WO2017108917A1 - Compositions pharmaceutiques pour une utilisation dans le traitement des bronchopneumopathies chroniques obstructives - Google Patents

Compositions pharmaceutiques pour une utilisation dans le traitement des bronchopneumopathies chroniques obstructives Download PDF

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WO2017108917A1
WO2017108917A1 PCT/EP2016/082124 EP2016082124W WO2017108917A1 WO 2017108917 A1 WO2017108917 A1 WO 2017108917A1 EP 2016082124 W EP2016082124 W EP 2016082124W WO 2017108917 A1 WO2017108917 A1 WO 2017108917A1
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pharmaceutical composition
copd
use according
glycopyrronium
aclidinium
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PCT/EP2016/082124
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Gonzalo De Miquel Serra
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Astrazeneca Ab
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • compositions for inhalation comprising a combination of a long-acting muscarinic antagonist (LAMA) and a long-acting beta-2 agonist (LABA) for use in the treatment of chronic obstructive pulmonary disease
  • LAMA long-acting muscarinic antagonist
  • LAA long-acting beta-2 agonist
  • COPD COPD
  • the specification describes pharmaceutical compositions comprising a combination of aclidinium, or a pharmaceutically acceptable salt thereof, and formoterol, or a pharmaceutically acceptable salt thereof, or a combination of glycopyrronium, or a pharmaceutically acceptable salt thereof, and formoterol, or a pharmaceutically acceptable salt thereof, and their use for the relief of COPD symptoms when needed.
  • COPD Respiratory diseases are a significant global health problem with an increasing incidence around the world.
  • COPD is a term which refers to a group of lung diseases which can interfere with normal breathing, and current clinical guidelines define COPD as a disease state characterised by airflow limitation that is not fully reversible.
  • the airfiow limitation is usually associated with an abnormal inflammatory response of the lungs to noxious gases and particles, such as tobacco smoke, and COPD patients have a wide variety of symptoms, including cough, shortness of breath (dyspnea), and excessive production of sputum.
  • COPD is generally a progressive disease and regular maintenance treatment is essential.
  • Medications used to treat COPD on a maintenance basis include long-acting beta-2 agonists (LABAs), long-acting muscarinic antagonists (LAMAs), inhaled corticosteroids (ICSs), and combinations thereof.
  • LAMAs long-acting beta-2 agonists
  • ICSs inhaled corticosteroids
  • LAMA such as tiotropium, umeclidinium, glycopyrronium or aclidinium.
  • LAMA such as tiotropium, umeclidinium, glycopyrronium or aclidinium.
  • LAMA/LABA combinations such as the combination of umeclidinium and vilanterol (AnoroTM), the combination of glycopyrronium and indacaterol (UltibroTM), the combination of tiotropium and olodaterol (StioltoTM), the combination of glycopyrronium and formoterol (Bevespi AerosphereTM) and the combination of aclidinium and formoterol (DuaklirTM).
  • AnoroTM, UltibroTM and Stiolto are all indicated for once-daily maintenance treatment of COPD.
  • Bevespi AerosphereTM and DuaklirTM are indicated for twice-daily maintenance treatment of COPD.
  • COPD chronic obstructive pulmonary disease
  • Characteristic respiratory symptoms of COPD include dyspnea (at rest and during exercise), chronic cough, sputum production, and other variable symptoms such as wheeze and chest tightness. While dyspnea is considered the hallmark symptom of COPD, cough is often the first COPD symptom to develop (Miravitlles M et al, Respiration, 2000, 67, 495-501). Patients report dyspnea to be the most distressing symptom of COPD, and this is the primary reason for patients seeking medical care (Chatila WM et al, Proc. Am. Thorac. Soc. 2008, 5, 549-555). Dyspnea onset is gradual and patients often mistakenly relate it to aging or a lack of fitness. Nonetheless, as lung function worsens, dyspnea becomes more persistent and intrusive, and is a major cause of anxiety for patients and a leading cause of disability.
  • COPD exacerbations have an enormous impact on patients' lives, in many cases requiring hospitalisation and extended recovery periods, and are estimated to result in 110,000 deaths and more than 500,000 hospitalisations per year (National Institutes of Health, National Heart, Lung and Blood Institute, Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung and Blood Diseases; Mannino DM et al., MMWR Surveill. Summ., 2002, 51, 1-16).
  • budesonide an inhaled corticosteroid
  • formoterol a long-acting beta-2 agonist
  • SYMBICORT ® a long-acting beta-2 agonist
  • compositions for use in the treatment of COPD, for symptomatic relief, when needed, and in addition to maintenance treatment.
  • composition for inhalation comprising, in admixture:
  • composition for inhalation comprising, in admixture:
  • the present specification further relates, in part, to a pharmaceutical composition for inhalation comprising, in admixture: (i) a first active ingredient which is a long-acting muscarinic antagonist or a pharmaceutically acceptable salt thereof; and
  • the present specification further relates, in part, to such compositions wherein the first active ingredient is aclidinium (or a pharmaceutically acceptable salt thereof) and the second active ingredient is formoterol (or a pharmaceutically acceptable salt thereof).
  • the present specification further relates, in part, to such compositions wherein the first active ingredient is glycopyrronium (or a pharmaceutically acceptable salt thereof) and the second active ingredient is formoterol (or a pharmaceutically acceptable salt thereof).
  • the present specification further relates, in part, to methods of treating COPD, comprising administering to a subject suffering from COPD an effective amount of such pharmaceutical compositions, and wherein the said compositions are administered in addition to maintenance treatment and are for the relief of COPD symptoms, when needed.
  • Examples of a "long-acting muscarinic antagonist” include aclidinium,
  • glycopyrronium tiotropium and umeclidinium, or a pharmaceutically acceptable salt thereof.
  • Examples of a "long-acting beta-2 agonist” include abediterol, arformoterol, bambuterol, clenbuterol, formoterol, indacaterol, olodaterol, salmeterol and vilanterol, or a pharmaceutically acceptable salt thereof.
  • Aclidinium is a long-acting muscarinic antagonist (LAMA) known to be useful in the treatment of respiratory diseases, in particular COPD.
  • LAMA muscarinic antagonist
  • the chemical name for aclidinium is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-l-(3-phenoxypropyl)-l- azoniabicyclo[2.2.2]octane.
  • Aclidinium contains a quarternary nitrogen atom, and typically aclidinium is administered in the form of a salt with an anion X, wherein X is a
  • aclidinium may exist in the form of solvates. Furthermore the different salts and solvates of aclidinium may exist in amorphous form or in the form of different polymorphs. More typically, aclidinium is administered as the bromide salt.
