Pharmaceutical Compositions and Methods for the Treatment of Asthma

Abstract

The present disclosure provides a method of treating asthma in a subject at risk of asthma exacerbation, comprising the step of administering, as needed, a composition comprising a therapeutically effective amount of albuterol and budesonide, and a method of treating or preventing bronchoconstriction in a subject as needed and / or preventing exacerbation in a subject having asthma, wherein the composition is administered by a metered-dose inhaler and the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation compared to administration of a composition comprising the same dose of albuterol alone. Also provided is a pharmaceutical composition comprising albuterol and budesonide in particulate form, a suspension medium comprising a hydrofluoroolefin (HFO) propellant and / or a hydrofluorocarbon propellant (HFC), and a plurality of respirable suspended particles, wherein the particles of albuterol and budesonide associate with the plurality of respirable suspended particles.

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 63 / 363,767, filed Apr. 28, 2022, the content of which is hereby incorporated by reference in its entirety for all purposes.

[0002] Field The present disclosure provides a method of treating asthma in a subject at risk of asthma exacerbation, comprising the step of administering, as needed, a composition comprising a therapeutically effective amount of albuterol and budesonide, and a method of treating or preventing bronchoconstriction in a subject as needed and / or preventing exacerbation in a subject having asthma, wherein the composition is administered by a metered-dose inhaler, and the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation, compared to administration of a composition comprising the same dose of albuterol alone. Also provided is a pharmaceutical composition comprising albuterol and budesonide in particulate form, a suspension medium comprising a hydrofluoroolefin (HFO) propellant and / or a hydrofluorocarbon (HFC) propellant, and a plurality of respirable suspended particles, wherein the particles of albuterol and budesonide associate with the plurality of respirable suspended particles.

Background Art

[0003] Asthma is a heterogeneous disease that presents as variable airflow obstruction with recurrent symptoms caused by underlying persistent but variable airway inflammation. When asthma control is lost, patients often focus on obtaining immediate symptom relief by relying on rescue medications, typically short-acting β2-agonists (SABAs). However, SABAs have little effect on underlying airway inflammation, and excessive dependence on SABAs serves as a criterion for poor asthma control associated with an increased risk of severe exacerbations. Since severe exacerbations contribute to significant morbidity and mortality, prevention of exacerbations is essential in asthma management.

Summary of the Invention

[0004] In some embodiments, the present disclosure provides a method of treating asthma in a subject at risk of asthma exacerbation, the method comprising administering, as needed, a composition comprising a therapeutically effective amount of albuterol and budesonide, wherein the composition is administered by a metered-dose inhaler, and wherein the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation as compared to administration of a composition comprising albuterol alone at the same dose.

[0005] In some embodiments, the method reduces the risk of severe asthma exacerbation by at least about 20% as measured by time to first severe asthma exacerbation as compared to administration of a composition comprising albuterol alone at the same dose. In some embodiments, the method reduces the risk of severe asthma exacerbation by at least about 25% as measured by time to first severe asthma exacerbation as compared to administration of a composition comprising albuterol alone at the same dose.

[0006] In some embodiments, the hazard ratio of the method as compared to administration of a composition comprising albuterol alone at the same dose is less than about 0.9. In some embodiments, the hazard ratio of the method as compared to administration of a composition comprising albuterol alone at the same dose is less than about 0.8. In some embodiments, the hazard ratio of the method as compared to administration of a composition comprising albuterol alone at the same dose is less than about 0.7.

[0007] In some embodiments, the annualized rate of severe asthma exacerbations of the method is at least about 20% lower as compared to administration of a composition comprising albuterol alone at the same dose. In some embodiments, the annualized rate of severe asthma exacerbations of the method is at least about 25% lower as compared to administration of a composition comprising albuterol alone at the same dose.

[0008] In some embodiments, the method reduces the number of subjects with severe asthma exacerbations requiring hospitalization by at least 30% compared to administration of a composition containing the same dose of albuterol alone. In some embodiments, the method reduces the number of subjects with severe asthma exacerbations requiring emergency and / or urgent care by at least 20% compared to administration of a composition containing the same dose of albuterol alone. In some embodiments, the method reduces the total systemic corticosteroid dose in terms of annualized dose per subject by at least 30% compared to administration of a composition containing the same dose of albuterol alone.

[0009] In some embodiments, the area under the curve of the forced expiratory volume in one second over 0 to 6 hours (FEV1 AUC 0-6 ) of the subject at 12 weeks after administration of the composition is greater than 110 mL. In some embodiments, the FEV1 AUC 0-6 of the subject at 12 weeks after administration of the composition is at least 10% higher compared to subjects administered the same dose of albuterol alone or the same dose of budesonide alone.

[0010] In some embodiments, the trough FEV1 of the subject at 12 weeks after administration of the composition is greater than 90 mL. In some embodiments, the trough FEV1 of the subject at 12 weeks after administration of the composition is at least 10% higher compared to subjects administered a composition containing the same dose of albuterol alone or the same dose of budesonide alone.

[0011] In some embodiments, administration comprises delivering one or more metered doses from a metered dose inhaler, and about 100 to about 300 μg of albuterol and about 25 to about 250 μg of budesonide are delivered. In some embodiments, about 120 to about 250 μg of albuterol are delivered. In some embodiments, about 150 to about 200 μg of albuterol are delivered. In some embodiments, about 180 μg of albuterol are delivered. In some embodiments, about 50 to about 200 μg of budesonide are delivered. In some embodiments, about 75 to about 175 μg of budesonide are delivered. In some embodiments, about 80 or about 160 μg of budesonide are delivered. In some embodiments, about 150 to about 200 μg of albuterol and about 75 to about 175 μg of budesonide are delivered. In some embodiments, about 180 μg of albuterol and about 80 or about 160 μg of budesonide are delivered.

[0012] In some embodiments, administration comprises delivering two metered doses from a metered dose inhaler, and each delivered dose comprises about 60 to about 125 μg of albuterol and about 25 to about 100 μg of budesonide. In some embodiments, each delivered dose comprises about 90 μg of albuterol and about 40 or about 80 μg of budesonide. In some embodiments, albuterol and budesonide are in a weight ratio of about 1:1 to about 3:1 in the composition. In some embodiments, albuterol and budesonide are in a weight ratio of about 1.1:1 to about 2.5:1 in the composition. In some embodiments, albuterol and budesonide are in a weight ratio of about 1.125:1 or about 2.25:1 in the composition.

[0013] In some embodiments, albuterol and budesonide are in particulate form, and at least 90 volume % of the particles have an optical diameter of about 1 μm to about 7 μm. In some embodiments, the albuterol particles comprise crystalline or micronized albuterol sulfate, and the budesonide particles comprise micronized budesonide. In some embodiments, the composition comprises a plurality of albuterol particles, a plurality of budesonide particles, a plurality of respirable suspension particles, and a suspension medium, and the plurality of albuterol particles, the plurality of budesonide particles, and the plurality of respirable suspension particles are co-suspended in the suspension medium to form a co-suspension. In some embodiments, the suspension medium is a pharmaceutically acceptable propellant selected from hydrofluoroalkane (HFA) propellants, hydrofluoroolefin (HFO) propellants, hydrofluorocarbon propellants (HFC), and combinations thereof. In some embodiments, the suspension medium is a pharmaceutical grade propellant of (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)).

[0014] In some embodiments, the respirable suspension particles have a volume median optical diameter of about 0.2 μm to about 50 μm. In some embodiments, the respirable suspension particles are about 1 mg / mL to about 30 mg / mL in the suspension medium. In some embodiments, the respirable suspension particles comprise a phospholipid. In some embodiments, the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). In some embodiments, the weight ratio of the total mass of the respirable suspension particles to the total mass of the albuterol and budesonide particles is about 1.5:1 to about 200:1.

[0015] In some embodiments, the present disclosure provides a method for treating or preventing bronchoconstriction in a subject as needed and / or preventing exacerbation in a subject with asthma, the method comprising administering, as needed, to the subject a composition comprising a therapeutically effective amount of albuterol and budesonide, wherein the composition is administered by a metered-dose inhaler and the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation as compared to administration of a composition comprising the same dose of albuterol alone.

[0016] In some embodiments, the subject is a human subject 12 years of age or older. In some embodiments, administration comprises delivering two metered doses from a metered-dose inhaler to the subject, wherein about 180 μg of albuterol and about 160 μg of budesonide are delivered. In some embodiments, the subject is a human subject from 4 to 11 years of age. In some embodiments, administration comprises delivering two metered doses from a metered-dose inhaler to the subject, wherein about 180 μg of albuterol and about 80 μg of budesonide are delivered. In some embodiments, the subject is not administered more than six metered doses over a 24-hour period.

[0017] In some embodiments, the present disclosure provides a pharmaceutical composition deliverable from a metered-dose inhaler, comprising a therapeutically effective amount of albuterol and budesonide for use in treating asthma in a subject at risk of asthma exacerbation, wherein treatment reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation as compared to administration of a composition comprising the same dose of albuterol alone.

[0018] In some embodiments, the present disclosure provides a pharmaceutical composition deliverable from a metered-dose inhaler for use in the treatment or prevention of bronchoconstriction in a subject as needed and / or the prevention of exacerbation in a subject having asthma, the composition comprising a therapeutically effective amount of albuterol and budesonide, wherein the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation as compared to administration of a composition comprising the same dose of albuterol alone.

[0019] In some embodiments, the pharmaceutical composition comprises a plurality of albuterol particles, a plurality of budesonide particles, a plurality of respirable suspension particles, and a suspension medium, wherein the plurality of albuterol particles, the plurality of budesonide particles, and the plurality of respirable suspension particles are co-suspended in the suspension medium to form a co-suspension. In some embodiments, the suspension medium is a pharmaceutical-grade propellant of (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)). In some embodiments, the respirable suspension particles comprise a phospholipid. In some embodiments, the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

[0020] In some embodiments, the hazard ratio of this treatment as compared to administration of a composition comprising the same dose of albuterol alone is less than about 0.9. In some embodiments, the annualized rate of severe asthma exacerbation of this treatment is at least about 20% lower as compared to administration of a composition comprising the same dose of albuterol alone.

[0021] The following drawings form a part of this specification and are included to further demonstrate exemplary embodiments of certain aspects of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0022]

Figure 1-1

Figure 1-2

Figure 2

Figure 3

DETAILED DESCRIPTION OF THE INVENTION

[0023] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless the context requires otherwise, terms in the singular shall include the plural, and terms in the plural shall include the singular.

[0024] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0025] The use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or unless the alternatives are mutually exclusive, but the present disclosure supports definitions that refer to alternatives only and to "and / or".

[0026] As used herein, the terms "comprising" (and any variant or form of "comprising", such as "comprise" and "comprises"), "having" (and any variant or form of "having", such as "have" and "has"), "including" (and any variant or form of "including", such as "includes" and "include"), or "containing" (and any variant or form of "containing", such as "contains" and "contain") are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0027] The use of the term "for example" and its corresponding abbreviation "e.g." means that the specific terms recited are representative examples and embodiments of the present disclosure not intended to be limited to the specific examples referred to or cited, unless otherwise expressly indicated.

[0028] As used herein, "about" can mean plus or minus 10% of the value provided. When ranges are provided, they include the boundary values. "About" can further or alternatively mean within 10% of the recited value, or within 5% of the recited value, or in some cases within 2.5% of the recited value; or "about" can mean rounded to the nearest significant digit.

[0029] As used herein, "between" refers to a range that includes the endpoints of the range. For example, numbers between x and y explicitly include the numbers x and y, as well as any number inside x and y.

[0030] As used herein, the term "active agent" includes any agent, drug, compound, composition, or other substance that can be used or administered to a subject, such as a human or animal subject, for any purpose, including therapeutic agents, pharmaceuticals, pharmacological agents, diagnostic agents, cosmetic agents, and prophylactic and immunomodulatory agents. The term "active agent" may be used interchangeably with the terms "drug", "pharmaceutical", "medicine", "pro-drug", and "therapeutic agent". In some embodiments, the active agents of the present disclosure include albuterol and / or budesonide.

