back pain; oral thrush or white patches in the mouth or throat; voice changes or loss of voice; cold symptoms including stuffy or runny nose, sneezing, and sinus pain; muscle aches; adrenal suppression or insufficiency characterized by fatigue, low blood pressure, and weakness; increased risk of pneumonia; fast, irregular, or pounding heartbeat; high blood sugar (hyperglycemia); low blood potassium (hypokalemia) with associated musclecramps and irregular heart rhythm; bone loss, reduced bone mineral density, and risk of osteoporosis with long-term use; eye problems including glaucoma, cataracts, and vision changes; slowed growth in children; allergic reactions including rash, itching, swelling, and trouble breathing; paradoxical bronchospasm (sudden worsening of breathing); seizures; and increased susceptibility to or risk of infections..Surprising and Unexpected Results

[0128] A key surprising and unexpected result of the invention is the ability to obtain and maintain true solution formulations of budesonide and formoterol, optionally with glycopyrronium, in environmentally friendly propellants at therapeutically relevant concentrations, despite these active ingredients historically being regarded as sparingly soluble in conventional propellant-cosolvent systems and therefore typically formulated as suspensions. By employing active pharmaceutical ingredients with controlled, reduced particle size and combining them with anhydrous ethanol, hydrochloric acid, and propellants such as HFA152a, HFO-1234ze, and / or HFA134a within defined concentration ranges, the compositions remain as single-phase solutions with no visible precipitate or suspended particulate over extended storage at typical stability conditions, an outcome that was not expected from prior systems. This true solution behavior allows the elimination of resuspension requirements before use and markedly improves dose uniformity per actuation, enabling lower nominal doses of budesonide and formoterol while preserving therapeutic efficacy and reducing unnecessary systemic exposure.

[0129] Another unexpected result is that, as demonstrated in in vitro aerosol characterization, actuation of these pressurized inhalation solutions can produce aerosols with mass median aerodynamic diameters in the range of about 0.8 to 3.5 micrometers, (e.g., in the range of about 1.0 to about 1.2 micrometers), and extrafine particle fractions greater than 50 percent, which preferentially reach and deposit in the small airways and distal regions of the lungs. Enhanced peripheral deposition increases local drug concentrations at sites particularly relevant todisease pathology in asthma and chronic obstructive pulmonary disease and supports clinical efficacy at reduced nominal doses of budesonide and formoterol, thereby allowing for reduced drug load while maintaining or improving treatment outcomes. The combination of these solution-state, extra-fine aerosol, and dosereduction features can lead to reduced total drug load, improved dose consistency, enhanced deep-lung delivery, and / or improved safety and tolerability profiles compared with higher-dose suspension-based inhalers, which together represent significant and commercially meaningful advantages of the invention.Specific Ranges, Values, and Embodiments

[0130] The specific embodiments describing the ranges and values provided below are for illustration purposes only, and do not otherwise limit the scope of the disclosed subject matter, as defined by the claims. The embodiments below embrace all values and ranges individually, as well as those in combination, across multiple embodiments.Pressurized pharmaceutical composition

[0131] In specific embodiments, the pressurized pharmaceutical composition is suitable for inhalation administration.

[0132] In specific embodiments, the pressurized pharmaceutical composition includes budesonide, formoterol, optionally glycopyrronium and one or more propellants selected from HFA134a, HFA152a, and HFO-1234ze.

[0133] In specific embodiments, the pressurized pharmaceutical composition includes budesonide, formoterol, optionally glycopyrronium, anhydrous ethanol, hydrochloric acid, and one or more propellants selected from HFA134a, HFA152a, and HFO-1234ze.

[0134] In specific embodiments, the pressurized pharmaceutical composition includes budesonide, formoterol, anhydrous ethanol, hydrochloric acid, and one or more propellants selected from HFA134a, HFA152a, and HFO-1234ze.

[0135] In specific embodiments, the pressurized pharmaceutical composition includes budesonide, formoterol, glycopyrronium, anhydrous ethanol, hydrochloric acid, and one or more propellants selected from HFA134a, HFA152a, and HFO-1234ze.

[0136] In specific embodiments, the pressurized pharmaceutical composition is an optically clear, single-phase solution.

[0137] In specific embodiments, the pressurized pharmaceutical composition is an optically clear, single-phase solution in which budesonide and formoterol are substantially dissolved.

[0138] In specific embodiments, the pressurized pharmaceutical composition is an optically clear, single-phase solution in which budesonide, glycopyrronium, and formoterol are substantially dissolved.

[0139] In specific embodiments, the pressurized pharmaceutical composition is suitable for inhalation administration without the need for shaking prior to actuation, due to its optically clear, single-phase solution state.

[0140] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 0.8-3.5 pm.

[0141] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 0.8-3.25 pm.

[0142] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about O.8-3.O pm.

[0143] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 0.8-2.75 pm.

[0144] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 0.8-2.5 pm.

[0145] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 0.8-2.25 pm.

[0146] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 0.8-2.0 pm.

[0147] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-3.5 pm.

[0148] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-3.25 pm.

[0149] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-3.0 pm.

[0150] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-2.75 pm.

[0151] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-2.5 pm.

[0152] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-2.25 pm.

[0153] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-2.0 pm.

[0154] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-1.75 pm.

[0155] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0-1.5 pm.

[0156] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol having a mass median aerodynamic diameter MMAD of about 1.0- 1.2 pm with an extra-fine particle fraction greater than 50% by mass.

[0157] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol wherein the ex-actuator dose of budesonide is 25-200 pg.

[0158] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol wherein the ex-actuator dose of formoterol is 1.5-5.7 pg.

[0159] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of budesonide of 25-200 pg and an ex-actuator dose of formoterol of 1.5-5.7 pg per actuation.

[0160] In specific embodiments, the ex-actuator doses of budesonide and formoterol are selected such that the composition provides therapeutic efficacy substantially comparable to a reference suspension product selected from SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6 while employing lower nominal amounts of budesonide and / or formoterol.

[0161] In specific embodiments, actuation of the pressurized pharmaceutical composition from a pressurized metered dose inhaler (pMDI) produces an aerosol that provides therapeutic efficacy substantially comparable to that of a reference suspension product selected from SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6, while employing lower nominal doses of budesonide and / or formoterol.

[0162] In specific embodiments, the pressurized pharmaceutical composition is suitable for inhalation administration, and includes: a) budesonide at a concentration of 0.17-0.71% w / w; b) formoterol at a concentration of 0.002 -0.0166% w / w; c) optionally, glycopyrronium at a concentration of 0.01-0.03% w / w; d) anhydrous ethanol in an amount of 8-20% w / w; e) hydrochloric acid in an amount sufficient to adjust the pH of the composition to 2-5; and f) one or more propellants selected from HFA134a, HFA152a, and HFO-1234ze in an amount sufficient to bring the total composition to 100% w / w; wherein the composition is an optically clear, single-phase pressurized inhalation solution in which budesonide and formoterol are substantially dissolved and, where present, glycopyrronium is substantially dissolved, and wherein, upon actuation from a pressurized metered dose inhaler pMDI, the composition produces an aerosol having a mass median aerodynamic diameter MMAD of about 0.8 to 3.5 pm, e.g., of about 1.0-1.2 pm and an extra-fine particle fraction greater than 50% by mass.Mass (in pMDI)

[0163] In specific embodiments, the pMDI contains 7-12 grams of drug product.

[0164] In specific embodiments, the pMDI contains 7.4-11.68 grams of drug product.

[0165] In specific embodiments, the pMDI contains 7+1 grams of drug product.

[0166] In specific embodiments, the pMDI contains 7.4+0.5 grams of drug product.

[0167] In specific embodiments, the pMDI contains 8+1 grams of drug product.

[0168] In specific embodiments, the pMDI contains 9+1 grams of drug product.

[0169] In specific embodiments, the pMDI contains 9.28+0.5 grams of drug product.

[0170] In specific embodiments, the pMDI contains 9.6+0.5 grams of drug product.

[0171] In specific embodiments, the pMDI contains 9.86+0.5 grams of drug product.

[0172] In specific embodiments, the pMDI contains 10+1 grams of drug product.

[0173] In specific embodiments, the pMDI contains 11+1 grams of drug product.

[0174] In specific embodiments, the pMDI contains 11.68+0.5 grams of drug product.

[0175] In specific embodiments, the pMDI contains 12+1 grams of drug product.Mass (delivered)

[0176] In specific embodiments, 45-75 mg of drug product is delivered with the actuation of the pMDI.

[0177] In specific embodiments, 45+5 mg of drug product is delivered with the actuation of the pMDI.

[0178] In specific embodiments, 46+2.5 mg of drug product is delivered with the actuation of the pMDI.

[0179] In specific embodiments, 50+5 mg of drug product is delivered with the actuation of the pMDI.

[0180] In specific embodiments, 55+5 mg of drug product is delivered with the actuation of the pMDI.

[0181] In specific embodiments, 58+2.5 mg of drug product is delivered with the actuation of the pMDI.

[0182] In specific embodiments, 60+5 mg of drug product is delivered with the actuation of the pMDI.

[0183] In specific embodiments, 60+2.5 mg of drug product is delivered with the actuation of the pMDI.

[0184] In specific embodiments, 65+5 mg of drug product is delivered with the actuation of the pMDI.

[0185] In specific embodiments, 70+5 mg of drug product is delivered with the actuation of the pMDI.

[0186] In specific embodiments, 73+2.5 mg of drug product is delivered with the actuation of the pMDI.

[0187] In specific embodiments, 75+5 mg of drug product is delivered with the actuation of the pMDI.PH

[0188] In specific embodiments, the pH of the drug product is 2-5.0.

[0189] In specific embodiments, the pH of the drug product is 2.5-4.0.

[0190] In specific embodiments, the pH of the drug product is 2.0+0.25.

[0191] In specific embodiments, the pH of the drug product is 2.25+0.25.

[0192] In specific embodiments, the pH of the drug product is 2.5+0.25.

[0193] In specific embodiments, the pH of the drug product is 2.75+0.25.

[0194] In specific embodiments, the pH of the drug product is 2.9+0.1.

[0195] In specific embodiments, the pH of the drug product is 3.0+0.25.

[0196] In specific embodiments, the pH of the drug product is 3.25+0.25.

[0197] In specific embodiments, the pH of the drug product is 3.5+0.25.

[0198] In specific embodiments, the pH of the drug product is 3.5+0.1.

[0199] In specific embodiments, the pH of the drug product is 3.6+0.1.

[0200] In specific embodiments, the pH of the drug product is 3.75+0.25.

[0201] In specific embodiments, the pH of the drug product is 4.0+0.25.