  • Aclidinium bromide has the chemical name 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)- 1 -(3-phenoxypropyl)- 1 - azoniabicyclo[2.2.2]octane bromide.
  • Aclidinium/formoterol refers to a fixed dose combination of aclidinium or a pharmaceutically acceptable salt thereof and formoterol or a pharmaceutically acceptable salt thereof.
  • a particular form of aclidinium/formoterol comprises a fixed dose combination of aclidinium bromide and formoterol fumarate, for example a fixed dose combination of aclidinium bromide and formoterol fumarate dihydrate.
  • DuaklirTM or “Duaklir GenuairTM” is a fixed dose combination of aclidinium bromide and formoterol fumarate dihydrate.
  • glycopyrronium is a long-acting muscarinic antagonist (LAMA) known to be useful in the treatment of respiratory diseases, in particular COPD.
  • LAMA muscarinic antagonist
  • the chemical name for glycopyrronium is 3 [(cyclopentylhydroxyphenylacetyl)oxy]- 1,1 -dimethyl pyrrolidinium.
  • Glycopyrronium contains a quarternary nitrogen atom, and typically glycopyrronium is administered in the form of a salt with an anion X, wherein X is a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • the different salts of glycopurronium may exist in the form of solvates. Furthermore the different salts and solvates of
  • glycopyrronium may exist in amorphous form or in the form of different polymorphs. More typically, glycopyrronium is administered as the bromide salt. Glycopyrronium bromide (also known as glycopyrrolate) has the chemical name
  • glycopyrronium or a pharmaceutically acceptable salt thereof and formoterol or a pharmaceutically acceptable salt thereof comprises a fixed dose combination of glycopyrronium bromide (also known as glycopyrrolate) and formoterol fumarate, for example a fixed dose combination of glycopyrronium bromide and formoterol fumarate dihydrate.
  • glycopyrronium bromide also known as glycopyrrolate
  • formoterol fumarate for example a fixed dose combination of glycopyrronium bromide and formoterol fumarate dihydrate.
  • Bevespi AerosphereTM is a fixed dose combination of glycopyrronium bromide and formoterol fumarate dihydrate.
  • CID Cosmetically important deterioration
  • FEV1 force expiratory volume in 1 second
  • SGRQ Saint George's Respiratory Questionnaire
  • COPD COPD exacerbations
  • COPD symptoms refers to one or more of the symptoms selected from dyspnea (at rest and during exercise), chronic cough, sputum production, and other variable symptoms such as wheeze and chest tightness. The incidence and severity of symptoms may be measured using a number of physician and patient-reported outcomes
  • Such questionnaires include the Baseline Dyspnea Index/Transitional Dyspnea Index (BDI/TDI), the Early Morning and Nocturnal Symptoms Questionnaire, and the EXAcerbations of Chronic obstructive pulmonary disease Tool (EXACT)-Respiratory Symptoms (E-RS) daily diary.
  • BDI/TDI Baseline Dyspnea Index/Transitional Dyspnea Index
  • EXACT Chronic obstructive pulmonary disease Tool
  • E-RS Chronic obstructive pulmonary disease Tool
  • “Daily” or “per day” refers to any given 24-hour period. Thus, by way of illustration, administration “once-daily” means administration once in any 24-hour period. Typically, once daily inhaled medications for COPD are prescribed to be taken during the first hour of the morning after waking, whilst twice daily medications are typically prescribed to be taken in the morning and in the evening, twelve hours apart.
  • Exacerbation is an episode which is characterised by an increase in a patient's baseline COPD symptoms that is beyond the normal day-to-day symptomatic variation experienced by that patient.
  • a “moderate exacerbation” is an exacerbation which results in the patient requiring treatment with antibiotics or corticosteroids.
  • a “severe exacerbation” is an exacerbation which results in the patient requiring hospitalisation.
  • the incidence of exacerbations may be measured by using either Health Care Resource Utilisation (HCRU) data or by using patient-reported outcome tools, such as the EXAcerbations of Chronic obstructive pulmonary disease Tool (EXACT)-Respiratory Symptoms (E-RS) daily diary data. Both the HCRU and EXACT standard definitions are known to those skilled in the art.
  • Formrol is a long-acting beta-2 agonist (LABA) known to be useful in the treatment of respiratory diseases, including COPD.
  • the chemical name for formoterol is ( ⁇ )-N-[2-hydroxy-5-[(lRS)- 1 -hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)- 1 - methylethyl] amino] ethyl] phenyl] formamide.
  • formoterol is administered in the form of a pharmaceutically acceptable salt.
  • the different salts of formoterol may exist in the form of solvates.
  • the different salts and solvates of aclidinium may exist in amorphous form or in the form of different polymorphs.
  • formoterol is administered as the fumarate salt.
  • Formoterol fumarate has the chemical name ( ⁇ )-N-[2- hydroxy-5 -[( 1 RS) - 1 -hydroxy-2- [ [( 1 RS)-2-(4-methoxyphenyl)- 1 - methylethyl] amino] ethyl]phenyl]formamide, (E)-2-butenedioate.
  • formoterol fumarate is administered as the dihydrate solvate, ie. formoterol fumarate dihydrate.
  • Maintenance treatment or “treatment on a maintenance basis” refers to the administration of any given COPD therapy in accordance with a regular, pre-defined, treatment cycle.
  • the treatment may be the administration of a given therapy once-daily or twice-daily, in accordance with relevant ATS or ERS treatment guidelines, or in accordance with the posology provided in the relevant Summary of Product
  • maintenance treatment includes the once-daily posology currently indicated for the combinations of umeclidinium and vilanterol (AnoroTM), of glycopyrronium and indacaterol (UltibroTM), and of tiotropium and olodaterol (StioltoTM), and the twice-daily posology currently indicated for the combination of glycopyrronium and formoterol (Bevespi AerosphereTM) and aclidinium and formoterol (DuaklirTM).
  • LAMA/LABA combinations have recently been indicated for COPD, such as the combination of umeclidinium and vilanterol (AnoroTM), the combination of glycopyrronium and indacaterol (UltibroTM), the combination of tiotropium and olodaterol (StioltoTM), the combination of glycopyrronium and formoterol (Bevespi AerosphereTM), and the combination of aclidinium and formoterol (DuaklirTM).
  • a number of fixed dose LAMA/LABA combinations have recently been indicated for COPD, such as the combination of umeclidinium and vilanterol (AnoroTM), the combination of glycopyrronium and indacaterol (UltibroTM), the combination of tiotropium and olodaterol (StioltoTM), the combination of glycopyrronium and formoterol (Bevespi AerosphereTM), and the combination of aclidinium and formoterol (DuaklirTM).