[0031] As used herein, the terms "associate", "associate with", and "association" refer to an interaction or relationship between chemical entities, compositions, or structures by approaching the surface of another chemical entity, composition, or structure, such as a surface. Association includes, for example, adsorption, adhesion, hydrogen bonding, ionic bonding and electrostatic attraction, Lifshitz van der Waals interactions, and polar interactions. As described herein, the active agent particles can associate with the suspended particles to form a co-suspension, and there is substantially no visible separation or flocculation between the suspended particles and the active agent particles due to the difference in buoyancy within the propellant.

[0032] As used herein, the term "respirable" refers to particles, aggregates, droplets, etc. of a size that can be inhaled and reach the airways of the lungs.

[0033] As used herein, "suspended particles" refers to a material or combination of materials that is acceptable for respiratory delivery and acts as a vehicle for the active agent particles. The suspended particles interact with the active agent particles to facilitate repeated administration, delivery, or transport of the active agent to a delivery target site, such as the airway (i.e., "respirable suspended particles"). In some embodiments, the suspended particles described herein are dispersed in a suspension medium that includes a propellant or propellant system and can be configured according to any shape, size, or surface characteristics suitable for achieving the desired suspension stability or active agent delivery performance. Exemplary suspended particles include particles that exhibit a particle size that facilitates respiratory delivery of the active agent and have a physical configuration suitable for formulation and delivery of a suspension stabilized as described herein.

[0034] As used herein, "mass median aerodynamic diameter" or "MMAD" refers to the aerodynamic diameter of an aerosol consisting of particles having an aerodynamic diameter such that 50% of the mass of the aerosol is composed of particles smaller than the MMAD, and the MMAD is calculated according to the United States Pharmacopeia (USP) monograph 601.

[0035] As used herein, "optical diameter" refers to the size of a particle when measured in the Fraunhofer diffraction mode using a laser diffraction particle size analyzer equipped with a dry powder dispenser (e.g., Sympatec GmbH, Clausthal-Zellerfeld, Germany).

[0036] As used herein, the term "suspending medium" refers to a substance that provides a continuous phase in which the active agent particles and the suspending particles are dispersed therein to provide a co-suspension formulation. In some embodiments, the suspending medium used in the co-suspension formulations described herein includes a propellant. As used herein, the term "propellant" refers to one or more pharmacologically inert substances that exert a vapor pressure high enough at normal room temperature to propel the medicament from the canister of a metered-dose inhaler (MDI) to the subject upon actuation of the metering valve of the MDI. The term "propellant" refers to both a single propellant and combinations of two or more different propellants that form a "propellant system".

[0037] As used herein, the term "co-suspension" refers to a suspension of two or more types of particles having different compositions within a suspending medium, wherein one type of particle at least partially associates with one or more of the other types of particles. The association results in an observable change in one or more properties of at least one of the individual types of particles suspended in the suspending medium. Properties modified by the association include, for example, the rate of aggregation or flocculation, separation, i.e., the rate and nature of sedimentation or creaming, the density of the cream or sediment layer, adhesion to the container wall, adhesion to the valve portion, and the rate and level of dispersion upon agitation. Exemplary methods for assessing the presence of a co-suspension are known to those of skill in the art, for example, as described in WO 2010 / 138862.

[0038] A "therapeutically effective amount" is the amount of a compound described herein, such as albuterol and / or budesonide, that achieves a therapeutic effect by suppressing a condition or disorder in a patient, such as asthma and / or bronchoconstriction, or by prophylactically suppressing or preventing the onset of the condition or disorder. A therapeutically effective amount may be an amount that alleviates to some extent one or more symptoms of a condition or disorder in a patient, partially or fully returns one or more physiological or biochemical parameters associated with or causative of the condition or disorder to normal, and / or reduces the likelihood of onset of the disordered condition.

[0039] Treatment of asthma In some embodiments, the present disclosure provides compositions and methods for the treatment of asthma, including treatment or prevention of bronchoconstriction as needed and prevention of asthma exacerbation.

[0040] Asthma is a chronic respiratory condition that causes inflammation and narrowing of the airways. As used herein, "asthma" refers to all types and origins of asthma, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial and / or viral infections. As used herein, "asthma" also includes infantile wheezing syndrome.

[0041] Asthma is diagnosed as "intermittent" or "persistent", and persistent asthma can be further classified as "mild", "moderate", and "severe". The severity of an individual's asthma diagnosis may be determined based on several factors, including but not limited to the frequency and severity of past and current asthma symptoms and the individual's lung volume, which can be measured using spirometry, peak flow measurement (i.e., the amount and speed of air that can be pushed out of the lungs), lung volume tests (i.e., the volume of air in the lungs), diffusion capacity tests (i.e., how easily oxygen enters the bloodstream), and / or exercise tests. A spirometry test measures forced expiratory volume (FEV), e.g., the amount of air pushed out of the lungs in one second (FEV1). Generally, an asthma diagnosis can be characterized as follows:

[0042] [Table 1]

[0043] Asthma exacerbation, also known as an asthma attack or acute exacerbation, refers to airway swelling and inflammation, i.e., bronchoconstriction, which results in a progressive increase in asthma symptoms, including cough, shortness of breath, wheezing, chest tightness, increased respiratory rate, increased heart rate, and / or decreased lung function. As used herein, "severe exacerbation" or "severe asthma exacerbation" refers to any worsening of asthma that results in at least one of the following conditions: (i) treatment with systemic glucocorticoids (SCS) for more than 3 consecutive days to treat worsening asthma symptoms; a single depot injection was considered equivalent to a 3-day burst, (ii) an emergency department or urgent care visit (defined as an evaluation and treatment in an emergency department or urgent care center for less than 24 hours) due to asthma that requires the above SCS, and (iii) hospitalization due to asthma (defined as admission to a hospital facility and / or evaluation of treatment in a medical facility for more than 24 hours).

[0044] In some embodiments, the present disclosure provides a method of treating asthma in a subject at risk of asthma exacerbation, the method comprising administering, as needed, a composition comprising a therapeutically effective amount of albuterol and budesonide, wherein the composition is administered by a metered-dose inhaler and the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation as compared to administration of the same dose of albuterol alone. In some embodiments, the present disclosure provides a pharmaceutical composition deliverable from a metered-dose inhaler comprising a therapeutically effective amount of albuterol and budesonide for use in the treatment of asthma in a subject at risk of asthma exacerbation, wherein treatment reduces the risk of severe asthma exacerbation by at least about 15% as compared to administration of a composition comprising the same dose of albuterol alone as measured by time to first severe asthma exacerbation.

[0045] In some embodiments, the present disclosure provides a method for treating or preventing bronchoconstriction as needed in a subject and / or preventing exacerbation in a subject having asthma, the method comprising administering, as needed, to the subject a composition comprising a therapeutically effective amount of albuterol and budesonide, wherein the composition is administered by a metered-dose inhaler and the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation compared to administration of the same dose of albuterol alone. In some embodiments, the present disclosure provides a pharmaceutical composition deliverable from a metered-dose inhaler comprising a therapeutically effective amount of albuterol and budesonide for use in treating or preventing bronchoconstriction as needed in a subject and / or preventing exacerbation in a subject having asthma, wherein the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation compared to administration of a composition comprising the same dose of albuterol alone.

[0046] As used herein, "albuterol," also known as salbutamol, refers to a compound having the chemical name 4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenol, or a pharmaceutically acceptable salt, solvate, or ester thereof. In some embodiments, the compositions described herein comprise albuterol sulfate, which is a racemic salt of albuterol. An example of albuterol sulfate has the chemical name α 1 -[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate (2:1) (salt) and has the following chemical structure:

[0047]

Chemical formula

[0048] Albuterol is a short-acting / rapid-acting β2-adrenergic receptor agonist (SABA) that induces airway smooth muscle relaxation and reduces or prevents bronchoconstriction. In clinical practice, albuterol is used as a “prn” (as needed) reliever therapy. See, e.g., Global Initiative for Asthma 2018. Generally, subjects who require frequent albuterol reliever therapy are at a higher risk of long-term adverse effects, including more frequent and / or more severe asthma exacerbations.

[0049] As used herein, “budesonide” refers to a corticosteroid having the chemical name (RS)-11β,21-dihydroxy-16α,17α-(butylidenebis(oxy))pregna-1,4-diene-3,20-dione. In some embodiments, the compositions described herein include a racemic mixture of budesonide. In some embodiments, the compositions described herein include the (22R) and (22S) epimers of budesonide. In some embodiments, budesonide has the following chemical structure (* indicates a stereocenter):

[0050] [Chemical formula]

[0051] Budesonide is an anti-inflammatory corticosteroid with potent glucocorticoid activity and weak mineralocorticoid activity, and is approved worldwide in oral inhalation formulations for the treatment of asthma and chronic obstructive pulmonary disease (COPD), both as a single agent and in combination with formoterol, a long-acting / rapid-acting β2-agonist (LABA), for maintenance therapy in individuals with moderate to severe asthma.

[0052] It has now been found that when exacerbation symptoms occur (i.e., administration as needed), co - administration of a composition comprising a short - acting beta - agonist (SABA), such as albuterol, and an inhaled corticosteroid (ICS), such as budesonide, provides both symptom relief and treatment of persistent airway inflammation to a subject without significantly increasing the overall steroid burden. Further, when a subject uses a combination of albuterol and budesonide for treatment as needed for exacerbation of asthma and / or treatment or prevention as needed for bronchoconstriction, the risk that the subject will experience further exacerbation of asthma has been found to be lower than that of a subject using albuterol alone.

[0053] In some embodiments, the subject is diagnosed with mild asthma. In some embodiments, the subject is diagnosed with moderate asthma. In some embodiments, the subject is diagnosed with severe asthma. In some embodiments, the subject exhibits symptoms associated with mild asthma. In some embodiments, the subject exhibits symptoms associated with moderate asthma. In some embodiments, the subject exhibits symptoms associated with severe asthma. In some embodiments, the subject is a human subject. In some embodiments, the subject is a human subject of 4 years of age or older. In some embodiments, the subject is a human subject from about 4 years to about 11 years of age. In some embodiments, the subject is a human subject of 12 years of age or older. In some embodiments, the subject is a human subject from about 12 years to about 17 years of age or older. In some embodiments, the subject is a human subject of 18 years of age or older. It will be understood by those skilled in the art that "X years of age" for a subject includes the subject from the day the subject turns X years old until the day the subject turns X + 1 years old.

[0054] Throughout this application, when comparing the effectiveness (e.g., as measured by time to first severe asthma exacerbation, hazard ratio, annualized rate of severe asthma exacerbation, number of severe asthma exacerbations, as described herein) of two or more compositions containing different active agents, e.g., a combination of albuterol and budesonide versus albuterol alone, the compositions are the same or substantially the same in other respects, except for the active agent shown, and are administered in the same or substantially the same manner, and, where appropriate, at the same or substantially the same dose or a dose equivalent for the subject, as will be understood by one of ordinary skill in the art. It is further understood that when comparing the effectiveness of two or more compositions, the comparison can be made in the same subject or multiple subjects.

[0055] As used herein, "time to first severe asthma exacerbation" is defined in the context of the period during which a subject is monitored, e.g., during a clinical trial study period, and is calculated as the time from the start of monitoring, e.g., the randomization date of the clinical trial study subject, to the start date of the first severe asthma exacerbation. One of ordinary skill in the art will understand that when comparing the effectiveness of the compositions described herein, the starting point for measuring the time to first severe asthma exacerbation is selected such that the timings are comparable. For example, in a clinical trial study in which a composition containing albuterol and budesonide is administered to a first group of subjects and albuterol alone is administered to a second group of subjects, the starting point for calculating the time to first severe asthma exacerbation is the randomization date of the study subject groups, thereby providing a comparison point for evaluating the time to first severe asthma exacerbation.

[0056] In some embodiments, a longer time to the first severe asthma exacerbation indicates higher drug efficacy for the prevention and / or treatment of asthma. In some embodiments, a longer time to the first severe asthma exacerbation correlates with a reduced risk of severe asthma exacerbation. In some embodiments, a 15% longer time to the first severe asthma exacerbation corresponds to a 15% reduction in the risk of severe asthma exacerbation. In some embodiments, a 20% longer time to the first severe asthma exacerbation corresponds to a 20% reduction in the risk of severe asthma exacerbation. In some embodiments, a 25% longer time to the first severe asthma exacerbation corresponds to a 25% reduction in the risk of severe asthma exacerbation.

