Inhalable formulations of fluticasone propionate and salbutamol sulfate for the treatment of asthma

Abstract

The present invention relates to a method of treating asthma comprising administering as rescue medication a fixed-dose dry powder inhalation composition comprising fluticasone propionate and salbutamol sulfate in patients aged > 4 years on an as-needed (PRN) basis, wherein the fluticasone propionate is administered at a delivered dose of 22-59 micrograms per inhalation, the salbutamol sulfate is administered at a delivered dose of 92-124 micrograms per inhalation, and the treatment provides one or more of: an extended time to first severe clinical asthma exacerbation compared to salbutamol sulfate rescue treatment, a reduced total annualized systemic corticosteroid (SCS) exposure compared to salbutamol sulfate rescue treatment, a reduced annualized rate of severe clinical asthma exacerbations compared to salbutamol sulfate rescue treatment. Also provided is a fixed-dose dry powder inhalation composition and a dry powder inhaler for use in performing the method of the invention.

Description

Background of the Invention

[0002] This invention relates to inhalable formulations of fluticasone propionate and salbutamol sulfate for the treatment of asthma, and more particularly to fixed-dose compositions thereof.

[0003] Asthma is one of the most common chronic diseases. It is a heterogeneous disease affecting the lung airways, characterized by airway inflammation and bronchial hyperresponsiveness, leading to varying degrees of reduction in expiratory airflow, the occurrence, frequency, and intensity of which vary over time. During an acute asthma attack, the airways become narrower and more obstructed, resulting in cough, wheezing, chest tightness, shortness of breath, and increased sputum production. In some individuals, asthma can cause chronic, irreversible changes in airway structure and function, increasing morbidity and mortality.

[0004] Inhaled corticosteroids and β2-agonists represent two classes of active ingredients that have been developed for the treatment of respiratory diseases, particularly asthma. Each class has different targets and effects.

[0005] Inhaled corticosteroids (ICS) are steroid hormones used for the long-term control of respiratory diseases. They work by reducing airway inflammation, controlling symptoms, and reducing the risk of future acute exacerbations and decline in lung function. They are often referred to as "control" or "maintenance" medications.

[0006] Currently marketed ICS include beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, and mometasone furoate. These compounds are well known in the art. For example, fluticasone propionate is named S-(fluoromethyl)-6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-thiocarboxylic acid-17-propionate.

[0007] Short-acting beta2-agonists (SABAs) are examples of bronchodilators used to dilate the bronchi and bronchioles, reducing airway resistance and thus increasing airflow into the lungs. Bronchodilators can be short-acting or long-acting. Short-acting bronchodilators provide rapid but short-term relief from acute bronchoconstriction (often referred to as "rescue" or "relief" medications), while long-acting bronchodilators help control symptoms for a longer period than SABAs.

[0008] SABAs are used acutely to provide rapid symptom relief and can be life-saving, but they do not address the underlying airway inflammation. Patients experience immediate relief with SABA medications when their asthma symptoms worsen, thus increasing their use. However, patients do not typically increase their use of ICS in a similar manner. SABA overuse (defined as ≥3 cans per year) is common and is a risk factor for adverse asthma outcomes and severe acute exacerbations.

[0009] Salbutamol (also known as salbutamol) is a short-acting β2-agonist used to treat or prevent bronchospasm in patients with asthma. Its name is 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol. Salbutamol is a commonly used bronchodilator in the management of acute asthma. It is usually administered in sulfate form, the structure of which is well known in the art.

[0010] According to the 2023 Global Initiative for Asthma (GINA) guidelines, a step-by-step approach is adopted for treatment. This approach is divided into Pathway 1 and Pathway 2.

[0011] In Pathway 1, steps 1-2 (representing mild asthma) administer a low-dose on-demand ICS-formoterol (ICS-formoterol, a fast-acting, long-acting β2-adrenergic receptor agonist (LABA)). Step 3 administers a maintenance low-dose ICS-formoterol. Step 4 increases to a medium-dose ICS-formoterol. Step 5 adds a LAMA (long-acting muscarinic antagonist) and considers a high-dose ICS-formoterol. Throughout all steps, the reliever is a low-dose on-demand ICS-formoterol. In Pathway 2, the reliever is either on-demand SABA or on-demand ICS-SABA. Step 1 involves administering ICS concurrently with SABA. Step 2 adds a low-dose maintenance ICS. Step 3 adds a low-dose maintenance ICS-LABA. Step 4 adds a medium / high-dose ICS-LABA. Step 5 adds a LAMA and considers a high-dose ICS-LABA.

[0012] The GINA guidelines recommend a similar step-by-step approach for pediatric patients (6-11 years old).

[0013] Interestingly, despite the availability of existing treatments, most asthma patients still experience poor control. Several factors can contribute to this poor control, one of which is poor adherence to prescribed maintenance therapy. This is a contributing factor to the high morbidity and mortality rates associated with asthma.

[0014] While regular daily maintenance therapy has benefits, poor adherence is common and associated with significant asthma-related morbidity. Most patients with persistent asthma rarely use ICS (Intracorporeal Membrane Syringe) therapy, for example, only using 2 to 4 bottles per year.

[0015] Therefore, there is still a need in the art to improve the treatment of asthma patients, which is the problem that this invention aims to solve. Summary of the Invention

[0016] Therefore, the present invention provides a method for treating asthma, the method comprising administering, on demand (PRN) a fixed-dose dry powder inhalation composition comprising fluticasone propionate and salbutamol sulfate as a rescue medication to patients aged ≥4 years, wherein the fluticasone propionate is administered at a delivery dose of 22-59 micrograms per inhalation, the salbutamol sulfate is administered at a delivery dose of 92-124 micrograms per inhalation, and the treatment provides one or more of the following: prolonged time to first severe clinical asthma exacerbation (CAE) compared to salbutamol sulfate rescue treatment, reduced total annualized systemic corticosteroid (SCS) exposure compared to salbutamol sulfate rescue treatment, and reduced annualized severe clinical asthma exacerbation (CAE) rate compared to salbutamol sulfate rescue treatment.

[0017] The present invention also provides a fixed-dose dry powder inhaler composition for treating asthma, the composition comprising fluticasone propionate and salbutamol sulfate, for use as a rescue medication on demand (PRN) in patients aged ≥4 years of age for the treatment of asthma, wherein the fluticasone propionate is administered in a delivery dose of 22-59 micrograms per inhalation, and the salbutamol sulfate is administered in a delivery dose of 92-124 micrograms per inhalation, and the treatment provides one or more of the following: prolonged time to first severe clinical asthma exacerbation (CAE) compared to salbutamol sulfate rescue treatment, reduced total annualized systemic corticosteroid (SCS) exposure compared to salbutamol sulfate rescue treatment, and reduced annualized rate of severe clinical asthma exacerbation (CAE) compared to salbutamol sulfate rescue treatment. The present invention also provides a dry powder inhaler comprising the fixed-dose dry powder inhaler composition.

[0018] In a preferred embodiment, the fixed-dose dry powder inhalation composition comprises fluticasone propionate, salbutamol sulfate, and lactose. Preferably, the lactose is α-lactose monohydrate.

[0019] Brief description of the attached figures

[0020] The present invention will now be described in detail with reference to the accompanying drawings, wherein: Figure 1 This is a front perspective view of a dry powder inhaler according to a preferred embodiment; Figure 2 yes Figure 1 The inhaler shown is an internal cross-sectional perspective view. Figure 3 yes Figure 1 An exploded perspective view of the exemplary inhaler shown; Figure 4 yes Figure 1 An exploded perspective view of the top cover and electronic module of the inhaler shown; Figure 5 It is a decomposition isometric view of the deaggregator according to this disclosure; Figure 6 yes Figure 5 A side view of the aggregator; Figure 7 yes Figure 5 Top view of the aggregator; Figure 8 yes Figure 5 Bottom view of the aggregator; Figure 9 It is along Figure 6 The line intercepted at 5'-5' Figure 5 A cross-sectional view of the aggregator; and Figure 10 It is along Figure 7 The line intercepted at 6'-6' Figure 5 A cross-sectional view of the aggregator. Detailed Implementation

[0021] This invention relates to a method of treating asthma by administering a fixed-dose dry powder inhalation composition containing APIs (fluticasone propionate and salbutamol sulfate).

[0022] In its most widespread implementation, the indication for treatment is asthma. In another preferred implementation, asthma treatment includes treating or preventing bronchospasm in patients aged 4 years and older with reversible obstructive airway disease. In yet another preferred implementation, asthma treatment includes preventing acute exacerbations in patients aged 4 years and older. Alternatively, the patient may be 6 years and older, 12 years and older, or 18 years and older.

[0023] In a preferred embodiment, the fixed-dose dry powder inhalation composition comprises fluticasone propionate, salbutamol sulfate, and lactose. Preferably, the lactose is α-lactose monohydrate.

[0024] The various APIs are also known in the art and have been discussed in the background section of this invention.

[0025] This invention relates to fixed-dose combinations (FDC), i.e., dry powder formulations. Alternatively, two APIs may be present in a suspension or solution formulation. When dry powder medications are involved, the two medications may be contained in the reservoir, capsule, or blister pack of an inhaler. Preferably, the two APIs are formulated together to provide a fixed-dose dry powder composition contained in the reservoir of an inhaler. In capsules or blister packs, the two APIs may be in the same or separate / different capsule / blister packs, as long as they are contained in the same device. Such inhalers are well known in the art and are described in more detail below. It should be noted that when a medication is contained in a pre-measured amount in a separate container (e.g., a capsule or blister pack), the dose may be referred to as the “expected dose” dose.

[0026] The fixed-dose combination of the present invention is administered as a backup medication on demand (PRN), meaning it is not used as maintenance therapy. In practice, patients can separately administer maintenance doses of any type of long-term asthma medication, such as ICS, LABA, LAMA, SAMA (short-acting muscarinic antagonist), various biologics, and combinations thereof. The ICS can be the same as the ICS in the fixed-dose dry powder inhaler composition, i.e., fluticasone propionate, or another ICS, a combination of ICS, or a combination of ICS with any of the active ingredients listed above. In fact, the advantage of the present invention is that the compositions of the present invention can be used as a backup medication for any background asthma maintenance therapy or as a backup medication without background treatment.

[0027] Examples of maintenance therapies that can be used with the present invention include ICS such as flunisolone, fluticasone propionate (approved products are HFA pMDI and DPI, such as ArmonAir® / AirDuo®), fluticasone furoate (approved products are DPI), beclomethasone dipropionate (approved products are DPI, such as Easyhaler® and HFA pMDI, such as Qvar®), budesonide (approved products are DPI), mometasone furoate (approved products are DPI and HFA pMDI), ciroxonide (approved products are HFA pMDI), and combinations thereof.

[0028] Examples of LABAs include formoterol, artotrorol, salmeterol, bambootrorol, clenbuterol, and combinations thereof. Ultra-long-acting LABAs, such as abediterol, indacaterol, olodaterol, vilanterol, carmoterol, and combinations thereof, can also be used.

[0029] Examples of LAMA include tiotropium, glycopyrronium, umeclidinium, acridium, darotropium, and combinations thereof. An example of SAMA is ipratropium bromide.

[0030] Examples of biological maintenance therapies that can be used with the present invention include tazepluzumab, dupilumab, mepolizumab, repetizumab, benrelizumab, omalizumab, palizumab, and combinations thereof.

[0031] Daily doses for maintenance therapy can be categorized as low, intermediate, or high based on the type of medication and the patient's age. For example, for patients aged 12 years and older, the daily doses are as follows: Beclomethasone dipropionate: low dose 200-500 mcg, intermediate dose >500-1,000 mcg, high dose >1,000 mcg. Beclomethasone dipropionate ultrafine granules: low dose 100-200 mcg, intermediate dose >200-400 mcg, high dose >400 mcg. Budesonide: low dose 200-400 mcg, intermediate dose >400-800 mcg, high dose >800 mcg. Cixone: low dose 80-160 mcg, intermediate dose >160-320 mcg, high dose >320 mcg. Fluticasone furoate: low and medium doses are 100 micrograms, high doses are 200 micrograms. Fluticasone propionate: low doses are 100-250 micrograms, medium doses are >250-500 micrograms, high doses are >500 micrograms. Mometasone furoate: low and medium doses are 200-400 micrograms, high doses are >400 micrograms.

[0032] For patients aged 6 years to <12 years, the daily dosage of ICS is as follows: Beclomethasone dipropionate: low dose 100-200 mcg, medium dose >200-400 mcg, high dose >400 mcg. Beclomethasone dipropionate ultrafine particles: low dose 50-100 mcg, medium dose >100-200 mcg, high dose >200 mcg. Budesonide: low dose 100-200 mcg, medium dose >200-400 mcg, high dose >400 mcg. Budesonide nebulizer solution: low dose 250-500 mcg, medium dose >500-1,000 mcg, high dose >1,000 mcg. Cixosonide: low dose 80 mcg, medium dose >80-160 mcg, high dose >160 mcg. Fluticasone furoate: low and medium doses are 50 micrograms. Fluticasone propionate: low doses are 50-100 micrograms, medium doses are >100-200 micrograms, and high doses are >200 micrograms. Mometasone furoate: low and medium doses are 100 micrograms, and high doses are 200 micrograms.

