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EP-4739295-A1 - AN INHALABLE FORMULATION OF FLUTICASONE PROPIONATE AND ALBUTEROL SULFATE FOR THE TREATMENT OF ASTHMA

EP4739295A1EP 4739295 A1EP4739295 A1EP 4739295A1EP-4739295-A1

Abstract

This invention relates to a method for the treatment of asthma comprising pro re nata (PRN) administration of a fixed-dose dry powder inhalation composition comprising fluticasone propionate and albuterol sulfate as a rescue medication in patients aged from ≥4 years to <18 years. Also provided is a fixed-dose dry powder inhalation composition and dry powder inhaler for performing the method of the present invention.

Inventors

  • SMALL, Calvin J.
  • EDELSON, Jeffrey
  • KROPOTOVA, ALEXANDRA
  • STOYANOV, Stanislav

Assignees

  • Norton (Waterford) Limited

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1 . A method of treatment of asthma comprising a pro re nata (PRN) administration of a fixed-dose dry powder inhalation composition comprising fluticasone propionate and albuterol sulfate as a rescue medication in patients aged from >4 years to <18 years.
  2. 2. The method of claim 1 , wherein the asthma treatment treats or prevents bronchospasm in patients aged >4 years to <18 years with reversible obstructive airways disease.
  3. 3. The method of claim 1 , wherein the asthma treatment prevents exacerbations in patients aged >4 years to <18 years old.
  4. 4. The method of claim 1 , wherein the asthma treatment comprises one or more of prolonging the time to first severe clinical asthma exacerbation (CAE) when compared to albuterol sulfate rescue treatment, reducing the total annualized systemic corticosteroid (SCS) exposure when compared to albuterol sulfate rescue treatment and reducing the annualized severe clinical asthma exacerbation (CAE) rate when compared to albuterol sulfate rescue treatment.
  5. 5. The method of claim 4, wherein the asthma treatment comprises one or more of prolonging the time to first severe clinical asthma exacerbation when compared to albuterol sulfate rescue treatment and reducing the total annualized systemic corticosteroid (SCS) exposure when compared to albuterol sulfate rescue treatment.
  6. 6. The method of claim 4, wherein the asthma treatment comprises one or more of reducing the total annualized systemic corticosteroid (SCS) exposure when compared to albuterol sulfate rescue treatment and reducing the annualized severe clinical asthma exacerbation (CAE) rate when compared to albuterol sulfate rescue treatment.
  7. 7. The method of claim 4, wherein the asthma treatment comprises one or more of prolonging the time to first severe clinical asthma exacerbation when compared to albuterol sulfate rescue treatment and reducing the annualized severe clinical asthma exacerbation (CAE) rate when compared to albuterol sulfate rescue treatment.
  8. 8. The method of claims 1 or 4, wherein the asthma treatment comprises one or more of prolonging the time between severe clinical asthma exacerbations when compared to albuterol sulfate rescue treatment and decreasing the amount of time a patient has a severe clinical asthma exacerbation when compared to albuterol sulfate rescue treatment.
  9. 9. The method of claims 1 , 4 or 8, wherein the treatment of asthma provides at least one of the following: achieving a decrease in the score from baseline value of at least 0.5 in the Asthma Control Questionnaire-5 (ACQ-5) response at week 24 when compared to albuterol sulfate rescue treatment.; and achieving an increase in the score from baseline of at least 0.5 in the AQLQ+12/PAQLQ (patients aged >7 years) response at week 24 when compared to albuterol sulfate rescue treatment.
  10. 10. The method of claim 9, wherein the treatment of asthma is in patients aged 6 to <18 years old.
  11. 11 . The method of claim 1 , wherein the patients are separately administered a maintenance dose of a long-term asthma medication.
  12. 12. The method of claim 11 , wherein the long-term asthma medication is an ICS, LABA, LAMA, SAMA, biological medication or combinations thereof.
  13. 13. The method of claim 12, wherein the ICS is selected from flunisolide, fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, mometasone furoate, ciclesonide and combinations thereof.
  14. 14. The method of claim 13, wherein the LABA is selected from formoterol, arformoterol, salmeterol, bambuterol, clenbuterol, abediterol, indacaterol, olodaterol, vilanterol, carmoterol and combinations thereof.
  15. 15. The method of claim 13, wherein the LAMA is selected from tiotropium, glycopyrronium, umeclidinium, aclidinium, darotropium and combinations thereof.
  16. 16. The method of claim 13, wherein the SAMA is ipratropium.
  17. 17. The method of claim 11 wherein the maintenance therapy daily metered dose is low-, medium- or high-dose depending on the type of medicament and patient's age.
  18. 18. The method of claim 17, wherein for patients aged 12 years <18 years old the ICS daily metered doses are: beclomethasone dipropionate, low-dose 200-500 mcg, medium-dose >500-1 ,000 mcg, high- dose >1 ,000 mcg; beclomethasone dipropionate ultra-fine particle, low-dose 100-200 mcg, mediumdose >200-400 mcg, high-dose >400 mcg; budesonide, low-dose 200-400 mcg, medium-dose >400- 800 mcg, high-dose >800 mcg; ciclesonide, low-dose 80-160 mcg, medium-dose >160-320 mcg, high- dose >320 mcg; fluticasone furoate, low-dose and medium-dose 100 mcg, high-dose 200 mcg; fluticasone propionate, low-dose 100-250 mcg, medium-dose >250-500 mcg, high-dose >500 mcg; and mometasone furoate, low-dose and medium-dose 200-400 mcg, high-dose is >400 mcg.
  19. 19. The method of claim 17, wherein for patients aged 6 to <12 years old the ICS daily metered doses are: beclomethasone dipropionate, low-dose 100-200 mcg, medium-dose >200-400 mcg, high-dose >400 mcg; beclomethasone dipropionate ultra-fine particle, 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 is >400 mcg; budesonide nebules, low-dose 250-500 mcg, medium-dose >500-1 ,000 mcg, high-dose >1 ,000 mcg; ciclesonide, low-dose 80 mcg, medium-dose >80-160 mcg, high-dose >160 mcg; fluticasone furoate, low-dose and medium-dose 50 mcg; fluticasone propionate, low-dose 50-100 mcg, medium-dose >100-200 mcg, high-dose >200 mcg; and mometasone furoate, low-dose and medium-dose 100 mcg, high-dose 200 mcg
  20. 20. The method of claim 1 , wherein patients aged from >4 years to <18 includes at least one of >4 to <12-year-old patients, >6 to <12 year old patients >12 to <18 year old patients and combinations thereof.