[0057] In some embodiments, administration of a composition comprising albuterol and budesonide described herein results in an increase in the time to the first severe asthma exacerbation, and thus a reduction in the risk of severe asthma exacerbation, compared to administration of a composition comprising the same dose of albuterol alone. In some embodiments, administration of a composition comprising albuterol and budesonide results in at least a 10%, at least an 11%, at least a 12%, at least a 13%, at least a 14%, at least a 15%, at least a 16%, at least a 17%, at least an 18%, at least a 19%, at least a 20%, at least a 21%, at least a 22%, at least a 23%, at least a 24%, at least a 25%, at least a 26%, at least a 27%, at least a 28%, at least a 29%, or at least a 30% increase in the time to the first severe asthma exacerbation compared to administration of a composition comprising the same dose of albuterol alone. In some embodiments, administration of a composition comprising albuterol and budesonide reduces the risk of severe asthma exacerbation by at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, or at least 30% compared to administration of a composition comprising the same dose of albuterol alone.

[0058] In some embodiments, administration of a composition comprising albuterol and budesonide as described herein results in at least a 15% increase in the time to first severe asthma exacerbation compared to administration of a composition comprising albuterol alone, and thus reduces the risk of severe asthma exacerbation by at least 15%. In some embodiments, administration of a composition comprising albuterol and budesonide results in at least a 20% increase in the time to first severe asthma exacerbation compared to administration of a composition comprising albuterol alone, and thus reduces the risk of severe asthma exacerbation by at least 20%. In some embodiments, administration of a composition comprising albuterol and budesonide results in at least a 25% increase in the time to first severe asthma exacerbation compared to administration of a composition comprising albuterol alone, and thus reduces the risk of severe asthma exacerbation by at least 25%.

[0059] In some embodiments, administration of a composition comprising albuterol and budesonide as described herein results in a hazard ratio of less than 1 compared to administration of a composition comprising albuterol alone. A hazard ratio indicates the relative hazard of two conditions, e.g., a treatment condition (e.g., administration of albuterol and budesonide) and a control condition (e.g., administration of albuterol alone). Thus, a hazard ratio of less than 1 for a treatment relative to a control condition indicates a lower hazard rate for the treatment compared to the control. In some embodiments, the hazard ratio is determined based on the time to first severe exacerbation as described herein. In some embodiments, administration of a composition comprising albuterol and budesonide results in a hazard ratio of less than 1, less than about 0.95, less than about 0.9, less than about 0.85, less than about 0.8, less than about 0.75, less than about 0.7, less than about 0.65, less than about 0.6, less than about 0.55, or less than about 0.5 compared to administration of a composition comprising albuterol alone. In some embodiments, administration of a composition comprising albuterol and budesonide results in a hazard ratio of less than about 0.9 compared to administration of a composition comprising albuterol alone. In some embodiments, administration of a composition comprising albuterol and budesonide results in a hazard ratio of less than 0.8 compared to administration of a composition comprising albuterol alone. In some embodiments, administration of a composition comprising albuterol and budesonide results in a hazard ratio of less than 0.7 compared to administration of a composition comprising albuterol alone.

[0060] In some embodiments, administration of a composition comprising albuterol and budesonide as described herein results in a lower rate of severe asthma exacerbation per year compared to administration of a composition comprising albuterol alone. As used herein, "rate of severe asthma exacerbation per year" is the average number of severe asthma exacerbations experienced by a subject in a year. In some embodiments, the rate of severe asthma exacerbation per year is calculated according to the following formula:

[0061]

Number

[0062] In some embodiments, the monitored treatment period is a defined period during which the composition described herein is administered to the subject, for example, the clinical trial study period described herein.

[0063] In some embodiments, the administration of the composition comprising albuterol and budesonide described herein has a rate of severe asthma exacerbation per year that is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% lower compared to the administration of a composition comprising the same dose of albuterol alone. In some embodiments, the administration of the composition comprising albuterol and budesonide has a rate of severe asthma exacerbation per year that is at least about 20% lower compared to the administration of a composition comprising the same dose of albuterol alone. In some embodiments, the administration of the composition comprising albuterol and budesonide has a rate of severe asthma exacerbation per year that is at least about 25% lower compared to the administration of a composition comprising the same dose of albuterol alone. In some embodiments, the administration of the composition comprising albuterol and budesonide has a rate of severe asthma exacerbation per year that is at least about 30% lower compared to the administration of a composition comprising the same dose of albuterol alone.

[0064] In some embodiments, administration of the compositions containing albuterol and budesonide described herein reduces the number of subjects with severe asthma exacerbations requiring hospitalization by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% compared to administration of a composition containing the same dose of albuterol alone. In some embodiments, administration of the compositions containing albuterol and budesonide described herein reduces the number of subjects with severe asthma exacerbations requiring emergency and / or urgent care by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% compared to administration of a composition containing the same dose of albuterol alone.

[0065] In some embodiments, administration of the compositions containing albuterol and budesonide described herein reduces the total systemic corticosteroid dose in terms of annualized dose per subject by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% compared to administration of a composition containing the same dose of albuterol alone. In some embodiments, the methods described herein reduce the number of severe asthma exacerbations, thereby reducing the need for systemic corticosteroid treatment, such as methylprednisolone, triamcinolone, prednisone, and prednisolone. High systemic corticosteroid exposure can have adverse effects including decreased bone density and osteoporosis, hypertension, gastrointestinal ulcers / bleeding, growth retardation or failure to thrive in children, diabetes, immunosuppression, development of cataracts, and mental disorders. See, for example, Bleecker et al., Am J Respir Crit Care Med 201(3), 276-293 (2020) and Price et al., Eur Repsir Rev 29, 190151 (2020).

[0066] As used herein, "total systemic corticosteroid dose in terms of annualized basis" is, for example, the average dose of corticosteroids, including glucocorticoids and mineralocorticoids, that a subject receives in one year for treating severe asthma exacerbation. In some embodiments, the total systemic corticosteroid exposure on an annualized basis is calculated according to the following formula:

[0067]

Number

[0068] In some embodiments, the systemic corticosteroid dose is normalized to the equipotent dose of prednisone, which is also referred to herein as "prednisone equivalent". In some embodiments, the treatment period to be monitored is a defined period during which the composition described herein is administered to the subject, for example, the clinical trial study period described herein.

[0069] In some embodiments, administration of the composition comprising albuterol and budesonide described herein improves the lung function of the subject, as measured, for example, by spirometry, peak flow measurement, lung volume measurement, diffusing capacity measurement, and / or exercise testing described herein. In some embodiments, administration of the composition comprising albuterol and budesonide described herein increases the area under the FEV1 curve (FEV1 AUC 0-6 ) of the subject from 0 to 6 hours after administration, i.e., the FEV1 of the subject calculated 0 to 6 hours after administration. In some embodiments, the FEV1 AUC of the subject at 12 weeks after administration of the composition comprising albuterol and budesonide described herein 0-6is greater than about 100 mL, greater than about 105 mL, greater than about 110 mL, greater than about 115 mL, greater than about 120 mL, greater than about 125 mL, greater than about 130 mL, greater than about 140 mL, greater than about 150 mL, greater than about 160 mL, greater than about 170 mL, greater than about 180 mL, greater than about 190 mL, or greater than about 200 mL. In some embodiments, the FEV1 AUC of a subject at 12 weeks after administration of the composition comprising albuterol and budesonide described herein 0-6 is the FEV1 AUC of a subject at 12 weeks after administration of albuterol alone, budesonide alone, or a placebo composition 0-6 by at least 10 mL, at least 15 mL, at least 20 mL, at least 25 mL, at least 30 mL, at least 35 mL, at least 40 mL, at least 45 mL, or at least 50 mL.

[0070] In some embodiments, the FEV1 AUC of a subject at 12 weeks after administration of the composition comprising albuterol and budesonide described herein 0-6 is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher compared to the FEV1 AUC of a subject at 12 weeks after administration of the same dose of albuterol alone 0-6 In some embodiments, the FEV1 AUC of a subject at 12 weeks after administration of the composition comprising albuterol and budesonide described herein 0-6 is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher compared to the FEV1 AUC of a subject at 12 weeks after administration of the same dose of budesonide alone 0-6 In some embodiments, the FEV1 AUC of a subject at 12 weeks after administration of the composition comprising albuterol and budesonide described herein 0-6is at least 15% higher compared to the subject's FEV1 AUC at 12 weeks after administration of the same dose of albuterol alone or the same dose of budesonide alone 0-6 and is at least 15% higher.

[0071] In some embodiments, administration of the composition comprising albuterol and budesonide described herein increases the subject's trough FEV1, i.e., the subject's FEV1 prior to administration (also known as "pre-dose FEV1"). In some embodiments, the subject's trough FEV1 at 12 weeks after administration of the composition comprising albuterol and budesonide described herein is greater than about 70 mL, greater than about 75 mL, greater than about 80 mL, greater than about 85 mL, greater than about 90 mL, greater than about 95 mL, greater than about 100 mL. In some embodiments, the subject's trough FEV1 at 12 weeks after administration of the composition comprising albuterol and budesonide described herein is at least 5 mL, at least 10 mL, at least 15 mL, at least 20 mL, at least 25 mL, at least 30 mL, at least 35 mL, at least 40 mL, at least 45 mL, or at least 50 mL greater than the subject's trough FEV1 at 12 weeks after administration of albuterol alone, budesonide alone, or a placebo composition.

[0072] In some embodiments, the trough FEV1 of the subject at 12 weeks after administration of the composition comprising albuterol and budesonide described herein is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher compared to the trough FEV1 of the subject at 12 weeks after administration of the same dose of albuterol alone. In some embodiments, the trough FEV1 of the subject at 12 weeks after administration of the composition comprising albuterol and budesonide described herein is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher compared to the trough FEV1 of the subject at 12 weeks after administration of the same dose of budesonide alone. In some embodiments, the trough FEV1 of the subject at 12 weeks after administration of the composition comprising albuterol and budesonide described herein is at least 10% higher compared to the trough FEV1 of the subject at 12 weeks after administration of the same dose of albuterol alone or the same dose of budesonide alone.

[0073] Metered-dose inhaler As described in connection with the methods provided herein, a composition comprising albuterol and budesonide described herein may be used in a metered dose inhaler (MDI) system. The MDI is configured to deliver a specific amount of medicament in aerosol form. In some embodiments, the MDI system includes a pressurized liquid phase formulation filled cannister disposed within an actuator formed using a mouthpiece. The MDI system may include a formulation described herein that includes a suspension medium, at least one active agent particle, and at least one suspending particle. The cannister used in the MDI may be of any suitable configuration, and in one exemplary embodiment, the cannister may have a volume in the range of about 5 mL to about 25 mL, for example, the cannister may have a volume of 19 mL. After shaking the device, the mouthpiece is inserted into the subject's mouth between the lips and teeth. The subject typically exhales deeply to empty the lungs and then inhales slowly and deeply while activating the MDI cartridge.

[0074] When activated, a specified volume of the formulation exits the actuator nozzle and moves into the expansion chamber, becoming a high-speed spray that is inhaled into the patient's lungs. In some embodiments, the dose of active agent, i.e., albuterol and budesonide, delivered until the MDI cannister is empty is not more than 20% greater than or less than 20% less than the average delivery dose. In some embodiments, the dose of active agent, i.e., albuterol and budesonide, delivered until the MDI cannister is empty is not more than 15% greater than or less than 15% less than the average delivery dose. In some embodiments, the dose of active agent, i.e., albuterol and budesonide, delivered until the MDI cannister is empty is not more than 10% greater than or less than 10% less than the average delivery dose.

[0075] Inside an exemplary cartridge, there is a metering valve that includes a metering chamber capable of holding a defined volume of formulation (e.g., 63 μL or any other suitable volume available in commercially available metering valves), which, when actuated, is released to an expansion chamber at the distal end of the valve stem. The actuator may also include a port that holds a cannister and has an actuator nozzle for receiving the valve stem of the metering valve. When actuated, a specified volume of formulation exits the actuator nozzle and moves to the expansion chamber, becoming a high-speed spray that is inhaled into the patient's lungs.

