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CA-3060020-C - A PROCESS FOR PREPARING A DRY POWDER FORMULATION COMPRISING AN ANTICHOLINERGIC, A CORTICOSTEROID AND A BETA-ADRENERGIC

CA3060020CCA 3060020 CCA3060020 CCA 3060020CCA-3060020-C

Abstract

The invention relates to a process for preparing a powder formulation for inhalation for use in a dry powder inhaler, said powder comprising : (A) a carrier comprising : (a) 80 to 95 percent by weight, based on the total weight of said carrier, of coarse particles of a physiologically acceptable excipient having a mean particle size of at least 175 micron; and (b) 19.6 to 4.9 percent by weight, based on the total weight of said carrier, of micronized particles of a physiologically acceptable excipient, and (c) 0.1 to 0.4 percent by weight, based on the total weight of said carrier, of a salt of a fatty acid; and (B) micronized particles of glycopyrronium bromide, a long-acting O2 -agonist (LABA) and an inhaled corticosteroid (ICS), as active ingredients, said process comprising : (i) preparing by co-milling microparticles consisting of glycopyrronium bromide and a first part of an ICS in a ratio ranging from 80:20 to 70:30 by weight, wherein the volume diameter of said microparticles is not more than 15 micron; (ii) mixing the coarse particles of a physiologically acceptable excipient, the salt of a fatty acid, a first part of said micronized particles of a physiologically acceptable excipient, the micronized particles of said LABA, the co-milled microparticles obtained in step (i), and the remaining part of said ICS in a vessel of a shaker mixer at a speed of rotation not lower than 16 r.p.m. for a time of not less than 60 minutes, to obtain a first mixture; and (iii) adding the remaining part of the micronized particles of a physiologically acceptable excipient to said first mixture, to obtain a second mixture, and mixing said second mixture at a speed of rotation not lower than 16 rpm for a time of at least 120 minutes to obtain a formulation.

Inventors

  • Alessandro CAVECCHI
  • Cristiana MERUSI
  • Fausto Pivetti
  • Francesca SCHIARETTI

Assignees

  • CHIESI FARMACEUTICI S.P.A.

Dates

Publication Date
20260505
Application Date
20180509
Priority Date
20170511

Claims (12)

  1. 26 CLAIMS 1. A process for preparing a powder formulation for inhalation for use in a dry powder inhaler, said powder comprising: 5 (A) a carrier comprising: (a) 80 to 95 percent by weight, based on the total weight of said carrier, of coarse particles of a physiologically acceptable excipient having a mean particle size of at least 175 microns; and (b) 19 .6 to 4.9 percent by weight, based on the total weight of said carrier, of micronized particles of a physiologically acceptable excipient, and 10 ( c) 0.1 to 0.4 percent by weight, based on the total weight of said carrier, of a salt of a fatty acid; and (B) micronized particles of glycopyrronium bromide, a long-acting P2-agonist (LABA) and an inhaled corticosteroid (JCS), as active ingredients, said process comprising: (i) preparing by co-milling microparticles consisting of glycopyrronium bromide and a first part of an JCS in a ratio ranging from 80:20 to 70 :30 by weight, wherein the volume diameter of said microparticles is not more than 15 microns; (ii) mixing the coarse particles of a physiologically acceptable excipient, the salt of a fatty acid, a first part of said micronized particles of a physiologically acceptable excipient, the 20 micronized particles of said LABA, the co-milled microparticles obtained in step (i), and the remaining part of said JCS in a vessel of a shaker mixer at a speed of rotation not lower than 16 r.p.m. for a time of not less than 60 minutes, to obtain a first mixture; and (iii) adding the remaining part of the micronized particles of a physiologically acceptable excipient to said first mixture, to obtain a second mixture, and mixing said second mixture at a 25 speed of rotation not lower than 16 rpm for a time of at least 120 minutes to obtain a formulation.
  2. 2. The process according to claim 1, further comprising: (iv) further mixing the formulation obtained in (iii) to achieve a homogeneous distribution of said active ingredients.
  3. 3. The process according to claim 1 or 2, wherein said first part of the micronized particles of a physiologically acceptable excipient is 40% to 60%, based on the total weight of all of said 30 micronized particles of a physiologically acceptable excipient. Date Re9ue/Date Received 2024-03-08 27
  4. 4. The process according to any one of claims 1 to 3, wherein the ICS compnses beclomethasone dipropionate or its monohydrate form, budesonide, fluticasone propionate, fluticasone furoate, or mometasone furoate.
  5. 5. The process according to any one of claims 1 to 4, wherein the LABA comprises 5 formoterol, salmeterol, indacaterol, olodaterol, or vilanterol.
  6. 6. The process according to claim 1, wherein the ICS is beclomethasone dipropionate, and the LABA is fonnoterol fumarate dihydrate.
  7. 7. The process according to claim 1, wherein the salt of a fatty acid comprises magnesium stearate; sodium stearyl fumarate; sodium stearyl lactylate; sodium lauryl sulfate, or magnesium 10 lauryl sulfate.
  8. 8. The process according to claim 7, wherein the salt of the fatty acid is magnesium stearate.
  9. 9. The process according to any one of claims 1 to 8, wherein in step ii) the mixing is performed at a speed of rotation comprised between 20 and 28 r.p.m. for a time comprised between 60 and 120 minutes. 15
  10. 10. The process according to any one of claims 1 to 9, wherein in step iii) the mixing is performed at a speed of rotation comprised between 16 and 32 r.p.m. for a time comprised between 120 and 180 minutes.
  11. 11. The process according to any one of claims 1 to 10, wherein the physiologically acceptable excipient is alpha-lactose monohydrate. 20
  12. 12. The process according to any one of claims 1 to 11, wherein the coarse particles have a mass diameter comprised between 210 and 360 μm. Date Re9ue/Date Received 2024-03-08