[0202] In specific embodiments, the pH of the drug product is 4.25+0.25.

[0203] In specific embodiments, the pH of the drug product is 4.5+0.25.

[0204] In specific embodiments, the pH of the drug product is 4.75+0.25.

[0205] In specific embodiments, the pH of the drug product is 5.0+0.25.Budesonide (ex-actuator dose)

[0206] In specific embodiments, the ex-actuator dose of budesonide is 25-200 pg.

[0207] In specific embodiments, the ex-actuator dose of budesonide is 25-175 pg.

[0208] In specific embodiments, the ex-actuator dose of budesonide is 25-150 pg.

[0209] In specific embodiments, the ex-actuator dose of budesonide is 32-36 pg.

[0210] In specific embodiments, the ex-actuator dose of budesonide is 80-90 pg.

[0211] In specific embodiments, the ex-actuator dose of budesonide is 64-72 pg.

[0212] In specific embodiments, the ex-actuator dose of budesonide is 128-145 pg.

[0213] In specific embodiments, the ex-actuator dose of budesonide is 25+5 pg.

[0214] In specific embodiments, the ex-actuator dose of budesonide is 30+5 pg.

[0215] In specific embodiments, the ex-actuator dose of budesonide is 30+1 pg.

[0216] In specific embodiments, the ex-actuator dose of budesonide is 31+1 pg.

[0217] In specific embodiments, the ex-actuator dose of budesonide is 32+1 pg.

[0218] In specific embodiments, the ex-actuator dose of budesonide is 33+1 pg.

[0219] In specific embodiments, the ex-actuator dose of budesonide is 34+1 pg.

[0220] In specific embodiments, the ex-actuator dose of budesonide is 35+5 pg.

[0221] In specific embodiments, the ex-actuator dose of budesonide is 35+1 pg.

[0222] In specific embodiments, the ex-actuator dose of budesonide is 36+1 pg.

[0223] In specific embodiments, the ex-actuator dose of budesonide is 37+1 pg.

[0224] In specific embodiments, the ex-actuator dose of budesonide is 38+1 pg.

[0225] In specific embodiments, the ex-actuator dose of budesonide is 39+1 pg.

[0226] In specific embodiments, the ex-actuator dose of budesonide is 40+5 pg.

[0227] In specific embodiments, the ex-actuator dose of budesonide is 45+5 pg.

[0228] In specific embodiments, the ex-actuator dose of budesonide is 40+1 pg.

[0229] In specific embodiments, the ex-actuator dose of budesonide is 50+5 pg.

[0230] In specific embodiments, the ex-actuator dose of budesonide is 55+5 pg.

[0231] In specific embodiments, the ex-actuator dose of budesonide is 60+5 pg.

[0232] In specific embodiments, the ex-actuator dose of budesonide is 61+1 pg.

[0233] In specific embodiments, the ex-actuator dose of budesonide is 62+1 pg.

[0234] In specific embodiments, the ex-actuator dose of budesonide is 63+1 pg.

[0235] In specific embodiments, the ex-actuator dose of budesonide is 64+1 pg.

[0236] In specific embodiments, the ex-actuator dose of budesonide is 65+5 pg.

[0237] In specific embodiments, the ex-actuator dose of budesonide is 65+1 pg.

[0238] In specific embodiments, the ex-actuator dose of budesonide is 66+1 pg.

[0239] In specific embodiments, the ex-actuator dose of budesonide is 67+1 pg.

[0240] In specific embodiments, the ex-actuator dose of budesonide is 68+1 pg.

[0241] In specific embodiments, the ex-actuator dose of budesonide is 69+1 pg.

[0242] In specific embodiments, the ex-actuator dose of budesonide is 70+5 pg.

[0243] In specific embodiments, the ex-actuator dose of budesonide is 70+1 pg.

[0244] In specific embodiments, the ex-actuator dose of budesonide is 71+1 pg.

[0245] In specific embodiments, the ex-actuator dose of budesonide is 72+1 pg.

[0246] In specific embodiments, the ex-actuator dose of budesonide is 73+1 pg.

[0247] In specific embodiments, the ex-actuator dose of budesonide is 74+1 pg.

[0248] In specific embodiments, the ex-actuator dose of budesonide is 75+5 pg.

[0249] In specific embodiments, the ex-actuator dose of budesonide is 75+1 pg.

[0250] In specific embodiments, the ex-actuator dose of budesonide is 80+5 pg.

[0251] In specific embodiments, the ex-actuator dose of budesonide is 85+5 pg.

[0252] In specific embodiments, the ex-actuator dose of budesonide is 90+5 pg.

[0253] In specific embodiments, the ex-actuator dose of budesonide is 91+2.5 pg

[0254] In specific embodiments, the ex-actuator dose of budesonide is 95+5 pg.

[0255] In specific embodiments, the ex-actuator dose of budesonide is 100+5 pg.

[0256] In specific embodiments, the ex-actuator dose of budesonide is 105+5 pg.

[0257] In specific embodiments, the ex-actuator dose of budesonide is 115+5 pg.

[0258] In specific embodiments, the ex-actuator dose of budesonide is 120+5 pg.

[0259] In specific embodiments, the ex-actuator dose of budesonide is 125+5 pg.

[0260] In specific embodiments, the ex-actuator dose of budesonide is 125+1 pg.

[0261] In specific embodiments, the ex-actuator dose of budesonide is 126+1 pg.

[0262] In specific embodiments, the ex-actuator dose of budesonide is 127+1 pg.

[0263] In specific embodiments, the ex-actuator dose of budesonide is 128+1 pg.

[0264] In specific embodiments, the ex-actuator dose of budesonide is 129+1 pg.

[0265] In specific embodiments, the ex-actuator dose of budesonide is 130+5 pg.

[0266] In specific embodiments, the ex-actuator dose of budesonide is 130+1 pg.

[0267] In specific embodiments, the ex-actuator dose of budesonide is 131+1 pg.

[0268] In specific embodiments, the ex-actuator dose of budesonide is 132+1 pg.

[0269] In specific embodiments, the ex-actuator dose of budesonide is 133+1 pg.

[0270] In specific embodiments, the ex-actuator dose of budesonide is 134+1 pg.

[0271] In specific embodiments, the ex-actuator dose of budesonide is 135+5 pg.

[0272] In specific embodiments, the ex-actuator dose of budesonide is 135+1 pg.

[0273] In specific embodiments, the ex-actuator dose of budesonide is 136+1 pg.

[0274] In specific embodiments, the ex-actuator dose of budesonide is 137+1 pg.

[0275] In specific embodiments, the ex-actuator dose of budesonide is 138+1 pg.

[0276] In specific embodiments, the ex-actuator dose of budesonide is 139+1 pg.

[0277] In specific embodiments, the ex-actuator dose of budesonide is 140+5 pg.

[0278] In specific embodiments, the ex-actuator dose of budesonide is 140+1 pg.

[0279] In specific embodiments, the ex-actuator dose of budesonide is 141+1 pg.

[0280] In specific embodiments, the ex-actuator dose of budesonide is 142+1 pg.

[0281] In specific embodiments, the ex-actuator dose of budesonide is 143+1 pg.

[0282] In specific embodiments, the ex-actuator dose of budesonide is 144+1 pg.

[0283] In specific embodiments, the ex-actuator dose of budesonide is 145+5 pg.

[0284] In specific embodiments, the ex-actuator dose of budesonide is 140+1 pg.

[0285] In specific embodiments, the ex-actuator dose of budesonide is 141+1 pg.

[0286] In specific embodiments, the ex-actuator dose of budesonide is 142+1 pg.

[0287] In specific embodiments, the ex-actuator dose of budesonide is 143+1 pg.

[0288] In specific embodiments, the ex-actuator dose of budesonide is 144+1 pg.

[0289] In specific embodiments, the ex-actuator dose of budesonide is 150+5 pg.

[0290] In specific embodiments, the ex-actuator dose of budesonide is 150+1 pg.

[0291] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of budesonide of 25-150 pg per actuation.

[0292] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of budesonide of 32-36 pg per actuation.

[0293] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of budesonide of 64-72 pg per actuation.

[0294] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of budesonide of 80-90 pg per actuation.

[0295] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of budesonide of 128-145 pg per actuation.Budesonide (ex-valve dose)

[0296] In specific embodiments, the ex-valve dose of budesonide is 35-250 pg.

[0297] In specific embodiments, the ex-valve dose of budesonide is 35-225 pg.

[0298] In specific embodiments, the ex-valve dose of budesonide is 35-200 pg.

[0299] In specific embodiments, the ex-valve dose of budesonide is 35-175 pg.

[0300] In specific embodiments, the ex-valve dose of budesonide is 35-165 pg.

[0301] In specific embodiments, the ex-valve dose of budesonide is 35+5 pg.

[0302] In specific embodiments, the ex-valve dose of budesonide is 40+10 pg.

[0303] In specific embodiments, the ex-valve dose of budesonide is 40+9 pg.

[0304] In specific embodiments, the ex-valve dose of budesonide is 40+8 pg.

[0305] In specific embodiments, the ex-valve dose of budesonide is 40+7 pg.

[0306] In specific embodiments, the ex-valve dose of budesonide is 40+6 pg.

[0307] In specific embodiments, the ex-valve dose of budesonide is 40+5 pg.

[0308] In specific embodiments, the ex-valve dose of budesonide is 40+4 pg.

[0309] In specific embodiments, the ex-valve dose of budesonide is 40+3 pg.

[0310] In specific embodiments, the ex-valve dose of budesonide is 40+2 pg.

[0311] In specific embodiments, the ex-valve dose of budesonide is 40+1 pg.

[0312] In specific embodiments, the ex-valve dose of budesonide is 45+5 pg.

[0313] In specific embodiments, the ex-valve dose of budesonide is 50+5 pg.

[0314] In specific embodiments, the ex-valve dose of budesonide is 55+5 pg.

[0315] In specific embodiments, the ex-valve dose of budesonide is 60+5 pg.

[0316] In specific embodiments, the ex-valve dose of budesonide is 65+5 pg.

[0317] In specific embodiments, the ex-valve dose of budesonide is 70+5 pg.

[0318] In specific embodiments, the ex-valve dose of budesonide is 75+5 pg.

[0319] In specific embodiments, the ex-valve dose of budesonide is 80+10 pg.

[0320] In specific embodiments, the ex-valve dose of budesonide is 80+9 pg.

[0321] In specific embodiments, the ex-valve dose of budesonide is 80+8 pg.

[0322] In specific embodiments, the ex-valve dose of budesonide is 80+7 pg.

[0323] In specific embodiments, the ex-valve dose of budesonide is 80+6 pg.

[0324] In specific embodiments, the ex-valve dose of budesonide is 80+5 pg.