[0033] Other maintenance therapies can be found in the GINA guidelines and are provided at approved or recommended doses. For example, in steps 1-2 of pathway 1, budesonide-formoterol is administered at a dose of 200 / 6 mcg (delivered dose 160 / 4.5 mcg) for patients aged 12 years and older. In steps 3-4 of pathway 1, the dose of budesonide-formoterol is 100 / 6 mcg (delivered dose 80 / 4.5 mcg) for patients aged 6-11 years, 200 / 6 mcg (delivered dose 160 / 4.5 mcg) for patients aged 12-17 years, and 200 / 6 mcg (delivered dose 160 / 4.5 mcg) or beclomethasone-formoterol at a dose of 100 / 6 mcg (delivered dose 84.6 / 5.0 mcg) for patients aged 18 years and older. In step 5 of pathway 1, for children aged 12-17, the dose of budesonide-formoterol is 200 / 6 micrograms (delivery of 160 / 4.5 micrograms), and for children aged 18 and above, the dose of budesonide-formoterol is 200 / 6 micrograms (delivery of 160 / 4.5 micrograms) or the dose of beclomethasone-formoterol is 100 / 6 micrograms (delivery of 84.6 / 5.0 micrograms).

[0034] This invention relates to a method for treating asthma, wherein a fixed-dose combination of fluticasone propionate and salbutamol sulfate is used as a remittent treatment to reduce acute exacerbations, systemic corticosteroid exposure, frequency of asthma exacerbations, and improve symptoms in asthma patients. While many patients use ICS or ICS / LABA combinations as part of their maintenance therapy, many do not adhere to this treatment. Multiple studies have shown that many asthma patients do not adhere to their maintenance therapy. As patients' asthma worsens, they experience symptoms, prompting the use of more emergency medications. By incorporating ICS (particularly fluticasone propionate) and salbutamol sulfate into a single inhaler, patients achieve symptom relief, and this combination also treats the underlying inflammation that contributes to increased symptoms, thus reducing acute exacerbations compared to salbutamol alone as an emergency treatment. Therefore, incorporating ICS (particularly fluticasone propionate) and salbutamol into a single inhaler minimizes the adverse effects (e.g., acute exacerbations, hospitalization, and death) of overuse of salbutamol (or its single enantiomer, levosalbutamol) as the sole emergency treatment.

[0035] Reducing corticosteroid exposure is another significant advantage of this approach. Short-term increases in ICS exposure are self-limiting, as patients either improve and use less emergency care, thus reducing ICS use, or they receive treatment for severe acute exacerbations, leading to systemic corticosteroid therapy and higher exposure. In a sense, patients are self-titting their dose according to their needs for treating asthma symptoms.

[0036] The fixed-dose dry powder inhalation composition of the present invention is used to treat asthma, particularly to treat or prevent bronchospasm and / or prevent acute exacerbations in patients aged 4 years and older with reversible obstructive airway disease, wherein the fixed-dose dry powder inhalation composition is administered as a resuscitation medication on demand (PRN), and wherein it comprises a delivery dose of 22-59 micrograms of fluticasone propionate and a delivery dose of 92-124 micrograms of salbutamol sulfate (per inhalation). Therefore, the present invention provides a method of treating asthma by treating or preventing bronchospasm and / or preventing acute exacerbations in patients aged 4 years and older with reversible obstructive airway disease, the method comprising administering on-demand (PRN) a fixed-dose dry powder inhalation composition comprising fluticasone propionate and salbutamol sulfate as a resuscitation medication, wherein the fluticasone propionate is administered at a delivery dose of 22-59 micrograms (per inhalation), and the salbutamol sulfate is administered at a delivery dose of 92-124 micrograms (per inhalation). This also includes doses that are bioequivalent to the doses of the present invention, particularly doses that are bioequivalent to the delivery dose.

[0037] Therefore, fluticasone propionate is administered at a delivery dose of 22-59 micrograms per inhalation, and salbutamol sulfate at a delivery dose of 92-124 micrograms per inhalation. Preferably, fluticasone propionate is administered at a delivery dose of 23-56 micrograms per inhalation, and salbutamol sulfate at a delivery dose of 97-119 micrograms per inhalation. More preferably, fluticasone propionate is administered at a delivery dose of 25-54 micrograms per inhalation, and salbutamol sulfate at a delivery dose of 103-113 micrograms per inhalation. In a particular embodiment, fluticasone propionate is administered at a delivery dose of 26 or 51 micrograms per inhalation, and salbutamol sulfate at a delivery dose of 108 micrograms per inhalation.

[0038] In addition, fluticasone propionate is typically administered at a dose of 26-63 micrograms per inhalation, and salbutamol sulfate at a dose of 99-135 micrograms per inhalation. Preferably, fluticasone propionate is administered at a dose of 27-61 micrograms per inhalation, and salbutamol sulfate at a dose of 105-129 micrograms per inhalation. More preferably, fluticasone propionate is administered at a dose of 29-58 micrograms per inhalation, and salbutamol sulfate at a dose of 111-123 micrograms per inhalation. In a particular embodiment, fluticasone propionate is administered at a dose of 30 or 55 micrograms per inhalation, and salbutamol sulfate at a dose of 117 micrograms per inhalation.

[0039] The compositions of this invention are administered as a first aid medicine on demand (PRN). Typically, the maximum daily dose does not exceed 6 doses, i.e., 12 inhalations (2 inhalations / dose).

[0040] The terms “measured dose” and “delivered dose” are conventional terms in the art and have their standard meanings. That is, the measured dose is the mass of active ingredient available within the aerosol generator per drive. This is the dose that is measured. The delivered dose is the mass of active ingredient actually available for oral inhalation per drive.

[0041] Specifically, the method / composition of the present invention provides one or more of the following: prolonging the time to first severe clinical asthma exacerbation (CAE) compared to emergency treatment with salbutamol sulfate, reducing total annualized systemic corticosteroid (SCS) exposure compared to emergency treatment with salbutamol sulfate, and reducing the annualized rate of severe clinical asthma exacerbation (CAE) compared to emergency treatment with salbutamol sulfate. In one embodiment, the method / composition provides one or more of the following: prolonging the time to first severe CAE compared to emergency treatment with salbutamol sulfate, and reducing total annualized systemic corticosteroid (SCS) exposure compared to emergency treatment with salbutamol sulfate. In another embodiment, the method / composition provides one or more of the following: reducing total annualized systemic corticosteroid (SCS) exposure compared to emergency treatment with salbutamol sulfate, and reducing the annualized rate of severe clinical asthma exacerbation (CAE) compared to emergency treatment with salbutamol sulfate. In another embodiment, the method / composition provides one or more of the following: prolonging the time to first occurrence of severe CAE compared with emergency treatment with salbutamol sulfate, and reducing the annualized rate of severe clinical asthma acute exacerbations (CAE) compared with emergency treatment with salbutamol sulfate.

[0042] In one embodiment, the method / composition of the present invention prolongs the time to first severe clinical acute exacerbation of asthma (CAE) compared with emergency treatment with salbutamol sulfate, and / or reduces total annualized systemic corticosteroid (SCS) exposure compared with emergency treatment with salbutamol sulfate, and / or reduces the annualized rate of severe CAE compared with emergency treatment with salbutamol sulfate.

[0043] In another embodiment, the method / composition of the present invention provides one or more of the following: prolonging the time between severe CAEs compared with emergency treatment with salbutamol sulfate, and reducing the time a patient has severe CAEs compared with emergency treatment with salbutamol sulfate.

[0044] In a preferred embodiment, the method / composition of the present invention provides one or more of the following: prolonging the time to first occurrence of severe CAE compared with emergency treatment with salbutamol sulfate, reducing total annualized SCS exposure compared with emergency treatment with salbutamol sulfate, and reducing the annualized rate of severe clinical asthma exacerbations (CAE) compared with emergency treatment with salbutamol sulfate, and also provides one or more of the following: prolonging the time between severe CAEs compared with emergency treatment with salbutamol sulfate, and reducing the time a patient has severe CAE compared with emergency treatment with salbutamol sulfate.

[0045] The salbutamol sulfate emergency treatment used in this article refers to the administration of salbutamol sulfate only as needed, where the patient may also receive maintenance therapy alone with any type of long-term asthma medication, such as ICS, LABA, LAMA, SAMA, various biologics, and combinations thereof. Preferably, the salbutamol sulfate dosage is 117 micrograms (and a delivery dose of 108 micrograms). If ICS is used as maintenance therapy, it can be administered as a single product or in combination with other long-term asthma medications. The ICS can be the same as the ICS in a fixed-dose dry powder inhaler composition, i.e., fluticasone propionate, or another ICS, or a combination of ICS with any of the active ingredients listed above (as described above).

[0046] As used herein, the time to the first occurrence of a severe CAE is calculated from the date of inhalation therapy according to the invention until the date of the first occurrence of a severe CAE. An acute exacerbation of asthma is considered severe if it results in at least one of the following: - Treat with SCS continuously for at least 3 days to manage asthma exacerbations. A single injection of corticosteroids is considered equivalent to a 3-day course of oral corticosteroids.

[0047] - Emergency care or emergency room visits for asthma require at least 3 consecutive days of SCS.

[0048] - Hospitalization for asthma (defined as admission to an inpatient facility or observation room) for ≥24 hours.

[0049] Two severe acute exacerbations (CAEs) must be spaced more than 7 days apart. If the end date of the first CAE and the start date of the second CAE are less than 7 days apart, it is counted as one severe acute exacerbation.

[0050] In an alternative embodiment, the invention also provides asthma improvement defined by feedback from the Asthma Control Questionnaire-5 (ACQ-5) at week 24, defined as a decrease of at least 0.5 points from baseline compared to emergency treatment with salbutamol sulfate, and / or feedback from the AQLQ+12 / PAQLQ (patient age ≥ 7 years) at week 24, defined as an increase of at least 0.5 points from baseline compared to emergency treatment with salbutamol sulfate. Asthma improvements presented in these questionnaires can be demonstrated in patients aged 6 years and older. In a preferred embodiment, for patients aged 6 years and older, improvement can be detected at week 12.

[0051] The fixed-dose combination of the present invention can be used to treat asthma patients aged ≥4 years. In another embodiment, the fixed-dose combination of the present invention can be used to treat asthma patients aged ≥6 years. In yet another embodiment, the fixed-dose combination of the present invention can be used to treat asthma patients aged ≥12 years. In yet another embodiment, the fixed-dose combination of the present invention can be used to treat asthma patients aged ≥18 years. In one embodiment, the present invention provides a method for treating asthma, wherein the age group of the asthma patients may include at least one of the following: 4-11 years, 6-11 years, 12-17 years, ≥18 years, and combinations thereof.

[0052] This invention is applicable to any patient in GINA 1-5, i.e., any patient who is a GINA 1-5 patient.

[0053] The fixed-dose dry powder inhalation composition of the present invention may be provided, for example, in two doses. One dose product is administered at an example dose of 30 micrograms of fluticasone propionate and 117 micrograms of salbutamol sulfate per inhalation (equivalent to a delivery dose of 26 micrograms and 108 micrograms per inhalation, respectively). The second dose product is administered at an example dose of 55 micrograms of fluticasone propionate and 117 micrograms of salbutamol sulfate per inhalation (equivalent to a delivery dose of 51 micrograms and 108 micrograms per inhalation, respectively). The amounts of salbutamol sulfate listed herein (e.g., 117 micrograms for the dose and 108 micrograms for the delivery dose) are based on the total weight of the salt. These specific values ​​correspond to 97.5 micrograms and 90 micrograms, respectively, based on the free base of salbutamol. Also included are doses bioequivalent to the doses of the present invention, particularly those bioequivalent to the delivery doses, as described above.

[0054] These dosages offer advantages compared to those used in other products.

[0055] Recently, two dose strengths of budesonide and salbutamol sulfate fixed-dose inhalers (FDC) as asthma rescue medications were evaluated in a randomized clinical trial (A. Papi et al., “Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma”, The New England Journal of Medicine, 2022, 386(22), 2071-2083). The study, entitled “A Study to Assess the Efficacy and Safety of Budesonide / Albuterol Metered-dose Inhaler (BDA MDI / PT027) in Asthmatic Adults and Children Aged 4 Years and Older (MANDALA),” was conducted in the ClinicalTrials.gov registry number: NCT03769090.

[0056] Adults and adolescents (≥12 years) were randomly assigned in a 1:1:1 ratio to one of three experimental groups: a fixed-dose combination of budesonide 160 mcg / salbutamol 180 mcg (each delivery dose consisted of two drives, 80 mcg and 90 mcg, respectively) (“high-dose” combination group); a fixed-dose combination of budesonide 80 mcg / salbutamol 180 mcg (each delivery dose consisted of two drives, 40 mcg and 90 mcg, respectively) (“low-dose” combination group); or 180 mcg salbutamol (each dose consisted of two drives, 90 mcg each) (“salbutamol monotherapy” group).

[0057] Children aged 4 to 11 years were randomly assigned to either the low-dose combination group or the salbutamol monotherapy group. The primary efficacy endpoint was a time-event analysis of the first occurrence of a severe clinical acute asthma exacerbation in the intention-to-treat population.