Description

1 A PROCESS FOR PREPARING A DRY POWDER FORMULATION COMPRISING AN ANTICHOLINERGIC, A CORTICOSTEROID AND A BETA-ADRENERGIC TECHNICAL FIELD The present invention relates to a powder formulation for administration by inhalation by means of a dry powder inhaler. In particular, the invention relates to a process for preparing a dry powder formulation comprising a combination of an anticholinergic, a beta2-adrenoceptor agonist and an inhaled 10 corticosteroid. BACKGROUND OF THE INVENTION Respiratory diseases are a common and important cause of illness and death around the world. In fact, many people are affected by inflammatory and/or obstructive lung diseases, a category characterized by inflamed and easily collapsible airways, obstruction to airflow, 15 problems exhaling and frequent medical clinic visits and hospitalizations. Types of inflammatory and/or obstructive lung disease include asthma, bronchiectasis, bronchitis and chronic obstructive pulmonary disease (COPD). In particular, chronic obstructive pulmonary disease (COPD) is a multi-component disease characterized by airflow limitation and airway inflammation. Exacerbations of COPD 20 have a considerable impact on the quality of life, daily activities and general well-being of patients and are a great burden on the health system. Thus, the aim of COPD management includes not only relieving symptoms and preventing disease progression but also preventing and treating exacerbations. While available therapies improve clinical symptoms and decrease airway inflammation, 25 they do not unequivocally slow long-term progression or address all disease components. With the burden of COPD continuing to increase, research into new and improved treatment strategies to optimize pharmacotherapy is ongoing, and in particular, combination therapies, with a view to their complementary modes of action enabling multiple components of the disease to be addressed. Evidence from recent clinical trials indicates that triple therapy, combining an 30 anticholinergic with an inhaled corticosteroid, and a long-acting ~2-adrenoceptor agonist, may Date Re9ue/Date Received 2024-03-08 2 provide clinical benefits additional to those associated with each treatment alone in patients with more severe COPD. Currently, there are several recommended classes of therapy for COPD, of which bronchodilators such as (32-agonists and anticholinergics are the mainstay of symptom 5 management in mild and moderate diseases, prescribed on an as-needed basis for mild COPD and as a maintenance therapy for moderate COPD. Said bronchodilators are efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material. For the treatment of more severe COPD, guidelines recommend the addition of inhaled 10 corticosteroids (ICSs) to long-acting bronchodilator therapy. Combinations of therapies have been investigated with a view to their complementary modes of action enabling multiple components of the disease to be addressed. Data from recent clinical trials indicates that triple therapy, combining an anticholinergic with a long-acting P2-agonist (LABA), and an JCS, may provide clinical benefits additional to those associated with each treatment alone in patients with 15 moderate to severe forms of respiratory diseases, particular moderate to severe COPD. An interesting triple combination, presently under investigation, includes: i) formoterol, particularly its fumarate salt (hereinafter indicated as FF), a long acting beta-2 adrenergic receptor agonist, currently used clinically in the treatment of asthma, COPD and related disorders; ii) glycopyrronium bromide, an anticholinergic (antimuscarinic) recently approved for the maintenance treatment of COPD; iii) beclometasone dipropionate (BDP) a potent anti-inflammatory corticosteroid, available under a wide number of brands for the prophylaxis and/or treatment of asthma and other respiratory disorders. 25 The solution formulation for administration by pressurized metered dose inhalers (pMDI) is disclosed in WO 2011/076843. Said formulation provides a high lung deposition and uniform distribution throughout the bronchial tree, and is characterized by the fact that is capable of delivering a high fraction of particles having a diameter equal or less than 2.0 micron for all the three active ingredients 30 (hereinafter defined as extrafine fraction). Date Re9ue/Date Received 2024-03-08 3 The major advantage of said formulation is related to the improved penetration into the bronchiole-alveolar distal part of the respiratory tree wherein inflammation is known to play a role in spontaneous exacerbations of asthma symptoms and wherein it is known that the density of the beta-2 adrenergic receptors is particularly high. 5 However, despite their popularity, pMDI formulation may have some disadvantages in particular in elderly and pediatric patients, mostly due to their difficulty to synchronize actuation from the devic