[0325] In specific embodiments, the ex-valve dose of budesonide is 80+4 pg.

[0326] In specific embodiments, the ex-valve dose of budesonide is 80+3 pg.

[0327] In specific embodiments, the ex-valve dose of budesonide is 80+2 pg.

[0328] In specific embodiments, the ex-valve dose of budesonide is 80+1 pg.

[0329] In specific embodiments, the ex-valve dose of budesonide is 85+5 pg.

[0330] In specific embodiments, the ex-valve dose of budesonide is 90+5 pg.

[0331] In specific embodiments, the ex-valve dose of budesonide is 95+5 pg.

[0332] In specific embodiments, the ex-valve dose of budesonide is 100+10 pg.

[0333] In specific embodiments, the ex-valve dose of budesonide is 100+9 pg.

[0334] In specific embodiments, the ex-valve dose of budesonide is 100+8 pg.

[0335] In specific embodiments, the ex-valve dose of budesonide is 100+7 pg.

[0336] In specific embodiments, the ex-valve dose of budesonide is 100+6 pg.

[0337] In specific embodiments, the ex-valve dose of budesonide is 100+5 pg.

[0338] In specific embodiments, the ex-valve dose of budesonide is 100+4 pg.

[0339] In specific embodiments, the ex-valve dose of budesonide is 100+3 pg.

[0340] In specific embodiments, the ex-valve dose of budesonide is 100+2 pg.

[0341] In specific embodiments, the ex-valve dose of budesonide is 100+1 pg.

[0342] In specific embodiments, the ex-valve dose of budesonide is 105+5 pg.

[0343] In specific embodiments, the ex-valve dose of budesonide is 110+5 pg.

[0344] In specific embodiments, the ex-valve dose of budesonide is 115+5 pg.

[0345] In specific embodiments, the ex-valve dose of budesonide is 120+5 pg.

[0346] In specific embodiments, the ex-valve dose of budesonide is 125+5 pg.

[0347] In specific embodiments, the ex-valve dose of budesonide is 130+5 pg.

[0348] In specific embodiments, the ex-valve dose of budesonide is 135+5 pg.

[0349] In specific embodiments, the ex-valve dose of budesonide is 140+5 pg.

[0350] In specific embodiments, the ex-valve dose of budesonide is 145+5 pg.

[0351] In specific embodiments, the ex-valve dose of budesonide is 150+5 pg.

[0352] In specific embodiments, the ex-valve dose of budesonide is 155+5 pg.

[0353] In specific embodiments, the ex-valve dose of budesonide is 160+10 pg

[0354] In specific embodiments, the ex-valve dose of budesonide is 160+9 pg.

[0355] In specific embodiments, the ex-valve dose of budesonide is 160+8 pg.

[0356] In specific embodiments, the ex-valve dose of budesonide is 160+7 pg.

[0357] In specific embodiments, the ex-valve dose of budesonide is 160+6 pg.

[0358] In specific embodiments, the ex-valve dose of budesonide is 160+5 pg.

[0359] In specific embodiments, the ex-valve dose of budesonide is 160+4 pg.

[0360] In specific embodiments, the ex-valve dose of budesonide is 160+3 pg.

[0361] In specific embodiments, the ex-valve dose of budesonide is 160+2 pg.

[0362] In specific embodiments, the ex-valve dose of budesonide is 160+1 pg.

[0363] In specific embodiments, the ex-valve dose of budesonide is 165+5 pg.

[0364] In specific embodiments, actuation from a pMDI delivers an ex-valve dose of budesonide of 35-165 pg per actuation.

[0365] In specific embodiments, actuation from a pMDI delivers an ex-valve dose of budesonide of 40-80 pg per actuation.

[0366] In specific embodiments, actuation from a pMDI delivers an ex-valve dose of budesonide of 80-120 pg per actuation.

[0367] In specific embodiments, actuation from a pMDI delivers an ex-valve dose of budesonide of 100-160 pg per actuation.

[0368] In specific embodiments, actuation from a pMDI delivers an ex-valve dose of budesonide of 45-75 pg per actuation.Budesonide (particle size, drug substance)

[0369] In specific embodiments, the budesonide drug substance has a particle size D10: 0.7 pm (NMT 1.2 pm).

[0370] In specific embodiments, the budesonide drug substance has a particle size D10: 1.1 pm (NMT 1.2 pm).

[0371] In specific embodiments, the budesonide drug substance has a particle size D10: NMT 1.2 pm.

[0372] In specific embodiments, the budesonide drug substance has a particle size D50: 1.5 pm (NMT 3.5 pm).

[0373] In specific embodiments, the budesonide drug substance has a particle size D50: 1.7 pm (NMT 3.5 m).

[0374] In specific embodiments, the budesonide drug substance has a particle size D50: 2.6 pm (NMT 3.5 pm).

[0375] In specific embodiments, the budesonide drug substance has a particle size D50: NMT 3.5 pm.

[0376] In specific embodiments, the budesonide drug substance has a particle size D90: 3.0 pm (NMT 7.0 pm).

[0377] In specific embodiments, the budesonide drug substance has a particle size D90: 3.6 pm (NMT 7.0 pm).

[0378] In specific embodiments, the budesonide drug substance has a particle size D90: 5.3 pm (NMT 7.0 pm).

[0379] In specific embodiments, the budesonide drug substance has a particle size D90: NMT 7.0 pm.

[0380] In specific embodiments, the budesonide drug substance has a particle size D97: 3.9 pm (NMT 10.0 pm).

[0381] In specific embodiments, the budesonide drug substance has a particle size D97: 5.0 pm (NMT 10.0 pm).

[0382] In specific embodiments, the budesonide drug substance has a particle size D97: 7.0 pm (NMT 10.0 pm).

[0383] In specific embodiments, the budesonide drug substance has a particle size D97: NMT 10.0 pm.Budesonide (MMAD, in vitro)

[0384] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.8- 3.5.

[0385] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.8- 3.25.

[0386] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.8-3.0.

[0387] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.8-2.75.

[0388] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.8- 2.5.

[0389] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.8- 2.25.

[0390] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.8-2.0.

[0391] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.9-2.7.

[0392] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.0-1.2.

[0393] In specific embodiments, the budesonide has an MMAD, in vitro, of 0.9+0.1.

[0394] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.0+0.1.

[0395] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.2+0.1.

[0396] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.3+0.1.

[0397] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.4+0.1.

[0398] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.5+0.1.

[0399] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.6+0.1.

[0400] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.7+0.1.

[0401] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.8+0.1.

[0402] In specific embodiments, the budesonide has an MMAD, in vitro, of 1.9+0.1.

[0403] In specific embodiments, the budesonide has an MMAD, in vitro, of 2.0+0.1.

[0404] In specific embodiments, the budesonide has an MMAD, in vitro, of 2.1+0.1.

[0405] In specific embodiments, the budesonide has an MMAD, in vitro, of 2.2+0.1.

[0406] In specific embodiments, the budesonide has an MMAD, in vitro, of 2.3+0.1.

[0407] In specific embodiments, the budesonide has an MMAD, in vitro, of 2.4+0.1.

[0408] In specific embodiments, the budesonide has an MMAD, in vitro, of 2.5+0.1.

[0409] In specific embodiments, the budesonide has an MMAD, in vitro, of 2.6+0.1.

[0410] In specific embodiments, the budesonide has an MMAD, in vitro, of 2.7+0.1.Formoterol (ex-actuator dose)

[0411] In specific embodiments, the ex-actuator dose of formoterol is 1.5-5.7 pg.

[0412] In specific embodiments, the ex-actuator dose of formoterol is 1.7-2.1 pg.

[0413] In specific embodiments, the ex-actuator dose of formoterol is 5-5.5 pg.

[0414] In specific embodiments, the ex-actuator dose of formoterol is 2.2-2.7 pg.

[0415] In specific embodiments, the ex-actuator dose of formoterol is 3.5-4 pg.

[0416] In specific embodiments, the ex-actuator dose of formoterol is 1.5+0.25 pg.

[0417] In specific embodiments, the ex-actuator dose of formoterol is 1.75+0.25 hg-

[0418] In specific embodiments, the ex-actuator dose of formoterol is 2.0+0.25 pg.

[0419] In specific embodiments, the ex-actuator dose of formoterol is 2.25+0.25 hg-

[0420] In specific embodiments, the ex-actuator dose of formoterol is 2.5+0.25 pg.

[0421] In specific embodiments, the ex-actuator dose of formoterol is 2.75+0.25 hg-

[0422] In specific embodiments, the ex-actuator dose of formoterol is 3.0+0.25 pg.

[0423] In specific embodiments, the ex-actuator dose of formoterol is 3.25+0.25 hg-

[0424] In specific embodiments, the ex-actuator dose of formoterol is 3.5+0.25 pg.

[0425] In specific embodiments, the ex-actuator dose of formoterol is 3.75+0.25 gg-

[0426] In specific embodiments, the ex-actuator dose of formoterol is 4.0+0.25 pg.

[0427] In specific embodiments, the ex-actuator dose of formoterol is 4.25+0.25 gg-

[0428] In specific embodiments, the ex-actuator dose of formoterol is 4.5+0.25 pg.

[0429] In specific embodiments, the ex-actuator dose of formoterol is 4.75+0.25 gg-

[0430] In specific embodiments, the ex-actuator dose of formoterol is 5.0+0.25 pg.

[0431] In specific embodiments, the ex-actuator dose of formoterol is 5.1+0.25 pg.

[0432] In specific embodiments, the ex-actuator dose of formoterol is 5.25+0.25 gg-

[0433] In specific embodiments, the ex-actuator dose of formoterol is 5.5+0.25 pg.

[0434] In specific embodiments, the ex-actuator dose of formoterol is 5.75+0.25 gg-

[0435] In specific embodiments, the ex-actuator dose of formoterol is 6.0+0.25 pg.

[0436] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of formoterol of 1.5-5.7 pg per actuation.

[0437] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of formoterol of 1.5-3.0 pg per actuation.

[0438] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of formoterol of 3.0-4.5 pg per actuation.

[0439] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of formoterol of 4.0-5.5 pg per actuation.

[0440] In specific embodiments, actuation from a pMDI delivers an ex-actuator dose of formoterol of 4.0-5.0 pg per actuation.Formoterol (ex-valve dose)

[0441] In specific embodiments, the ex-valve dose of formoterol is 2-6.5 pg.

[0442] In specific embodiments, the ex-valve dose of formoterol is 2+0.25 pg.

[0443] In specific embodiments, the ex-valve dose of formoterol is 2.25+0.25 pg.

[0444] In specific embodiments, the ex-valve dose of formoterol is 2.3+0.25 pg.