[0058] The low-dose group showed inconsistent results across different age groups. Patients aged 4–11 years failed to demonstrate a treatment response, while results in patients aged 12–18 years were contradictory, showing a treatment trend in the low-dose group but a tendency towards an active control in the high-dose group. Therefore, the low-dose group has not been approved even in adults, and no treatment for patients aged 4–17 years has been approved.

[0059] Therefore, surprisingly, the present invention provides effective treatment at both fluticasone propionate doses (i.e., 30 micrograms or 26 micrograms delivered, and 55 micrograms or 51 micrograms delivered).

[0060] The fixed-dose dry powder inhalation composition of the present invention is a dry powder formulation for inhalation. This means that the product provides a powder carrier, such as lactose, particularly α-lactose monohydrate.

[0061] This type of carrier is referred to as a "coarse" carrier to distinguish it from the fine particles carried to the lungs. They are well-known in the art and readily available from a variety of commercial sources. Coarse carriers typically contain fine particles of the same material (inherently present and / or intentionally added). Such fine particles facilitate the release of the active ingredient from the coarse carrier.

[0062] Typically, the particle size of the α-lactose monohydrate carrier should be such that it can be entrained in the airflow but cannot be deposited at key target sites in the lungs. Therefore, the α-lactose monohydrate preferably has the following particle size distribution as measured by laser diffraction: d10 of 20-40 µm; d50 of 55-65 µm; and d90 of 80-100 µm.

[0063] Lactose may contain an inherent fine powder content (i.e., fine lactose), or it may be intentionally added to the formulation. The particle size of this lactose is less than 10 µm, more likely 1-5 µm, as determined by laser diffraction. In a preferred embodiment, the weight / weight% of particles smaller than 10 µm is less than 6, as determined by laser diffraction.

[0064] Dry powder inhalable formulations may also contain ternary excipients. Ternary excipients are well known in the art and are used, for example, to provide additional stability to the active ingredient. Typically, additional stability is provided by reducing water adsorption and promoting the release of the active ingredient from the coarse carrier particles.

[0065] Ternary excipients are also known as force control agents, lubricants, or anti-adhesion agents. They are used because a third material, in addition to the active ingredient and the carrier, is added to the formulation. It should be noted that the coarse carrier (i.e., α-lactose monohydrate) typically contains fine particles of the same material (either inherently present or intentionally added). These fine particles, composed of the same material as the coarse carrier, are not ternary excipients.

[0066] In one embodiment, the dry powder inhalable formulation of the present invention does not include a ternary excipient. For example, the formulation may consist of fluticasone propionate, salbutamol sulfate, and lactose (e.g., an α-lactose monohydrate carrier, optionally containing fine α-lactose monohydrate particles).

[0067] In another embodiment, the dry powder inhalable formulation of the present invention further includes a ternary excipient.

[0068] Typical examples of ternary excipients that can be formulated into the formulations of the present invention include metal stearates (such as magnesium stearate and calcium stearate), fatty acids (such as stearic acid), amino acids (such as leucine) and phospholipids (such as lecithin).

[0069] Preferably, the ternary excipient formulated in the formulation of the present invention is magnesium stearate. More preferably, the proportion of magnesium stearate contained in the formulation is 0.01-3.0% by weight of the formulation. The ternary excipient can be used to provide additional stability.

[0070] The fixed-dose dry powder composition of the present invention is preferably prepared by mixing fluticasone propionate, salbutamol sulfate, and lactose. In the formulation of the present invention, the 99 wt% fluticasone propionate particles and salbutamol sulfate particles, as measured by laser diffraction, are each less than 10 µm; preferably, the 90 wt% fluticasone propionate particles are less than 6 µm, as measured by laser diffraction. Furthermore, the 90 wt% salbutamol sulfate particles are less than 5 µm, as measured by laser diffraction.

[0071] The fluticasone propionate used in the method of this invention has a particle size (mass median aerodynamic diameter, MMAD) of less than 10 µm, more preferably 1-4 µm, and most preferably less than 3 µm. MMAD can be measured using a next-generation impactor (NGI).

[0072] The salbutamol sulfate used in the method of the present invention has a particle size (mass median aerodynamic diameter, MMAD) of less than 10 µm, more preferably 1-4 µm, and most preferably less than 2 µm. MMAD can be measured using a new generation impactor (NGI).

[0073] This particle size ensures that the particles adhere effectively to the carrier during mixing, and also ensures that the particles are dispersed and entrained in the airflow and deposited in the lower lung (i.e., when the inhaler device is activated).

[0074] The dry powder formulation can be metered and filled into capsules, such as gelatin or hydroxypropyl methylcellulose capsules, so that the capsule contains a unit dose of the active ingredient. When the dry powder is in a capsule containing a unit dose of the active ingredient, the total amount of the composition will depend on the size of the capsule and the characteristics of the inhalation device used with the capsule. However, a typical example of the total dry powder filling weight per capsule is 1-25 mg. The formulation can also be filled into blister packs. Alternatively, the dry powder composition of the present invention can be filled into the reservoir of a multi-dose dry powder inhaler (MDPI).

[0075] Preferably, the multi-dose dry powder inhaler includes a cyclone de-aggregator for breaking down agglomerates of the active ingredient and carrier. This occurs before the patient inhales the powder. The de-aggregator includes an inner wall, a dry powder supply port, two inlet ports, and an outlet port, the inner wall defining a vortex chamber extending along an axis from a first end to a second end.

[0076] A supply port is located at the first end of the vortex chamber, providing fluid communication between the dry powder delivery channel of the inhaler and the first end of the vortex chamber. An inlet port is located in the inner wall of the vortex chamber, adjacent to the first end of the vortex chamber, and provides fluid communication between the area outside the de-aggregator and the vortex chamber. An outlet port provides fluid communication between the second end of the vortex chamber and the area outside the de-aggregator.

[0077] The low pressure at the outlet port caused by breathing draws airflow into the vortex chamber through the dry powder supply port and the inlet port. Before exiting through the outlet port, the airflow collides with each other and with the walls of the vortex chamber, thus separating the active material from the carrier (lactose). The de-aggregator also includes blades located at the first end of the vortex chamber to generate additional collisions and impacts on entrained powder.

[0078] A first respiratory drive airflow is used to carry dry powder from the inhaler into the first end of a chamber that extends longitudinally between the first end and the second end, the first airflow being guided in the longitudinal direction.

[0079] The second breath drives the airflow in a substantially lateral direction to the first end of the chamber, causing the airflow to collide and essentially mix.

[0080] Then, a portion of the combined airflow is deflected toward the second end of the chamber in a generally longitudinal direction, and the remainder of the combined airflow is guided toward the second end of the chamber in a spiral path. All the combined airflow and any dry powder entrained therein are then delivered from the second end of the chamber to the patient's oral cavity.

[0081] The de-aggregator ensures that the particles of the active substance are small enough to allow the powder to fully penetrate the bronchial region of the patient's lungs during inhalation.

[0082] Therefore, preferably, when the dry powder formulation of the present invention is used in combination with a multi-dose dry powder inhaler device, the de-aggregator of the inhaler device includes: an inner wall defining a vortex chamber extending along an axis from a first end to a second end; a dry powder supply port within the first end of the vortex chamber for providing fluid communication between the dry powder delivery channel of the inhaler and the first end of the vortex chamber; at least one inlet port in the inner wall of the vortex chamber adjacent to the first end of the vortex chamber, the inlet port providing fluid communication between a region outside the de-aggregator and the first end of the vortex chamber; an outlet port providing fluid communication between the second end of the vortex chamber and the region outside the de-aggregator; and blades at the first end of the vortex chamber, the blades extending at least partially radially outward from the axis of the chamber, each blade having an inclined surface at least partially facing transversely to the axial direction; thereby, the low pressure at the outlet port caused by breathing leads to airflow into the vortex chamber through the dry powder supply port and the inlet port.

[0083] In a preferred embodiment, the inhaler has a flow rate of 59-71 L / min at a pressure drop of 4 kPa, most preferably 63 L / min. The flow resistance is preferably 0.028-0.034 kPa. 0.5 / L / minute.

[0084] The inhaler preferably has a reservoir for containing a formulation and means for delivering a metered dose of the formulation from the reservoir. The reservoir is typically a pressure system. The inhaler preferably includes: a sealed reservoir including a dispensing port; a channel communicating with the dispensing port and including a pressure relief port; a conduit providing fluid communication between the sealed reservoir and the pressure relief port of the channel; and a cup assembly movably received in the channel and including a recess adapted to receive the formulation when aligned with the dispensing port, a first sealing surface adapted to seal the dispensing port when the recess is not aligned with the dispensing port, and a second sealing surface adapted to seal the pressure relief port when the recess is aligned with the dispensing port and to release the pressure relief port when the recess is not aligned with the dispensing port.

[0085] The inhaler preferably has a dose counter. The inhaler includes a mouthpiece for patient inhalation, a dose metering device, and a dose counter, wherein the dose metering device includes a pawl that can move along a predetermined path during the delivery of a dose of the formulation into the mouthpiece via the dose metering device.

[0086] In a preferred embodiment, the dose counter includes a spool, a rotatable reel, and a wound tape rotatable about the axis of the spool. The tape has markings that extend continuously between a first end of the tape fixed to the reel and a second end of the tape located on the spool. The dose counter also includes teeth extending radially outward from the reel, the teeth entering a predetermined path of a pawl such that during dose measurement to the nozzle, the reel is rotated by the pawl, and the tape is wound onto the reel.

[0087] Preferred inhalers include a simple, accurate, and consistent mechanical dosing system that dispenses dry powder formulations for patient inhalation in discrete amounts or doses, a reservoir pressure system that ensures consistent dose dispensing, and a dose counter that indicates the number of doses remaining in the inhaler.

[0088] The inhaler used in this invention may also have electronic connectivity. This provides an inhalation detection system comprising: an inhaler including a drug delivery device configured to deliver a fixed-dose product of the invention to a user during inhalation; an inhalation monitoring device configured to collect data during inhalation for determining measurements of the user's lung function and / or lung health and / or inhalation technique; and a processor configured to receive the data from the inhalation monitoring device and use the data to determine measurements of the user's lung function and / or lung health. Further details can be found in WO 2016 / 090260 and WO 2020 / 222146.

[0089] Figure 1-4 A view of an inhaler 100 is provided for administering a dry powder inhalation composition according to any of the embodiments described herein.

[0090] The inhaler 100 may include a top cover 102, a main housing 104, a mouthpiece 106, a mouthpiece cap 108, a vent 109, and an electronics module 120. The mouthpiece cap 108 may be hinged to the main housing 104 so that it can be opened and closed to expose the mouthpiece 106. Although illustrated as a hinged connection, the mouthpiece cap 106 may be connected to the inhaler 100 via other types of connectors. Furthermore, although the electronics module 120 is illustrated as being housed within the top cover 102 atop the main housing 104, the electronics module 120 may be integrated and / or housed within the body 104 of the inhaler 100.

[0091] Figure 2An internal cross-sectional perspective view of an exemplary inhaler 100 is provided. Inside the main housing 104, the inhaler 100 may include a drug reservoir 110 (e.g., a hopper), a bellows 112, a bellows spring 114, a yoke (not visible), a dose cup 116, a dose chamber 117, a de-aggregator 10', and a flow path 119. The drug reservoir 110 may contain a drug, particularly a dry powder inhalation composition, to be delivered to the subject. When the mouthpiece cap 108 is moved from a closed position to an open position, the bellows 112 can compress to deliver a dose of drug from the drug reservoir 110 to the dose cup 116. The subject can then inhale through the mouthpiece 106 to attempt to receive the dose of drug.

[0092] In a preferred embodiment, the volume of the dosing cup 116 is 5-10 mm. 3 More preferably, it is the No. 3 dosing cup 116, which corresponds to 7 mm 3 The capacity.

[0093] The airflow generated by the subject's inhalation causes the deaggregator 10' to aerosolize the drug dose by breaking up agglomerates in the dosing cup 116. The deaggregator 10' can be configured to aerosolize the drug when the airflow through the flow path 119 reaches or exceeds a specific rate, or is within a specific range. Upon aerosolization, the drug dose can enter the dosing chamber 117 from the dosing cup 116, pass through the flow path 119, and then exit from the nozzle 106 to reach the subject. If the airflow through the flow path 119 does not reach or exceed the specific rate, or is not within the specific range, the drug may remain in the dosing cup 116. If the drug in the dosing cup 116 is not aerosolized by the deaggregator 10', another dose may not be delivered from the drug reservoir 110 when the nozzle cap 108 is subsequently opened. Therefore, a single dose of drug may remain in the dosing cup until that dose is aerosolized by the deaggregator 10'.

[0094] When the subject inhales through mouthpiece 106, air can enter vent 109 to provide an airflow for delivering medication to the subject. Flow path 119 may extend from dose chamber 117 to the end of mouthpiece 106 and includes the internal portion of dose chamber 117 and mouthpiece 106. Dosage cup 116 may be located within or adjacent to dose chamber 117. Furthermore, inhaler 100 may include dose counter 111 configured to initially set the total number of medication doses in medication reservoir 110 and decrement by one each time mouthpiece cap 108 is moved from an open position to a closed position.

