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CA-3059824-C - A PROCESS FOR PREPARING A DRY POWDER FORMULATION COMPRISING AN ANTICHOLINERGIC, A CORTICOSTEROID AND A BETA-ADRENERGIC

CA3059824CCA 3059824 CCA3059824 CCA 3059824CCA-3059824-C

Abstract

The invention relates to a process for preparing a powder formulation for inhalation for use in a dry powder inhaler, said powder formulation comprising: (A) a carrier, comprising : (a) a fraction of coarse particles of a physiologically acceptable carrier having a particle size of at least 60 micron; and optionally (b) a fraction of fine particles comprising a physiologically acceptable excipient, wherein at least 90% of all said fine particles has a volume diameter lower than 15 micron, (B) micronized particles of glycopyrronium bromide, an inhaled corticosteroid (ICS), and optionally a long-acting O2 -agonist (LABA), as active ingredients, wherein said process comprises: (i) preparing by co-milling microparticles consisting of glycopyrronium bromide and a first part of the ICS in a ratio ranging from 80:20 to 70:30 by weight, wherein the volume diameter of said microparticles is not higher than 15 micron; (ii) mixing the carrier, the remaining part of said ICS, and optionally the long-acting O2 -agonist, to obtain a first mixture; and (iii) adding the co-milled microparticles obtained in step (i) to the first mixture obtained in step (ii), to obtain a second, final, mixture.

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. 28 CLAIMS 1. A process for preparing a powder formulation for inhalation for use in a dry powder inhaler, said powder formulation comprising: (A) a carrier, comprising: (a) a fraction of coarse particles of a physiologically acceptable carrier having a particle size of at least 60 microns; and optionally (b) a fraction of fine particles comprising a physiologically acceptable excipient, wherein at least 90% of all said fine particles have a volume diameter lower than 15 microns, (B) micronized particles of glycopyrronium bromide, an inhaled corticosteroid (ICS), and optionally a long-acting P2-agonist (LABA), as active ingredients, wherein said process comprises: (i) preparing by co-milling microparticles consisting of glycopyrronium bromide and a first part of the ICS in a ratio ranging from 80:20 to 70:30 by weight, wherein the volume diameter of said microparticles is not higher than 15 microns; (ii) mixing the carrier, the remaining part of said ICS, and optionally the long-acting P2- agonist, to obtain a first mixture; and (iii) adding the co-milled microparticles obtained in step (i) to the first mixture obtained in step (ii), to obtain a second, final, mixture.
  2. 2. The process for preparing a powder formulation for inhalation for use in a dry powder inhaler according to claim 1, wherein said powder formulation comprises: (A) a carrier which comprises: (a) the fraction of coarse particles of a physiologically acceptable carrier with a mass median particle size of at least 175 microns; and (b) the fraction of fine particles consisting of a mixture of 90 to 99 .5 percent by weight of particles of a physiologically acceptable excipient and 0.5 to 10 percent by weight of a salt of a fatty acid; wherein the weight ratio of said fine particles to said coarse particles is 5:95 to 30:70; and (B) the active ingredients including a long-acting P2-agonist; Date Re9ue/Date Received 2024-03-08 29 and wherein in said process: - the mixing of step (ii) is carried out 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 the first mixture; and - the second mixture obtained in step (iii) is blended at a speed of rotation not higher than 16 r.p.m. for a time of not more than 40 minutes to obtain a blend.
  3. 3. The process according to claim 2, further comprising: (iv) further mixing the blend obtained in step (iii) to achieve a homogeneous distribution of said active ingredients.
  4. 4. The process according to any one of claims 1 to 3, wherein the ICS is 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 is formoterol, salmeterol, indacaterol, olodaterol, or vilanterol.
  6. 6. The process according to claim 1 or 2, wherein the ICS is beclomethasone dipropionate and the LABA is formoterol fumarate dihydrate.
  7. 7. The process according to claim 2, wherein the salt of a fatty acid is magnesium stearate, sodium stearyl fumarate, sodium stearyl lactylate, sodium lauryl sulphate, or magnesium lauryl sulphate.
  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 2 to 8, wherein in step ii) the mixing is performed at 16-32 r.p.m., for a time comprised between 60 and 120 minutes.
  10. 10. The process according to any one of claims 2 to 9, wherein in step iii) is performed for a time comprised between 20 and 40 minutes.
  11. 11. The process according to any one of claims 1 to 10, wherein the physiologically acceptable excipient is alpha-lactose monohydrate.
  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 f32-agonists and anti-cholinergics 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 f32-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; 20 ii) glycopyrronium bromide, an anticholinergic 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 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 device with inspiration. Dry powder inhalers (DPis) constitute a valid alternative to MD Is for the administration of drugs to airways. Date Re9ue/Date Received 2024-03-08 3 Typically, drugs intended for inhalation as dry powders should be used in the form of micronized particles. For example, powder formulations for inhalation by Dry Powder Inhalers (DPis) containing all said three active ingredients in a micronized form are disclosed in 5 WO 2015/004243. Said formulation takes advantage of the technology platform disclosed in WO 01/78693, entailing the use of carrier constituted of a fraction of coarse excipient particles and a fraction made of fine excipient particles and magnesium stearate. In the specification, possible processes for preparing micronized glycopyrronium bromide are described, but no preference is given. 10 On