[0445] In specific embodiments, the ex-valve dose of formoterol is 2.5+0.25 pg.

[0446] In specific embodiments, the ex-valve dose of formoterol is 2.75+0.25 pg.

[0447] In specific embodiments, the ex-valve dose of formoterol is 3+0.25 pg.

[0448] In specific embodiments, the ex-valve dose of formoterol is 3.25+0.25 pg.

[0449] In specific embodiments, the ex-valve dose of formoterol is 3.5+0.25 pg.

[0450] In specific embodiments, the ex-valve dose of formoterol is 3.75+0.25 pg.

[0451] In specific embodiments, the ex-valve dose of formoterol is 4+0.25 pg.

[0452] In specific embodiments, the ex-valve dose of formoterol is 4.25+0.25 pg.

[0453] In specific embodiments, the ex-valve dose of formoterol is 4.5+0.25 pg.

[0454] In specific embodiments, the ex-valve dose of formoterol is 4.75+0.25 pg.

[0455] In specific embodiments, the ex-valve dose of formoterol is 4.8+0.25 pg.

[0456] In specific embodiments, the ex-valve dose of formoterol is 5+0.25 pg.

[0457] In specific embodiments, the ex-valve dose of formoterol is 5.25+0.25 pg.

[0458] In specific embodiments, the ex-valve dose of formoterol is 5.5+0.25 pg.

[0459] In specific embodiments, the ex-valve dose of formoterol is 5.75+0.25 pg.

[0460] In specific embodiments, the ex-valve dose of formoterol is 6+0.25 pg.

[0461] In specific embodiments, the ex-valve dose of formoterol is 6.25+0.25 pg.

[0462] In specific embodiments, the ex-valve dose of formoterol is 6.5+0.25 pg.

[0463] In specific embodiments, the ex-valve dose of formoterol is 6.75+0.25 pg.

[0464] In specific embodiments, the ex-valve dose of formoterol is 7+0.25 pg.

[0465] In specific embodiments, actuation from a pMDI delivers an ex -valve dose of formoterol of 2-6.5 pg per actuation.

[0466] In specific embodiments, actuation from a pMDI delivers an ex-valve dose of formoterol of 2.0-4.0 pg per actuation.

[0467] In specific embodiments, actuation from a pMDI delivers an ex -valve dose of formoterol of 3.0-5.0 pg per actuation.

[0468] In specific embodiments, actuation from a pMDI delivers an ex -valve dose of formoterol of 4.0-6.0 pg per actuation.In specific embodiments, actuation from a pMDI delivers an ex -valve dose of formoterol of 4.0-5.5 pg per actuation.Formoterol (particle size, drug substance)

[0469] In specific embodiments, the formoterol drug substance has a particle size DIO: 0.8 pm (NMT 1.0 pm).

[0470] In specific embodiments, the formoterol drug substance has a particle size D10: NMT 1.0 pm.

[0471] In specific embodiments, the formoterol drug substance has a particle size D50: 1.9 pm (NMT 3.0 pm).

[0472] In specific embodiments, the formoterol drug substance has a particle size D50: NMT 3.0 pm.

[0473] In specific embodiments, the formoterol drug substance has a particle size D90: 3.5 pm (NMT 5.0 pm).

[0474] In specific embodiments, the formoterol drug substance has a particle size D90: 3.6 pm (NMT 5.0 pm).

[0475] In specific embodiments, the formoterol drug substance has a particle size D90: NMT 5.0 pm.

[0476] In specific embodiments, the formoterol drug substance has a particle size D97: 4.3 pm (NMT 10.0 pm).

[0477] In specific embodiments, the formoterol drug substance has a particle size D97: NMT 10.0 pm.Formoterol (MM AD, in vitro)

[0478] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.8-3.5.

[0479] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.8- 3.25.

[0480] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.8-3.0.

[0481] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.8-2.75.

[0482] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.8-2.5.

[0483] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.8- 2.25.

[0484] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.8-2.0.

[0485] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.9-2.7.

[0486] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.0- 1.2.

[0487] In specific embodiments, the formoterol has an MMAD, in vitro, of 0.9+0.1.

[0488] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.0+0.1.

[0489] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.2+0.1.

[0490] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.3+0.1.

[0491] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.4+0.1.

[0492] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.5+0.1.

[0493] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.6+0.1.

[0494] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.7+0.1.

[0495] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.8+0.1.

[0496] In specific embodiments, the formoterol has an MMAD, in vitro, of 1.9+0.1.

[0497] In specific embodiments, the formoterol has an MMAD, in vitro, of 2.0+0.1.

[0498] In specific embodiments, the formoterol has an MMAD, in vitro, of 2.1+0.1.

[0499] In specific embodiments, the formoterol has an MMAD, in vitro, of 2.2+0.1.

[0500] In specific embodiments, the formoterol has an MMAD, in vitro, of 2.3+0.1.

[0501] In specific embodiments, the formoterol has an MMAD, in vitro, of 2.4+0.1.

[0502] In specific embodiments, the formoterol has an MMAD, in vitro, of 2.5+0.1.

[0503] In specific embodiments, the formoterol has an MMAD, in vitro, of 2.6+0.1.

[0504] In specific embodiments, the formoterol has an MMAD, in vitro, of 2.7+0.1.Budesonide concentration (% w / w)

[0505] In specific embodiments, the pressurized inhalation solution includes budesonide in < 0.71% (w / w).

[0506] In specific embodiments, the pressurized inhalation solution includes budesonide in < 0.70% (w / w).

[0507] In specific embodiments, the pressurized inhalation solution includes budesonide in < 0.65% (w / w).

[0508] In specific embodiments, the pressurized inhalation solution includes budesonide in < 0.675% (w / w).

[0509] In specific embodiments, the pressurized inhalation solution includes budesonide in < 0.60% (w / w).

[0510] In specific embodiments, the pressurized inhalation solution includes budesonide in < 0.56% (w / w).

[0511] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.03-0.71% (w / w).

[0512] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.05-0.71% (w / w).

[0513] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.075-0.71% (w / w).

[0514] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.10-0.71% (w / w).

[0515] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.125-0.71% (w / w).

[0516] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.15-0.71% (w / w).

[0517] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.175-0.71% (w / w).

[0518] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.20-0.71% (w / w).

[0519] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.10-0.60% (w / w).

[0520] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.17-0.56% (w / w).

[0521] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.03+0.01% (w / w).

[0522] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.05+0.01% (w / w).

[0523] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.10+0.05% (w / w).

[0524] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.10+0.025% (w / w).

[0525] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.17+0.03% (w / w).

[0526] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.17+0.02% (w / w).

[0527] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.17+0.01% (w / w).

[0528] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.17% (w / w).

[0529] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.28+0.06% (w / w).

[0530] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.28+0.05% (w / w).

[0531] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.28+0.04% (w / w).

[0532] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.28% (w / w).

[0533] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.56+0.125% (w / w)

[0534] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.56+0.1% (w / w).

[0535] In specific embodiments, the pressurized inhalation solution includes budesonide in 0.56+0.05% (w / w).

[0536] In specific embodiments, the pressunzed inhalation solution includes budesonide in 0.56% (w / w).Formoterol concentration (% n’ / u’J

[0537] In specific embodiments, the pressurized inhalation solution includes formoterol in < 0.017% (w / w).

[0538] In specific embodiments, the pressurized inhalation solution includes formoterol in < 0.0166% (w / w).

[0539] In specific embodiments, the pressurized inhalation solution includes formoterol in < 0.014% (w / w).

[0540] In specific embodiments, the pressurized inhalation solution includes formoterol in < 0.012% (w / w).

[0541] In specific embodiments, the pressurized inhalation solution includes formoterol in < 0.0103% (w / w).

[0542] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.002-0.017% (w / w).

[0543] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.002-0.0166% (w / w).

[0544] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.002-0.014% (w / w).

[0545] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.002-0.012% (w / w).

[0546] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0042+0.009% (w / w).

[0547] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0042+0.007% (w / w).

[0548] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0042+0.004% (w / w).

[0549] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0042% (w / w).

[0550] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0052+0.0010% (w / w).

[0551] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0052+0.0005% (w / w).

[0552] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0052+0.0002% (w / w).

[0553] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0052% (w / w).

[0554] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0067+0.0015% (w / w).

[0555] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0067+0.0010% (w / w).

[0556] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0067+0.0005% (w / w).

[0557] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0067% (w / w).

[0558] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0083+0.0017% (w / w).

[0559] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0083+0.0008% (w / w).

[0560] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0083+0.0005% (w / w).

[0561] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0083% (w / w).

[0562] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0103+0.0021% (w / w).

[0563] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0103+0.0015% (w / w).

[0564] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0103+0.0010% (w / w).

[0565] In specific embodiments, the pressurized inhalation solution includes formoterol in 0.0103% (w / w).Glycopyrronium concentration (% w / w)

[0566] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in < 0.025% (w / w).

[0567] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in < 0.021% (w / w).

[0568] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.017-0.021% (w / w).

[0569] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.017+0.0035% (w / w).

[0570] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.017+0.0017% (w / w).

[0571] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.017+0.001% (w / w).

[0572] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.017% (w / w).

[0573] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.021+0.0045% (w / w).

[0574] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.021+0.0025% (w / w).

[0575] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.021+0.001% (w / w).

[0576] In specific embodiments, the pressurized inhalation solution includes glycopyrronium in 0.021% (w / w).PCT01209EX-ACTUATOR DOSE (formoterol; budesonide)

[0577] In specific embodiments, the ex-actuator dose (formoterol; budesonide) is any one of those shown below.EX-ACTUATOR DOSE (formoterol; budesonide)PCT01209EX-VALVE DOSE (formoterol; budesonide)

[0578] In specific embodiments, the ex-valve dose (formoterol; budesonide) is any one of those shown below.Ethanol (anhydrous)

[0579] In specific embodiments, the ethanol is anhydrous.

[0580] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.89-1.1832 g.

[0581] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.152-1.1832 g.

[0582] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.80+0.05 g.

[0583] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.85+0.05 g.

[0584] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.90+0.05 g.

[0585] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.95+0.05 g.

[0586] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.00+0.05 g.

[0587] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.05+0.05 g.

[0588] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.10+0.05 g.

[0589] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.15+0.05 g.

[0590] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.150+0.005 g.

[0591] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.155+0.005 g.

[0592] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.160+0.005 g.

[0593] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.165+0.005 g.

[0594] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.170+0.005 g.

[0595] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.175+0.005 g.

[0596] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.180+0.005 g.

[0597] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.185+0.005 g.

[0598] In specific embodiments, the ethanol (anhydrous) is present in the can in 8-20% w / w.