  • administration of a fixed dose LAMA/LABA combination when needed, for the relief of COPD symptoms, and in addition to maintenance treatment, may be beneficial to a COPD patient.
  • Such an alternative treatment can provide better control of a patient's COPD symptoms, and can reduce the risk of that patient progressing towards a COPD
  • exacerbation such as a moderate or severe COPD exacerbation
  • requiring further treatment or hospitalisation or avoid or delay the time to a clinically important
  • a patient suffering from COPD who, in spite of their regular maintenance treatment with a LAMA/LABA combination (such as
  • aclidinium/formoterol or glycopyrronium/formoterol feels or detects an increase in their COPD symptoms beyond their normal day-to-day variation, would be instructed to take additional doses of a LAMA/LABA combination (such as aclidinium/formoterol or glycopyrronium/formoterol) on top of their maintenance treatment. This should provide better control over the patient's symptoms when compared with the current treatment alternative of multiple doses of a SABA or a SAMA on top of maintenance treatment.
  • a LAMA/LABA combination such as aclidinium/formoterol or glycopyrronium/formoterol
  • aclidinium/formoterol or glycopyrronium/formoterol should, in turn, reduce the probability of the patient's symptomatic changes evolving into a COPD exacerbation or into a clinically important deterioration.
  • Pharmaceutical compositions for use in the treatment of COPD should, in turn, reduce the probability of the patient's symptomatic changes evolving into a COPD exacerbation or into a clinically important deterioration.
  • composition for inhalation comprising, in admixture:
  • composition for inhalation comprising, in admixture:
  • the first active ingredient is glycopyrronium or a
  • composition for inhalation comprising, in admixture:
  • composition for inhalation comprising, in admixture:
  • the first active ingredient is glycopyrronium or a
  • composition for inhalation comprising, in admixture:
  • COPD clinically important deteriorations
  • composition for inhalation comprising, in admixture:
  • COPD clinically important deteriorations
  • the first active ingredient is glycopyrronium or a
  • a method of treating COPD comprising administering to a subject suffering from COPD an effective amount of a pharmaceutical composition for inhalation comprising, in admixture:
  • composition wherein the pharmaceutical composition is administered in addition to maintenance treatment and is for the relief of COPD symptoms, when needed.
  • a method of treating COPD comprising administering to a subject suffering from COPD an effective amount of a pharmaceutical composition for inhalation comprising, in admixture:
  • composition wherein the pharmaceutical composition is administered in addition to maintenance treatment and is for the relief of COPD symptoms, when needed.
  • the first active ingredient is glycopyrronium or a
  • a method of treating COPD comprising administering to a subject suffering from COPD an effective amount of a pharmaceutical composition for inhalation comprising, in admixture:
  • a second active ingredient which is a long-acting beta-2 agonist or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition is administered in addition to maintenance treatment and is for the relief of COPD symptoms, when needed, and wherein said treatment results in one of more of:
  • a method of treating COPD comprising administering to a subject suffering from COPD an effective amount of a pharmaceutical composition for inhalation comprising, in admixture:
  • composition is administered in addition to maintenance treatment and is for the relief of COPD symptoms, when needed, and wherein said treatment results in one of more of:
  • the first active ingredient is glycopyrronium or a
  • a method of treating COPD comprising administering to a subject suffering from COPD an effective amount of a pharmaceutical composition for inhalation comprising, in admixture:
  • composition is administered in addition to maintenance treatment and is for the relief of COPD symptoms, when needed, and wherein said treatment results in a reduction in the incidence of clinically important deteriorations (CID).
  • CID clinically important deteriorations
  • a method of treating COPD comprising administering to a subject suffering from COPD an effective amount of a pharmaceutical composition for inhalation comprising, in admixture:
  • composition is administered in addition to maintenance treatment and is for the relief of COPD symptoms, when needed, and wherein said treatment results in a reduction in the incidence of clinically important deteriorations (CID).
  • CID clinically important deteriorations
  • the first active ingredient is glycopyrronium or a
  • compositions described herein are administered when needed in total no more than four times a day.
  • the compositions described herein are administered when needed in total no more than two times a day.
  • the compositions described herein are administered when needed in total no more than once a day.
  • the compositions described herein are administered when needed no more than twice within any 12-hour time period.
  • the compositions described herein are administered when needed no more than once within any 12-hour time period.
  • compositions when needed is limited to a period of not more than 20 weeks, for example not more than 16 weeks, not more than 15 weeks, not more than 14 weeks, not more than 13 weeks, or not more than 12 weeks.
  • compositions described herein comprise glycopyrronium in the form of glycopyrronium bromide.
  • compositions described herein comprise formoterol in the form of formoterol fumarate.
  • compositions described herein comprise formoterol in the form of formoterol fumarate dihydrate.
  • compositions described herein comprise aclidinium in the form of aclidinium bromide.
  • compositions described herein comprise formoterol in the form of formoterol fumarate.
  • compositions described herein comprise formoterol in the form of formoterol fumarate dihydrate.
  • compositions of the present disclosure may be administered by oral inhalation in any suitable form and using any suitable inhaler device.
  • suitable inhalers are known to those skilled in the art and include manual or breath-actuated inhalers.
  • Suitable inhaler devices may include metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulisers and soft mist inhalers.
  • compositions of the present disclosure are
  • the inhaler is a metered dose inhaler or a dry powder inhaler.
  • the compositions described herein are administered via a dry powder inhaler.
  • the compositions described herein are administered via a breath-activated, multidose, dry powder inhaler.
  • the compositions described herein are administered via the Genuair/Pressair device.
  • the compositions described herein are administered via a metered dose inhaler, such as a pressurised metered dose inhaler (pMDI).
  • pMDI pressurised metered dose inhaler
  • each administration of the compositions of the present disclosure comprises a single actuation of the inhaler.
  • the compositions described herein are administered for use when needed in a total of no more than four actuations per day, such as two actuations per day, for example one actuation per day.
  • no more than two actuations are administered for use when needed within a 12-hour time period, such as no more than one actuation within a 12-hour time period.
  • no more than two actuations are administered for use when needed at any one time.
  • the metered (or nominal) dose of aclidinium/formoterol per actuation of the inhaler comprises about 343 ⁇ g of aclidinium (equivalent to about 400 ⁇ g of aclidinium bromide) and about 12 ⁇ g of formoterol fumarate dihydrate.
  • the metered (or nominal) dose is the maximum theoretical dose of the inhaler per actuation.
  • the delivered dose of aclidinium/formoterol per actuation of the inhaler comprises about 340 ⁇ g of aclidinium (equivalent to about 396 ⁇ g of aclidinium bromide) and about 1 1.8 ⁇ g of formoterol fumarate dihydrate.