[0076] Exemplary MDIs and methods of using them are further described, for example, in WO 2010 / 138862, WO 2010 / 138868, and WO 2010 / 138884.

[0077] Dosage In some embodiments, administration includes delivering one or more metered doses from an MDI via inhalation to a subject, with about 100 to about 300 μg of albuterol and about 25 to about 250 μg of budesonide being delivered. In some embodiments, about 120 to about 250 μg of albuterol and about 50 to about 200 μg of budesonide are delivered. In some embodiments, about 140 to about 230 μg of albuterol and about 60 to about 180 μg of budesonide are delivered. In some embodiments, about 150 to about 200 μg of albuterol and about 75 to about 175 μg of budesonide are delivered. In some embodiments, about 170 to about 190 μg of albuterol and about 80 to about 160 μg of budesonide are delivered. In some embodiments, about 180 μg of albuterol and about 80 μg of budesonide are delivered. In some embodiments, about 180 μg of albuterol and about 160 μg of budesonide are delivered.

[0078] In some embodiments, administration comprises delivering one metered dose to a subject by inhalation over a 24-hour period. In some embodiments, administration comprises the subject inhaling two metered doses over a 24-hour period. In some embodiments, administration comprises the subject inhaling three metered doses over a 24-hour period. In some embodiments, administration comprises the subject inhaling four metered doses over a 24-hour period. In some embodiments, administration comprises the subject inhaling five metered doses over a 24-hour period. In some embodiments, administration comprises the subject inhaling six metered doses over a 24-hour period. In some embodiments, six or fewer metered doses are administered to the subject over a 24-hour period. Unless otherwise specified, each metered dose comprises one actuation of a metered-dose inhaler.

[0079] In some embodiments, administration comprises delivering one or more metered doses from an MDI to a subject via inhalation, and the total daily delivery dose is from about 100 to about 300 μg of albuterol and from about 25 to about 250 μg of budesonide. The term "total daily delivery dose" refers to the cumulative amount of active agent, e.g., albuterol and budesonide, delivered over a 24-hour period, regardless of the number of metered doses administered. In some embodiments, the total daily delivery dose is from about 200 to about 600 μg of albuterol and from about 50 to about 500 μg of budesonide. In some embodiments, the total daily delivery dose is from about 300 to about 900 μg of albuterol and from about 75 to about 750 μg of budesonide. In some embodiments, the total daily delivery dose is from about 400 to about 1200 μg of albuterol and from about 100 to about 1000 μg of budesonide. In some embodiments, the total daily delivery dose is from about 500 to about 1500 μg of albuterol and from about 125 to about 1250 μg of budesonide. In some embodiments, the total daily delivery dose is from about 600 to about 1800 μg of albuterol and from about 150 to about 1500 μg of budesonide.

[0080] In some embodiments, the total daily delivered dose is from about 170 to about 190 μg of albuterol and from about 80 to about 160 μg of budesonide. In some embodiments, the total daily delivered dose is from about 340 to about 3800 μg of albuterol and from about 160 to about 320 μg of budesonide. In some embodiments, the total daily delivered dose is from about 510 to about 570 μg of albuterol and from about 240 to about 480 μg of budesonide. In some embodiments, the total daily delivered dose is from about 680 to about 760 μg of albuterol and from about 320 to about 640 μg of budesonide. In some embodiments, the total daily delivered dose is from about 850 to about 950 μg of albuterol and from about 400 to about 800 μg of budesonide. In some embodiments, the total daily delivered dose is from about 1020 to about 1140 μg of albuterol and from about 480 to about 960 μg of budesonide.

[0081] In some embodiments, administration comprises delivering two metered doses by inhalation from an MDI, each delivered dose comprising from about 50 to about 150 μg of albuterol and from about 12 to about 125 μg of budesonide. In some embodiments, each delivered dose comprises from about 60 to about 125 μg of albuterol and from about 25 to about 100 μg of budesonide. In some embodiments, each delivered dose comprises from about 80 to about 100 μg of albuterol and from about 30 to about 90 μg of budesonide. In some embodiments, each delivered dose comprises about 90 μg of albuterol and about 40 μg of budesonide. In some embodiments, each delivered dose comprises about 90 μg of albuterol and about 80 μg of budesonide. In some embodiments, each delivered dose comprises about 45 μg of albuterol and about 20 or about 40 μg of budesonide. In some embodiments, each metered dose comprises one actuation of a metered dose inhaler.

[0082] In some embodiments, the subject is a human subject 12 years of age or older, and administration comprises delivering two metered doses from an MDI to the subject by inhalation, each delivered dose comprising (a) about 90 μg of albuterol, and (b) about 60 to about 100 μg of budesonide, or about 70 to about 90 μg of budesonide, or about 80 μg of budesonide. In some embodiments, the subject is a human subject 12 years of age or older, and administration comprises delivering two metered doses from an MDI to the subject, each delivered dose comprising (a) about 60 to about 130 μg of albuterol, or about 70 to about 120 μg of albuterol, or about 80 to about 100 μg of albuterol, or about 90 μg of albuterol, and (b) about 80 μg of budesonide. In some embodiments, a total of (a) about 180 μg of albuterol, and (b) about 120 to about 200 μg of budesonide, or about 140 to about 180 μg of budesonide, or about 160 μg of budesonide is delivered by two metered doses. In some embodiments, a total of (a) about 120 to about 250 μg of albuterol, or about 140 to about 230 μg of albuterol, or about 150 to about 200 μg of albuterol, or about 180 μg of albuterol, and (b) about 160 μg of budesonide is delivered by two metered doses. In some embodiments, the subject is not administered more than six metered doses over a 24-hour period.

[0083] In some embodiments, the subject is a human subject from 4 to 11 years of age, and administration comprises delivering two metered doses from an MDI to the subject by inhalation, each delivered dose comprising (a) about 90 μg of albuterol, and (b) about 20 to about 60 μg of budesonide, or about 30 to about 50 μg of budesonide, or about 40 μg of budesonide. In some embodiments, the subject is a human subject from 4 to 11 years of age, and administration comprises delivering two metered doses from an MDI to the subject, each delivered dose comprising (a) about 60 to about 130 μg of albuterol, or about 70 to about 120 μg of albuterol, or about 80 to about 100 μg of albuterol, or about 90 μg of albuterol, and (b) about 40 μg of budesonide. In some embodiments, a total of (a) about 180 μg of albuterol, and (b) about 40 to about 120 μg of budesonide, or about 60 to about 100 μg of budesonide, or about 80 μg of budesonide is delivered by two metered doses. In some embodiments, a total of (a) about 120 to about 250 μg of albuterol, or about 140 to about 230 μg of albuterol, or about 150 to about 200 μg of albuterol, or about 180 μg of albuterol, and (b) about 80 μg of budesonide is delivered by two metered doses. In some embodiments, more than six metered doses are not administered to the subject over a 24-hour period.

[0084] In some embodiments, from about 110 to about 280 μg of albuterol is delivered. In some embodiments, from about 120 to about 250 μg of albuterol is delivered. In some embodiments, from about 140 to about 230 μg of albuterol is delivered. In some embodiments, from about 150 to about 200 μg of albuterol is delivered. In some embodiments, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, or about 200 μg of albuterol is delivered. In some embodiments, about 180 μg of albuterol is delivered. In some embodiments, administration comprises delivering two metered doses from an MDI, and each delivered dose comprises from about 50 to about 150 μg, or from about 60 to about 130 μg, or from about 70 to about 120 μg, or from about 80 to about 100 μg, or about 90 μg of albuterol.

[0085] In some embodiments, from about 40 to about 250 μg of budesonide is delivered. In some embodiments, from about 50 to about 200 μg of budesonide is delivered. In some embodiments, from about 75 to about 175 μg of budesonide is delivered. In some embodiments, from about 80 to about 160 μg of budesonide is delivered. In some embodiments, from about 40 to about 120 μg of budesonide is delivered. In some embodiments, from about 60 to about 100 μg of budesonide is delivered. In some embodiments, from about 120 to about 200 μg of budesonide is delivered. In some embodiments, from about 140 to about 180 μg is delivered. In some embodiments, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 μg of budesonide is delivered. In some embodiments, about 80 μg of budesonide is delivered. In some embodiments, about 160 μg of budesonide is delivered. In some embodiments, administration comprises delivering two metered doses from an MDI, each delivered dose comprising from about 20 to about 130 μg, or from about 30 to about 100 μg, or from about 35 to about 90 μg, or from about 40 to about 80 μg, or from about 20 to about 60 μg, or from about 30 to about 50 μg, or from about 60 to about 100 μg, or from about 70 to about 90 μg of budesonide. In some embodiments, each delivered dose comprises about 40 μg of budesonide. In some embodiments, each delivered dose comprises about 80 μg of budesonide.

[0086] Composition In some embodiments, the present disclosure provides a composition comprising (a) a plurality of active agent particles comprising albuterol and budesonide, (b) a suspension medium, and (c) a plurality of respirable suspension particles, wherein the active agent particles of albuterol and budesonide are associated with the plurality of respirable suspension particles. In some embodiments, the present disclosure provides a composition comprising (a) albuterol and budesonide in the form of particles described herein, (b) a suspension medium comprising an HFO propellant and / or an HFC propellant, and (c) a plurality of respirable suspension particles, wherein the particles of albuterol and budesonide are associated with the plurality of respirable suspension particles. In some embodiments, the plurality of active agent particles comprises a first plurality of albuterol particles and a second plurality of budesonide particles. That is, the plurality of albuterol particles and the plurality of budesonide particles are separate and distinct particle species. In some embodiments, the composition is a co-suspension composition, and the plurality of active agent particles, i.e., the plurality of albuterol particles and the plurality of budesonide particles, and the plurality of respirable suspension particles are co-suspended in the suspension medium to form a co-suspension. In some embodiments, the composition is for use in the treatment of asthma in a subject in need thereof.

[0087] In some embodiments, albuterol and budesonide are present in the composition in a weight ratio of from about 1:1 to about 5:1. In some embodiments, albuterol and budesonide are present in the composition in a weight ratio of from about 1:1 to about 4:1. In some embodiments, albuterol and budesonide are present in the composition in a weight ratio of from about 1:1 to about 3:1. In some embodiments, albuterol and budesonide are present in the composition in a weight ratio of from about 1.1:1 to about 2.8:1. Albuterol and budesonide are present in the composition in a weight ratio of from about 1.1:1 to about 2.5:1. In some embodiments, albuterol and budesonide are present in the composition in a weight ratio of about 1.1:1 or about 2.3:1. In some embodiments, albuterol and budesonide are present in the composition in a weight ratio of about 1.125:1 or about 2.25:1. In some embodiments, albuterol and budesonide are present in the composition in a weight ratio of about 1.125:1. In some embodiments, albuterol and budesonide are present in the composition in a weight ratio of about 2.25:1.

[0088] In some embodiments, when the composition is administered by a metered dose inhaler, it delivers from about 50 to about 150 μg of albuterol and from about 10 to about 130 μg of budesonide per one or two metered doses. In some embodiments, when the composition is administered by a metered dose inhaler, it delivers from about 75 to about 100 μg of albuterol and from about 30 to about 90 μg of budesonide per one or two metered doses. In some embodiments, when the composition is administered by a metered dose inhaler, it delivers about 90 μg of albuterol and about 40 or about 80 μg of budesonide per one or two metered doses. In some embodiments, when the composition is administered by a metered dose inhaler, it delivers about 45 μg of albuterol and about 20 or about 40 μg of budesonide per one or two metered doses. Delivery of the compositions provided herein, such as by a metered dose inhaler, is further described herein.

[0089] Active agent particles In some embodiments, albuterol and budesonide in the composition are in particulate form. In some embodiments, the composition comprises a first plurality of albuterol particles and a second plurality of budesonide particles. In some embodiments, the composition comprising albuterol and budesonide described herein is a co-suspension. As used herein, a co-suspension comprises two or more types of particles within a suspension medium, and one type of particle at least partially associates with one or more of the other types of particles. In some embodiments, the co-suspension comprises a suspension medium comprising particles of albuterol and budesonide (also referred to herein as "active agent particles"), a propellant, and suspending particles. In some embodiments, the active agent particles associate with the suspending particles such that separation of the active agent particles from the suspending particles is substantially prevented, such that the active agent particles and the suspending particles coexist within the suspension medium. Co-suspension compositions are further described, for example, in WO 2010 / 138862.