[0095] When a dose of medication is delivered, the dosage confirmation can be stored as dosage confirmation information in the memory included in the electronic module 120.

[0096] The top cover 102 can be attached to the main housing 104. For example, the top cover 102 can be attached to the main housing 104 using one or more clips that engage with recesses on the main housing 104. When attached, the top cover 102 can cover a portion of the main housing 104, for example, to create a substantially airtight seal 103 between the top cover 102 and the main housing 104.

[0097] Figure 3 This is an exploded perspective view of an exemplary inhaler 100 with the top cover 102 removed to expose the electronic module 120. (See attached image.) Figure 3 As shown, the top surface of the main housing 104 may include one or more (e.g., two) apertures 146. One or more (e.g., two) apertures 146 may be configured to receive a slider 140. For example, when the top cover 102 is attached to the main housing 104, the slider 140 may protrude through one of the apertures 146 through the top surface of the main housing 104.

[0098] Figure 4 This is an exploded perspective view of the top cover 102 and the electronic module 120 of an exemplary inhaler 100. Figure 4 As shown, slider 140 may define arm 142, stop 144, and distal end 145. Distal end 145 may be the bottom portion of slider 140. Distal end 145 of slider 140 may be configured to abut a yoke located within main housing 104 (e.g., when nozzle cap 108 is in a closed or partially open position). Distal end 145 may be configured to abut the top surface of the yoke in any radial direction. For example, the top surface of the yoke may include multiple holes (not shown), and distal end 145 of slider 140 may be configured to abut the top surface of the yoke, for example, regardless of whether one of the holes is aligned with slider 140.

[0099] The top cover 102 may include a slider guide 148 configured to receive a slider spring 146 and a slider 140. The slider spring 146 may be located within the slider guide 148. The slider spring 146 may engage an inner surface of the top cover 102, and the slider spring 146 may engage (e.g., abut) an upper portion (e.g., proximal end) of the slider 140. When the slider 140 is mounted within the slider guide 148, the slider spring 146 may be partially compressed between the top of the slider 140 and the inner surface of the top cover 102. For example, the slider spring 146 may be configured to maintain yoke contact at the distal end 145 of the slider 140 when the nozzle cap 108 is closed. The distal end 145 of the slider 145 may also maintain yoke contact when the nozzle cap 108 is being opened or closed. The stop 144 of the slider 140 can engage the stop of the slider guide 148, for example, so that the slider 140 is held within the slider guide 148 during the opening and closing of the nozzle cover 108, and vice versa. The stop 144 and the slider guide 148 can be configured to limit the vertical (e.g., axial) movement of the slider 140. This limitation can be less than the vertical movement of the yoke. Thus, when the nozzle cover 108 is moved to the fully open position, the yoke can continue to move vertically toward the nozzle 106, but the stop 144 can stop the vertical movement of the slider 140 so that the distal end 145 of the slider 140 is no longer in contact with the yoke.

[0100] More generally, the yoke may be mechanically connected to the mouthpiece cap 108 and configured to move to compress the bellows spring 114 when the mouthpiece cap 108 is opened from the closed position, and then release the compressed bellows spring 114 when the mouthpiece cap reaches the fully open position, thereby causing the bellows 112 to deliver the dose from the drug reservoir 110 to the dosage cup 116. When the mouthpiece cap 108 is in the closed position, the yoke may contact the slider 140. The slider 140 may be configured to be moved by the yoke when the mouthpiece cap 108 is opened from the closed position and to disengage from the yoke when the mouthpiece cap 108 reaches the fully open position.

[0101] Movement of slider 140 during dose measurement can cause slider 140 to engage and actuate switch 130. Switch 130 can trigger electronic module 120 to record dose measurement. In this example, slider 140 can be viewed as a device configured to record doses measured by a used etermination system, each measurement thus indicating that the subject has inhaled once using inhaler 100.

[0102] The slider 140 can also drive the switch 130, for example, to cause the electronic module 120 to transition from a first power state to a second power state and sense the object being sucked in from the nozzle 106.

[0103] Electronic module 120 may include printed circuit board (PCB) assembly 122, switch 130, power supply (e.g., battery 126), and / or battery holder 124. (See reference) Figure 3 and Figure 4 PCB assembly 122 may include surface-mounted components such as sensor system 128, wireless communication circuitry 129, switch 130, and / or one or more indicators (not shown), such as one or more light-emitting diodes (LEDs). Electronic module 120 may include a controller (e.g., a processor) and / or memory. The controller and / or memory may be physically separate components of PCB assembly 122. Alternatively, the controller and memory may be part of another chipset mounted on PCB assembly 122; for example, wireless communication circuitry 129 may include the controller and / or memory of electronic module 120. The controller of electronic module 120 may include a microcontroller, programmable logic device (PLD), microprocessor, application-specific integrated circuit (ASIC), field-programmable gate array (FPGA), or any suitable processing device or control circuitry.

[0104] The controller can access information from and store data in the memory. The memory can include any suitable type of memory, such as non-removable memory and / or removable memory. The non-removable memory can include random access memory (RAM), read-only memory (ROM), or any other type of memory storage device. The removable memory can include a user identity module (SIM) card, memory stick, secure digital storage (SD) card, etc. The memory can be internal to the controller. The controller can also access and store data from memory not physically located within the electronic module 120 (e.g., on a server or smartphone).

[0105] Sensor system 128 may include one or more sensors. Sensor system 128 may include one or more sensors, such as different types of sensors, including, but not limited to, one or more pressure sensors, temperature sensors, humidity sensors, orientation sensors, acoustic sensors, and / or optical sensors. One or more pressure sensors may include barometric pressure sensors (e.g., atmospheric pressure sensors), differential pressure sensors, absolute pressure sensors, and / or similar sensors. Sensors may employ microelectromechanical systems (MEMS) and / or nanoelectromechanical systems (NEMS) technologies. Sensor system 128 may be configured to provide instantaneous readings (e.g., pressure readings) and / or time-accumulated readings (e.g., pressure readings) to the controller of electronic module 120. Figure 2 and Figure 3 As shown, the sensor system 128 may be located outside the flow path 119 of the inhaler 100, but may be pneumatically connected to the flow path 119.

[0106] The controller of the electronic module 120 can receive signals corresponding to measurements from the sensor system 128. The controller can use the signals received from the sensor system 128 to calculate or determine one or more airflow parameters. These airflow parameters can indicate the airflow profile through the flow path 119 of the inhaler 100. For example, if the sensor system 128 records a pressure change of 0.3 kPa, the electronic module 120 can determine that this change corresponds to an airflow rate of approximately 45 liters per minute (Lpm) through the flow path 119.

[0107] Pressure measurement readings and / or calculated airflow indices can indicate the quality or intensity of inhalation by the inhaler 100. For example, readings and / or indices can be used to categorize inhalation into a certain type of event, such as a good inhalation event, a low inhalation event, a no-inhalation event, or an over-inhalation event, compared to a specific threshold or range of values. Inhalation categorization can be used as a parameter for personalized data stored as an object.

[0108] No-inhalation events can be associated with pressure measurement readings and / or airflow parameters falling below a specific threshold, such as an airflow rate less than 30 Lpm. A no-inhalation event can occur when a subject does not inhale from the mouthpiece 106 after opening the mouthpiece cap 106 and during the measurement cycle. A no-inhalation event can also occur when the subject's inspiratory effort is insufficient to ensure proper drug delivery through the flow path 119, for example, when the airflow generated by the inspiratory effort is insufficient to activate the de-aggregator 10' to aerosolize the drug in the dosing cup 116.

[0109] Low inhalation events can be associated with pressure measurement readings and / or airflow indices falling below a specific threshold, such as an airflow rate between 30 Lpm and 45 Lpm. A low inhalation event can occur when a subject inhales from the mouthpiece 106 after opening the mouthpiece cap 106, and the subject's inspiratory effort results in at least a partial dose of the drug being delivered through the flow path 119. That is, inhalation is sufficient to activate the deaggregator 10', causing at least a portion of the drug to be aerosolized from the dose cup 116.

[0110] A good inhalation event can be associated with pressure measurement readings and / or airflow indices that are higher than those of a low inhalation event, such as an airflow rate between 45 Lpm and 200 Lpm. A good inhalation event occurs when the subject inhales from the mouthpiece 106 after opening the mouthpiece cap 106, and the subject's inhalation effort is sufficient to ensure proper delivery of the drug through the flow path 119, for example, when the inhalation effort generates sufficient airflow to activate the de-aggregator 10' and aerosolize the full dose of drug in the dosing cup 116.

[0111] Overinhalation events can be associated with pressure measurement readings and / or airflow parameters exceeding those of a good inhalation event, such as an airflow rate exceeding 200 Lpm. An overinhalation event can occur when the subject's inhalation effort exceeds the normal operating parameters of the inhaler 100. An overinhalation event can also occur if the inhaler 100 is not properly positioned or held during use, even if the subject's inhalation effort is within the normal range. For example, if the vent 109 is blocked or obstructed (e.g., by a finger or thumb) when the subject inhales through the mouthpiece 106, the calculated airflow rate may exceed 200 Lpm.

[0112] Any suitable threshold or range can be used to classify a particular event. Some or all events can be used. For example, no inhalation events may be associated with airflow rates below 45 Lpm, while good inhalation events may be associated with airflow rates between 45 Lpm and 200 Lpm. Therefore, in some cases, low inhalation events may not be used at all.

[0113] Pressure measurement readings and / or calculated airflow indices can also indicate the direction of airflow through flow path 119 of inhaler 100. For example, if a pressure measurement reading reflects a negative pressure change, the reading may indicate that air is flowing out of mouthpiece 106 through flow path 119. For example, if a pressure measurement reading reflects a positive pressure change, the reading may indicate that air is flowing into mouthpiece 106 through flow path 119. Therefore, pressure measurement readings and / or airflow indices can be used to determine whether a subject is exhaling into mouthpiece 106, which may indicate that the subject is not using inhaler 100 correctly.

[0114] Personalized data collected from or calculated based on the use of inhaler 100 (e.g., pressure parameters, airflow parameters, pulmonary function parameters, dose confirmation information, etc.) can also be calculated and / or evaluated (e.g., partially or entirely) by external devices. More specifically, the wireless communication circuitry 129 in electronic module 120 may include a transmitter and / or receiver (e.g., a transceiver) and additional circuitry. For example, wireless communication circuitry 129 may include a Bluetooth chipset (e.g., a Bluetooth Low Energy chipset), a ZigBee chipset, a Thread chipset, etc. Therefore, electronic module 120 can wirelessly provide personalized data, such as pressure measurements, airflow parameters, pulmonary function parameters, dose confirmation information, and / or other conditions related to the use of inhaler 100, to external devices (including smartphones). Personalized data can be provided to external devices in real time to enable the generation of an assessment of the subject's respiratory disease status based on real-time data from inhaler 100, indicating usage time, how inhaler 100 is used, and personalized data about the inhaler user, such as real-time data related to the subject's pulmonary function and / or medical treatment. External devices may include software for processing received information and providing compliance and adherence feedback to the user of inhaler 100 via a graphical user interface (GUI).

[0115] The airflow metrics may include personalized data collected in real time from the inhaler 100, such as one or more of the following: average inhalation / exhalation flow rate, peak inhalation / exhalation flow rate (e.g., maximum received inhalation volume), inhalation / exhalation volume, time to peak inhalation / exhalation, and / or duration of inhalation / exhalation. The airflow metrics may also indicate the direction of airflow through the flow path 119. That is, a negative pressure change may correspond to inhalation from the mouthpiece 106, while a positive pressure change may correspond to exhalation into the mouthpiece 106. When calculating the airflow metrics, the electronics 120 may be configured to eliminate or minimize any distortion caused by environmental conditions. For example, the electronics 120 may be zeroed before or after calculating the airflow metrics to account for changes in atmospheric pressure. One or more pressure measurements and / or airflow metrics may be timestamped and stored in the memory of the electronics 120.

[0116] In addition to the airflow metric, inhaler 100 or another computing device can use the airflow metric to generate additional personalized data. For example, the controller of the electronic module 120 of inhaler 100 can convert the airflow metric into other metrics understood by a medical practitioner, indicating the subject's lung function and / or lung health, such as peak inspiratory flow rate, peak expiratory flow rate, and / or forced expiratory volume in one second (FEV1). The electronic module 120 of the inhaler can use mathematical models (e.g., regression models) to determine measurements of the subject's lung function and / or lung health. Mathematical models can identify the correlation between total inhaled volume and FEV1. Mathematical models can identify the correlation between peak inspiratory flow rate and FEV1. Mathematical models can identify the correlation between total inhaled volume and peak expiratory flow rate. Mathematical models can identify the correlation between peak inspiratory flow rate and peak expiratory flow rate.

[0117] Battery 126 can power components of PCB assembly 122. Battery 126 can be any suitable source for powering electronic module 120, such as a button cell battery. Battery 126 can be rechargeable or non-rechargeable. Battery 126 can be housed by battery holder 124. Battery holder 124 can be secured to PCB assembly 122 such that battery 126 maintains continuous contact with PCB assembly 122 and / or electrical connection with components of PCB assembly 122. Battery 126 may have a specific battery capacity, which can affect battery life. As will be further discussed below, power distribution from battery 126 to one or more components of PCB assembly 122 can be managed to ensure that battery 126 can power electronic module 120 for the duration of the inhaler 100 and / or the medication contained therein.