  • the delivered dose is the dose emitted from the mouthpiece of the inhaler and may be determined as described in European Pharmacopoeia Monograph 0671 "Preparations for Inhalation” (Section 0671) and in US Pharmacopoeia ⁇ 601> "Aerosols, Nasal Sprays, Metered Dose Inhalers, and Dry Powder Inhalers” using an appropriate inhalation test system, consisting, for example, of a differential pressure meter, a pressure meter, a volumetric flow meter, a time controlled two-way valve, and a pump.
  • a metered dose of "about 343 ⁇ g of aclidinium” refers to a dose of 343 ⁇ g of aclidinium subject to variation within the normal limits of acceptance for the delivery system, such as 223-463 ⁇ g of aclidinium (plus/minus 35%), 257-429 ⁇ g of aclidinium (plus/minus 25%), 292-394 ⁇ g of aclidinium (plus/minus 15%) or 309-377 ⁇ g of aclidinium (plus/minus 10%).
  • a metered dose of "about 12 ⁇ g of formoterol fumarate dihydrate” refers to a dose of 12 ⁇ g of formoterol fumarate dihydrate subject to variation within the normal limits of acceptance for the delivery system, such as 7.8-16.2 ⁇ g of formoterol fumarate dihydrate (plus/minus 35%), 9-15 ⁇ g of formoterol fumarate dihydrate (plus/minus 25%), 10.2-13.8 ⁇ g of formoterol fumarate dihydrate (plus/minus 15%) or 10.8-13.2 ⁇ g of formoterol fumarate dihydrate (plus/minus 10%).
  • a delivered dose of "about 340 ⁇ g of aclidinium” and a delivered dose of "about 11.8 ⁇ of formoterol fumarate dihydrate” refers to the said delivered doses subject to variation within the normal limits of acceptance for the delivery system, such as plus/minus 35%, or plus/minus 25%, or plus/minus 15%, or plus/minus 10%, as described above.
  • compositions described herein comprise a delivered dose of about 340 ⁇ g of aclidinium per administration.
  • the aclidinium is in the form of aclidinium bromide and the delivered dose of aclidinium bromide is about 396 ⁇ g per administration.
  • the compositions described herein comprise a delivered dose of about 11.8 ⁇ of formoterol fumarate dihydrate per administration.
  • compositions described herein comprise a metered dose of about 343 ⁇ g of aclidinium per administration.
  • the aclidinium is in the form of aclidinium bromide and the metered dose of aclidinium bromide is about 400 ⁇ g per administration.
  • the compositions described herein comprise a metered dose of about 12 ⁇ of formoterol fumarate dihydrate per administration.
  • compositions described herein are administered for use when needed in a total of no more than four actuations per day.
  • the compositions described herein comprise a total delivered daily dose of aclidinium for use when needed of no more than about 1360 ⁇ g.
  • the aclidinium is in the form of aclidinium bromide and the total delivered daily dose of aclidinium bromide for use when needed is no more than about 1584 ⁇ g.
  • the formoterol is in the form of formoterol fumarate dihydrate and the total delivered daily dose of formoterol fumarate dihydrate for use when needed is no more than about 47.2 ⁇ g.
  • a delivered dose of "about 1360 ⁇ g ,, of aclidinium” or “about 1584 ⁇ g ,, of aclidinium bromide or “about 47.2 ⁇ g ,, of formoterol fumarate dihydrate refers to the said delivered doses subject to variation within the normal limits of acceptance for the delivery system, such as plus/minus 35%, or plus/minus 25%, or plus/minus 15%, or plus/minus 10%, as previously described above.
  • compositions described herein comprise a total metered daily dose of aclidinium for use when needed of no more than about 1372 ⁇ g.
  • the aclidinium is in the form of aclidinium bromide and the total metered daily dose of aclidinium bromide for use when needed is no more than about 1600 ⁇ g.
  • the formoterol is in the form of formoterol fumarate dihydrate and the total metered daily dose of formoterol fumarate dihydrate for use when needed is no more than about 48 ⁇ g.
  • a metered dose of "about 1372 ⁇ ' of aclidinium” or "about 1600 ⁇ " of aclidinium bromide or "about 48 ⁇ " of formoterol fumarate dihydrate refers to the said metered doses subject to variation within the normal limits of acceptance for the delivery system, such as plus/minus 35%, or plus/minus 25%, or plus/minus 15%, or plus/minus 10%, as previously described above.
  • compositions comprising glycopyrronium/formoterol
  • each administration of the compositions of the present disclosure comprises two actuations of the inhaler.
  • the compositions described herein are administered for use when needed in a total of no more than eight actuations per day, such as four actuations per day, for example two actuations per day.
  • no more than four actuations are administered for use when needed within a 12-hour time period, such as no more than two actuations within a 12-hour time period.
  • no more than four actuations are administered for use when needed at any one time.
  • the metered (or nominal) dose of glycopyrronium/formoterol per actuation of the inhaler comprises about 8.3 ⁇ g of glycopyrronium (equivalent to about 10.3 ⁇ g of glycopyrronium bromide) and about 5.8 ⁇ g of formoterol fumarate dihydrate.
  • the metered (or nominal) dose is the maximum theoretical dose of the inhaler per actuation.
  • the delivered dose of glycopyrronium/formoterol per actuation of the inhaler comprises about 7.2 ⁇ g of glycopyrronium (equivalent to about 9.0 ⁇ g of glycopyrronium bromide) and about 5.0 ⁇ g of formoterol fumarate dihydrate.
  • the delivered dose is the dose emitted from the mouthpiece of the inhaler and may be determined as described in European Pharmacopoeia Monograph 0671 "Preparations for Inhalation” (Section 0671) and in US Pharmacopoeia ⁇ 601> "Aerosols, Nasal Sprays, Metered Dose Inhalers, and Dry Powder Inhalers” using an appropriate inhalation test system, consisting, for example, of a differential pressure meter, a pressure meter, a volumetric flow meter, a time controlled two-way valve, and a pump.
  • a metered dose of "about 8.3 ⁇ g of glycopyrronium” refers to a dose of 8.3 ⁇ g of glycopyrronium subject to variation within the normal limits of acceptance for the delivery system, such as 5.4-11.2 ⁇ g of glycopyrronium (plus/minus 35%), 6.2-10.4 ⁇ g of glycopyrronium (plus/minus 25%), 7.1-9.5 ⁇ g of glycopyrronium (plus/minus 15%) or 7.5- 9.1 ⁇ g of glycopyrronium (plus/minus 10%).