[0090] In some embodiments, the active agent particles (e.g., particles of albuterol and particles of budesonide) are formed of a material capable of being dispersed and suspended within the suspension medium and are sized to facilitate delivery of respirable particles from the co-suspension. In some embodiments, the active agent particles are provided as micronized material, and at least 90 volume % of the active agent particles exhibit an optical diameter of about 7 μm or less, or about 6 μm or less, or about 5 μm or less, or about 4 μm or less, or about 3 μm or less. In some embodiments, the active agent particles are provided as micronized material, and at least 90 volume % of the active agent particles exhibit an optical diameter of about 1 μm to about 7 μm, about 2 μm to about 5 μm, or about 2 μm to about 3 μm. In some embodiments, the active agent particles are provided as micronized material, and at least 50 volume % of the active agent particle material exhibits an optical diameter of about 4 μm or less, or about 3 μm or less, or about 2 μm or less, or about 1.5 μm or less, or about 1 μm or less, or about 1 μm to about 4 μm, or about 1 μm to about 3 μm, or about 1 μm to about 2 μm, or about 1.3 μm to about 1.9 μm.

[0091] The active agent particles (e.g., particles of albuterol and particles of budesonide) may be formed entirely of the active agent (e.g., albuterol and budesonide, separately or in combination), or may be formulated to include one or more active agents in combination with one or more excipients or adjuvants. In some embodiments, the active agent particles include a first plurality of active agent particles and a second plurality of active agent particles. In some embodiments, the first plurality of active agent particles includes albuterol and the second plurality of active agent particles includes budesonide. In some embodiments, the first plurality of active agent particles includes a crystalline form of albuterol. In some embodiments, the second plurality of active agent particles includes an amorphous form of budesonide. In some embodiments, the first plurality of active agent particles includes an amorphous form of albuterol. In some embodiments, the second plurality of active agent particles includes a crystalline form of budesonide. In some embodiments, the active agent particles include both crystalline and amorphous forms of albuterol and budesonide. In some embodiments, one of albuterol and budesonide is provided in crystalline form and the other is provided in amorphous form. When the active agent particles described herein include an active agent in combination with one or more excipients or adjuvants, the excipients and adjuvants can be selected based on the chemical and physical properties of the active agent used. Further, excipients suitable for the formulation of the active agent particles include those described herein in connection with suspension particles. In some embodiments, the active agent particles are formulated with one or more of, for example, lipids, phospholipids, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, synthetic or natural polymers, or surfactant materials, as described in connection with suspension particles.

[0092] Any suitable process can be used to achieve micronized active agent materials, i.e., particles of albuterol and budesonide, for inclusion in the compositions described herein. To produce active agent particles suitable for use in the co-suspension formulations described herein, various processes can be used including, but not limited to, micronization by milling or grinding processes, crystallization or recrystallization processes, and processes using precipitation from supercritical or near-supercritical solvents, spray drying, spray freeze drying, or freeze drying. Suitable methods for obtaining micronized active agent particles include, for example, US 6,063,138, US 5,858,410, US 5,851,453, US 5,833,891, US 5,707,634, and WO 2007 / 009164.

[0093] Where appropriate, the active agents provided in the composition (i.e., albuterol and budesonide) may be used in the form of salts (e.g., alkali metal salts or amine salts, or as acid addition salts), or as esters, solvates (hydrates), derivatives, or their free bases. Further, the active agents (i.e., albuterol and budesonide) may be in any crystalline form or isomeric form or mixture of isomeric forms, such as pure enantiomers, as a mixture of enantiomers, as a racemate, or as a mixture thereof. The appropriate form of the active agent for inclusion in the compositions described herein can be selected by those skilled in the art. In some embodiments, the albuterol in the composition is albuterol sulfate. In some embodiments, the albuterol in the composition is crystalline albuterol sulfate particles. In some embodiments, the albuterol in the composition is micronized albuterol sulfate particles. In some embodiments, the albuterol in the composition is micronized crystalline albuterol sulfate particles. The structure of an exemplary albuterol sulfate compound is provided herein. In some embodiments, the budesonide in the composition comprises a racemic mixture of the (22R) and (22S) stereoisomers of budesonide, as described herein. The structure of budesonide is provided herein. In some embodiments, the budesonide in the composition is micronized budesonide particles. In some embodiments, the albuterol in the composition comprises crystalline albuterol sulfate particles and the budesonide in the composition comprises micronized budesonide particles. In some embodiments, the albuterol in the composition comprises micronized albuterol sulfate particles and the budesonide in the composition comprises micronized budesonide particles.

[0094] Suspended particles The suspension particles contained in the co-suspension composition described herein facilitate the stabilization and delivery of the active agents contained in the composition, namely albuterol and budesonide. Although various forms of suspension particles can be used, the suspension particles are typically formed from a pharmacologically inert material that is substantially insoluble in the propellant that is acceptable and selected for inhalation. Generally, the majority of the suspension particles are of a size within the respirable range. Thus, the terms "suspension particles" and "respirable suspension particles" are used interchangeably throughout the present disclosure. In some embodiments, the mass median aerodynamic diameter (MMAD) of the suspension particles does not exceed about 10 μm but is not less than about 500 nm. In some embodiments, the MMAD of the suspension particles is from about 750 nm to about 5 μm. In some embodiments, the MMAD of the suspension particles is from about 1 μm to about 3 μm. In some embodiments, the MMAD of the suspension particles is from 1 μm to 10 μm.

[0095] To achieve respirable suspension particles within the described MMAD range, the suspension particles typically exhibit a volume median optical diameter of from about 0.2 μm and about 50 μm. In some embodiments, the suspension particles exhibit a volume median optical diameter not exceeding about 25 μm. In some embodiments, the suspension particles exhibit a volume median optical diameter of from about 0.5 μm to about 15 μm, or from about 1.5 μm to about 10 μm, or from about 2 μm to about 5 μm.

[0096] The concentration of the suspension particles contained in the composition containing albuterol and budesonide described herein can be adjusted, for example, depending on the amount of the active agent particles and the suspension medium used. In some embodiments, the suspension particles are contained in the suspension medium at a concentration of from about 1 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 15 mg / mL, from about 3 mg / mL to about 10 mg / mL, from 5 mg / mL to about 8 mg / mL, or about 6 mg / mL. In some embodiments, the suspension particles are contained in the suspension medium at a concentration of up to about 30 mg / mL. In some embodiments, the suspension particles are contained in the suspension medium at a concentration of up to about 25 mg / mL.

[0097] The relative amount of suspension particles to the active agent particles (i.e., particles of albuterol and budesonide) is selected to achieve the co-suspension described herein. When the amount of suspension particles measured by mass exceeds the amount of active agent particles, a co-suspension composition can be achieved. In some embodiments, the ratio of the total mass of the suspension particles to the total mass of the active agent particles is from about 3:1 to about 15:1, or from about 2:1 to about 8:1. In some embodiments, the ratio of the total mass of the suspension particles to the total mass of the active agent particles is greater than about 1, e.g., up to about 1.5, up to about 5, up to about 10, up to about 15, up to about 17, up to about 20, up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150, and up to about 200, depending on the nature of the suspension particles and active agent particles used. In some embodiments, the ratio of the total mass of the suspension particles to the total mass of the active agent particles is from about 1.5:1 to about 200:1. In some embodiments, the ratio of the total mass of the suspension particles to the total mass of the active agent particles is from about 10 to about 200, from about 60 to about 200, from about 15 to about 60, from about 15 to about 170, from about 15 to about 60, about 16, about 60, or about 170.

[0098] In some embodiments, the suspension particles comprise excipients selected from lipids, phospholipids, nonionic detergents, polymers, surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, or combinations thereof. In some embodiments, the suspension particles enhance the storage stability of the active agent, i.e., albuterol and budesonide. In some embodiments, the suspension particles comprise a pharmaceutically acceptable glass-stabilizing excipient having a Tg of at least 55°C, at least 75°C, or at least 100°C. Exemplary suspension particles are provided, for example, in WO 2010 / 138862, US RE 37,872, US 5,928,469, US 6,258,341, and US 6,309,671. As used herein, Tg means the glass transition temperature, i.e., the temperature range in which a polymeric substrate changes from a hard glassy material to a soft (non-molten) material, and is typically measured with respect to rigidity or modulus.

[0099] In some embodiments, the suspended particles contain phospholipids. In some embodiments, the phospholipid has a phase transition from gel to liquid crystal at greater than about 40°C. Exemplary phospholipids include saturated lipids with relatively long chains (i.e., C 16 ~C 22 ), such as phosphatidylcholine having an acyl chain length of 16 or 18 carbons (palmitoyl and stearoyl). Exemplary phospholipids include phosphoglycerides such as dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dipalmitoleoyl phosphatidylcholine, dibehenoyl phosphatidylcholine, diphosphatidylglycerol, short-chain phosphatidylcholine, long-chain saturated phosphatidylethanolamine, long-chain saturated phosphatidylserine, long-chain saturated phosphatidylglycerol, and long-chain saturated phosphatidylinositol. Further excipients are described in WO 96 / 32149, US 6,358,530, US 6,372,258, and US 6,518,239. In some embodiments, the suspended particles are phospholipid particles containing 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

[0100] In some embodiments, the suspended particles are porous microstructures comprising DSPC and calcium chloride. Porous microstructures are described, for example, in WO 2010 / 138862 and are structures that define, or include, a structural matrix that exhibits, defines, or includes voids, pores, defects, cavities, spaces, interstitial spaces, openings, perforations, or holes that allow the surrounding suspension medium, such as the materials and preparations described in US 6,309,623, US 8,815,258, US 9,463,161, and US 2011 / 0135737, to penetrate, fill, or saturate the microstructure. In some embodiments, the suspended particles comprise a porous microstructure. When the porous microstructures are used as suspended particles in the compositions described herein, they can include at least one of lipids, phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants, and combinations thereof, particularly those approved for use in the lung. Exemplary surfactants that can be used in the preparation of the porous microstructures include poloxamer 188, poloxamer 407, and poloxamer 338. Other exemplary surfactants include oleic acid or its alkali salts. In some embodiments, the porous microstructure comprises more than about 10% w / w surfactant.

[0101] Propellant In some embodiments, for example, a composition comprising albuterol and budesonide in the form of particles as described herein further comprises a suspension medium, the particles of albuterol and budesonide are in the suspension medium, and the suspension medium further comprises a pharmaceutically acceptable propellant. In some embodiments, the suspension medium is a pharmaceutically acceptable propellant. In some embodiments, the suspension medium is a pharmaceutical grade (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)) propellant. Generally, a suitable propellant is a propellant gas that can be liquefied under pressure at room temperature and is safe and toxicologically harmless upon inhalation or topical use. In some embodiments, the pharmaceutically acceptable propellant comprises hydrofluoroalkane (HFA), hydrofluoroolefin (HFO), hydrofluorocarbon (HFC), perfluorinated compound (PFC), chlorofluorocarbon (CFC), or a combination thereof. Exemplary propellants are described, for example, in WO 2010 / 138862.

[0102] In some embodiments, the compositions described herein comprise HFA propellants, such as, for example, HFA-134a (1,1,1,2-tetrafluoroethane) and HFA-227 (1,1,1,2,3,3,3-heptafluoropropane, also known as HFA-227ea). In some embodiments, the compositions described herein comprise an HFO propellant and / or an HFC propellant. In some embodiments, the HFO propellant and / or the HFC propellant can provide consistent dosing characteristics and are easy to formulate, i.e., can provide a stable formulation that does not require modification, for example, by the addition of a co-solvent, anti-solvent, solubilizer, or adjuvant.

[0103] In some embodiments, the compositions described herein include an HFO propellant. In some embodiments, the HFO propellant is the pharmaceutical grade (1E)-1,3,3,3-tetrafluoropropene (HFO-1234ze(E)). As used herein, the term "pharmaceutical grade propellant" refers to a propellant that complies with GMP regulations for human use. In some embodiments, the pharmaceutical grade HFO-1234ze(E) has a purity of at least about 99.90%.