[0118] In the connected state, the communication circuitry and memory are powered on, and the electronic module 120 can be "paired" with an external device (such as a smartphone). The controller can retrieve data from the memory and wirelessly transmit it to the external device. The controller can retrieve and transmit data currently stored in the memory. The controller can also retrieve and transmit partial data currently stored in the memory. For example, the controller can determine which parts have already been transmitted to the external device and then transmit the parts that have not been transmitted before. Alternatively, the external device can request specific data from the controller, such as any data collected by the electronic module 120 after a specific time or after the last transmission to the external device. The controller can retrieve the specific data (if any) from the memory and transmit that specific data to the external device.

[0119] Data stored in the memory of the electronic module 120 (e.g., signals generated by the switch 130, pressure readings acquired by the sensor system 128, and airflow parameters calculated by the controller of the PCB assembly 122) can be transmitted to an external device that can process and analyze the data to determine usage parameters related to the inhaler 100. Furthermore, a mobile application installed on a mobile device can generate feedback for the user based on data received from the electronic module 120. For example, the mobile application can generate daily, weekly, or monthly reports, provide confirmation of error events or notifications, and offer guidance feedback.

[0120] refer to Figure 5-10 The deaggregator 10' breaks up agglomerates of dry powder formulations or formulations and carriers before they leave the inhaler 100 through the mouthpiece 106. Therefore, agglomerates of dry powder formulations or formulations and carriers are broken up by the deaggregator 10' before the patient inhales the formulation.

[0121] Typically, the de-aggregator 10' includes an inner wall 12' defining a vortex chamber 14' along axis A' (see...). Figure 10 The vortex chamber 14' extends from the first end 18' to the second end 20'. The vortex chamber 14' includes an annular cross-sectional area arranged transversely to the axis A', which decreases from the first end 18' to the second end 20', such that any airflow traveling from the first end to the second end of the vortex chamber is restricted and at least partially collides with the inner wall 12' of the chamber.

[0122] Preferably, the cross-sectional area of ​​the vortex chamber 14' decreases monotonically. Furthermore, the inner wall 12' is preferably convex, i.e., arched inward toward axis A', as shown below. Figure 10 As shown in the best example.

[0123] like Figure 5 , 7As shown in Figure 10, the de-aggregator 10' also includes a dry powder supply port 22' located at the first end 18' of the vortex chamber 14', for providing fluid communication between the dry powder delivery channel of the inhaler and the first end 18' of the vortex chamber 14'. Preferably, the dry powder supply port 22' faces a direction substantially parallel to axis A', such that the airflow entering chamber 14' through the supply port 22' (e.g., Figure 10 (As indicated by the middle arrow 1') Its direction is parallel to the axis A' of the chamber, at least initially.

[0124] refer to Figure 5-10 The de-aggregator 10' further includes at least one inlet port 24' on the inner wall 12' of the vortex chamber 14', adjacent to or near the first end 18' of the vortex chamber, providing fluid communication between the region outside the de-aggregator and the first end 18' of the vortex chamber 14'. Preferably, the at least one inlet port comprises two radially opposed inlet ports 24', 25', extending in a direction substantially transverse to the axis A' and substantially tangential to the annular cross-section of the vortex chamber 14'. Thus, as Figure 5 and 9 As indicated by arrows 2' and 3', the airflow entering chamber 14' through the inlet port is initially transverse to the chamber axis A' and collides with the airflow 1' entering through the supply port 22' to generate turbulence. Combined airflows (such as...) Figure 9 and 10 (As indicated by the middle arrow 4') It then collides with the inner wall 12' of chamber 14', forming a vortex, and generating additional turbulence as it moves toward the second end 20' of the chamber.

[0125] refer to Figure 5-7 And 10, the de-converger 10' includes blades 26' located at the first end 18' of the vortex chamber 14', the blades 26' extending at least partially radially outward from the axis A' of the chamber. Each blade 26' has an inclined surface 28' that faces at least partially in a direction transverse to the axis A' of the chamber. The dimensions of the blades 26' are such that at least a portion 4A' of the combined airflow 4' collides with the inclined surface 28', as... Figure 10 As shown. Preferably, the blade comprises four blades 26', each blade extending between the hub 30' aligned with the axis A' and the wall 12' of the vortex chamber 14'.

[0126] like Figure 5-10As shown, the de-aggregator 10' also includes an outlet port 32' for providing fluid communication between the second end 20' of the vortex chamber 14' and a region outside the de-aggregator. Low pressure caused by breathing at the outlet port 32' leads to airflow 1' through the supply port 22', airflows 2' and 3' through the inlet port, and draws combined airflow 4' into the vortex chamber 14'. The combined airflow 4' then exits the de-aggregator through the outlet port 32'. Preferably, the outlet port 32' extends substantially transversely to axis A', such that airflow 4' will collide with the inner wall of the outlet port 32' and generate further turbulence. The term "substantially transversely" is intended to cover the outlet port 32' extending perpendicularly to (i.e. at a 90-degree angle) axis A', but also to cover the outlet port 32' extending at other angles relative to axis A', provided that the aforementioned further turbulence can be generated by the collision of airflow 4' with the inner wall of the outlet port 32'. For example, the outlet port 32' may extend at an angle of approximately 15 degrees relative to the perpendicular of axis A'.

[0127] During use of the deconcentrator 10' in conjunction with the inhaler, the patient inhales at the outlet port 32', causing airflows 1', 2', and 3' to enter through the dry powder supply port 22' and the inlet port, respectively. Although not shown, the airflow 1' through the supply port 22' entrains dry powder into the vortex chamber 14'. The airflow 1' and the entrained dry powder are guided longitudinally into the chamber by the supply port 22', while the airflows 2' and 3' from the inlet port are guided laterally, causing the airflows to collide and essentially combine.

[0128] Part of the combined airflow 4' and the entrained dry powder subsequently collide with the inclined surface 28' of the blade 26', causing dry powder particles and any agglomerates to impact the inclined surface and collide with each other. The geometry of the vortex chamber 14' allows the combined airflow 4' and the entrained dry powder to pass through the chamber along a turbulent, spiral, or vortex path. It should be understood that the decreasing cross-section of the vortex chamber 14' continuously alters the direction of the vortex combined airflow 4' and the entrained dry powder and increases their velocity. Therefore, dry powder particles and any agglomerates continuously impact and collide with the wall 12' of the vortex chamber 14', resulting in mutual grinding or crushing effects between particles and agglomerates. Furthermore, particles and agglomerates deviating from the inclined surface 28' of the blade 26' cause further impacts and collisions.

[0129] Upon exiting the vortex chamber 14', the combined airflow 4' and the entrained dry powder change direction again to a lateral direction relative to axis A', passing through outlet port 32'. The combined airflow 4' and the entrained dry powder retain the vortex component of the airflow, causing the airflow 4' and the entrained dry powder to vortex through outlet port 32'. The vortex in outlet port 32' induces additional impact, resulting in further breakup of any remaining agglomerates before they are inhaled by the patient.

[0130] like Figure 5-10As shown, the de-aggregator is preferably assembled from two parts: a cup-shaped base 40' and a cover 42'. The base 40' and the cover 42' are connected to form a vortex chamber 14'. The cup-shaped base 40' includes a chamber wall 12' and a second end 20', and defines an outlet port 32'. The base 40' also includes an inlet port of the vortex chamber 14'. The cover 42' forms blades 26' and defines a supply port 22'.

[0131] The base 40' and cover 42' of the deaggregator are preferably made of plastic, such as ABS for the base and polypropylene for the cover, but may also be made of metal or other suitable materials. The base 40' and cover 42' can be connected to each other by any suitable means, such as ultrasonically welding the base 40' to the spacer 38', while the cover 42' is pushed into the underside of the spacer 38' and secured in place.

[0132] Figure 1-4 The inhaler 100 shown may include reference Figure 5-10 The specific de-aggregator 10' is mentioned. However, the inhaler 100 is not limited to... Figure 1-4 It can be used with the de-aggregator shown, or with other types of de-aggregators or simple vortex chambers.

[0133] It should also be noted that the inhaler 100 with electronic connectivity is not intended to be limiting. In this respect, the inhaler 100 contemplated in this disclosure has the aforementioned references. Figure 1-10 The basic mechanical structure described herein, or the mechanical structure described in US 2015 / 099726 A1, but with electronic module 120 omitted.

[0134] Regarding the mechanical structure of the inhaler and / or deconvergent, the disclosure of US 2015 / 099726 A1 is incorporated herein by reference in its entirety.

[0135] In the event of any conflict between the meaning or definition of a term in this document and the meaning or definition of the same term in referenced literature (e.g., US 2015 / 099726A1), the meaning or definition given to that term in this document shall prevail.

[0136] The present invention will now be described with reference to the following embodiments, which are not intended to be limiting.

[0137] Example

[0138] Example 1 – Fixed-dose fluticasone propionate and salbutamol sulfate formulation

[0139] 55 micrograms FP / 117 micrograms ABS

[0140] 0.1760 kg of fluticasone propionate (Fp) was blended with 7.8240 kg of α-lactose monohydrate carrier using a PharmaConnect high-shear mixer at 433 rpm for 10 minutes to obtain an 8 kg blend. 0.9400 kg of salbutamol sulfate (ABS) was blended with 19.0600 kg of α-lactose monohydrate carrier using a PharmaConnect high-shear mixer at 300 rpm for 7 minutes to obtain a 20 kg blend. The 8 kg Fp-containing blend and the 8 kg ABS-containing blend were then mixed using a PharmaConnect low-shear mixer at 15 rpm for 20 minutes to obtain a final composite blend containing 1.1 wt% fluticasone propionate (for a 51 µg dose, size 3 dosing cup) and 2.35 wt% salbutamol sulfate (for a 90 µg salbutamol base / dose, size 3 dosing cup). The final blend is then filled into the reservoir of the dry powder inhaler unit. The unit is conditioned at 30°C / 65% relative humidity for 4 weeks, and then packaged in a foil bag with desiccant.

[0141] 30 micrograms of FP / 117 micrograms of ABS

[0142] 0.0873 kg of fluticasone propionate (Fp) was blended with 7.9127 kg of α-lactose monohydrate carrier using a PharmaConnect high-shear mixer at 150 rpm for 12 minutes to obtain an 8 kg blend. 0.9400 kg of salbutamol sulfate (ABS) was blended with 19.0600 kg of α-lactose monohydrate carrier using a PharmaConnect high-shear mixer at 300 rpm for 7 minutes to obtain a 20 kg blend. The 8 kg Fp-containing blend and the 8 kg ABS-containing blend were then mixed using a PharmaConnect low-shear mixer at 15 rpm for 20 minutes to obtain a final composite blend containing 0.55 wt% fluticasone propionate (for a 26 µg dose, size 3 dosing cup) and 2.35 wt% salbutamol sulfate (for a 90 µg salbutamol base / dose, size 3 dosing cup). The final blend is then filled into the reservoir of the dry powder inhaler unit. The unit is conditioned at 30°C / 65% relative humidity for 4 weeks, and then packaged in a foil bag with desiccant.

[0143] Example 2 – Analysis Method

[0144] Salbutamol sulfate PSD measurement

[0145] Particle size testing methods (Sympatec)

[0146] Operating conditions of RODOS M dry powder disperser and Aspiros

[0147] Dispersion methods: Atmospheric pressure: 3.0 bar Feeder: Aspiros Feed rate / speed: 18 mm / s Lens: R3 Channel: None Triggering conditions Start with: Optical concentration > 2% Effective: Always Stop: Optical concentration ≤ 2% for 2 seconds or real-time for 5 seconds Time base: 2.0 ms Weigh approximately 50 mg of dry ABS powder into an Aspiros test tube, then insert the test tube into the Aspiros and run the method. The measurement is then triggered by compressed air blowing the powder through the measurement area via a RODOS M dry powder disperser.

[0148] Fluticasone propionate particle size measurement

[0149] Measurement parameters: Reagents: Milli-Q deionized water Tween 80 reagent grade TA-10X FG Defoamer N / A equipment: Instrument: Malvern Laser Diffraction Mastersizer 2000 Attachment Name: Hydro 2000s Equipment parameters: Measurement range: 0.02-2000 micrometers Model type: General purpose Sensitivity: Normal Particle shape: Irregular Model: Wet dispersion Dispersant name: Deionized water Dispersant RI: 1.33 Material RI: 1.53 Absorption rate: 3.0 Measurement time: 10 seconds (10,000 snapshots).

[0150] Background measurement time: 10 seconds (10,000 snapshots).

[0151] Speed / mixing speed: 2,000 rpm.

[0152] Equal sample size: 1

[0153] Measurement: 3 times for each aliquot sample.

[0154] Delay: 0 seconds between measurements.