  • a metered dose of "about 5.8 ⁇ g of formoterol fumarate dihydrate” refers to a dose of 5.8 ⁇ g of formoterol fumarate dihydrate subject to variation within the normal limits of acceptance for the delivery system, such as 3.8-7.8 ⁇ g of formoterol fumarate dihydrate (plus/minus 35%), 4.4-7.3 ⁇ g of formoterol fumarate dihydrate (plus/minus 25%), 4.9-6.7 ⁇ g of formoterol fumarate dihydrate
  • a delivered dose of "about 7.2 ⁇ g of glycopyrronium” and a delivered dose of "about 5.0 ⁇ g of formoterol fumarate dihydrate” refers to the said delivered doses subject to variation within the normal limits of acceptance for the delivery system, such as plus/minus 35%, or plus/minus 25%, or plus/minus 15%, or plus/minus 10%, as described above.
  • compositions described herein comprise a delivered dose of about 7.2 ⁇ g of glycopyrronium per actuation of the inhaler.
  • glycopyrronium is in the form of glycopyrronium bromide and the delivered dose of glycopyrronium bromide is about 9.0 ⁇ g per actuation.
  • compositions described herein comprise a delivered dose of about 5.0 ⁇ g of formoterol fumarate dihydrate per actuation.
  • compositions described herein comprise a metered dose of about 8.3 ⁇ g of glycopyrronium per actuation of the inhaler.
  • glycopyrronium is in the form of glycopyrronium bromide and the metered dose of glycopyrronium bromide is about 10.3 ⁇ g per actuation.
  • the metered dose of glycopyrronium bromide is about 10.3 ⁇ g per actuation.
  • compositions described herein comprise a metered dose of about 5.8 ⁇ g of formoterol fumarate dihydrate per actuation.
  • compositions described herein comprise a delivered dose of about 14.4 ⁇ g of glycopyrronium per administration.
  • glycopyrronium is in the form of glycopyrronium bromide and the delivered dose of glycopyrronium bromide is about 18.0 ⁇ g per administration.
  • compositions described herein comprise a delivered dose of about 10.0 ⁇ g of formoterol fumarate dihydrate per administration.
  • compositions described herein comprise a metered dose of about 16.6 ⁇ g of glycopyrronium per administration.
  • the glycopyrronium is in the form of glycopyrronium bromide and the metered dose of glycopyrronium bromide is about 20.6 ⁇ g per administration.
  • the compositions described herein comprise a metered dose of about 11.6 ⁇ g of formoterol fumarate dihydrate per administration.
  • compositions described herein are administered for use when needed in a total of no more than four administrations (a total of 8 actuations) per day.
  • the compositions described herein comprise a total delivered daily dose of glycopyrronium for use when needed of no more than about 57.6 ⁇ g.
  • the glycopyrronium is in the form of glycopyrronium bromide and the total delivered daily dose of glycopyrronium bromide for use when needed is no more than about 72 ⁇ g.
  • the formoterol is in the form of formoterol fumarate dihydrate and the total delivered daily dose of formoterol fumarate dihydrate for use when needed is no more than about 40 ⁇ g.
  • a delivered dose of "about 57.6 ⁇ g" of aclidinium” or "about 72.0 ⁇ £' of glycopyrronium bromide or "about 40 ⁇ g" of formoterol fumarate dihydrate refers to the said delivered doses subject to variation within the normal limits of acceptance for the delivery system, such as plus/minus 35%, or plus/minus 25%, or plus/minus 15%, or plus/minus 10%, as previously described above.
  • compositions described herein comprise a total metered daily dose of glycopyrronium for use when needed of no more than about 66.4 ⁇ g.
  • glycopyrronium is in the form of glycopyrronium bromide and the total metered daily dose of glycopyrronium bromide for use when needed is no more than about 82.4 ⁇ g.
  • formoterol is in the form of formoterol fumarate dihydrate and the total metered daily dose of formoterol fumarate dihydrate for use when needed is no more than about 46.4 ⁇ g.
  • a metered dose of "about 66.4 ⁇ g” of glycopyrronium” or “about 82.4 ⁇ g” of glycopyrronium bromide or "about 46.4 ⁇ g” of formoterol fumarate dihydrate refers to the said metered doses subject to variation within the normal limits of acceptance for the delivery system, such as plus/minus 35%, or plus/minus 25%, or plus/minus 15%, or plus/minus 10%, as previously described above.
  • the compositions described herein When administered in the form of a dry powder, the compositions described herein must be suitably formulated. In one aspect, therefore, the compositions described herein comprise a dry powder formulation suitable for inhalation.
  • Medicaments for administration by inhalation generally have a controlled particle size.
  • the optimum particle size for inhalation into the bronchial system is usually 1 -5 ⁇ , for example 2-5 ⁇ .
  • Particles having a size above 10 ⁇ are generally too large when inhaled to reach the small airways.
  • the particles of the active ingredient(s) as produced may be reduced in size by conventional means, for example by micronisation.
  • the desired fraction may be separated out by, for example, air classification.
  • the particles of the present disclosure may be crystalline.
  • the desired dose of the active ingredient is often too low to be reliably delivered alone. Therefore administration with an additional excipient, such as lactose, is generally employed.
  • the particle size of the excipient is in most cases much greater than the particle size of the active ingredient(s).
  • lactose it will typically be present as lactose particles, such as crystalline lactose particles, for example crystalline lactose monohydrate, such as crystalline alpha-lactose monohydrate.
  • the excipient will have an average particle size range of 20-1000 ⁇ , for example 90-150 ⁇ .
  • the median particle size approximately corresponds to the average, and is the diameter where 50% of the particles by mass have a larger equivalent diameter, and the other 50% by mass have a smaller equivalent diameter.
  • the average particle size is generally referred to in the art as equivalent d50.
  • other equivalent diameters can be used in addition to d50, such as dlO or d90.
  • dlO is the equivalent diameter where 10%> of the particles by mass have a smaller diameter.
  • d90 is the equivalent diameter where 90% of the particles by mass have a smaller diameter.
  • the lactose particles for use in formulations described herein have a dlO of 90-160 ⁇ , a d50 of 170-270 ⁇ , and a d90 of 290-400 ⁇ .
  • Suitable lactose materials are commercially available, and include, among others, Respitose GR-001, Respitose SV-001 and Respitose SV-003 (DMW International), Capsulac 60, Inhalac 70, and Lactohale 100-200, Lactohale 200-300 and Lactohale 100- 300 (Borculo Domo).
  • the ratio between the lactose particles and the active ingredient(s) by weight will depend on the inhaler device used.
  • the ratio by weight of lactose particles to aclidinium is 5: 1 to 100:1, for example 25: 1 to 75: 1, for example 25: 1 to 50: 1, such as 30: 1 to 35: 1.