[0599] In specific embodiments, the ethanol (anhydrous) is present in the can in 10-20% w / w.

[0600] In specific embodiments, the ethanol (anhydrous) is present in the can in 12-20% w / w.

[0601] In specific embodiments, the ethanol (anhydrous) is present in the can in 15-20% w / w.

[0602] In specific embodiments, the ethanol (anhydrous) is present in the can in 8-18% w / w.

[0603] In specific embodiments, the ethanol (anhydrous) is present in the can in 8-17.5% w / w.

[0604] In specific embodiments, the ethanol (anhydrous) is present in the can in 8-15% w / w.

[0605] In specific embodiments, the ethanol (anhydrous) is present in the can in 12% w / w.

[0606] In specific embodiments, the ethanol (anhydrous) is present in the can in 12+2% w / w.

[0607] In specific embodiments, the ethanol (anhydrous) is present in the can in 12+1.5% w / w.

[0608] In specific embodiments, the ethanol (anhydrous) is present in the can in 12+1% w / w.

[0609] In specific embodiments, the ethanol (anhydrous) is present in the can in 12+0.5% w / w.

[0610] In specific embodiments, the ethanol (anhydrous) is present in the can in 12+0.25% w / w.

[0611] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.1832+0.035 g.

[0612] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.1832+0.030 g.

[0613] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.1832+0.025 g.

[0614] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.1832+0.020 g.

[0615] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.1832+0.015 g.

[0616] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.1832+0.010 g.

[0617] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.1832+0.005 g.

[0618] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.1832 g.

[0619] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.152+0.025 g.

[0620] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.152+0.020 g.

[0621] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.152+0.015 g.

[0622] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.152+0.010 g.

[0623] In specific embodiments, the ethanol (anhydrous) is present in the can in 1.152 g.

[0624] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.89+0.05 g.

[0625] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.89+0.04 g.

[0626] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.89+0.03 g.

[0627] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.89+0.02 g.

[0628] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.89+0.01 g.

[0629] In specific embodiments, the ethanol (anhydrous) is present in the can in 0.89 g.Acid

[0630] In specific embodiments, the acid is at least one of hydrochloric acid, sulfuric acid, nitric acid, maleic acid, and citric acid.

[0631] In specific embodiments, the acid is HC1.

[0632] In specific embodiments, the acid is IN HC1.

[0633] In specific embodiments, the acid is present as 0.85-3.5 mg IN HC1.

[0634] In specific embodiments, the acid is present as 1-3 mg IN HC1.

[0635] In specific embodiments, the acid is present as 1+0.25 mg IN HC1.

[0636] In specific embodiments, the acid is present as 1.25+0.25 mg IN HC1.

[0637] In specific embodiments, the acid is present as 1.5+0.25 mg IN HC1.

[0638] In specific embodiments, the acid is present as 1.75+0.25 mg IN HC1.

[0639] In specific embodiments, the acid is present as 2+0.25 mg IN HC1.

[0640] In specific embodiments, the acid is present as 2.25+0.25 mg IN HC1.

[0641] In specific embodiments, the acid is present as 2.5+0.25 mg IN HC1.

[0642] In specific embodiments, the acid is present as 2.75+0.25 mg IN HC1.

[0643] In specific embodiments, the acid is present as 3+0.25 mg IN HC1.

[0644] In specific embodiments, the acid is present as 3.25+0.25 mg IN HC1.

[0645] In specific embodiments, the acid is present as 3.5+0.25 mg IN HC1.Co-solvent

[0646] In specific embodiments, the co-solvent is glycerol.

[0647] In specific embodiments, the glycerol is present in the can in 6.72+1.5 mg.

[0648] In specific embodiments, the glycerol is present in the can in 6.72+1.25 mg.

[0649] In specific embodiments, the glycerol is present in the can in 6.72+1 mg.

[0650] In specific embodiments, the glycerol is present in the can in 6.72+0.75 mg.

[0651] In specific embodiments, the glycerol is present in the can in 6.72+0.5 mg.

[0652] In specific embodiments, the glycerol is present in the can in 6.72+0.25 mg.

[0653] In specific embodiments, the glycerol is present in the can in 6.72+0.1 mg.

[0654] In specific embodiments, the glycerol is present in the can in 6.72+0.05 mg.

[0655] In specific embodiments, the glycerol is present in the can in 6.72 mg.

[0656] In specific embodiments, the glycerol is present in the can in 0.3-3.0% w / w.

[0657] In specific embodiments, the glycerol is present in the can in 0.3-2.0% w / w.

[0658] In specific embodiments, the glycerol is present in the can in 0.3-1.2% w / w.

[0659] In specific embodiments, the glycerol is present in the can in 0.4-1.0% w / w.

[0660] In specific embodiments, the glycerol is present in the can in 0.5-0.9% w / w.

[0661] In specific embodiments, the glycerol is present in the can in 0.5-0.8% w / w.Propellant

[0662] In specific embodiments, the propellant is present in the can in 8-9 g.

[0663] In specific embodiments, the propellant is present in the can in 8.40-8.70 g.

[0664] In specific embodiments, the propellant is present in the can in 6.48+0.5 g.

[0665] In specific embodiments, the propellant is present in the can in 8.40+0.5 g.

[0666] In specific embodiments, the propellant is present in the can in 8.43+0.5 g.

[0667] In specific embodiments, the propellant is present in the can in 8.45+0.5 g.

[0668] In specific embodiments, the propellant is present in the can in 8.50+0.5 g.

[0669] In specific embodiments, the propellant is present in the can in 8.55+0.5 g.

[0670] In specific embodiments, the propellant is present in the can in 8.60+0.5 g.

[0671] In specific embodiments, the propellant is present in the can in 8.65+0.5 g.

[0672] In specific embodiments, the propellant is present in the can in 8.66+0.5 g.

[0673] In specific embodiments, the propellant is present in the can in 8.70+0.5 g.

[0674] In specific embodiments, the propellant is HFA134a.

[0675] In specific embodiments, the propellant is HFA134a, present in the can in 8.40-8.70 g.

[0676] In specific embodiments, the propellant is HFA134a, present in the can in 8.40+0.5 g.

[0677] In specific embodiments, the propellant is HFA134a, present in the can in 8.43+0.5 g.

[0678] In specific embodiments, the propellant is HFA134a, present in the can in 8.45+0.5 g.

[0679] In specific embodiments, the propellant is HFA134a, present in the can in 8.50+0.5 g.

[0680] In specific embodiments, the propellant is HFA134a, present in the can in 8.55+0.5 g.

[0681] In specific embodiments, the propellant is HFA134a, present in the can in 8.60+0.5 g.

[0682] In specific embodiments, the propellant is HFA134a, present in the can in 8.65+0.5 g.

[0683] In specific embodiments, the propellant is HFA134a, present in the can in 8.66+0.5 g.

[0684] In specific embodiments, the propellant is HFA134a, present in the can in 8.70+0.5 g.

[0685] In specific embodiments, the propellant is HFA152a.

[0686] In specific embodiments, the propellant is HFA152a, present in the can in 6.48+0.5 g.

[0687] In specific embodiments, the propellant is HFO1234ze.

[0688] In specific embodiments, the propellant is HFO1234ze, present in the can in 8.66+0.5 g.Volume of liquid

[0689] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 25-100 microliters (pL).

[0690] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 50-75 microliters (pL).

[0691] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 50-65 microliters (pL).

[0692] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 50-63 microliters (pL).

[0693] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 50-62.5 microliters (pL).

[0694] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 56.5+6.5 microliters (pL).

[0695] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 56.5+6 microliters (pL).

[0696] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 56.5+5.5 microliters (pL).

[0697] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 56.5+5 microliters (pL).

[0698] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 56.5+4.5 microliters (pL).

[0699] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 56.5+4 microliters (pL).

[0700] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 56.5+3.5 microliters (pL).

[0701] In specific embodiments, the volume of liquid dispensed, per actuation by the pressurized metered dose inhaler (pMDI), is 56.5+3 microliters (pL).Pressurized inhalation, solution

[0702] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA.

[0703] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid (e.g., budesonide) and LABA (e.g., formoterol).

[0704] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes budesonide and formoterol.

[0705] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA.

[0706] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid (e.g., budesonide), LABA (e.g., formoterol), and LAMA (glycop yrronium) .

[0707] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes budesonide, formoterol, and glycopyrronium.

[0708] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide and formoterol.

[0709] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, and HFA134a.

[0710] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, glycop yrronium, formoterol, ethanol, HC1, and HFA134a.

[0711] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, and HFA152a.

[0712] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, and HFO1234ze.

[0713] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, and HFA152a.

[0714] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, and HFO1234ze.

[0715] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, and HFA152a.

[0716] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, and HFO1234ze.

[0717] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, glycerol, and HFA152a.

[0718] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, glycerol, and HFO1234ze.

[0719] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, glycerol, and HFA152a.

[0720] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, glycerol, and HFO1234ze.

[0721] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, glycerol, and HFA152a.

[0722] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide, formoterol, ethanol, HC1, glycerol, and HFO1234ze.

[0723] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide (0.17-0.56% w / w) and formoterol (0.0042-0.0103% w / w).

[0724] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide (0.17-0.56% w / w) and formoterol (0.0042-0.0103% w / w) and propellant HFA134a, HFA152a, or HFO-1234ze (q.s.).

[0725] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide (0.17-0.56% w / w), formoterol (0. 0042-0.0103% w / w), ethanol (12.5-20% w / w), IN HC1 (q.s. to pH 2.5-4), optionally glycerol (0.3-3.0% w / w), and propellant HFA134a, HFA152a, or HFO-1234ze (q.s.).

[0726] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) that includes budesonide (<0.71% w / w), formoterol (<0.0166% w / w), ethanol (8-20% w / w), HC1 (q.s. to pH 2-5), optionally glycerol (0.3-3% w / w), and propellant HFA134a, HFA152a, or HFO-1234ze (q.s.).

[0727] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is suitable for inhalation administration without the need for shaking prior to actuation.Ratio, corticosteroid:LABA

[0728] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA.

[0729] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02 to 1:0.10, respectively.

[0730] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.04 to 1:0.08, respectively.

[0731] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.06, respectively.

[0732] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.0247 to 1:0.0187, respectively.

[0733] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02470, respectively.

[0734] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02427, respectively.

[0735] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02384, respectively.

[0736] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02341, respectively.

[0737] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02299, respectively.

[0738] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02256, respectively.

[0739] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02213, respectively.

[0740] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02170, respectively.

[0741] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02127, respectively.

[0742] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02084, respectively.

[0743] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.02041, respectively.

[0744] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.01999, respectively.

[0745] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.01956, respectively.

[0746] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.01913, respectively.