[0104] In some embodiments, the compositions described herein include an HFC propellant. In some embodiments, the HFC propellant is the pharmaceutical grade 1,1-difluoroethane (also known as HFC-152a, HFA-152a). In some embodiments, the pharmaceutical grade HFC-152a has a purity of at least about 99.90%.

[0105] In some embodiments, the present disclosure provides a pharmaceutical composition comprising albuterol and budesonide in particulate form, a suspension medium comprising a hydrofluoroolefin (HFO) propellant, such as pharmaceutical grade HFO-1234ze(E), or a hydrofluorocarbon (HFC) propellant, such as pharmaceutical grade HFC-152a, and a plurality of suspended particles, wherein the particles of albuterol and budesonide associate with the plurality of respirable suspended particles. In some embodiments, the present disclosure provides a pharmaceutical composition deliverable from a metered dose inhaler, the pharmaceutical composition comprising a plurality of budesonide particles, a plurality of albuterol particles, a plurality of phospholipid particles, and a propellant of pharmaceutical grade (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)) having a purity of at least about 99.90%, wherein the budesonide particles, the albuterol particles, and the phospholipid particles are co-suspended in the propellant to form a co-suspension. In some embodiments of the co-suspension, the budesonide particles comprise micronized budesonide. In some embodiments of the co-suspension, the albuterol particles comprise micronized crystalline albuterol sulfate. In some embodiments, the composition comprises from about 1 mg / mL to about 30 mg / mL in the suspension medium, or from about 5 mg / mL to about 25 mg / mL in the suspension medium. In some embodiments, the pharmaceutical composition comprises albuterol having a particle size of from about 1 μm to about 7 μm. In some embodiments, the present disclosure provides an MDI canister comprising the pharmaceutical composition described herein.

[0106] In some embodiments, a pharmaceutical composition comprising a plurality of budesonide particles, a plurality of albuterol particles, a plurality of lipid particles, and a pharmaceutical grade HFO-1234ze(E) propellant exhibits similar or equivalent bioavailability of the active agents (i.e., budesonide and albuterol) compared to a reference pharmaceutical composition comprising a plurality of budesonide particles, a plurality of albuterol particles, a plurality of lipid particles, and a pharmaceutical grade HFA-134a propellant. In some embodiments, a pharmaceutical composition comprising a plurality of budesonide particles, a plurality of albuterol particles, a plurality of lipid particles, and a pharmaceutical grade HFO-1234ze(E) propellant is biologically equivalent to a reference pharmaceutical composition comprising a plurality of budesonide particles, a plurality of albuterol particles, a plurality of lipid particles, and a pharmaceutical grade HFA-134a propellant. As used herein, "reference pharmaceutical composition" means an alternative pharmaceutical composition containing the same active agent particles (i.e., budesonide particles and albuterol particles) and the same suspension particles at the same respective concentrations as the pharmaceutical composition comprising a pharmaceutical grade HFO-1234ze(E) propellant. For example, the pharmaceutical composition and the reference pharmaceutical composition contain the same active agent particles (i.e., budesonide particles and albuterol particles) and the same lipid particles at the same respective concentrations, but the reference pharmaceutical composition contains a pharmaceutical grade HFA-134a propellant, while the pharmaceutical composition contains a pharmaceutical grade HFO-1234ze(E) propellant. In one embodiment, similar or equivalent bioavailability or biological equivalence may be shown, and the geometric mean ratio of the log-transformed C max , AUC inf or AUC last is from about 0.80 to about 1.25, regardless of the presence or absence of 90% confidence interval (CI) limits.

[0107] Compositions formulated in accordance with the present disclosure can inhibit the degradation of the active agents contained therein, namely albuterol and budesonide. For example, in some embodiments, the compositions described herein inhibit one or more of flocculation, aggregation, and Ostwald ripening of the active agent(s) contained in the composition, namely albuterol and budesonide. Even when the active agent to be delivered is very potent and the delivery dose of the active agent is selected from a dose below one of 100 μg, 80 μg, 40 μg, 20 μg, 10 μg, 9 μg, 8 μg, 7 μg, 6 μg, 5 μg, 4 μg, 3 μg, 2 μg, 1 μg, 0.5 μg, and 0.1 μg per actuation of the MDI, the stability provided by the compositions described herein allows the composition to be dispensed in a manner that achieves the desired delivery dose uniformity ("DDU") until the MDI canister is empty. In some embodiments, the compositions described herein can achieve a DDU of ±30% or better for each of the active agents contained in the composition, namely albuterol and budesonide. In some embodiments, the compositions described herein achieve a DDU of ±25% or better for each of the active agents contained in the composition, namely albuterol and budesonide. In some embodiments, the compositions described herein achieve a DDU of ±20% or better, ±15% or better, or ±10% or better for each of the active agents contained in the composition, namely albuterol and budesonide.

[0108] Furthermore, the compositions according to this description help to substantially retain the fine particle fraction (FPF) and fine particle dose (FPD) performance until the MDI canister is empty even after undergoing accelerated decomposition conditions. For example, the compositions according to this description maintain 80%, 85%, 90%, 95% or more of the original FPF and FPD performance. The compositions described herein provide the additional advantage of achieving such performance while being formulated using non-CFC and non-HFA propellants. In some embodiments, the compositions described herein are formulated using a suspension medium comprising only one or more HFO propellants and / or HFC propellants and, for example, achieve one or more of the desired target DDU, FPF, and FPD performance without the need to modify the properties of the HFO propellants and / or HFC propellants by the addition of one or more co-solvents, anti-solvents, solubilizers, adjuvants or other propellant modifying materials.

[0109] The stability and physical properties of the compositions described herein are supported by several methods. In some embodiments, methods for formulating pharmaceutical compositions for the respiratory delivery of active agents are provided herein. The method includes providing a suspension medium comprising an HFO propellant and / or an HFC propellant described herein, albuterol and budesonide particles, and suspension particles described herein, and combining the components to form a composition such that the albuterol and budesonide particles associate with the suspension particles such that the co-suspension described herein is formed. In some embodiments, the association of the albuterol and budesonide particles with the suspension particles is such that they do not separate due to their different buoyancies in a propellant, for example, an HFO and / or HFC propellant described herein.

[0110] The entire contents of all publications, patents, and patent applications referenced herein are hereby incorporated by reference into this specification.

[0111] The specific examples included in this specification are for illustrative purposes only and should not be considered as limiting the present disclosure. Further, the compositions, systems, and methods provided herein are described in relation to certain of their embodiments, and many details are provided for purposes of explanation. It will be apparent to those skilled in the art that there is room for additional embodiments and that some of the details described herein may be changed without departing from the basic principles of the present disclosure. Any active agents and reagents used in the following examples are either commercially available or can be prepared by those skilled in the art following standard literature procedures with the aid of the descriptions provided herein.

Example

[0112] Example 1. Phase 3 Clinical Trial - Fixed Dose Combination (FDC) of Albuterol and Budesonide vs Albuterol Alone A worldwide, phase 3, randomized, double-blind, parallel-group, event-driven trial was conducted in patients with uncontrolled moderate to severe asthma receiving an inhaled corticosteroid maintenance medication, which was maintained throughout the trial. Adults and adolescents were randomized to all three arms: a fixed dose combination (FDC) of albuterol-budesonide 180 / 160 μg or 180 / 80 μg (delivered dose; two puffs of 90 / 80 μg and 90 / 40 μg respectively), or albuterol 180 μg (two puffs of 90 μg). Children aged 4 - 11 years were randomized to the lower albuterol-budesonide dose only or albuterol 180 μg. The primary efficacy endpoint was time to first severe asthma exacerbation, and secondary endpoints included annualized rate of severe exacerbations and total systemic corticosteroid exposure.

[0113] Method Patients Patients aged 4 years or older with symptomatic asthma who had had one or more severe asthma exacerbations in the past 12 months (defined as an exacerbation of asthma [worsening or new onset of symptoms] resulting in one or more of the following for exacerbation history and primary endpoint: continuous treatment with systemic glucocorticoids for 3 or more days to treat worsening asthma symptoms [single depot injection was considered equivalent to a 3-day burst]; hospitalization to the emergency department (ED) or urgent care that required less than 24 hours of the above systemic glucocorticoid treatment; or hospitalization for more than 24 hours due to asthma). Additional inclusion criteria were a forced expiratory volume in 1 second (FEV1) of more than 40% and less than 90% of predicted normal values for adults (no upper limit for patients aged 4 to 17 years and demonstrating an in-hospital reversibility of FEV1 of 12% or more) and an asthma control questionnaire (ACQ-5) score of 1.5 or more at the second visit (day 1 of double-blind study drug), which indicated inadequately controlled asthma. 25 Patients continued maintenance medications throughout the trial. The main exclusion criteria included chronic obstructive pulmonary disease or other serious lung diseases, use of systemic glucocorticoids within 3 months before screening, and use of biologic therapies within 3 months or 5 half-lives before screening. Patients were receiving medium-dose to high-dose inhaled glucocorticoids or low-dose to high-dose inhaled glucocorticoids - long-acting beta2-agonist (LABA) as defined by GINA 1 for 3 or more months and had been administered stably for more than 4 weeks before the first visit.

[0114] Study Design The clinical trial was a worldwide, phase 3, randomized, double-blind, parallel-group, event-driven trial, and the minimum period of 24 weeks was conducted at 295 sites. The trial continued until more than 570 severe exacerbation events were reported.

[0115] Adults and adolescents were randomized to all three study arms (1:1:1 ratio): albuterol-budesonide 90 / 80 μg, 90 / 40 μg, and albuterol 90 μg, each administered as two puffs as needed, or to albuterol-budesonide 180 / 160 μg or albuterol-budesonide 180 / 80 μg, or albuterol 180 μg delivered by pressurized metered-dose inhaler (pMDI). Children aged 4 to 11 years were randomized only to the lower doses of albuterol-budesonide or albuterol 180 μg due to the potential concern of higher doses of inhaled glucocorticoids in this younger population. Patients were instructed on appropriate MDI technique, which was confirmed by the site staff. Patients were instructed to use the investigational drug as needed in response to symptoms and were able to use the investigational drug prior to exercise. Throughout the trial, rescue use was limited to the investigational drug only; additional short-acting bronchodilators, including nebulizers, were prohibited for rescue use. Changes to maintenance therapy were permitted.

[0116] Endpoint The primary efficacy endpoint was time to first severe asthma exacerbation (i.e., the instantaneous risk of experiencing the first severe asthma exacerbation at any given time). Secondary efficacy endpoints were annualized rate of severe exacerbations, total systemic glucocorticoid exposure for asthma over the treatment period, and responder analysis at week 24 for ACQ-5 (validated in patients 6 years and older), Asthma Quality of Life Questionnaire (AQLQ+12) for patients 12 years and older, and Pediatric Asthma Quality of Life Questionnaire (PAQLQ) for patients 7 to 11 years; patients 4 to 6 years completed the PAQLQ with the assistance of a caregiver. 27 The ACQ-5 is scored on a scale of 0 to 6 (lower numbers indicate better asthma control; minimal clinically important difference [MCID], 0.5 points), and the AQLQ+12 and PAQLQ are scored on a scale of 1 to 7 (higher scores indicate better asthma-related quality of life; MCID, 0.5 points). 28 ; for ACQ-5, responder analysis at week 24, Asthma Quality of Life Questionnaire (AQLQ+12) for patients 12 years and older, and Pediatric Asthma Quality of Life Questionnaire (PAQLQ) for patients 7 to 11 years; patients 4 to 6 years completed the PAQLQ with the assistance of a caregiver. 29 The ACQ-5 is scored on a scale of 0 to 6 (lower numbers indicate better asthma control; minimal clinically important difference [MCID], 0.5 points), and the AQLQ+12 and PAQLQ are scored on a scale of 1 to 7 (higher scores indicate better asthma-related quality of life; MCID, 0.5 points). 30、31Responders were defined as patients with a decrease of 0.5 or more (ACQ-5) or an increase (AQLQ+12 / PAQLQ) from the baseline score.

[0117] Safety endpoints (adverse events [AE] and serious adverse events [SAE]) were evaluated from the date of informed consent / assent until the safety follow-up.