  • the ratio by weight of lactose particles to formoterol is 500: 1 to 2000: 1, for example 750: 1 to 1500: 1, such as 900: 1 to 1000: 1.
  • compositions described herein are administered in the form of a dry powder formulation of aclidinium bromide in admixture with formoterol fumarate dihydrate and lactose.
  • the lactose is lactose monohydrate.
  • the lactose is alpha-lactose monohydrate.
  • the aclidinium particles have an average particle size of from 2-5 ⁇ in diameter, such as between 0.01 and 3 ⁇ in diameter.
  • the lactose particles have a dlO of 90-160 ⁇ , a d50 of 170-270 ⁇ , and a d90 of 290-400 ⁇ .
  • each actuation of the inhaler provides a delivered dose of about 11.6 mg of lactose (for example lactose monohydrate, such as alpha-lactose monohydrate), wherein "about 11.6 mg of lactose” refers to the said delivered dose subject to variation within the normal limits of acceptance for the delivery system, such as plus/minus 35%, or plus/minus 25%>, or plus/minus 15%>, or plus/minus 10%>, as previously described above.
  • lactose for example lactose monohydrate, such as alpha-lactose monohydrate
  • about 11.6 mg of lactose refers to the said delivered dose subject to variation within the normal limits of acceptance for the delivery system, such as plus/minus 35%, or plus/minus 25%>, or plus/minus 15%>, or plus/minus 10%>, as previously described above.
  • compositions described herein When administered in the form of an aerosol, the compositions described herein must be suitably formulated.
  • the compositions described herein comprise a formulation suitable for inhalation via a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • Medicaments for administration by inhalation via an MDI generally have a controlled particle size and the optimum particle size for inhalation into the bronchial system is usually 1-5 ⁇ , for example 2-5 ⁇ .
  • the active ingredient particles of the present disclosure may be crystalline.
  • Suitable formulations for use in an MDI may be achieved by combining the active ingredients with additional excipients in a suitable propellant to form a suspension.
  • suitable formulations include formulations in which the active ingredients are mixed with suspending particles in a suspension medium to form a co-suspension, for example as described in WO 2010/138884.
  • Suitable suspension media are propellant gases that can be liquefied under pressure at room temperature, are suitable for inhalation use, and are relatively non-reactive with the suspending particles and active ingredients.
  • suitable propellants include hydrofluoroalkanes (HFAs), perfluorinated compounds (PFCs) and chlorofluorocarbons (CFCs), such as HFA-134a, HFA-227, perfluoroethane, monochloro-fluoroethane and 1,1- difluroethane.
  • the active ingredients may be provided in any suitable concentration within the suspension medium, and in particular, the active agent particles may be present in a concentration of between 0.05 mg/mL to 20 mg/mL, such as between 0.05 mg/mL to 10 mg/mL, such as between 0.05 mg/mL to 5 mg/mL.
  • Suitable suspending particles are pharmaceutically acceptable excipients that are suitable for inhaled delivery and do not substantially degrade or dissolve in the suspension medium.
  • the suspending particles are sized within a respirable range, for example between 0.75 and 5 um, such as between 1 and 3 ⁇ .
  • suitable suspending particles may take the form of perforated microstructures, in which the suspending particles include a structural matrix that comprises voids, pores, defects, hollows, interstitial spaces, apertures, perforations or holes that allow the surrounding suspension medium to permeate, fill or pervade the microstructure.
  • Such perforated microstructures may comprise approximately spherical shapes, such as hollow, suspending, spray-dried microspheres.
  • Exemplary excipients which may be used to form suspending particles include carbohydrates, amino acids, metal and organic salts, peptides and proteins, synthetic or natural polymers, and synthetic or natural phospholipids.
  • Exemplary phospholipids include phosphoglycerides such as l,2-distearoyl-sn-glycero-3- phosphocholine (DSPC).
  • Exemplary metal salts include calcium salts, such as calcium chloride.
  • the ratio of the total mass of suspending particle to active ingredient may be between 1 : 10 and about 200: 1, for example between about 1 : 10 and 100: 1, such as between about 1 : 10 and 50:1, between about 1 : 10 and 30: 1, between about 1 : 1 and 25: 1, between about 5: 1 and 20: 1, between about 1 : 1 and 10: 1 and between about 10: 1 and 20: 1.
  • compositions described herein are administered in the form of an MDI formulation of glycopyrronium bromide in admixture with formoterol fumarate dihydrate.
  • the compositions comprise a suspension medium such as an HFA propellant, for example HFA-134a.
  • the compositions comprise suspending particles, such as a phospholipid, for example DSPC.
  • the suspending particles further comprise a metal salt, such as a calcium salt, e.g. calcium chloride.
  • the suspending particle is in the form of a perforated microstructure.
  • the glycopyrronium particles have an average particle size of from 2-5 ⁇ in diameter, such as between 0.01 and 3 ⁇ in diameter. In a still further aspect, the suspending particles have an average size of from 0.75 to 5 ⁇ , such as between 1 and 3 ⁇ .
  • Use of the pharmaceutical compositions when needed according to the present disclosure may result in the relief of COPD symptoms, and may provide the patient with better control of his or her symptoms during periods of increased symptoms, or with better control of COPD progression.
  • the use of the compositions as described herein results in the relief of COPD symptoms compared with maintenance treatment.
  • use of the compositions as described herein results in a reduction in the severity of COPD symptoms compared with maintenance treatment.
  • the use of the compositions as described herein results in a reduction in the frequency of COPD symptoms compared with maintenance treatment.
  • compositions as described herein may result in a reduction in the severity of COPD symptoms compared with maintenance treatment of over 5%, for example over 10%, over 15%, over 20%, over 25%, over 30%, or over 35%, such as over 20%.
  • the said reduction in the severity of COPD symptoms may be measured using the E-RS questionnaire.
  • compositions as described herein may result in an improvement in the severity of COPD symptoms compared with maintenance treatment, and as measured using the E-RS questionnaire, of more than 0.25 points, for example more than 0.30 points, more than 0.40 points, more than 0.50 points, more than 0.60 points, or more than 0.65 points.
  • compositions as described herein may result in an improvement in the percentage of patients responding by more than 2.0 points as compared with maintenance treatment, and as measured using the E-RS questionnaire, of over 5%, for example over 10%, over 15%, or over 20%.
  • compositions as described herein may result in a reduction in the level of COPD symptoms compared with maintenance treatment, as measured by an improvement in the TDI scoring, of more than 0.2 points, for example more than 0.3 points, more than 0.4 points, or more than 0.5 points.