[0747] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a binary system that includes corticosteroid and LABA in a weight ratio of 1:0.01870, respectively.Ratio, corticosteroid:LABA :LAMA

[0748] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA.

[0749] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.06:0.05, respectively.

[0750] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.02471:0.10 to 1:0.01482:0.0375, respectively.

[0751] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.02471:0.10000, respectively.

[0752] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.02400:0.09554, respectively.

[0753] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.02330:0.09107, respectively.

[0754] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.02259:0.08661, respectively.

[0755] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.02188:0.08214, respectively.

[0756] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.02118:0.07768, respectively.

[0757] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.02047:0.07321, respectively.

[0758] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.01976:0.06875, respectively.

[0759] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.01906:0.06429, respectively.

[0760] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.01835:0.05982, respectively.

[0761] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includescorticosteroid, LABA, and LAMA in a weight ratio of 1:0.01765:0.05536, respectively.

[0762] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.01694:0.05089, respectively.

[0763] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.01623:0.04643, respectively.

[0764] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.01553:0.04196, respectively.

[0765] In specific embodiments, the formulation is a solution contained within a pMDI (pressurized metered dose inhaler) and is a ternary system that includes corticosteroid, LABA, and LAMA in a weight ratio of 1:0.01482:0.03750, respectively.Preparation Methods and Methods of Use

[0766] In specific embodiments, the pressurized inhalation solution is prepared by (1) dissolving the active ingredients (e.g., budesonide and formoterol) in solvent (e.g., anhydrous ethanol and optionally glycerol) with addition of acid (e.g., IN HC1) under nitrogen, followed by (2) addition of propellant (e.g., HFA152a or HFO1234ze) under pressure, and the resulting solution is (3) filled into a metered-dose inhaler canister, and (4) crimped; wherein all steps are performed at 20-25°C.

[0767] In specific embodiments, the pressurized inhalation solution is prepared as follows: to manufacture the formulation, a mixture of acid (e.g., IN hydrochloricacid) and solvent (e.g., anhydrous ethanol) was first prepared. The active ingredients (e.g., budesonide and formoterol), in the amounts required for the batch, were then weighed precisely and added to the acid- solvent mixture. The resulting combination was homogenized until a clear solution was obtained. This solution was subsequently transferred to a mixing vessel, where it was combined with the remaining quantity of propellant (e.g., HFA152a or HFO1234ze or HFA134a) and thoroughly mixed. The finished solution was then recirculated through the filling line and dispensed into pre-crimped canisters. Following filling, the canisters were placed in quarantine and the formulation was evaluated for aerodynamic particle size distribution.

[0768] Further disclosed here is a method of preventing or treating respiratory disorder according to any embodiment of the invention, wherein the respiratory disorder is selected from asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid resistant asthma, severe asthma, pediatric asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis and interstitial lung disease.

[0769] Also disclosed here is a method of administering the invention compositions for preventing or treating respiratory disorder, wherein the respiratory disorder is selected from asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid resistant asthma, severe asthma, pediatric asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis and interstitial lung disease. In further embodiments, the combination composition can be administered using pMDI, or BAI or nebulizer.

[0770] In specific embodiments, administration of the composition provides therapeutic efficacy equivalent to a commercially available budesonide / formoterol inhalation aerosol at higher formoterol dosages, despite containing a lower amountof formoterol and / or budesonide, thereby reducing the risk of formoterol-associated side effects and / or budesonide-associated side effects.

[0771] In specific embodiments, administration of the composition provides therapeutic efficacy equivalent to SYMBICORT 160 / 4.5 (budesonide / formoterol) inhalation aerosol at higher formoterol dosages, or a reference formulation containing 160 pg budesonide and 4.5 pg formoterol per actuation, despite containing a lower amount of formoterol and / or budesonide, thereby reducing the risk of formoterol-associated side effects and / or budesonide-associated side effects.

[0772] In specific embodiments, administration of the composition provides therapeutic efficacy equivalent to FORACORT 400 / 6 (budesonide / formoterol) inhalation aerosol at higher formoterol dosages, or a reference formulation containing 400 pg budesonide and 6 pg formoterol per actuation, despite containing a lower amount of formoterol and / or budesonide, thereby reducing the risk of formoterol-associated side effects and / or budesonide-associated side effects.

[0773] In specific embodiments, administration of the composition provides extrafine particle size distribution of the aerosol that leads to increased deposition of budesonide and formoterol in the peripheral airways relative to coarser particle compositions, resulting in enhanced management of respiratory disorders at reduced active pharmaceutical ingredient dosages.

[0774] The inventive composition prepared or disclosed herein are stable compositions where the budesonide or formoterol or salt or ester thereof remains stable over the shelf life. Specifically, the impurities in the stable composition remain well below the standard limits as per ICH guidelines.

[0775] In certain embodiments, the pressurized pharmaceutical compositions described herein exhibit physical and chemical stability under ICH long-term storage conditions. For example, representative budesonide-formoterol solution formulations according to the invention were filled into pMDI canisters and stored at 25 °C / 60% relative humidity for at least 12 weeks. Over this storage period, theformulations remained optically clear, single-phase solutions, with no visible precipitate or suspended particulate detectable in any canister when inspected under normal laboratory viewing conditions. Assay values for each active ingredient remained within predefined acceptance criteria, related substances / impurities remained within limits consistent with ICH guidelines, pH remained within the specified range, and dose uniformity and aerodynamic particle size distribution (including MMAD and extra-fine particle fraction) were maintained within target ranges. These observations demonstrate that, at 25 °C / 60% RH for at least 12 weeks, the inventive pressurized pharmaceutical compositions retain their true solution character and do not exhibit visible precipitation or formation of suspended particulate.

[0776] The invention is described in more detail by the following Examples.

[0777] Examples below (and in accompanying tables) illustrate representative formulae, dosing ranges, and manufacturing methods, and demonstrate the performance of the inventive solutions compared to conventional suspensions.EXAMPLES

[0778] Example 1Table 1*Strengths considered are Budesonide / Formoterol Fumarate: 100 / 3, 100 / 4.8, 100 / 6 pg.Table 2*Strengths: considered are Budesonide / Formoterol Fumarate: 200 / 3, 200 / 4.8, 200 / 6 pigTable 3*Strengths: considered are Budesonide / Formoterol Fumarate: 400 / 3, 400 / 4.8, 400 / 6 pgManufacturing process:(a) A mixture of IN HC1 and ethanol anhydrous was prepared.(b) Budesonide and Formoterol required for batch manufacturing were weighed. (c) Step (b) was added to above step (a) and homogenized to get the clear solution. (d) Step (c) was transferred to the mixing vessel and mixed with the remaining quantity of propellant HFA134a.(e) After step (d), solution was recirculated through the filling line and filled in precrimped canister.(f) After step (e), the solution was quarantined and evaluated for the aerodynamic particle size distribution.

[0779] Example 2Table 4*Strengths: considered are Budesonide / Glycopyrronium / Formoterol Fumarate: 100 / 12.5 / 3, 100 / 12.5 / 4.8, 100 / 12.5 / 6 pgTable 5*Strengths: considered are Budesonide / Glycopyrronium / Formoterol Fumarate: 200 / 12.5 / 3, 200 / 12.5 / 4.8, 200 / 12.5 / 6 pgTable 6*Strengths: considered are Budesonide / Glycopyrronium / Formoterol Fumarate: 400 / 12.5 / 3, 400 / 12.5 / 4.8, 400 / 12.5 / 6 pgManufacturing process:(a) A mixture of IN HC1 and ethanol anhydrous was prepared.(b) Budesonide, Formoterol and Glycopyrronium required for batch manufacturing were weighed.(c) Step (b) was added to above step (a) and homogenized to get the clear solution.(d) Step (c) was transferred to the mixing vessel and mixed with the remaining quantity of propellant HFA134a.(e) After step (d), solution was recirculated through the filling line and filled in precrimped canister.(f) After step (e), the solution was quarantined and evaluated for the aerodynamic particle size distribution

[0780] Example 3Table 7Budesonide / Formoterol with HFA152aTable 8Budesonide / Formoterol with Glycerol & HFO-1234zeTable 9Budesonide / Formoterol with Glycerol & HFA152aTable 10Budesonide / Formoterol with HFO-1234zeTable 11Higher Strengths with HFA152a or HFO-1234ze or Glycerol Budesonide / Formoterol (0.36% / 0.0054-0.0107%) + Ethanol + HFA152aTable 12Budesonide / Formoterol (0.36% / 0.0054-0.0107%) + Glycerol + HFA152aTable 13Budesonide / Formoterol (0.71% / 0.0054-0.0107%) + Ethanol + HFA152aTable 14Budesonide / Formoterol (0.71% / 0.0054-0.0107%) + Glycerol + HFA152aTable 15Budesonide / Formoterol (0.56% / 0.0042-0.0083%) + Glycerol + HFO1234zeManufacturing process:IN HC1 was mixed with ethanol anhydrous.API required for batch manufacturing was weighed.- API was added to the above solution homogenized to get the clear solution.Clear solution was transferred to the mixing vessel and mixed with the remaining quantity of Propellant HFA152a / HFO1234ze.After completion of mixing, solution was recirculated through the filling line and filled in pre-crimped canister.After filling canisters were quarantined and evaluated for the Aerodynamic particle size distribution.

[0781] Example 4Table 16Inhalation solutions, formulation

[0782] This formulation was prepared by dissolving budesonide and formoterol in anhydrous ethanol containing hydrochloric acid to afford a clear concentrate, combining the concentrate with the selected propellant(s) under pressure, and filling 5 the resulting solution into pre-crimped pMDI canisters as described herein. A stability study was conducted on the filled canisters stored at [25 °C / 60% RH and 40 °C / 75% RH] for at least 3 months.Table 17Inhalation solutions, particle size and MMAD

[0783] Example 5: Pharmacokinetic Evaluation

[0784] Two strengths of the inventive formulations were manufactured, namely budesonide-formoterol fumarate HFA pMDI 100 / 3 pg and budesonide-formoterol fumarate HFA pMDI 100 / 4.8 pg. These products were evaluated in a single-dose pharmacokinetic (PK) study in healthy volunteers to assess comparative bioavailability versus the existing commercially available product FORACORT 200 / 6. The following treatments were dosed in a comparative PK study conducted in healthy male volunteers (Table 18). Pharmacokinetic parameters for formoterol are summarized in Table 19, which compares the inventive solution formulations to FORACORT 200 / 6 suspension, and pharmacokinetic parameters for budesonide are summarized in Table 20.Table 18 - Investigational and reference treatments evaluated in the single-dose pharmacokinetic study

[0785] The PK results demonstrated that the inventive 100 / 3 pg and 100 / 4.8 pg 5 solution formulations were bioequivalent to FORACORT 200 / 6 with respect to Cmax and AUC for both budesonide and formoterol, with 90% confidence intervals falling within standard acceptance ranges. The 90% confidence intervals for the ratios of geometric mean Cmax and AUC for formoterol and budesonide, comparing each inventive solution formulation (100 / 3 pg and 100 / 4.8 pg strengths, dosed as two 10 actuations for total doses of 200 / 6 pg and 200 / 9.6 pg, respectively) to FORACORT 200 / 6, fell within standard bioequivalence limits of about 80-125%, indicating comparable systemic exposure between the solution formulations and the reference suspension for both active ingredients. Results of the comparative bioavailability study are presented in Table 19 and Table 20 for formoterol and budesonide, 15 respectively.Table 19 - Pharmacokinetic parameters comparing formoterol solution vs formoterol suspension formulation

[0786] The 90% confidence intervals for the ratios of geometric mean Cmax and AUC for formoterol were within standard bioequivalence limits (approximately 80-125%), indicating comparable systemic exposure between the inventive solution formulations and the FORACORT 200 / 6 suspension under the studied dosing conditions.