[0118] Statistical analysis For the primary endpoint, the type I error was controlled for the comparison of each albuterol-budesonide dose with albuterol using the Hochberg method. Secondary endpoints were controlled using a sequence of hierarchical tests for the treatment comparisons of albuterol-budesonide 180 / 160 μg versus albuterol, and albuterol-budesonide 180 / 80 μg versus albuterol, grouped by secondary endpoint. A sample size of 1000 adults and adolescents per treatment group and 570 first serious exacerbation events, assuming a 5% two-sided significance level and an exacerbation incidence rate of 0.22 for albuterol 26 provided 87% power to detect a 25% reduction in the risk of serious exacerbation with albuterol-budesonide compared to albuterol. Additionally, the goal was to enroll 100 children aged 4 to 11 years according to the regulatory input.

[0119] A primary efficacy analysis was designed to investigate the benefits of albuterol-budesonide compared to albuterol in patients who did not change maintenance therapy and did not discontinue randomized therapy. Data collected during treatment before treatment discontinuation or change in maintenance therapy were used 26 . A supportive analysis was performed using all available data, including after any change in maintenance therapy or early discontinuation of the investigational drug as needed; that is, the treatment policy strategy was (virtually) adopted for the event.

[0120] All randomized patients who received any amount of the investigational drug were classified by the investigational drug to which they were randomized and included in the efficacy analysis comparing albuterol-budesonide 180 / 80 μg with albuterol. Children aged 4 to 11 years were excluded from the 180 / 160 μg dose analysis because these children were not randomized to this arm. All patients who received any amount of randomized investigational drug and were classified by the investigational drug actually received were included for all safety analyses.

[0121] The primary endpoint of time to first severe asthma exacerbation was analyzed using a Cox proportional hazards regression model adjusted for randomized stratification factors (age group, region) and the number of severe exacerbations in the 12 months prior to screening.

[0122] The rate of severe asthma exacerbations per year was analyzed using a negative binomial regression model adjusted for age, region, the number of severe exacerbations in the 12 months prior to screening, and time at risk. The total systemic glucocorticoid exposure per patient was calculated as the total systemic glucocorticoid dose in mg / year. The Wilcoxon rank sum test was used to show differences between treatment groups at the site and the spread of the total systemic glucocorticoid dose in mg / year. The responder outcome variables (ACQ-5 and AQLQ+12 / PAQLQ) at week 24 were analyzed using a logistic regression model adjusted for baseline values, randomized stratification factors (age group, region), and the number of severe exacerbations in the 12 months prior to screening to compare treatment groups.

[0123] Results Patients The trial enrolled 5,620 patients and randomized 3,132 (Figure 1A). As shown in Figure 1A, patients on treatment at Week 24 refer to patients randomized at Week 24, and patients on treatment at End of Study (EOS) visit were defined as patients who participated in the EOS visit while randomized. The number of patients who discontinued included patients who discontinued the study during the extension period (after Week 24). The data presented are from the primary database lock; 37 children and adolescents remained in the trial to complete 24 weeks.

[0124] Patient characteristics at screening are presented in Figure 1B. The data shown in Figure 1B are for all patients. Throughout the trial, rescue use was limited to the investigational drug only; additional short-acting bronchodilators including nebulizers were prohibited. Additional controller medications were used by approximately 15% of patients, with approximately 10% using LTRA, 4% using LAMA, and 2.2% using xanthine. Changes to maintenance therapy were permitted. At baseline, the mean ACQ-5 score across treatment groups was 2.6, indicating that asthma was not well controlled. During the trial, patients reported taking maintenance medication on an average of 74.7% of days (median 84.6%, standard deviation 25.6). Adherence was similar across treatment groups. Overall, 39 (1.2%) patients changed maintenance therapy during the study period.

[0125] Primary endpoint Both doses of albuterol-budesonide demonstrated a significant reduction in the risk of severe exacerbation compared with albuterol, as measured by time to first severe asthma exacerbation (Figure 2). The data shown in Figure 2 are for all patients. The comparison of albuterol-budesonide 180 / 160 μg vs albuterol excluded children; thus, the albuterol cohort was n = 1,014. In the comparison of albuterol-budesonide 180 / 160 μg vs albuterol, the number (%) of patients with a severe exacerbation was 207 (20.4%) in the albuterol-budesonide 180 / 160 μg group and 266 (26.2%) in the albuterol 180 μg group. In the comparison of albuterol-budesonide 180 / 80 μg vs albuterol, the number (%) of patients with a severe exacerbation was 241 (22.9%) in the albuterol-budesonide 180 / 80 μg group and 276 (26.1%) in the albuterol 180 μg group.

[0126] Figure 2 shows that albuterol-budesonide reduced the risk of severe exacerbation by 27% at the 180 / 160 μg dose (hazard ratio [HR] 0.7328; 95% confidence interval [CI] 0.6110, 0.8788; p < 0.001) and by 17% at the 180 / 80 μg dose (HR 0.8349; 95% CI 0.7024, 0.9925; p = 0.041).

[0127] Secondary endpoint The secondary endpoint results are shown in Figure 3. The data in Figure 3 are presented for all patients unless otherwise stated. The comparison of albuterol-budesonide 180 / 160 μg versus albuterol excluded children, and thus the albuterol population was smaller in these comparisons. The p-values for the total annualized dose of systemic glucocorticoids were calculated separately by the Wilcoxon rank sum test for albuterol-budesonide 180 / 160 μg versus albuterol 180 μg, and for albuterol-budesonide 180 / 80 μg versus albuterol 180 μg. Responders in the treatment groups were defined as patients having a decrease (ACQ-5) or increase (AQLQ+12) from a baseline score of at least 0.5. The multiple testing procedure was stopped after testing for the total annualized dose of systemic glucocorticoids (hierarchical testing procedure); thus, treatment effects could not be inferred using 95% confidence intervals. ACQ-5 is scored on a scale of 0–6, with lower numbers indicating better asthma control; the minimal important difference in clinical practice is 0.5 points. AQLQ(S)+12 is scored on a scale of 1–7, with higher scores indicating better asthma-related quality of life; the minimal important difference clinically is 0.5 points.

[0128] The annualized rate of severe exacerbations was 0.45 (95% CI 0.34, 0.60) (rate ratio [RR] 0.76; 95% CI 0.62, 0.93; p = 0.008) for albuterol / budesonide 180 / 160 μg compared with 0.59 (95% CI 0.44, 0.78) for albuterol, and 0.49 (95% CI 0.37, 0.64) (RR 0.80; 95% CI 0.66, 0.98; p = 0.028; Figure 3) for albuterol / budesonide 180 / 80 μg compared with 0.61 (95% CI 0.46, 0.80) for albuterol. There were 9, 10, and 17 severe exacerbations requiring hospitalization in the albuterol-budesonide 180 / 160 μg, albuterol-budesonide 180 / 80 μg, and albuterol arms, respectively, and 49, 50, and 66 severe exacerbations requiring an ED or urgent care visit, respectively.

[0129] Total systemic glucocorticoid exposure (prednisone equivalent) in annual terms for albuterol-budesonide 180 / 160 μg (median 0.0 mg / year; 5–95th percentile [0.0, 496.1]), compared with albuterol (median 0.0 mg / year; 5–95th percentile [0.0, 622.1]), was significantly different (p = 0.002; Figure 3); this difference corresponded to a 33% reduction with budesonide 180 / 160 μg. The comparison between albuterol-budesonide 180 / 80 μg (median 0.0 mg / year; 5–95th percentile [0.0, 487.0]) and albuterol (median 0.0 mg / year; 5–95th percentile [0.0, 615.9]) was not significant (p = 0.060; Figure 3). Further statistical testing of secondary endpoints was not controlled for type I error.

[0130] Results of responder analyses for ACQ-5, AQLQ+12, and PAQLQ are also presented in Figure 3.

[0131] Investigational drug use The overall pattern of as-needed investigational drug use was similar across treatment groups and increased before and after asthma exacerbations. For most of the study days, patients reported use of less than 2 inhalations (mean % of study days, albuterol-budesonide 180 / 160 μg: 53.7%; albuterol-budesonide 180 / 80 μg: 52.6%; albuterol 180 μg: 51.0%), and more than 8 inhalations were less than 2% of study days. Mean as-needed use per day was similar across treatment arms and was 2.6, 2.7, and 2.8 inhalations per day in patients treated with albuterol-budesonide 180 / 160 μg, albuterol-budesonide 180 / 80 μg, and albuterol 180 μg, respectively, which corresponded to approximately 1.3, 1.4, and 1.4 doses of investigational drug per day.

[0132] Safety endpoints The frequency of any AE was similar among the randomized treatment groups: 46.2%, 47.1%, and 46.4% for albuterol-budesonide 180 / 160 μg, albuterol-budesonide 180 / 80 μg, and albuterol, respectively. The frequency of SAE including death was 5.2%, 3.8%, and 4.5% for albuterol-budesonide 180 / 160 μg, albuterol-budesonide 180 / 80 μg, and albuterol, respectively, and the frequency of AE leading to treatment discontinuation was 1.0%, 0.9%, and 0.9%, respectively. There were 7 deaths: 4 in the albuterol-budesonide 180 / 160 μg group (2 cases of COVID-19, 1 case of elevated glucose, 1 case of cardiac arrest), 2 in the albuterol-budesonide 180 / 80 μg group (1 case of COVID-19, 1 case of pulmonary metastasis with pneumothorax), and 1 in the albuterol group (COVID-19). The deaths were not considered treatment-related.

[0133] The most common AEs included nasopharyngitis, headache, and upper respiratory tract infection. The frequency of inhaled corticosteroid-related adverse events was similar across treatment arms, ranging from 1.3% for albuterol to 2.0% for albuterol-budesonide 180 / 160 μg. The three most commonly reported treatment-related investigator-assessed AEs across the albuterol-budesonide 180 / 160 μg, albuterol-budesonide 180 / 80 μg, and albuterol 180 μg treatment groups were oral candidiasis (1.0%, 0.9%, 0.5%), dysphonia (0.4%, 0.6%, 0.4%), and oropharyngeal candidiasis (0.3%, 0.3%, 0.1%), respectively.

[0134]

Table 2

[0135] Discussion In patients with uncontrolled moderate to severe asthma receiving maintenance therapy with inhaled glucocorticoids, as-needed albuterol-budesonide FDC at doses of 180 / 160 μg (two puffs of 90 / 80 μg) and 180 / 80 μg (two puffs of 90 / 40 μg) significantly reduced the risk of severe exacerbations compared to as-needed albuterol. Compared to albuterol, significant reductions in the annualized rate of severe asthma exacerbations were observed at both doses of albuterol-budesonide, and a significant reduction in total systemic glucocorticoid exposure was observed at the 180 / 160 μg albuterol-budesonide dose. Both doses of albuterol-budesonide demonstrated tolerability consistent with the active ingredients, and no safety concerns were identified.

[0136] In terms of both average overall use and increased use before and after asthma exacerbations, the pattern of rescue medication use was similar between treatment groups. An average of less than 1.5 drug doses per day across treatment arms demonstrated that patients used albuterol-budesonide as they would albuterol. Unlike albuterol monotherapy, this FDC allows for self-adjustment of the inhaled glucocorticoid dose in response to the use of a bronchodilator according to the patient's own symptoms during exacerbations of asthma episodes.

[0137] In summary, both doses of as-needed albuterol-budesonide FDC used in addition to maintenance therapy with inhaled glucocorticoids significantly reduced the risk and proportion of severe asthma exacerbations compared to albuterol in patients with uncontrolled moderate to severe asthma, and the 180 / 160 μg dose of albuterol-budesonide also significantly reduced systemic glucocorticoid exposure.

[0138] References (incorporated herein in their entirety) TIFF2025518628000008.tif204161TIFF2025518628000009.tif244161TIFF2025518628000010.tif202161

[0139] Example 2. Phase 3 Clinical Trial - Albuterol-Budesonide Combination vs. Single Components The Phase 3 clinical trial evaluated the contribution of single components of albuterol and budesonide, and the albuterol / budesonide combination, to efficacy in patients with mild to moderate asthma for over 4 years. Patients aged 12 years and older were randomized 1:1:1:1:1 to albuterol / budesonide 180 / 160 or 180 / 80 μg four times daily, albuterol 180 μg, budesonide 160 μg, or placebo for 12 weeks; patients aged 4 - 11 years were not included in this analysis set.