[0155] Ultrasound quality: 100%

[0156] Light blocking level: 10-30%

[0157] Measurement Procedure

[0158] Sample preparation for wet measurement: To prepare 1% (w / v) Tween 80: Add 30 mL of deionized water to a clean 50 mL glass bottle containing a magnetic stir bar. Add 0.3 g of Tween 80 to the glass container and stir for about 10 minutes until a homogeneous solution is obtained.

[0159] Preparation of 1% (w / v) TA-10X FG defoamer: Add 10 mL of deionized water to a clean 25 mL glass vial. Add 0.1 g of TA-10X FG defoamer. Tighten the cap on the vial and then manually shake for about 30 seconds. Shake the resulting emulsion for a few seconds before each use.

[0160] Sampling preparation: Transfer approximately 1-10 g of sample to a sufficiently large glass bottle to allow the powder to tumble freely, ensuring the sample is homogeneous throughout the bottle. Gently invert the bottle 10 times, then rotate it 10 times clockwise.

[0161] Sample preparation: Transfer approximately 50 mg of sample powder to a clean 25 mL glass container containing a magnetic stir bar using a spatula. Add 10 mL of deionized water containing 1% Tween 80 to the glass container. Stir the suspension at a moderate speed with a magnetic stirrer for 2 minutes. The sample can then be loaded into a wet dispersion unit.

[0162] Manual measurement

[0163] Manually add approximately 150 mL of deionized water to the Hydro 2000S dispersion unit tank. Set the ultrasonic level to 100% and sonicate for 30 seconds to dissipate air, then turn it off. Increase the pump / stirrer speed to the highest (3500 rpm) and then reduce it to zero to remove any air bubbles.

[0164] Add approximately 0.3 mL of 1% TA-10X FG defoamer to the container, then restart the pump / stirrer at 2000 rpm. Measure the background by slowly adding one of the three prepared samples dropwise into the dispersion unit until a stable initial opacity of 10-20% is achieved. Stir the sample in the dispersion unit at 2000 rpm for approximately 1 minute, then turn on the sonication and set the level to 100%. Measure the sample and calculate the results after approximately one minute.

[0165] Lactose monohydrate PSD measurement

[0166] Instrument: Sympatec HELOS / BR particle size analyzer. Reference SOPM000564

[0167] Ensure that PSD composite samples are used for testing.

[0168] Set the following operating conditions using a vibratory feeder and funnel adapter.

[0169] Instrument settings

[0170] Parameter settings

[0171] Sympatec dispersion method: 1.5 bar Vibri 75%

[0172] Lens type: R4

[0173] Dispersant: RODOS M

[0174] Measurement range: R4: 0.5 / 1.8...350 micrometers

[0175] Triggering conditions

[0176] Name: Channel 9, Optical Concentration ≥ 0.5%

[0177] Reference duration: 4 seconds (per shot)

[0178] Time base: 100 ms

[0179] Focusing before first measurement: Yes

[0180] Normal measurement: Standard mode

[0181] Start: 0.000s, Channel 9 optical density ≥ 0.5%

[0182] Effective: Always

[0183] Channel 9 optical concentration < 0.5% - stop after 1 second

[0184] Or stop after 60,000 seconds, in real time.

[0185] Repeated measurements: 0 times

[0186] Repeat focus: No

[0187] Dispersant conditions

[0188] Name: 1.5 bar; 75%; 2 mm

[0189] Dispersion type: RODOS M

[0190] Syringe: 4mm

[0191] Features: 0 cascaded elements

[0192] Initial pressure: 1.5 bar

[0193] Always automatically adjust before reference measurement: No

[0194] Feeder type: VIBRI

[0195] Feed rate: 75%

[0196] Gap width: 2 mm

[0197] Funnel rotation: 0%

[0198] Cleaning time: 10s

[0199] Use VIBRI control: No

[0200] Vacuum extraction type: Nilfisk

[0201] Delay: 5s

[0202] Mix the sample by rotating / twisting for 20 seconds. Weigh and transfer approximately 5.0 g of sample from the composite container into the VIBRI funnel of the sample unit using a suitable transfer container. The measurement is then triggered by compressed air blowing it through the measurement area via a RODOS dry powder disperser.

[0203] Example 3 – Clinical Trial

[0204] This embodiment describes a randomized, double-blind, multicenter, positive-controlled, parallel-group study to evaluate the efficacy and safety of a fixed-dose fluticasone propionate / salbutamol sulfate combination for acute exacerbations of severe clinical asthma in patients with asthma.

[0205] Overall research design

[0206] This was an event-driven, phase 3, multicenter, randomized, double-blind, positive-controlled, parallel-group, fixed-dose study to evaluate the efficacy and safety of the novel combination product Fp / ABS eMDPI (electronic metered dry powder inhaler) as an emergency treatment compared to ABS eMDPI. Fp / ABS eMDPI was evaluated at two dose intensities: HD (55 / 117 μg) and LD (30 / 117 μg) to assess the reduction in severe CAE in adults and pediatric patients (≥4 years) with asthma compared to ABS eMDPI (117 μg) (baseline ICS levels: low, intermediate, or high; GINA 2022).

[0207] The patient must be 4 years of age or older (or as permitted by local regulations), have a clinical diagnosis of asthma for at least 1 year, consistent with GINA 2022, and (if applicable) have a smoking history of ≤10 pack-years. The patient must have a history of at least one severe CAE within the past 12 months with demonstrated reversibility of ≥12% (or a history of reversibility), and an ACQ-5 score ≥1.5 during the screening assessment period (except for patients aged 4–5 years), despite being on a stable dose of a prescription inhaled asthma control medication ± another control (oral or inhaled). Patients taking prohibited medications (including prohibited monoclonal antibodies) must adhere to a washout period (for biologics used to treat asthma, 5 half-lives; democitabine, prohibited with any exposure; monoclonal antibodies used to treat malignancies, prohibited with any exposure; any other investigational drugs, 5 half-lives; corticosteroids (oral, intravenous, intra-articular, intramuscular), 30 days; immunologically active biologics, 90 days; immunosuppressive therapy, 90 days; immunotherapy, to be started within 90 days or the dose changed within 30 days; strong cytochrome P3A4 inhibitors, 14 days; inhaled cromoglycine preparations, 14 days; inhaled short-acting muscarinic antagonists (SAMA), to be discontinued at screening visit (v1); phosphodiesterase 4 inhibitors, 5 half-lives; monoamine oxidase inhibitors, 14 days; tricyclic antidepressants, 14 days; and non-selective β2-adrenergic blockers, including ophthalmic medications, 14 days).

[0208] Patients continued to use their existing prescription asthma control medications (not provided by the sponsor) throughout the study. Changes to their control medications were not permitted if their asthma was stable; otherwise, such changes were considered protocol deviations unless they were due to a change in the prescription set and the medication was based on a similar (or equivalent generic) ICS dose (low, medium, or high), and only after consultation with a medical monitor and obtaining their consent. Patients were randomized 1:1:1 to receive HD Fp / ABS eMDPI, LD Fp / ABSeMDPI, or ABS eMDPI as their emergency medication. Patients discontinued all other emergency therapies, including nebulized SABA or short-acting muscarinic antagonists (SAMA). IMP was administered orally via a blinded eMDPI inhaler (inhaled twice as needed to control asthma symptoms).

[0209] The study consisted of a screening period of approximately 2 weeks, a run-in period (approximately 2 to 4 weeks), and a double-blind treatment period. Patients who experienced severe CAE remained in the study and continued to participate in regular follow-up visits.

[0210] Because this study is event-driven, the study endpoint (EOS) depends on the number of patients experiencing severe CAE for the first time in both the HD Fp / ABS eMDPI and ABSeMDPI groups. The study continues until a total of (minimum) 599 patients in both groups experience severe CAE.

[0211] Once the study accumulated a total of 599 first severe CAEs in the HD Fp / ABS eMDPI group and the positive control group, patients who had completed Visit 5 (V5) (24 weeks) were scheduled for an EOS visit within 30 days, while randomized patients who had not completed V5 were scheduled in the standard manner until they completed V5, which served as their EOS visit. Through simulation, the total study duration to complete the study was estimated to be approximately 35 months; however, due to the event-driven nature of this study, the duration may vary.

[0212] After obtaining informed consent (or consent for children aged 4 to <18 years or as required by local regulations) during the screening visit (Visit 1 [V1]), other procedures are completed. Screening visits are conducted over several days over approximately two weeks as needed.

[0213] During the screening period, pulmonary function tests (breath volume measurement and reversibility testing) will be conducted using on-site equipment (provided by the sponsor) between 05:30 and 11:00 AM. Patients must discontinue their asthma maintenance medication before the pulmonary function test; for once-daily medications, this discontinuation should be approximately 24 hours, or for twice-daily or more frequently medications, 12 hours. If a patient has taken asthma maintenance medication within 24 ± 2 hours (daily dose) or 12 ± 2 hours (twice-daily or more frequently dose) before the planned pulmonary function test, or taken SABA (introduction-phase emergency medication) / IMP within 6 hours before the planned pulmonary function test, or used ICS / long-acting beta-agonist (LABA) as an emergency medication within 12 hours before the planned pulmonary function test, the visit will be rescheduled.

[0214] At screening, a pre-albuterol pulmonary function test was performed using central respiratory volume measurement, followed by a repeat FEV1 measurement after SABA administration to demonstrate airway reversibility (response to bronchodilator testing), measured by FEV1. Patients were assessed as having airway reversibility and continued the screening process if their FEV1 improved by at least 12% between tests, and patients ≥18 years of age showed an increase of 200 mL (or a history of ≥12% reversibility within the past 18 months). Note: One retest is permitted during screening if required to demonstrate the necessary pre- and post-albuterol use study requirements. For patients ≥12 years of age, reversibility testing with four SABA inhalations is permitted. Patients 4 to <12 years of age should receive two SABA inhalations or a single nebulized dose of salbutamol (salbutamol) at the investigator's discretion. All patients should attempt to demonstrate ≥12% reversibility, even with a history of reversibility; however, patients under 12 years of age may be included even without demonstrating a 12% response.

[0215] Patient history, asthma history (including asthma medications and history of acute exacerbations), physical examination, serum chemistry, urine medication screening, vital sign measurements, serum β-human chorionic gonadotropin (β-HCG) pregnancy test (for all women of childbearing potential [CBP]), serum follicle-stimulating hormone (FSH) test only for postmenopausal women, complete blood count (CBC) and differential, and concomitant medication history are also assessed during screening. Note: Documentation of acute asthma exacerbations within the past 12 months must be available. This includes medical or hospital records, or a prescription for SCS used during an acute exacerbation provided by the patient. Patients who meet other eligibility criteria may enter the induction phase while attempting to collect medical records documenting acute asthma exacerbations, but will not be randomized at V3 if records have not yet been obtained and verified.

[0216] Patients meeting all eligibility criteria continued their current prescribed asthma control medications but discontinued their current emergency medications. Patients were given the study-specific emergency medication (ProAir® RespiClick® or equivalent) and then entered the study introduction period (Visit 2 [V2]). Patients were provided with and trained on the use of an electronic diary (eDiary), an air-inhaler device, and a handheld device for measuring lung function. During the introduction period, patients measured FEV1 (forced expiratory volume in the first second after maximal inspiration) and PEF (peak expiratory flow rate) using a handheld device every morning (where possible) before using the introduction emergency medication and before taking their regular asthma maintenance medication. Patients also recorded their asthma symptom scores (daytime or nighttime) and emergency (i.e., randomized IMP) medication (number of inhalations) (whether used or not) twice daily and confirmed each evening whether they had taken their regular asthma maintenance medication that day (yes or no). Patients who did not experience ineligible events during the introduction period underwent the remaining baseline assessment.

[0217] Patients may be assessed for randomization in V3 after a minimum of 14 days and a maximum of 31 days (28±3 days) during the introductory period (V2 to V3). In addition to confirming inclusion / exclusion criteria, baseline procedures and assessments will be performed prior to randomization and trial supply management (RTSM) system randomization and IMP distribution. This will include a comprehensive physical examination; vital sign measurements; review of diary data to confirm eligibility; establishment of baseline pulmonary function testing; training on proper inhaler use using an empty demonstration eMDPI inhaler device or the device specified in the pharmacy manual (training inhaler), and assessment of usage; ACQ-5 assessment and confirmation of an ACQ-5 score ≥1.5 (ACQ-5 is not required for patients aged 4–5 years); urine pregnancy test (for all CBP female patients); ECG recording; concomitant medication review (including contraceptive review); CAE review; and adverse event review.

[0218] At baseline visits, patients randomized into the study were blinded and randomly assigned to one of three treatment groups (HD Fp / ABSeMDPI, LD Fp / ABS eMDPI 3, or ABS eMDPI). Patients were stratified across all three treatment groups by geographic region, age group, and the number of exacerbations in the previous year at screening (indicating the control medication in use) to ensure a similar distribution of patients. Randomized patients received IMP to control asthma symptoms, two inhalations (as needed) for asthma relief, and daily usage (whether used or not) was recorded in the eDiary throughout the treatment period, along with FEV1 and PEF measured at home each morning. Patients returned to the research center according to a pre-specified visit schedule (quarterly [i.e., every 12 weeks]) and were assessed by telephone approximately monthly between research center visits. Patients continued the study, with quarterly visits and monthly telephone contact, until a sufficient number of exacerbations occurred. Randomized patients who did not complete at least 24 weeks of treatment should continue until they completed V5, even if the required number of exacerbations had been reached. Throughout the study, pulmonary function tests, AQLQ+12 (or PAQLQ), ACQ-5 (age ≥6 years only), eDiary reviews (asthma symptoms and adherence), and safety monitoring (adverse events, vital sign measurements, physical examination, and concomitant medications) will be conducted. In addition to sponsor-led safety monitoring, IDMC will review safety data periodically.