[0787] As illustrated in Table 19, in certain embodiments a 100 / 3 pg budesonide-formoterol HFA solution formulation administered as two actuations (total 200 / 6 pg) yields a mean formoterol Cmax of about 10.14 ± 2.95pg / mL, and a 100 / 4.8 pg solution formulation administered as two actuations (total 200 / 9.6 pg) yields a mean formoterol Cmax of about 15.69 ±6.07pg / mL. In some embodiments, formoterol Cmax values for such solution formulations fall within a range of about 5 to about 25 pg / mL under comparable dosing conditions.Table 20 - Pharmacokinetic parameters comparing budesonide solution vs budesonide suspension formulation

[0788] Except where otherwise indicated, the 90% confidence intervals (Cis) for the ratios of geometric mean pharmacokinetic parameters (Cmax and AUC) fall within standard bioequivalence limits of about 80-125%.

[0789] As illustrated in Table 20, in certain embodiments a 100 / 3 pg budesonide-formoterol HFA solution formulation administered as two actuations (total 200 / 6 pg) yields a mean budesonide Cmax of about 1304 ± 144 pg / mL, and a 100 / 4.8 pg solution formulation administered as two actuations (total 200 / 9.6 pg) yields a mean formoterol Cmax of about 1276 + 917 pg / mL. In some embodiments, budesonide Cmax values for such solution formulations fall within a range of about 350 to about 2200 pg / mL under comparable dosing conditions.

[0790] The above data indicate that, when budesonide-formoterol fumarate HFA solution is administered to healthy volunteers at the same nominal dose level as FORACORT (equivalent to 400 / 12 pg), it can, in certain embodiments, result in overall higher systemic bioavailability relative to the FORACORT suspension.

[0791] The pharmacokinetic parameters for both formoterol (Table 19) and budesonide (Table 20) showed systemic exposure for the inventive solution formulations that was generally comparable to, and in some cases modestly higher than, that observed with FORACORT 200 / 6, consistent with maintaining therapeutic efficacy at reduced nominal total drug load.

[0792] In specific embodiments, administration of a budesonide-formoterol HFA solution formulation in a total single dose corresponding to about 200 pg budesonide and about 6 pg formoterol (for example, two actuations of a 100 / 3 pg strength) provides systemic exposure characterized by a formoterol Cmax of about 5 to about 25 pg / mL and an AUCo-t of about 20 to about 70 hr-pg / mL, and a budesonide Cmax of about 350 to about 2200 pg / mL and anAUCo-t of about 1500 to about 3300 hr-pg / mL.

[0793] In specific embodiments, the budesonide and formoterol Cmax and AUCo-t values for such solution formulations are within about 80-125% of the corresponding pharmacokinetic parameters obtained with a reference suspension product comprising 200 pg budesonide and 6 pg formoterol per dose, such as FORACORT 200 / 6.

[0794] In specific embodiments, following single-dose administration of two actuations of a budesonide-formoterol HFA solution formulation delivering a total of about 200 pg budesonide and about 6 pg formoterol, the median Tmax for budesonide is in the range of about 0.02 to about 0.75 hours, and in particular embodiments is about 0.05 hours

[0795] In specific embodiments, under the same dosing conditions, the median Tmax for formoterol is in the range of about 0.05 to about 0.20 hours, for example about 0.05 to about 0.17 hours in certain embodiments, and in particular embodiments is about 0.08 hours.

[0796] As illustrated in Table 20, in certain embodiments a 100 / 3 pg budesonide-formoterol HFA solution formulation administered as two actuations (total 200 / 6 pg) yields a mean budesonide Cmax of about 1304 ± 144 pg / mL, and a 100 / 4.8 pg solution formulation administered as two actuations (total 200 / 9.6 pg) yields a mean budesonide Cmax of about 1276 + 917 pg / mL. In some embodiments, budesonide Cmax values for such solution formulations fall within a range of about 350 to about 2200 pg / mL under comparable dosing conditions.

Claims

1. CLAIMS1. A pressurized pharmaceutical composition suitable for inhalation administration comprising:(a) budesonide at a concentration of less than 0.71% w / w;(b) formoterol at a concentration of less than 0.0166% w / w;(c) pharmaceutically acceptable propellant system comprising at least one of HFA152a, HFO-1234ze, and HFA134a, in an amount sufficient to make up 100% w / w in combination with the other ingredients;wherein,the composition is a true solution, with budesonide and formoterol both substantially dissolved, andupon actuation from a pressurized metered dose inhaler (pMDI), the composition produces aerosol particles having a mass median aerodynamic diameter (MMAD) between 0.8 and 3.5 microns.

2. A pressurized pharmaceutical composition suitable for inhalation administration comprising:(a) budesonide at a concentration of less than 0.71% w / w;(b) formoterol at a concentration of less than 0.0166% w / w;(c) anhydrous ethanol in an amount of 8% w / w to 20% w / w;(d) pharmaceutically acceptable propellant system comprising at least one of HFA152a, HFO-1234ze, and HFA134a, in an amount sufficient to make up 100% w / w in combination with the other ingredients;(e) hydrochloric acid in an amount sufficient to adjust the pH to between 2.5 and 5; and(f) optionally glycerol at a concentration of 0.3-3% w / w;wherein,the composition is a true solution, with budesonide and formoterol both substantially dissolved, andupon actuation from a pressurized metered dose inhaler (pMDI), the composition produces aerosol particles having a mass median aerodynamic diameter (MMAD) between 0.8 and 3.5 microns.

3. The pressurized pharmaceutical composition of claim 2, wherein the budesonide is present at a concentration of 0.03% w / w to 0.71% w / w.

4. The pressurized pharmaceutical composition of claim 2, wherein the formoterol is present at a concentration of 0.002% w / w to 0.0166% w / w.

5. The pressurized pharmaceutical composition of claim 2, wherein the pressurized composition is contained in a pre-crimped canister and formulated to dispense through a pressurized metered dose inhaler (pMDI).

6. The pressurized pharmaceutical composition of claim 2, wherein the budesonide and formoterol are substantially dissolved in a visually single-phase, optically clear pressurized inhalation solution that does not exhibit visible precipitate or suspended particulate under normal inspection conditions after at least 12 weeks of storage at 25°C / 60% relative humidity.

7. The pressurized pharmaceutical composition of claim 2, further comprising glycop yrronium at a concentration of 0.01% w / w to 0.03% w / w, and wherein the glycopyrronium is substantially dissolved.

8. The pressurized pharmaceutical composition of claim 2, further comprising glycopyrronium at a concentration of 0.01-0.03% w / w, wherein the glycopyrronium is substantially dissolved in a visually single-phase, optically clear pressurized inhalation solution that does not exhibit visible precipitate or suspended particulate under normal inspection conditions after at least 12 weeks of storage at 25°C / 60% relative humidity.

9. The pressurized pharmaceutical composition of claim 2, wherein the composition is a pressurized inhalation solution that, upon actuation from a pressurized metered dose inhaler pMDI, delivers budesonide and formoterol with a mass median aerodynamic diameter MMAD of about 1.0-1.2 pm and an extra-fine particle fraction greater than 50% by mass, thereby increasing deposition of the active ingredients in the small peripheral airways compared to suspension-based budesonide / formoterol inhalers with coarser particle size distributions.

10. The pressurized pharmaceutical composition of claim 2, wherein the ex-actuator doses of budesonide and formoterol are selected within 25-200 pg and 1.5-5.7 pg, respectively, such that the composition provides therapeutic efficacy substantially comparable to a reference suspension product selected from SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6 while employing lower nominal amounts of budesonide and / or formoterol and thereby reducing the risk of corticosteroid- and beta-2 agonist-associated side effects.

11. A method of treating asthma or COPD, the method comprising administering to a human in need thereof the composition of any one of claims 2-10 by inhalation.

12. The method of claim 11, wherein administration of the composition provides therapeutic efficacy equivalent to a commercially available budesonide / formoterol inhalation aerosol at higher formoterol dosages, despite containing a lower amount of formoterol and / or budesonide, thereby reducing the risk of formoterol-associated side effects and / or budesonide-associated side effects.

13. The method of claim 11, wherein administration of the composition provides therapeutic efficacy equivalent to SYMBICORT 160 / 4.5 (budesonide / formoterol) inhalation aerosol at higher formoterol dosages, or a reference formulation containing 160 pg budesonide and 4.5 pg formoterol per actuation, despite containing a lower amount of formoterol and / or budesonide, thereby reducing the risk of formoterol-associated side effects and / or budesonide-associated side effects.

14. The method of claim 11, wherein administration of the composition provides therapeutic efficacy equivalent to FORACORT 400 / 6 (budesonide / formoterol) inhalation aerosol at higher formoterol dosages, or a reference formulation containing 400 pg budesonide and 6 pg formoterol per actuation, despite containing a lower amount of formoterol and / or budesonide, thereby reducing the risk of formoterol-associated side effects and / or budesonide -associated side effects.

15. The method of claim 11, wherein the extra- fine particle size distribution of the aerosol leads to increased deposition of budesonide and formoterol in the peripheral airways relative to coarser particle compositions, resulting in enhanced management of respiratory disorders at reduced active pharmaceutical ingredient dosages.

16. The method of claim 11, having reduced occurrence, frequency, and / or severity of formoterol-associated side effects and / or having reduced occurrence, frequency, and / or severity of budesonide-associated side effects, compared to SYMBICORT 160 / 4.5 (budesonide / formoterol) inhalation aerosol, or a reference formulation containing 160 pg budesonide and 4.5 pg formoterol per actuation.