Description

AN INHALABLE FORMULATION OF FLUTICASONE PROPIONATE AND ALBUTEROL SULFATE FOR THE TREATMENT OF ASTHMA Background of the invention This invention relates to an inhalable formulation, and particularly to a fixed-dose composition, of fluticasone propionate and albuterol sulfate for the treatment of asthma. Asthma is one of the most common chronic diseases. It is a heterogeneous condition that affects the airways of the lungs and is characterized by airway inflammation and bronchial hyper-responsiveness, resulting in variable reductions in expiratory airflow that vary over time in their occurrence, frequency, and intensity. During acute asthmatic episodes, the airway passages become narrower and more obstructed, resulting in coughing, wheezing, tightness of the chest, shortness of breath, and increased mucus production. In some subjects, asthma may lead to chronic irreversible changes in airway structure and function, increasing morbidity and mortality. Inhaled corticosteroids and p2-agonists represent two classes of active ingredient that have been developed to treat respiratory disorders, particularly asthma. Each class has differing targets and effects. Inhaled corticosteroids (ICSs) are steroid hormones used in the long-term control of respiratory disorders. They function by reducing the airway inflammation, controlling symptoms and reducing future risks of exacerbation and lung function decline. They are often termed “controller” or “maintenance” medicines. Presently marketed ICSs are for example beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate and mometasone furoate. The compounds are all well- known in the art. For example, fluticasone propionate is named as S-(fluoromethyl)-6a,9-difluoro- 11 p,17-dihydroxy-16a-methyl-3-oxoandrosta-1 ,4-diene-17p-carbothioate-17-propanoate. Short-acting p2-agonists (SABAs) are examples of bronchodilators, and are employed to dilate the bronchi and bronchioles, decreasing resistance in the airways, and thereby increasing the airflow to the lungs. Bronchodilators may be short-acting or long-acting. Short-acting bronchodilators provide a rapid but short-term relief from acute bronchoconstriction (and are often called “rescue” or “reliever” medicines), whereas long-acting bronchodilators typically help control symptoms over a longer period of time compared to SABAs. SABAs are used acutely to provide rapid symptom relief and can be lifesaving, but they do not address underlying airway inflammation. When patients experience worsening asthma symptoms, they gain immediate relief with SABA medication and therefore increase its use. However, patients generally do not increase the use of ICS in a similar manner. SABA overuse, defined as use of >3 canisters per year is common and is a risk factor for poor asthma outcomes and severe exacerbation. Albuterol (also known as salbutamol) is a short-acting p2-agonist that is indicated for the treatment or prevention of bronchospasm in patients with asthma. It is named as 4-[2-(tert-butylamino)-1- hydroxyethyl]-2-(hydroxymethyl)-phenol. Albuterol is the usual bronchodilator used in acute asthma management. It is typically administered as the sulfate salt, the structure of which is well-known in the art. According to the Global Initiative for Asthma (GINA) 2023 guidelines, a step-wise approach is taken to treatment. For adults and adolescents (aged >12 years), the approach is divided into track 1 and track 2. In track 1 , at steps 1-2, which represent a mild form of asthma, the patient is given an as-needed low- dose ICS-formoterol (a long-acting p2 adrenoceptor agonist (LABA) with a rapid onset of action). At step 3, a maintenance low-dose ICS-formoterol is given. At step 4, this is increased to a medium-dose ICS-formoterol. At step 5, an add on LAMA (long-acting muscarinic antagonist) is included, and a high- dose ICS-formoterol is considered. Over all steps, the reliever is an as-needed low-dose ICS- formoterol. In track 2, the reliever is an as-needed SABA or an as-needed ICS-SABA. Step 1 is to take an ICS whenever the SABA is taken. Step 2 adds a low-dose maintenance ICS. Step 3 is a low-dose maintenance ICS-LABA. Step 4 is a medium/high-dose ICS-LABA. At step 5, an add on LAMA is included, and a high-dose ICS-LABA is considered. A similar approach for pediatric patients (aged 6-11) is recommended in the GINA guidelines. Step 1 is to take an ICS whenever the SABA is taken. Step 2 adds a low-dose maintenance ICS. Step 3 is a low-dose maintenance ICS-LABA, or medium-dose maintenance ICS, or very low dose ICS-formoterol maintenance and reliever (MART). Step 4 is a medium-dose ICS-LABA or low dose ICS-formoterol maintenance and reliever (MART). At step 5, a high-dose ICS-LABA or add-on therapy is considered. The reliever is an as-needed SABA or low-dose ICS-formoterol for MART in steps 3 and 4. Interestingly, despite the availability of the present therapies the majority of asthmatic patient