  • the use of the compositions as described herein may result in an improvement in the percentage of patients responding by more than 1.0 points as compared with maintenance treatment, and as measured using the TDI questionnaire, of over 5%, for example over 10%, over 15%, or over 20%.
  • the use of the compositions described herein may result in a reduction in the level of COPD symptoms compared with maintenance treatment, and as measured by a reduction in the total score of either one or both of the Nocturnal or the Early Morning Symptoms questionnaires, of more than 0.1 points, for example more than 0.2 points, more than 0.3 points, more than 0.4 points, or more than 0.5 points.
  • Use of the pharmaceutical compositions when needed according to the present disclosure may result in the reduction in the number of exacerbations, or to a reduction in the severity of symptoms of exacerbations.
  • use according to the present disclosure may result in a reduction in the risk of any given COPD patient suffering from an exacerbation of any severity, such as a moderate exacerbation (requiring treatment with antibiotics or corticosteroids) or a severe exacerbation (requiring hospitalisation).
  • compositions described herein may result in a reduction in the number of exacerbations, or to a reduction in the severity of symptoms of exacerbations, or to a reduction in the time to first exacerbation, compared with maintenance treatment.
  • exacerbations are moderate or severe exacerbations.
  • the administration of the compositions described herein may result in an additional reduction in the percentage of patients experiencing an exacerbation of any severity compared with maintenance treatment of over 5%, for example over 10%, over 15%, over 20%>, over 25%, over 30%, over 35%, or over 40%.
  • the reduction in the incidence of exacerbation may be measured using either HCRU or EXACT data.
  • the administration of the compositions described herein may result in a reduction in the rate of exacerbations of any severity per patient per year compared with maintenance treatment, as measured using HCRU or EXACT data, to a rate ratio of less than 0.9, for example less than 0.85, less than 0.80, less than 0.75, less than 0.70, less than 0.65 or less than 0.60.
  • the administration of the compositions described herein may result in a reduction in the rate of exacerbations of moderate or severe severity per patient per year compared with maintenance treatment, as measured using HCRU data, to a rate ratio of less than 0.9, for example less than 0.85, less than 0.80, less than 0.75, less than 0.70, less than 0.65, or less than 0.60.
  • compositions when needed according to the present disclosure may result in the reduction in the incidence of clinically important deteriorations (CID).
  • CBD clinically important deteriorations
  • the administration of the composition provides a reduction in the incidence of clinically important deteriorations suffered by a COPD patient compared with maintenance treatment.
  • the administration of the composition provides an additional reduction in the percentage of patients experiencing a CID compared with
  • CID chronic obstructive diffraction
  • maintenance treatment of over 5%, for example over 10%, over 15%, over 20%, over 25%o, over 30%>, over 35%, such as over 20%>.
  • the reduction in the incidence of CID may be measured over a period of 3, 6 or 12 months, using the composite indices described herein.
  • the administration of the composition reduces the risk of a COPD patient experiencing a CID compared with maintenance treatment by over 10%, for example over 15%, over 20%> , over 25%, or over 30%>.
  • the risk of a COPD patient experiencing a CID compared with maintenance treatment by over 10%, for example over 15%, over 20%> , over 25%, or over 30%>.
  • compositions described herein may result in a reduction in the number of CID deteriorations per patient per year compared with maintenance treatment, to a rate ratio of less than 1.0, for example less than 0.9, less than 0.8, less than 0.7, or less than 0.60.
  • compositions when needed according to the present disclosure may result in an improvement in a patient's COPD status compared with maintenance treatment as measured by one or more of the following additional, clinically- relevant, endpoints, each of which are familiar to those skilled in the art:
  • Medications used to treat COPD on a maintenance basis include long-acting beta-2 agonists (LABAs), long-acting muscarinic antagonists (LAMAs), inhaled corticosteroids (ICSs), and combinations thereof.
  • LABA long-acting beta-2 agonists
  • LAMAs long-acting muscarinic antagonists
  • ICSs inhaled corticosteroids
  • the maintenance treatment is a LABA, such as formoterol, arformoterol, vilanterol, indacaterol, salmeterol or olodaterol.
  • the maintenance treatment is a LAMA, such as aclidinium, tiotropium, umeclidinium or glycopyrronium.
  • the maintenance treatment is an ICS, such as budesonide or fluticasone.
  • the maintenance treatment is a combination of a LABA, a LAMA or an ICS.
  • the maintenance treatment may be a fixed dose combination, or an open combination, and may be a dual combination (such as a LAMA/LABA or ICS/LABA) or a triple combination (such as an ICS/LAM A/LAB A).
  • Dual combinations as maintenance treatment include formoterol and budesonide, salmeterol and fluticasone, aclidinium and formoterol, glycopyrronium and formoterol, umeclidinium and vilanterol, glycopyrronium and indacaterol and tiotropium and olodaterol.
  • Triple combinations as maintenance treatment include budesonide and glycopyrronium and formoterol, fluticasone and umeclidinium and vilanterol, and beclamethasone and glycopyrronium and formoterol.
  • a pharmaceutical composition comprising a combination of a long-acting muscarinic antagonist (LAMA) and a long-acting beta-2 agonist (LABA), such as aclidinium and formoterol (or pharmaceutically acceptable salts thereof, for example aclidinium bromide and formoterol fumarate dihydrate), or such as glycopyrronium and formoterol (or pharmaceutically acceptable salts thereof, for example glycopyrronium bromide and formoterol fumarate dihydrate)
  • LAMA long-acting muscarinic antagonist
  • LAA long-acting beta-2 agonist
  • compositions in which the only active ingredients contained therein are a long-acting muscarinic antagonist (LAMA) and a long-acting beta-2 agonist (LABA), such as aclidinium and formoterol (or pharmaceutically acceptable salts thereof, for example aclidinium bromide and formoterol fumarate dihydrate) or such as glycopyrronium and formoterol (or pharmaceutically acceptbale salts thereof, for example glycopyrronium bromide and formoterol fumarate dihydrate).
  • LAMA long-acting muscarinic antagonist
  • LAA long-acting beta-2 agonist
  • a still further aspect of the disclosure is the said pharmaceutical composition in which a third active ingredient is present.
  • the third active ingredient is an inhaled corticosteroid, such as beclamethasone, budesonide, ciclesonide, flunisolide, fluticasone and mometasone.
  • an inhaled corticosteroid such as beclamethasone, budesonide, ciclesonide, flunisolide, fluticasone and mometasone.
  • a further aspect is the said pharmaceutical composition in which budesonide is present.
  • an additional aspect of the disclosure is the use of the said pharmaceutical composition in the manufacture of a medicament for use in the treatment of COPD.