[0219] Asthma exacerbation alert criteria have been established to ensure patient safety and will be monitored throughout the study starting at V2. If any of the following criteria are met or there is no data transmission for at least 3 consecutive days, investigators, clinical research center staff, and medical monitors will be automatically notified via the portal. Meeting any of these criteria does not automatically require additional treatment for the patient; rather, a clinical evaluation is necessary to determine whether the patient's asthma can continue to be managed under the current protocol, requires a change in maintenance medication, or indicates the need for severe CAE treatment.

[0220] An alert will be generated if any one or more of the following occur for at least two consecutive days, based on daily diary data: - Morning PEF is below the PEF stability limit. PEF < 80% of the baseline value measured at V3 (average of the highest morning PEF [3 times per day] in the 7 days prior to V3).

[0221] - Nocturnal asthma symptom score is higher than baseline score by ≥2. Baseline score is the average score over the 7 days prior to V3, rounded to the nearest whole number.

[0222] - Daytime asthma symptom score is higher than baseline and ≥3. The baseline score is the average score over the 7 days prior to V3, rounded to the nearest whole number.

[0223] - Emergency medication (i.e., IMP) use >4 inhalations / day and ≥2 more inhalations than baseline (baseline is defined as the average number of inhalations / day in the 7 days prior to V3, rounded to the nearest whole number).

[0224] Patients who meet these criteria and require a change in asthma medication or experience a severe CAE are considered to have experienced an asthma exacerbation. This is considered an event until the criteria are no longer met or until it becomes unmeasurable. Each event is counted once until the criteria are not met for at least 3 consecutive days. Furthermore, when an investigator assesses that a patient has experienced a clinically significant asthma exacerbation, the investigator must record this designated clinical cause, even if the patient does not meet the above criteria.

[0225] During treatment, patients are contacted by phone approximately once a month (every 4 weeks) to assess CAE, adverse events, concomitant medications, and to confirm diary adherence after reviewing the diary adherence information on the portal.

[0226] Primary and secondary research objectives and endpoints

[0227] The primary and secondary research objectives and endpoints are as follows:

[0228] Time to first severe acute exacerbation (CAE) event is a well-established clinical indicator of benefit associated with all severities of asthma. From a clinical trial perspective, it avoids the situation where a single patient may contribute to multiple events when using time-weighted event counts in the primary analysis. Its usage complies with the American Thoracic Society's 2009 statement on asthma control and acute exacerbations, as well as consensus recommendations for the standardized definition and assessment of acute asthma exacerbations in clinical trials.

[0229] The main estimates in this study are defined by the following properties:

[0230] ABS = Salbutamol Sulfate; CAE = Clinical Asthma Acute Exacerbation; COVID-19 = Coronavirus Disease 2019; eMDPI = Electronic Modular Multi-Dose Dry Powder Inhaler; Fp = Fluticasone Propionate; GINA = Global Initiative for Asthma; HD = High Dose; ICE = Event During the Period; LD = Low Dose; SCS = Systemic Corticosteroids Exploratory endpoint The exploratory objective of this study is to characterize the emergency treatment (i.e., IMP) utilization patterns of HD or LDF Fp / ABS eMDPI compared to ABS eMDPI, and will be assessed through the following endpoints: The following are the destinations: Vital signs, physical examination (including oropharynx), clinical laboratory tests and ECG findings Combined medication use throughout the study period Study medication usage patterns (daily inhalation frequency determined based on the patient's eDiary). Change in ACQ-5 from baseline (Visit 3 [V3]) at week 12 (patient age ≥6 years) The ACQ-5 feedback at week 12 was defined as a decrease of at least 0.5 points from baseline (for patients aged ≥6 years). Changes in AQLQ+12 / PAQLQ from baseline at week 12 (PAQLQ for patients aged 7 to <12 years) Changes in AQLQ+12 / PAQLQ from baseline at week 24 (PAQLQ for patients aged 7 to <12 years) Week 12 AQLQ+12 / PAQLQ feedback is defined as an increase of at least 0.5 points from baseline (PAQLQ for patients aged 7 to <12 years). Change in trough FEV1 from baseline at week 12 (patient age ≥12 years) The expected change in the percentage of FEV1 from baseline at the trough of week 12 (patient age ≥ 4 years) Change from baseline at week 24 trough FEV1 (patient age ≥12 years) The change from baseline in the weekly average of morning FEV1 measured by a handheld device during weeks 1 to 24 (patients ≥12 years old). Note: Baseline here is the average of morning FEV1 in the first 7 days of V3.

[0231] The change in the trough-predicted FEV1 percentage from baseline at week 24 (patient age ≥4 years). Baseline is the average of the predicted FEV1 percentage within the first 7 days of V3.

[0232] Variation from baseline in weekly average morning peak expiratory flow (PEF) measured by a handheld device during weeks 1 to 24. Note: Baseline here is the average morning PEF over the first 7 days of V3.

[0233] The change from baseline in the weekly mean of daily asthma symptom scores (defined as the average of daytime and nighttime scores) over weeks 1 through 24. Note: The baseline here is the average score over the first 7 days of V3.

[0234] Percentage of symptom-free days in 24 weeks (defined as a 24-hour period with an asthma symptom score of 0) Percentage of days of asthma control within 24 weeks (defined as a 24-hour period in which the asthma symptom score is zero and no emergency medical intervention (IMP) is used). The percentage of days without using emergency (i.e., IMP) medication (defined as the number of days in 24 weeks without using emergency [i.e., IMP]). The first time asthma exacerbation requires a change in asthma treatment (including patients who have experienced severe CAE). Change from baseline in weekly average daily (24-hour) IMP use (inhalation frequency) during week 24. Note: Baseline here is the average number of inhalations over the first 7 days of V3.

[0235] Planned number of patients and countries

[0236] Approximately 4,880 patients were screened to reach approximately 2,196 randomized patients (approximately 10% were pediatric patients aged 4 to <12 years and approximately 10% were adolescent patients aged 12 to <18 years).

[0237] The planned total number of patients is approximately 732 per treatment group.

[0238] Patient inclusion criteria

[0239] Patients can only be included in this study if they meet all of the following criteria: (a) The patient is able to sign an informed consent form (aged ≥18 years). Patients aged 4 to <18 years (or as applicable and required by local regulations) are able to provide a consent statement and must have written consent from their parent / legal guardian prior to the execution of any research procedure.

[0240] (b) The patient is male or female and is 4 years of age or older at the time of signing the informed consent form / consent statement, or meets the age requirements stipulated by local regulations.

[0241] (c) The patient has been diagnosed with asthma for at least 1 year according to the 2022 GINA guidelines.

[0242] (d) The patient’s ACQ-5 score is ≥1.5 (this criterion is not required for patients aged 4-5 years).

[0243] (e) The patient has a history of at least one serious CAE within the past 12 months prior to screening.

[0244] Note: Documentation of acute asthma exacerbations within the past 12 months must be available. This includes medical or hospital records, or a prescription for SCS used during an acute exacerbation provided by the patient. Other eligible patients may enter the introductory phase while attempting to collect medical records of acute asthma exacerbations, but must not be randomized at Visit 3 (V3) if the records have not yet been obtained and verified.

[0245] (f) The patient is using any prescription inhaled asthma control medication (with a stable dose for 1 month prior to the screening visit). Examples include the following: - Low to high doses of ICS - Low to high doses of ICS plus one of the following additional maintenance therapies: leukotriene receptor antagonists (LTRA), long-acting muscarinic antagonists (LAMA), or theophylline. - Low to high doses of ICS combined with LABA, with or without one of the following additional maintenance therapies: LTRA, LAMA, or theophylline. - Patients aged 4 to <6 years may participate if they meet the minimum ICS dose specified in the "Permitted Drugs" section.

[0246] (g) For patients aged ≥12 years, FEV1 before bronchodilator administration was ≥40% to <90% of the expected normal value; for patients aged 4 to 11 years, FEV1 after discontinuation of designated medications [including SABA (introduction emergency medication) for respiratory rate measurement] was ≥60% to <100% of the expected normal value (Quanjer et al., 2012).

[0247] (h) Before the induction phase (V2) and IMP dispensing (V3), patients should use the training inhaler according to the instructions of use, demonstrating correct technique. Note: Interval devices should not be used with the eMDPI device to be used in this study, as they are incompatible.

[0248] (i) Patients demonstrated age-appropriate performance on respiratory rate measurement during the screening period (i.e., meeting the American Thoracic Society / European Respiratory Society acceptability / reproducibility criteria) (Graham BL et al., 2019). Note: For patients aged 4 to <12 years, two acceptable and reproducible curves are sufficient.

[0249] (j) Based on the researchers’ judgment, patients were able to use handheld devices to measure PEF / FEV1.

[0250] (k) Bronchodilator responsiveness test (“reversibility test”): Patients (for those 12 years and older) demonstrate airway reversibility via a β-2 agonist challenge test using central respiratory volume measurement after administration of salbutamol (provided by the initiator), i.e., an increase in FEV1 relative to baseline (≥12%). Patients 18 years and older must also demonstrate an increase in FEV1 of 200 mL from baseline. One retest for reversibility is permitted during screening prior to the second visit.

[0251] or

[0252] The patient has a history of FEV1 ≥ 12% airway reversibility within the past 18 months.

[0253] Note: All patients, including those aged 4 to 11, must undergo a reversibility test.

[0254] (l) The patient must be willing and able to comply with the study restrictions and stay at the research center for the required duration during the study and any subsequent procedures and assessments, and be willing to return to the research center for further visits (if applicable).

[0255] (m) If female, the patient is not currently pregnant, not breastfeeding, not attempting pregnancy (at least 30 days prior to the screening visit and throughout the study period), or has no CBP, defined as any of the following: - Premenstrual period - Women who have been postmenopausal for at least 1 year (at least 12 months without menstruation and without other medical reasons, and whose FSH concentration exceeds 35 U / L and who are not using hormonal contraception or hormone replacement therapy) - Surgical sterilization (bilateral tubal ligation, bilateral oophorectomy, salpingectomy, or hysterectomy) - Congenital infertility (assessed by a doctor) - Diagnosed with infertility and did not receive reversal treatment for infertility Alternatively, if it is CBP, a negative serum β-HCG test at the screening visit, and a commitment to use a medically approved, highly effective method of contraception throughout the study, as defined below: - Hormonal contraception using a combination of estrogen and progestin (oral, intravaginal, transdermal) associated with ovulation suppression; these should be initiated at least 30 days before the first IMP administration and maintained throughout the study period.

[0256] - Hormonal contraceptives (oral, injectable, implantable) that involve ovulation suppression and are progestin-only; these should be started at least 30 days before the first IMP dose and maintained throughout the study.

[0257] - Intrauterine contraceptive devices and intrauterine hormone-releasing systems need to be in place at least 2 months before screening and maintained throughout the study.

[0258] - Bilateral tubal occlusion, excluding hysteroscopic bilateral tubal ligation, requires hysterosalpingography (HSG) 3 months post-surgery to assess surgical success.

[0259] - The partner has undergone a vasectomy, provided he is the only sexual partner and has successfully undergone the procedure and received a medical evaluation.

[0260] - Sexual abstinence - Avoid heterosexual intercourse during the research period

[0261] It should be noted that if female patients have entered puberty and reached menarche (as determined by the investigator), they must be informed of the unknown risks that IMP may pose during pregnancy (if necessary, with the permission of their parents / legal guardians).

[0262] The investigational drug product used in the study

[0263] The IMP used in the study is defined as the experimental IMP and the positive control. The positive control is authorized and used in accordance with the marketing authorization terms of its respective country (although ProAir® is currently only approved in the United States and Canada, and ProAir® Digihaler® is currently only approved in the United States).

[0264] Drug products for experimental research

[0265] The test IMP was an Fp / ABS eMDPI inhalation powder, further described in the table below.

[0266] Patients received the trial IMP at either HD (55 / 117 mcg) or LD (30 / 117 mcg) frequency of on-demand (PRN) twice daily to control asthma symptoms. The maximum daily dose in the trial was 12 inhalations (6 doses) per day. The number of times patients inhaled more than 12 times (6 doses) per day was reported in the study report.

[0267] It is also recommended that patients rinse their mouths with water after inhalation and not swallow.

[0268] Positive control

[0269] The positive control was ABS eMDPI inhalation powder, further described in the table below. For more details, see the ProAir® Digihaler® PI, June 2022 and the ProAir® RespiClick® PI, September 2020.

[0270] Patients will receive a positive control with a dosing frequency of 2 inhalations as needed (108 micrograms per delivery) to control asthma symptoms.

[0271] The maximum daily dose is 12 inhalations (6 doses) per day. The study report reported the number of times patients inhaled more than 12 times (6 doses) per day.