17. The method of claim 11, having reduced occurrence, frequency, and / or severity of formoterol-associated side effects and / or having reduced occurrence, frequency, and / or severity of budesonide-associated side effects, compared to FORACORT 400 / 6 (budesonide / formoterol) inhalation aerosol, or a reference formulation containing 400 pg budesonide and 6 pg formoterol per actuation.

18. The method of claim 11, having reduced occurrence, frequency, and / or severity of any one or more of the following adverse effects:• upper respiratory tract infections, cough, nasal congestion, sore throat, and sinus infections;• headache;• throat pain or irritation;• stomach discomfort, nausea, or vomiting;• back pain;• oral thrush or white patches in the mouth or throat;• voice changes or loss of voice;• cold symptoms including stuffy or runny nose, sneezing, or sinus pain; • muscle aches;• adrenal suppression or insufficiency;• increased risk of pneumonia;• fast, irregular, or pounding heartbeat;• high blood sugar (hyperglycemia);• low blood potassium (hypokalemia), including muscle cramps or arrhythmias;• bone loss, reduced bone mineral density, or osteoporosis;• eye problems including glaucoma, cataracts, or vision changes;• slowed growth in children;• allergic reactions including rash, itching, swelling, or trouble breathing; • paradoxical bronchospasm (sudden worsening of breathing);• seizures; andincreased susceptibility to or risk of infections.;compared to SYMBICORT 160 / 4.5 (budesonide / formoterol) inhalation aerosol, or a reference formulation containing 160 pg budesonide and 4.5 pg formoterol per actuation.

19. The method of claim 11, having reduced occurrence, frequency, and / or severity of any one or more of the following:• upper respiratory tract infections (URTIs), such as cough, nasal congestion, sore throat, and sinus infections;• headache;• throat pain or irritation;• stomach discomfort, nausea, or vomiting;• back pain;• oral thrush (white patches in the mouth or throat);• voice changes or loss of voice;• cold symptoms (stuffy or runny nose, sneezing, sinus pain);• muscle aches;• adrenal suppression or insufficiency (fatigue, low blood pressure, weakness);• increased risk of pneumonia;• fast, irregular, or pounding heartbeat;• high blood sugar (hyperglycemia);• low blood potassium (hypokalemia) with associated muscle cramps, irregular heart rhythm;• bone loss (reduced bone mineral density, risk of osteoporosis with longterm use);• eye problems (glaucoma, cataracts, vision changes);• slowed growth in children;• allergic reactions (rash, itching, swelling, trouble breathing);• paradoxical bronchospasm (sudden worsening of breathing);• seizures;• increased risk of infections;compared to FORACORT 400 / 6 (budesonide / formoterol) inhalation aerosol, or a reference formulation containing 400 pg budesonide and 6 pg formoterol per actuation.

20. A method of treating asthma or chronic obstructive pulmonary disease in a subject in need thereof, comprising administering to the subject, by oral inhalation from a pressurized metered dose inhaler pMDI, a pressurized pharmaceutical composition according to any one of claims 2-10, thereby delivering budesonide and formoterol as an extra-fine aerosol having a mass median aerodynamic diameter MMAD of about 1.0-1.2 pm and an extra-fine particle fraction greater than 50% by mass, and achieving therapeutic efficacy substantially comparable toa reference suspension product selected from SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6 while employing lower nominal doses of budesonide and / or formoterol.

21. A method of reducing systemic exposure to corticosteroid and / or beta-2 agonist in a subject receiving maintenance therapy for asthma or chronic obstructive pulmonary disease, the method comprising replacing a suspension-based budesonide / formoterol inhalation therapy selected from SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6 with twice-daily administration, by oral inhalation from a pressurized metered dose inhaler pMDI, of a pressurized pharmaceutical composition according to any one of claims 2-10, wherein the pressurized pharmaceutical composition provides substantially the same or improved clinical control of asthma or COPD symptoms at lower nominal doses of budesonide and / or formoterol, thereby reducing the risk of corticosteroid- and beta-2 agonist-associated side effects.

22. A pressurized metered dose inhaler pMDI comprising a canister charged with a pressurized pharmaceutical composition according to any one of claims 2-10 and an actuator configured to deliver said composition as an inhalation aerosol, for use in the treatment of asthma or chronic obstructive pulmonary disease (COPD) in a subject in need thereof.

23. Use of a pressurized pharmaceutical composition according to any one of claims 2-10 for the manufacture of a medicament for the treatment of asthma or chronic obstructive pulmonary disease (COPD).

24. A pressurized pharmaceutical composition for inhalation comprising budesonide and formoterol, or pharmaceutically acceptable salts thereof, formulated as a true solution in a hydrofluoroalkane and / or hydrofluoroolefin propellant system with anhydrous ethanol, wherein upon administration by inhalation to a human subject in a single dose corresponding to about 200 pg budesonide and about 6 pg formoterol, the composition provides systemic exposureto budesonide and formoterol characterized by pharmacokinetic parameters selected from:a formoterol Cmax of about 5 to about 25 pg / mL and an AUCo-t of about 25 to about 70 hr- pg / mL; andwherein the budesonide and formoterol Cmax and AUCo-t values are within about 80-125% of the corresponding values obtained with a reference suspension product comprising 200 pg budesonide and 6 pg formoterol per dose.

25. The composition of claim 24, wherein administration of the composition provides a median Tmax for budesonide of about 0.05 to about 0.75 hours.

26. The composition of claim 25, wherein the median Tmax for budesonide is about 0.05 hours, with a range of about 0.02 to about 0.75 hours.

27. The composition of any one of claims 24-26, wherein administration of the composition provides a median Tmax for formoterol of about 0.05 to about 0.20 hours.

28. The composition of claim 27, wherein the median Tmax for formoterol is about 0.08 hours, with a range of about 0.05 to about 0.17 hours.

29. The composition of any one of claims 24-28, wherein, following single-dose administration of two actuations delivering a total of about 200 pg budesonide and about 6 pg formoterol, formoterol exhibits a mean Cmax of about 5 to about 25 pg / mL.

30. The composition of claim 29, wherein the mean formoterol Cmax is about 10.14 ± 2.95 pg / mL when the composition delivers about 100 pg budesonide and about 3 pg formoterol per actuation.

31. The composition of claim 29, wherein the mean formoterol Cmax is about 15.69 ± 6.07 pg / mL when the composition delivers about 100 pg budesonide and about 4.8 pg formoterol per actuation.

32. The composition of any one of claims 24-28, wherein, following single-dose administration of two actuations delivering a total of about 200 pg budesonide and about 6 pg formoterol, budesonide exhibits a mean Cmax of about 350 to about 2200 pg / mL.

33. The composition of claim 32, wherein the mean budesonide Cmax is about 1304.3 ± 144.10 pg / mL when the composition delivers about 100 pg budesonide and about 3 pg formoterol per actuation.

34. The composition of claim 32, wherein the mean budesonide Cmax is about 1276.4 ± 917.42 pg / mL when the composition delivers about 100 pg budesonide and about 4.8 pg formoterol per actuation.

35. The composition of any one of claims 24-34, wherein the ratios of geometric mean Cmax and AUCo-t for formoterol relative to FORACORT 200 / 6 pg suspension fall within standard bioequivalence limits of about 80-125%.

36. The composition of any one of claims 24-35, wherein the ratios of geometric mean Cmax and AUCo-t for budesonide relative to FORACORT 200 / 6 pg suspension fall within about 80-125%.

37. A method of treating asthma or chronic obstructive pulmonary disease in a human subject, comprising administering by inhalation the composition of any one of claims 24-36 in one or more actuations, wherein the treatment provides systemic exposure characterized by:a median Tmax for budesonide of about 0.02 to about 0.75 hours and a median Tmax for formoterol of about 0.05 to about 0.17 hours; and budesonide and formoterol Cmax values within about 80-125% of those of a reference suspension product containing 200 pg budesonide and 6 pg formoterol per dose.

38. The method of claim 37, wherein the systemic exposure is achieved at a lower nominal total drug load of budesonide and / or formoterol in the canister compared to the reference suspension product, while maintaining substantially the same efficacy.

39. A method of treating or preventing asthma or chronic obstructive pulmonary disease in a human subject, comprising administering by oral inhalation from a pressurized metered dose inhaler a pressurized pharmaceutical composition comprising budesonide and formoterol, or pharmaceutically acceptable salts thereof, formulated as an optically clear, single -phase pressurized inhalation solution in a hydrofluoroalkane and / or hydrofluoroolefin propellant system with anhydrous ethanol and acid,wherein:one or more actuations of the inhaler deliver ex-actuator doses of budesonide in the range of about 25-200 pg and ex-actuator doses of formoterol in the range of about 1.5-5.7 pg per actuation; andat a total daily dose that provides therapeutic efficacy substantially comparable to a reference suspension product comprising budesonide and formoterol selected from SYMBICORT 160 / 4.5, FORACORT 200 / 6, and FORACORT 400 / 6, the subject’s systemic exposure to at least one of budesonide or formoterol, as measured by Cmax and / or AUC, is reduced to not more than about 90% of the corresponding systemic exposure produced by the reference suspension product at its labeled dose.

40. The method of claim 39, wherein the systemic exposure to budesonide, as measured by Cmax and AUC, is reduced to not more than about 85% of the budesonide Cmax and AUC produced by the reference suspension product at its labeled dose, while maintaining therapeutic efficacy substantially comparable to the reference suspension product.

41. The method of claim 39 or 40, wherein the reduced systemic exposure to budesonide and / or formoterol is associated with a reduced incidence and / or severity, relative to treatment with the reference suspension product, of one or more of the following adverse effects:• upper respiratory tract infections, cough, nasal congestion, sore throat, and sinus infections;• headache;• throat pain or irritation;• stomach discomfort, nausea, or vomiting;• back pain;• oral thrush or white patches in the mouth or throat;• voice changes or loss of voice;• cold symptoms including stuffy or runny nose, sneezing, or sinus pain; • muscle aches;• adrenal suppression or insufficiency;• increased risk of pneumonia;• fast, irregular, or pounding heartbeat;• high blood sugar (hyperglycemia);• low blood potassium (hypokalemia), including muscle cramps or arrhythmias;• bone loss, reduced bone mineral density, or osteoporosis;• eye problems including glaucoma, cataracts, or vision changes;• slowed growth in children;• allergic reactions including rash, itching, swelling, or trouble breathing; • paradoxical bronchospasm (sudden worsening of breathing);• seizures; and• increased susceptibility to or risk of infections.a budesonide Cmax of about 350 to about 2200 pg / mL and an AU Co- / of about 1500 to about 3300 hr- pg / mL;

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