  • an additional aspect of the disclosure is a method of treating COPD in a patient in need of such treatment, comprising the administration of the said pharmaceutical composition.
  • a pharmaceutical composition in a batch size of 80 Kg comprising aclidinium bromide, formoterol fumarate dihydrate and alpha-lactose monohydrate having a dlO of 90-160 ⁇ , a d50 of 170-270 ⁇ and a d90 of 290-400 ⁇ , was prepared.
  • GenuairTM H. Chrystyn et al, Int. Journal of Clinical Practice, 2009, 66, 309-317
  • GenuairTM H. Chrystyn et al, Int. Journal of Clinical Practice, 2009, 66, 309-317
  • cartridges were filled with the composition.
  • the cartridges were calibrated to provide 30 or 60 metered doses.
  • Each actuation of the GenuairTM provided a metered dose of 12 mg of the composition described above.
  • the mean delivered dose per actuation (per inhalation) was 340 ⁇ g aclidinium (aclidinium free ammonium cation), which corresponds to 396 ⁇ g aclidinium bromide.
  • the accepted variance defined by the Committee for Medicinal Products for Human Use (CHMP) Guidelines on the Pharmaceutical Quality on Inhalation and Nasal Products was 289-391 ⁇ g aclidinium (aclidinium free ammonium cation), which corresponds to 337-455 ⁇ g aclidinium bromide.
  • the mean delivered dose per actuation (per inhalation) was 11.8 ⁇ g formoterol fumarate dihydrate.
  • the accepted variance was 10-13.6 ⁇ g formoterol fumarate dihydrate.
  • a pharmaceutical composition in the form of a suspension was prepared by adding glycopyrronium bromide, formoterol fumarate dihydrate and phospholipid suspending particles to an addition vessel and thereafter adding HFA134a propellant. The mixture was homogenized and the homogenized slurry transferred to a bulk filling vessel. The glycopyrronium bromide and formoterol fumarate active ingredient particles were provided as micronized, crystalline material.
  • the suspending particles were manufactured via spray dried emulsion at a feed stock concentration of 80 mg/mL with a composition of 93.44% DSPC (l,2-Distearoyl-sft-glycero-3-phosphocholine) and 6.56% anhydrous calcium chloride (equivalent to a 2: 1 DSPC:CaCb mole/mole ratio).
  • Metered dose inhaler ('MDF) canisters were filled with the pharmaceutical composition, and MDIs were prepared using the filled canisters. Each canister was charged with an amount of the pharmaceutical composition sufficient to provide 120 actuations.
  • the mean delivered dose per actuation (per inhalation) was 7.2 ⁇ g glycopyrronium (glycopyrronium free ammonium cation), which corresponds to 9.0 ⁇ g glycopyrronium bromide.
  • the accepted variance defined by the Committee for Medicinal Products for Human Use (CHMP) Guidelines on the Pharmaceutical Quality on Inhalation and Nasal Products was 5.4-9.0 ⁇ g glycopyrronium (glycopyrronium free ammonium cation), which corresponds to 6.8-11.3 ⁇ g glycopyrronium bromide.
  • the mean delivered dose per actuation (per inhalation) was 5.0 ⁇ g formoterol fumarate dihydrate.
  • the accepted variance was 3.8-6.3 ⁇ g formoterol fumarate dihydrate.
  • Example 3 Use of additional doses of aclidinium bromide/formoterol fumarate dihydrate when needed
  • a COPD patient on once-daily or twice-daily maintenance treatment for example with a fixed dose LAMA/LABA combination (such as umeclidinium/vilanterol, glycopyrronium/ indacaterol, tiotropium/olodaterol, or aclidinium bromide/formoterol fumarate dihydrate), who feels or detects an increase in their COPD symptoms beyond their normal day-to-day variation takes doses of the fixed dose combination of aclidinium bromide/formoterol fumarate dihydrate (metered dose of 400/12 ⁇ g) when needed in order to relieve those symptoms.
  • LAMA/LABA combination such as umeclidinium/vilanterol, glycopyrronium/ indacaterol, tiotropium/olodaterol, or aclidinium bromide/formoterol fumarate dihydrate
  • the patient continues to take additional doses of aclidinium bromide/formoterol fumarate dihydrate when needed until their COPD symptoms return to a tolerable and stable level.
  • This treatment approach may be prolonged over several weeks if necessary, and may be used intermittently several times a year. However, if the patient finds that this treatment approach is required for daily control of their COPD symptoms for periods longer than 16 weeks, the patient should return to their health care practitioner for further evaluation.
  • Example 4 Use of additional doses of glycopyrronium bromide/formoterol fumarate dihydrate when needed
  • a COPD patient on once-daily or twice-daily maintenance treatment for example with a fixed dose LAMA/LABA combination (such as umeclidinium/vilanterol, glycopyrronium/ indacaterol, tiotropium/olodaterol, glycopyrronium bromide/formoterol fumarate dihydrate or aclidinium bromide/formoterol fumarate dihydrate), who feels or detects an increase in their COPD symptoms beyond their normal day-to-day variation takes further administrations of the fixed dose combination of glycopyrronium
  • glycopyrronium bromide/formoterol fumarate dihydrate when needed in order to relieve those symptoms (two actuations per administration, delivered dose per actuation of 9.0/5.0 ⁇ g, total delivered dose per administration of 18.0/10.0 ⁇ g).
  • the patient continues to take additional administrations of glycopyrronium bromide/formoterol fumarate dihydrate when needed until their COPD symptoms return to a tolerable and stable level.

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Abstract

L'invention concerne des compositions pharmaceutiques pour inhalation comprenant une combinaison d'un antagoniste muscarinique à action prolongée et d'un agoniste des récepteurs bêta-2 adrénergiques à action prolongée, telles qu'une combinaison d'aclidinium, ou d'un sel pharmaceutiquement acceptable de ce dernier, et de formotérol, ou d'un sel pharmaceutiquement acceptable de ce dernier, ou une combinaison de glycopyrronium, ou d'un sel pharmaceutiquement acceptable de ce dernier, et de formotérol, ou d'un sel pharmaceutiquement acceptable de ce dernier, pour une utilisation dans le traitement de bronchopneumopathies chroniques obstructives (BPCO), l'utilisation visant au soulagement des symptômes de la BPCO, lorsque cela est nécessaire.
PCT/EP2016/082124 2015-12-22 2016-12-21 Compositions pharmaceutiques pour une utilisation dans le traitement des bronchopneumopathies chroniques obstructives WO2017108917A1 (fr)

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WO2020023486A1 (fr) * 2018-07-23 2020-01-30 Trevi Therapeutics, Inc. Traitement de la toux chronique, de la respiration difficile et de la dyspnée
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