[0272] It is also recommended that patients rinse their mouths with water after inhalation and not swallow.

[0273] Adjunctive drug products

[0274] During the introduction phase, patients were provided with ProAir® RespiClick® (salbutamol [salbutamol] inhalation powder 117 mcg / inhalation) as an emergency medication (as permitted by local regulations) and treated as an adjunct medicine product. This formulation was identical to the positive control in this study. Use of the platform during the introduction phase (2–4 weeks) will allow patients to become familiar with the correct use of the device after training. During study treatment, IMP was used as an emergency medication, using the same device platform. Use of ProAir® RespiClick® during the introduction phase also allows for standardized treatment across multiple regions, providing a consistent study design.

[0275] Inhaler device

[0276] The inhaler device manufactured by Teva presented in this study is the eMDPI (Digihaler) device, which, as described herein, contains a built-in electronic module that detects, records, and stores data related to inhaler events.

[0277] In this study, the electronic module components are not used in conjunction with the mobile application. The inhaler returns to the central site, and the data is downloaded in compliance with global data privacy regulations.

[0278] All patients received training on the use of the training inhaler device during V2 and V3. Note: Due to incompatibility, patients must be able to use the device without the spacer. Spacers are not permitted for use with the eMDPI device. Training was conducted after the screening visit, when patients were deemed eligible for inclusion and the introductory phase began. Each patient reviewed the device's usage instructions. The inhaler training device was then provided to the patient. This training device was empty and contained no active drug. Patients practiced using the device and were asked to demonstrate their understanding of the correct technique. To ensure correct technique, the training procedure was repeated and documented at each clinical visit throughout the study duration for patients exhibiting incorrect technique during the inhaler use assessment. The site was responsible for marking and storing the training inhaler device between visits (further explained in the study reference manual).

[0279] Instructions for proper use of the inhaler are provided by the initiator.

[0280] The investigational pharmaceutical products and devices used in the study

[0281] ABS = Salbutamol Sulfate; eMDPI = Multi-dose Dry Powder Inhaler with Integrated Electronic Module; Fp = Fluticasone Propionate; IMP = Investigational Pharmaceutical Product.

[0282] Permitted drugs

[0283] The drugs listed in the table below are permitted during the study period, but with restrictions: List of permitted ICS doses for patients ≥12 years of age included in the study

[0284] a Excluding ICS / LABA used as emergency medications

[0285] b. To determine the dosage or delivery dose, consult the prescription information.

[0286] c ArmonAir® Respiclick® USPI (revised July 2021), ArmonAir® Digihaler® USPI (revised March 2022), AirDuo RespiClick® USPI (revised July 2021), AirDuo Digihaler® USPI (revised July 2021).

[0287] d EASYHALER beclomethasone dipropionate SmPC (Revised April 2017).

[0288] e QVAR REDIHALER USPI (revised January 2021), QVAR 100 Autohaler SmPC (revised November 2019), QVAR 50 Easi-Breathe SmPC (revised November 2020).

[0289] f depends on the DPI device – see product information.

[0290] DPI = Dry Powder Inhaler; HFA = Hydrofluoroalkane; ICS = Inhaled Corticosteroids; LABA = Long-Acting Beta Agonist; pMDI = Pressurized Dose Inhaler; SmPC = Product Features Summary; USPI = US Prescription Information.

[0291] Note: Any dose (including low dose) of ICS / LABA fixed-dose combination is permitted. This is also permitted if the patient's background medications at screening include inhaled long-acting muscarinic antagonists.

[0292] Source: GINA 2022.

[0293] List of permissible ICS doses for patients aged 6 to <12 years included in the study

[0294] a CLENIL MODULITE SmPC (Revised December 2018).

[0295] b EASYHALER Beclomethasone Dipropionate SmPC (Revised April 2017)

[0296] c QVAR REDIHALER USPI (revised January 2021), QVAR 100 Autohaler SmPC (revised November 2019), QVAR 50 Easi-Breathe SmPC (revised November 2020).

[0297] DPI = Dry Powder Inhaler; HFA = Hydrofluoroalkane; ICS = Inhaled Corticosteroids; MDI = Metered-Dose Inhaler; SmPC = Product Features Summary; USPI = US Prescription Information.

[0298] Source: GINA 2022.

[0299] List of permissible ICS doses for patients aged 4–5 years included in the study

[0300] DPI = Dry Powder Inhaler; HFA = Hydrofluoroalkane; ICS = Inhaled Corticosteroids; MDI = Metered-Dose Inhaler.

[0301] Source: GINA 2022.

[0302] In addition to the above, the following drugs are also permitted for use during the study period, but with restrictions: - Long-term and on-demand use of low-potency topical corticosteroids (e.g., 1% hydrocortisone cream, desonide, 0.01% fluocinolone acetonide cream) for the treatment of skin conditions is permitted, not exceeding 20% ​​of the body surface area. Topical corticosteroids of any strength are prohibited from use with occlusive dressings.

[0303] - Long-term stable doses of intranasal corticosteroids are permitted for at least 30 days prior to V1. Initiation of intranasal corticosteroids is prohibited during the study period.

[0304] - Long-term stable doses of ophthalmic steroids are permitted for use for at least 30 days prior to V1.

[0305] - Immunotherapy for allergies is permitted via any route, provided that treatment begins 90 days or earlier before V1 and the patient's dose remains stable for 30 days or longer before V1. The treatment regimen must remain stable throughout the study period.

Claims

1. A method of treating asthma, the method comprising administering, on demand (PRN) a fixed-dose dry powder inhalation composition comprising fluticasone propionate and salbutamol sulfate as a rescue medication to patients aged ≥4 years, wherein the fluticasone propionate is administered at a delivery dose of 22-59 micrograms per inhalation, the salbutamol sulfate is administered at a delivery dose of 92-124 micrograms per inhalation, and wherein the treatment provides one or more of the following: prolonging the time to first severe clinical asthma exacerbation (CAE) compared to salbutamol sulfate rescue treatment; reducing total annualized systemic corticosteroid (SCS) exposure compared to salbutamol sulfate rescue treatment; and reducing the annualized rate of severe clinical asthma exacerbation (CAE) compared to salbutamol sulfate rescue treatment.

2. The method of claim 1, wherein the asthma treatment comprises one or more of the following: prolonging the time to first severe clinical acute exacerbation of asthma compared to emergency treatment with salbutamol sulfate, and reducing total annualized systemic corticosteroid (SCS) exposure compared to emergency treatment with salbutamol sulfate.

3. The method of claim 1, wherein the asthma treatment comprises one or more of the following: reducing total annualized systemic corticosteroid (SCS) exposure compared to salbutamol sulfate emergency treatment, and reducing the annualized rate of severe clinical asthma acute exacerbations (CAEs) compared to salbutamol sulfate emergency treatment.

4. The method of claim 1, wherein the asthma treatment comprises one or more of the following: prolonging the time to first severe clinical asthma exacerbation compared with salbutamol sulfate emergency treatment, and reducing the annualized rate of severe clinical asthma exacerbation (CAE) compared with salbutamol sulfate emergency treatment.

5. The method of claim 1, wherein the treatment provides one or more of the following: prolonging the time between severe clinical asthma exacerbations compared to emergency treatment with salbutamol sulfate, and reducing the time a patient has severe clinical asthma exacerbations compared to emergency treatment with salbutamol sulfate.

6. The method of claim 1 or 5, wherein the asthma treatment is for the treatment or prevention of bronchospasm in patients aged 4 years and older with reversible obstructive airway disease.

7. The method of claim 1 or 5, wherein the asthma treatment prevents acute exacerbations in patients aged 4 years and older.

8. The method of claim 1 or 5, wherein the asthma treatment provides at least one of the following: a decrease of at least 0.5 points from baseline in the week 24 Asthma Control Questionnaire-5 (ACQ-5) feedback compared to emergency treatment with salbutamol sulfate; and an increase of at least 0.5 points from baseline in the week 24 AQLQ+12 / PAQLQ (patients aged ≥7 years) feedback compared to emergency treatment with salbutamol sulfate.

9. The method of claim 8, wherein the asthma treatment is performed in patients aged 6 years and older.

10. The method of claim 1, wherein the patient is given a maintenance dose of a long-term asthma medication alone.

11. The method of claim 10, wherein the long-term asthma medication is an ICS, LABA, LAMA, SAMA, a biologic, or a combination thereof.

12. The method of claim 11, wherein the ICS is selected from: flunisolone, fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, mometasone furoate, ciroxone, and combinations thereof.

13. The method of claim 11, wherein the LABA is selected from formoterol, aforterol, salmeterol, bambuterol, clenbuterol, abetaterol, indaterol, adaterol, vilanterol, carmoterol, and combinations thereof.

14. The method of claim 11, wherein the LAMA is selected from tiotropium bromide, glycopyrronium bromide, umebromium bromide, adehydrobromide, darotropium bromide, and combinations thereof.

15. The method of claim 11, wherein the SAMA is ipratropium bromide.

16. The method of claim 11, wherein the biological agent is selected from: tazepluzumab, dupilumab, mepolizumab, retizumab, benrelizumab, omalizumab, pallizumab, and combinations thereof.

17. The method of claim 10, wherein the daily dose of maintenance therapy is categorized as low, medium, or high dose based on the drug type and patient age.

18. The method of claim 17, wherein for patients aged ≥12 years, the daily dose of ICS is: beclomethasone dipropionate, low dose 200-500 mcg, medium dose >500-1,000 mcg, high dose >1,000 mcg; ultrafine beclomethasone dipropionate, low dose 100-200 mcg, medium dose >200-400 mcg, high dose >400 mcg; budesonide, low dose 200-400 mcg, medium dose >400-800 mcg. 0 micrograms, high dose >800 micrograms; cicsolone, low dose 80-160 micrograms, medium dose >160-320 micrograms, high dose >320 micrograms; fluticasone furoate, low and medium doses 100 micrograms, high dose 200 micrograms; fluticasone propionate, low dose 100-250 micrograms, medium dose >250-500 micrograms, high dose >500 micrograms; and mometasone furoate, low and medium doses 200-400 micrograms, high dose >400 micrograms.

19. The method of claim 17, wherein for patients aged 6 years to <12 years, the daily dose of ICS is: beclomethasone dipropionate, low dose 100-200 μg, medium dose >200-400 μg, high dose >400 μg; ultrafine beclomethasone dipropionate, low dose 50-100 μg, medium dose >100-200 μg, high dose >200 μg; budesonide, low dose 100-200 μg, medium dose >200-400 μg, high dose >400 μg; Budesonide nebulized solution: low dose 250-500 mcg, medium dose >500-1,000 mcg, high dose >1,000 mcg; ciroxonide: low dose 80 mcg, medium dose >80-160 mcg, high dose >160 mcg; fluticasone furoate: low and medium doses 50 mcg; fluticasone propionate: low dose 50-100 mcg, medium dose >100-200 mcg, high dose >200 mcg; and mometasone furoate: low and medium doses 100 mcg, high dose 200 mcg.

20. The method of claim 1, wherein the patient age group is ≥6 years old.

21. The method of claim 20, wherein the patient age group is ≥12 years.

22. The method of claim 21, wherein the patient age group is ≥18 years.

23. The method of claim 1, wherein the age group of the asthma patients includes at least one of the following: 4-11, 6-11, 12-17 and ≥18.

24. The method of claim 23, wherein the patient age group is 4-11 years old.

25. The method of claim 23, wherein the patient age group is 12-17 years old.

26. The method of claim 1, wherein the patient is any level 1 patient in GINA 1-5.

27. The method of claim 1, wherein fluticasone propionate is administered in a delivery dose of 23-56 micrograms per inhalation, and salbutamol sulfate is administered in a delivery dose of 97-119 micrograms per inhalation.

28. The method of claim 27, wherein fluticasone propionate is administered at a delivery dose of 25-54 micrograms per inhalation, and salbutamol sulfate is administered at a delivery dose of 103-113 micrograms per inhalation.

29. The method of claim 28, wherein fluticasone propionate is administered at a delivery dose of 26 or 51 micrograms per inhalation, and salbutamol sulfate is administered at a delivery dose of 108 micrograms per inhalation.

30. The method of claim 1, wherein fluticasone propionate is administered at a dose of 26-63 micrograms per inhalation and salbutamol sulfate is administered at a dose of 99-135 micrograms per inhalation.

31. The method of claim 30, wherein fluticasone propionate is administered at a dose of 27-61 micrograms per inhalation and salbutamol sulfate is administered at a dose of 105-129 micrograms per inhalation.

32. The method of claim 31, wherein fluticasone propionate is administered at a dose of 29-58 micrograms per inhalation and salbutamol sulfate is administered at a dose of 111-123 micrograms per inhalation.

33. The method of claim 32, wherein fluticasone propionate is administered at a dose of 30 or 55 micrograms per inhalation, and salbutamol sulfate is administered at a dose of 117 micrograms per inhalation.

34. The method of claim 1, wherein the fixed-dose combination of fluticasone propionate and salbutamol sulfate is administered at a maximum daily dose not exceeding 12 inhalations.

35. The method of claim 1, wherein the fixed-dose dry powder inhalation composition comprises fluticasone propionate, salbutamol sulfate, and α-lactose monohydrate.

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