[0140] Methods In this study, 1001 patients with mild to moderate asthma were randomized 1:1:1:1:1 to ABD 180 / 160 μg or 180 / 80 μg, albuterol (A) 180 μg, budesonide (B) 160 μg, or placebo, all four times daily (QID) for 12 weeks. The two primary endpoints were the change from baseline in the area under the forced expiratory volume in 1 second curve (FEV1, AUC 0-6h ) over 0 - 6 hours over 12 weeks and in trough FEV1 at week 12. Secondary endpoints included time to onset and duration of effect as measured by a 15% improvement in FEV1 within 30 minutes on day 1, and analysis of the Asthma Control Questionnaire - 7 (ACQ - 7) responders (reduction of 0.5 points or more from baseline) at week 12.

[0141] Results Of the 1001 randomized patients, 989 were 12 years and older (mean age 48.9 years, 62.2% female). FEV1 AUC over 12 weeks 0-6hThe change from baseline in [study name] was greater for budesonide than for albuterol / budesonide 180 / 160 μg (the only dose tested) (least squares mean [LSM] difference 80.7 mL, 95% confidence interval [CI] 28.4–132.9; p = 0.003; Table 2). The change in trough FEV1 at week 12 was greater for albuterol / budesonide 180 / 160 and 180 / 80 μg than for albuterol (LSM differences 132.8 mL [95% CI 63.6–201.9] and 120.8 mL [95% CI 51.5–190.1], respectively; both p < 0.001; Table 2). The median time to onset and duration of effect on day 1 (responders: 49.7%, 44.0%, and 42.9%) were 7.5 minutes and 7.0 minutes vs 9.5 minutes, and 186.9 minutes and 191.4 minutes vs 168.2 minutes for albuterol / budesonide 180 / 160 or 180 / 80 μg and albuterol, respectively. At week 12, the percentage of ACQ-7 responders was 66.5% and 65.5% vs 47.2% for albuterol / budesonide 180 / 160 or 180 / 80 μg vs albuterol (odds ratio [OR] 2.3 [95% CI 1.5–3.7] and OR 2.3 [95% CI 1.5–3.6]; both nominally significant). The safety profiles of both doses of albuterol / budesonide were similar to those of the single components.

[0142] Discussion Both single components contributed to the efficacy of albuterol / budesonide, and the combination demonstrated an excellent effect on lung function. At the start of treatment, no difference was seen in the improvement in FEV1 between the combination of albuterol / budesonide and albuterol 180 μg. With repeated use over 1–4 weeks, no difference was seen in bronchodilation between albuterol 180 μg and placebo, whereas the combination of albuterol / budesonide was superior to albuterol 180 μg, and the difference increased over time.

[0143]

Table 3

Claims

1. A method for treating asthma in a subject at risk of asthma exacerbation, comprising the step of administering, as needed, a composition comprising a therapeutically effective amount of albuterol and budesonide, wherein the composition is administered by a metered-dose inhaler, The method, when measured by the time to the first severe asthma exacerbation, reduces the risk of severe asthma exacerbation by at least about 15% compared to administration of a composition comprising the same dose of albuterol alone.

2. The method according to claim 1, wherein the method reduces the risk of severe asthma exacerbation by at least about 20% compared to administration of a composition comprising the same dose of albuterol alone, when measured by the time to the first severe asthma exacerbation.

3. The method according to claim 1 or 2, wherein the method reduces the risk of severe asthma exacerbation by at least about 25% compared to administration of a composition comprising the same dose of albuterol alone, when measured by the time to the first severe asthma exacerbation.

4. The method according to any one of claims 1 to 3, wherein the hazard ratio of the method, compared to administration of a composition comprising the same dose of albuterol alone, is less than about 0.

9.

5. The method according to any one of claims 1 to 4, wherein the hazard ratio of the method, compared to administration of a composition comprising the same dose of albuterol alone, is less than about 0.

8.

6. The method according to any one of claims 1 to 5, wherein the hazard ratio of the method, compared to administration of a composition comprising the same dose of albuterol alone, is less than about 0.

7.

7. The method according to any one of claims 1 to 6, wherein the annualized rate of severe asthma exacerbation of the method is at least about 20% lower compared to administration of a composition comprising the same dose of albuterol alone.

8. The method according to any one of claims 1 to 7, wherein the annualized exacerbation rate of severe asthma is at least about 25% lower compared to the administration of a composition containing albuterol alone at the same dose.

9. The method according to any one of claims 1 to 8, wherein the method reduces the number of subjects with severe asthma exacerbations requiring hospitalization by at least 30% compared to the administration of a composition containing albuterol alone at the same dose.

10. The method according to any one of claims 1 to 9, wherein the method reduces the number of subjects with severe asthma exacerbations requiring emergency and / or urgent care by at least 20% compared to the administration of a composition containing albuterol alone at the same dose.

11. The method according to any one of claims 1 to 10, wherein the method reduces the total systemic corticosteroid dose in the subject on an annualized basis by at least 30% compared to the administration of a composition containing albuterol alone at the same dose.

12. The area under the curve (AUC) of the forced expiratory volume in 1 second (FEV 1 AUC 0-6 ) from 0 to 6 hours in the subject 12 weeks after administration of the composition is greater than 110 mL, according to the method of any one of claims 1 to 11.

13. The FEV 1 AUC 0-6 of the subject 12 weeks after administration of the composition is at least 10% higher compared to a subject administered albuterol alone at the same dose or budesonide alone at the same dose, according to the method of any one of claims 1 to 12.

14. The trough FEV 1 of the subject 12 weeks after administration of the composition is greater than 90 mL, according to the method of any one of claims 1 to 13.

15. The trough FEV 1The method according to any one of claims 1 to 14, which is at least 10% higher compared to a subject administered a composition containing the same dose of albuterol alone or the same dose of budesonide alone. **Claim 16** The method according to any one of claims 1 to 15, wherein the administration comprises delivering one or more metered doses from a metered-dose inhaler, and about 100 to about 300 μg of albuterol and about 25 to about 250 μg of budesonide are delivered. **Claim 17** The method according to claim 16, wherein about 120 to about 250 μg of albuterol are delivered. **Claim 18** The method according to claim 16 or 17, wherein about 150 to about 200 μg of albuterol are delivered. **Claim 19** The method according to any one of claims 16 to 18, wherein about 180 μg of albuterol are delivered. **Claim 20** The method according to any one of claims 1 to 19, wherein about 50 to about 200 μg of budesonide are delivered. **Claim 21** The method according to any one of claims 1 to 20, wherein about 75 to about 175 μg of budesonide are delivered. **Claim 22** The method according to any one of claims 1 to 21, wherein about 80 or about 160 μg of budesonide are delivered. **Claim 23** The method according to any one of claims 1 to 22, wherein about 150 to about 200 μg of albuterol and about 75 to about 175 μg of budesonide are delivered. **Claim 24** The method according to any one of claims 1 to 23, wherein about 180 μg of albuterol and about 80 or about 160 μg of budesonide are delivered. **Claim 25** The method according to any one of claims 1 to 16, wherein the administration comprises delivering two metered doses from a metered-dose inhaler, and each delivered dose comprises from about 60 to about 125 μg of albuterol and from about 25 to about 100 μg of budesonide. **Claim 26** The method according to claim 25, wherein each delivered dose comprises about 90 μg of albuterol and about 40 or about 80 μg of budesonide. **Claim 27** The method according to any one of claims 1 to 26, wherein albuterol and budesonide are in a weight ratio of from about 1:1 to about 3:1 in the composition. **Claim 28** The method according to any one of claims 1 to 27, wherein albuterol and budesonide are in a weight ratio of from about 1.1:1 to about 2.5:1 in the composition. **Claim 29** The method according to any one of claims 1 to 28, wherein albuterol and budesonide are in a weight ratio of about 1.125:1 or about 2.25:1 in the composition. **Claim 30** The method according to any one of claims 1 to 29, wherein albuterol and budesonide are in particulate form, and at least 90 volume % of the particles have an optical diameter of from about 1 μm to about 7 μm. **Claim 31** The method according to claim 30, wherein the albuterol particles comprise crystalline or micronized albuterol sulfate and the budesonide particles comprise micronized budesonide. **Claim 32** The method according to any one of claims 1 to 31, wherein the composition comprises a plurality of albuterol particles, a plurality of budesonide particles, a plurality of respirable suspension particles, and a suspension medium, and the plurality of albuterol particles, the plurality of budesonide particles, and the plurality of respirable suspension particles are co-suspended in the suspension medium to form a co-suspension. **Claim 33** The method according to claim 32, wherein the suspension medium is a pharmaceutically acceptable propellant selected from hydrofluoroalkane (HFA) propellants, hydrofluoroolefin (HFO) propellants, hydrofluorocarbon propellants (HFC), and combinations thereof.

34. The method according to claim 32 or 33, wherein the suspension medium is a propellant of pharmaceutical grade (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)).

35. The method according to any one of claims 32 to 34, wherein the respirable suspension particles comprise a volume median optical diameter of about 0.2 μm to about 50 μm.

36. The method according to any one of claims 32 to 35, wherein the respirable suspension particles are about 1 mg / mL to about 30 mg / mL in the suspension medium.

37. The method according to any one of claims 32 to 36, wherein the respirable suspension particles comprise phospholipids.

38. The method according to claim 37, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

39. The method according to any one of claims 32 to 38, wherein the weight ratio of the total mass of the respirable suspension particles to the total mass of the albuterol and budesonide particles is about 1.5:1 to about 200:

1.

40. A method of treating or preventing bronchoconstriction in a subject as needed and / or preventing exacerbation in a subject with asthma, comprising administering, as needed, a composition comprising a therapeutically effective amount of albuterol and budesonide, wherein the composition is administered by a metered-dose inhaler, The method, when measured by the time to the first severe asthma exacerbation, reduces the risk of severe asthma exacerbation by at least about 15% compared to the administration of a composition comprising albuterol alone at the same dose.

41. The method according to claim 40, wherein the subject is a human subject 12 years of age or older.

42. The method according to claim 41, wherein the administration comprises delivering two metered doses from a metered-dose inhaler to the subject, and about 180 μg of albuterol and about 160 μg of budesonide are delivered.

43. The method according to claim 40, wherein the subject is a human subject from 4 to 11 years of age.

44. The method according to claim 43, wherein the administration comprises delivering two metered doses from a metered-dose inhaler to the subject, and about 180 μg of albuterol and about 80 μg of budesonide are delivered.

45. The method according to any one of claims 40 to 44, wherein the subject is not administered more than six metered doses in a 24-hour period.

46. A pharmaceutical composition deliverable from a metered-dose inhaler, comprising a therapeutically effective amount of albuterol and budesonide for use in the treatment of asthma in a subject at risk of asthma exacerbation, wherein the treatment reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation compared to administration of a composition containing the same dose of albuterol alone.

47. A pharmaceutical composition deliverable from a metered-dose inhaler, comprising a therapeutically effective amount of albuterol and budesonide for use in the treatment or prevention of bronchoconstriction as needed in a subject, and / or the prevention of exacerbation in a subject having asthma, wherein the method reduces the risk of severe asthma exacerbation by at least about 15% as measured by time to first severe asthma exacerbation compared to administration of a composition containing the same dose of albuterol alone.

48. The pharmaceutical composition for use according to claim 46 or 47, wherein the composition comprises a plurality of albuterol particles, a plurality of budesonide particles, a plurality of respirable suspension particles, and a suspension medium, and the plurality of albuterol particles, the plurality of budesonide particles, and the plurality of respirable suspension particles are co-suspended in the suspension medium to form a co-suspension.

49. The pharmaceutical composition for use according to claim 48, wherein the suspension medium is a pharmaceutical grade propellant of (1E)-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E)).

50. The pharmaceutical composition for use according to claim 48 or 49, wherein the respirable suspension particles contain phospholipids.

51. The pharmaceutical composition for use according to claim 50, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

52. The pharmaceutical composition for use according to any one of claims 46 to 51, wherein the hazard ratio of treatment is less than about 0.9 as compared to the administration of a composition containing the same dose of albuterol alone.

53. The pharmaceutical composition for use according to any one of claims 46 to 52, wherein the annualized rate of severe asthma exacerbation in treatment is at least about 20% lower as compared to the administration of a composition containing the same dose of albuterol alone.

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